September 2014

The Annual Clinical Reference

Antimicrobial Stewardship: Current State of Affairs Lilian M. Abbo, MD Marissa Tysiak, PharmD

IDSE.net

Volume 17 • 2014

Overview of the Management of Clostridium difficile Infections Julia Garcia-Diaz, MD Arnab Ray, MD Karla Rivera Rivera, MD

Current Issues in and Approaches to Antimicrobial Resistance

The Accentuated Challenges of Aging with HIV

Ari Frenkel, MD Paul Cook, MD

Kelly A. Gebo, MD Jennifer A. Schrack, PhD

New Molecular Diagnostic Technologies: Opportunities for Infection Control?

The Changing HCV Landscape: Update on Diagnosis and Treatment

Brian Currie, MD, MPH

Sonal Kumar, MD, MPH Ira M. Jacobson, MD

Treatment Options in HIV Jonathan Z. Li, MD Paul E. Sax, MD

Individual patients, different journeys, one goal STRIBILD is the first complete integrase inhibitor–based single-tablet regimen recommended in the DHHS guidelines* and is indicated for the treatment of HIV-1 infection in antiretroviral-naïve adults1-3 % of subjects with HIV-1 RNA <50 copies/mL

Noninferior efficacy at week 96 regardless of baseline viral load4,5 100 80

84% 84%

82% 80%

86% 81%

%

81% 83

60 STRIBILD

40

ATV + RTV + FTC/TDF

20 203

0

214

150

141

>100,000

100,000

230

236

116

n

EFV/FTC/TDF

>100,000

100,000

Study 103

116

Study 102 Baseline viral load (copies/mL)

Important Safety Information BOXED WARNING LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of STRIBILD, in combination with other antiretrovirals.

• STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications • Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.

Do not use with drugs that strongly induce CYP3A as this may

lead to loss of efficacy and possible resistance to STRIBILD. Use with the following drugs is contraindicated: alfuzosin, rifampin, dihydroergotamine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, pimozide, sildenafil for pulmonary arterial hypertension, triazolam, oral midazolam, and St. John’s wort.

Warnings and precautions • New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF and STRIBILD. In all patients, monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein prior to initiating and during therapy. In patients with or at risk for renal impairment, additionally monitor serum phosphorus. Do not initiate STRIBILD in patients with CrCl <70 mL/min. Discontinue STRIBILD if CrCl declines to <50 mL/min. Cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function; patients with an increase in serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety. Avoid concurrent or recent use with a nephrotoxic agent. Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function.

Prescribed HIV Treatment Regimen for Antiretroviral-Naïve Adults Source: Ipsos HIV US Scope Q3 and Q4 2013.

Important Safety Information ( (continued d) Warnings and precautions (continued) • Other antiretroviral products: STRIBILD is a complete regimen for the treatment of HIV-1 infection. Do not coadminister with other antiretroviral products, including products containing any of the same active components; products containing lamivudine; products containing ritonavir; or with adefovir dipivoxil.

• Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered.

• Fat redistribution and accumulation have been observed in patients receiving antiretroviral therapy.

• Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.

Adverse reactions • Common adverse drug reactions in clinical studies (incidence 5%; all grades) were nausea (16%), diarrhea (12%), abnormal dreams (9%), and headache (7%).

Drug interactions • CYP3A substrates: STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Do not use with drugs highly dependent on these factors for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events.

• CYP3A inducers: Drugs that induce CYP3A can decrease the concentrations of components of STRIBILD. Do not use with drugs that strongly induce CYP3A as this may lead to loss of efficacy and possible resistance to STRIBILD. • Drugs affecting renal function: Coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir and the risk of adverse reactions.

• Antacids: Separate STRIBILD and antacid administration by at least 2 hours.

• Prescribing information: Consult the full prescribing information for STRIBILD for more information on potentially significant drug interactions, including clinical comments.

Dosage and administration • Adult dosage: One tablet taken orally once daily with food.

• Renal impairment: Do not initiate in patients with CrCl below 70 mL/min. Discontinue in patients with CrCl below 50 mL/min.

• Hepatic impairment: Not recommended in patients with severe hepatic impairment.

• Testing prior to initiation: Test patients for HBV infection and document baseline CrCl, urine glucose, and urine protein.

Pregnancy and breastfeeding • Pregnancy Category B: There are no adequate and wellcontrolled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk. An Antiretroviral Pregnancy Registry has been established.

• Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed. *Only for patients with pretreatment estimated creatinine clearance ≥70 mL/min.

Study designs: STRIBILD was assessed in 2 randomized, double-blind, active-controlled, phase 3, noninferiority clinical trials in treatment-naïve, HIV-1–infected subjects with baseline estimated creatinine clearance ≥70 mL/min. Study 103 compared STRIBILD (n = 353) to ATV + RTV + FTC/TDF (n = 355); Study 102 compared STRIBILD (n = 348) to a singletablet regimen consisting of EFV/FTC/TDF (n = 352). The primary endpoint of both studies was the proportion of subjects with viral suppression (<50 copies/mL) at week 48 according to FDA snapshot analysis; the FDA snapshot analysis at week 96 was a secondary endpoint.

Baseline characteristics: Viral load: In Studies 103 and 102, respectively, 41% and 33% of subjects had baseline viral loads >100,000 copies/mL. CD4 count: Mean baseline CD4+ cell count was 370 cells/mm3 (range 5 to 1132) in Study 103, and 386 cells/mm3 (range 3 to 1348) in Study 102; 13% of subjects in both studies had CD4+ cell counts <200 cells/mm3.

Abbreviations: ATV, atazanavir; EFV, efavirenz; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.

including BOXED WARNING, on the following pages.

Performance by design Learn more at www.STRIBILD.com/hcp

STRIBILD® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief summary of full Prescribing Information. See full Prescribing Information. Rx only.

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of STRIBILD, in combination with other antiretrovirals [See Warnings and Precautions]. ] STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued emtricitabine or tenofovir DF, which are components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions]. ] INDICATIONS AND USAGE: STRIBILD is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naive.

DOSAGE AND ADMINISTRATION: See Warnings and Precautions, s Adverse Reactions, s and Use in Specific Populationss for additional information.

Adult Dosage: One tablet taken orally once daily with food.

Renal Impairment: Do not initiate in patients with estimated creatinine clearance (CrCl) <70 mL/min. Discontinue if CrCl declines to <50 mL/min during treatment.

Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No data are available regarding use in patients with severe hepatic impairment (Child-Pugh Class C). STRIBILD is not recommended for patients with severe hepatic impairment.

Testing Prior to Initiation: Test patients for HBV infection and document CrCl, urine glucose, and urine protein.

CONTRAINDICATIONS: Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events, or with drugs that strongly induce CYP3A as this may decrease STRIBILD plasma concentrations leading to a loss of efficacy and possible resistance to STRIBILD [See Drug Interactions]:] • Alpha 1-adrenoreceptor antagonist: alfuzosin. Potential for hypotension.

• Antimycobacterial: rifampin. May lead to a loss of efficacy and possible resistance.

• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine. Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

• GI motility agents: cisapride. Potential for cardiac arrhythmias.

• Herbal products: St. John’s wort. May lead to a loss of efficacy and possible resistance.

• HMG CoA reductase inhibitors: lovastatin, simvastatin. Potential for myopathy, including rhabdomyolysis.

• Neuroleptics: pimozide. Potential for cardiac arrhythmias.

• PDE-5 inhibitors: sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension. Increased potential for sildenafil-associated adverse events (visual disturbances, hypotension, priapism, and syncope).

• Sedative/hypnotics: orally administered midazolam, triazolam. Potential for prolonged or increased sedation or respiratory depression.

WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.

Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV: All patients with HIV-1 should be tested for chronic HBV infection before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment: Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF and with STRIBILD. In clinical trials through 96 weeks, 10 (1.4%) subjects in the STRIBILD group (N=701) and 2 (0.3%) subjects in the combined comparator groups (N=707) discontinued study drug due to a renal adverse reaction. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to 0 in the comparator groups. Two of these 4 subjects had renal impairment (CrCl <70 mL/min) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation. Renal replacement therapy was not required. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Drug Interactions].] Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients

with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function. Monitoring:: CrCl, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Do not initiate in patients with CrCl <70 mL/min. Routinely monitor CrCl, urine glucose, and urine protein during therapy in all patients. Additionally monitor serum phosphorus in patients at risk for renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function [See Adverse Reactions],] patients with a confirmed increase in serum creatinine of >0.4 mg/dL from baseline should be closely monitored for renal safety.

Discontinue STRIBILD if CrCl declines to <50 mL/min.

Use with Other Antiretroviral Products: STRIBILD is a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended. Do not coadminister with products containing any of the same active components; with products containing lamivudine; with products containing ritonavir; or with adefovir dipivoxil.

Bone Effects of tenofovir DF: Bone Mineral Density (BMD):: In clinical trials in HIV-1 infected adults, tenofovir DF was associated with decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For additional information, consult the VIREAD (tenofovir DF) full Prescribing Information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Consider assessing BMD in patients with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected appropriate consultation should be obtained. Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF. [See Adverse Reactions] Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome (IRS): IRS has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (e.g., Graves’ disease, polymyositis, and Guillain-Barre syndrome) have been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

ADVERSE REACTIONS: See BOXED WARNING and Warnings and Precautions for additional serious adverse reactions. s The safety assessment of STRIBILD is based on pooled data from two Phase 3 trials in antiretroviral treatment-naive HIV-1 infected adults. A total of 701 subjects received STRIBILD once daily for at least 96 weeks. 4.6% of subjects discontinued STRIBILD due to adverse events, regardless of severity.

Adverse Reactions: Treatment emergent adverse reactions (all grades) reported in ≥5% of subjects receiving STRIBILD (N=701) through week 96 were: nausea (16%), diarrhea (12%), abnormal dreams (9%), and headache (7%). Frequencies are based on all treatment emergent adverse reactions attributed to study drugs. See Warnings and Precautionss for more information on renal adverse reactions.

Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 3-4) occurring in ≥2% of subjects receiving STRIBILD (N=701) through 96 weeks were: creatine kinase ≥10.0x ULN (7%); urine RBC (hematuria) >75 RBC/HPF (3%); amylase >2.0x ULN (3%); and AST >5.0x ULN (2%). For subjects with serum amylase >1.5x ULN, lipase test was performed; increased lipase (Grades 3-4) occurring in STRIBILD (N=61) was 15%. Proteinuria (all grades) occurred in 46% of subjects receiving STRIBILD. Cobicistat has been shown to decrease CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function; decreases in CrCl occurred early in treatment with STRIBILD after which they stabilized. Mean ±SD changes after 96 weeks of treatment were: serum creatinine, 0.13 ±0.13 mg/dL; and eGFR by Cockcroft-Gault, -13.2 ±15.7 mL/min. Elevation in serum creatinine (all grades) occurred in 10% of subjects. BMD was assessed by DEXA in a non-random subset; mean decreases in BMD from baseline to Week 96 in the STRIBILD group (N=47) were comparable to the comparator group at the lumbar spine (-2.0%) and the hip (-3.2%). Bone fractures occurred in 14 subjects (2.0%) in the STRIBILD group.

Serum Lipids: In clinical trials, 11% of subjects receiving STRIBILD were on lipid lowering agents at baseline; through Week 96, an additional 8% of subjects were started on lipid lowering agents.

Mean changes from baseline in fasting serum lipids in subjects receiving STRIBILD (N=701) through 96 weeks were: total cholesterol: week 96 change +12 (N=571; baseline 166 mg/dL); HDL-cholesterol: week 96 change +7 (N=571; baseline 43 mg/dL); LDL-cholesterol: week 96 change +12 (N=572; baseline 100 mg/dL); triglycerides: week 96 change +8 (N=571; baseline 122 mg/dL). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.

Consult the respective full Prescribing Information for each available individual component of STRIBILD for additional information regarding adverse reactions, including laboratory abnormalities and postmarketing events.

DRUG INTERACTIONS: See Contraindicationss for additional serious drug interactions.

STRIBILD is a complete regimen for the treatment of HIV-1 infection. STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection.

Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

Potential for STRIBILD to Affect Other Drugs: Cobicistat is an inhibitor of CYP3A and CYP2D6 and the transporters p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the concentrations of CYP2C9 substrates.

Potential for Other Drugs to Affect STRIBILD: Elvitegravir and cobicistat are metabolized by CYP3A. Cobicistat is also metabolized to a minor extent by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased concentrations of cobicistat and elvitegravir, which may lead to loss of efficacy and development of resistance. Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the concentration of cobicistat.

Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, which may increase the incidence of adverse reactions [see Warnings and Precautions].]

Established and Other Potentially Significant Interactions: The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD. The list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with STRIBILD: • Acid Reducing Agents: antacids. Separate STRIBILD and antacid administration by at least 2 hours.

• Antiarrhythmics: amiodarone, bepridil, digoxin, disopyramide, flecainide, systemic lidocaine mexiletine, propafenone, quinidine. Caution warranted and therapeutic concentration monitoring recommended.

• Antibacterials: clarithromycin, telithromycin. Clarithromycin: no dose adjustment required for patients with CrCl ≥60 ml/min; the dose should be reduced by 50% for patients with CrCl between 50 and 60 mL/min. Telithromycin: concentrations of telithromycin and/or cobicistat may be increased.

• Anticoagulants: warfarin. International normalized ratio (INR) monitoring recommended.

• Anticonvulsants: carbamazepine, oxcarbazepine phenobarbital, phenytoin, clonazepam, ethosuximide. Phenobarbital, phenytoin, carbamazepine, and oxcarbazepine: may lead to loss of efficacy and possible resistance to STRIBILD. Alternative anticonvulsants should be considered.

Clonazepam and ethosuximide: clinical monitoring recommended.

• Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), trazodone. Dose titration of the antidepressant and monitoring for antidepressant response recommended.

• Antifungals: itraconazole, ketoconazole, voriconazole. Ketoconazole and itraconazole: the maximum daily dose should not exceed 200 mg/day. Voriconazole: an assessment of benefit/risk ratio is recommended to justify use.

• Anti-gout: colchicine. Do not coadminister in patients with renal or hepatic impairment. For other patients, modify the dose and/or regimen as described in the full PI for STRIBILD. • Antimycobacterials: rifabutin, rifapentine. May lead to loss of efficacy and possible resistance to STRIBILD. Coadministration not recommended.

• Beta-Blockers: metoprolol, timolol. Clinical monitoring recommended and a dose decrease of the beta blocker may be necessary.

• Calcium Channel Blockers: amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil.

Caution warranted and clinical monitoring recommended.

• Corticosteroids (Systemic): dexamethasone. May lead to loss of efficacy and possible resistance to STRIBILD. • Corticosteroids (Inhaled/Nasal): fluticasone. Alternative corticosteroids should be considered, particularly for long term use.

• Endothelin Receptor Antagonists: bosentan. Discontinue bosentan at least 36 hours prior to initiating STRIBILD. For patients taking STRIBILD for at least 10 days, start or resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.

• HMG CoA Reductase Inhibitors: atorvastatin. Initiate with the lowest starting dose and titrate carefully while monitoring for safety.

• Hormonal Contraceptives: norgestimate/ethinyl estradiol. Coadministration with STRIBILD resulted in decreased plasma concentrations of ethinyl estradiol and an increase in norgestimate. The effects of increased progesterone exposure are not fully known. The potential risks and benefits of coadministration should be considered, particularly in women who have risk factors for progesterone exposure. Alternative (non hormonal) methods of contraception can be considered.

• Immunosuppressants: cyclosporine, rapamycin, sirolimus, tacrolimus. Therapeutic monitoring recommended.

• Narcotic Analgesics: buprenorphine, naloxone. Closely monitor for sedation and cognitive effects.

• Inhaled Beta Agonist: salmeterol. Coadministration not recommended due to the increased risk of salmeterol cardiovascular adverse events, including QT prolongation, palpitations, and sinus tachycardia.

• Neuroleptics: perphenazine, risperidone, thioridazine. Decrease in dose of the neuroleptic may be needed.

• Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil, tadalafil, vardenafil. Dosage for erectile dysfunction: sildenafil, a single dose not exceeding 25 mg in 48 hours; vardenafil, a single dose not exceeding 2.5 mg in 72 hours; tadalafil, a single dose not exceeding 10 mg in 72 hours; increase monitoring for PDE-5 associated adverse reactions. Dosage for pulmonary arterial hypertension (PAH): tadalafil: stop tadalafil at least 24 hours prior to initiating STRIBILD; start or resume at 20 mg once daily in patients receiving STRIBILD for at least 1 week and increase to 40 mg once daily based on individual tolerability.

• Sedative/hypnotics: Benzodiazepines. Parenteral midazolam: coadministration should be done in a setting ensuring close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation; dose reduction should be considered, especially if more than a single dose is administered. Other sedative/hypnotics: dose reduction may be necessary and clinical monitoring recommended.

Consult the full PI prior to and during treatment with STRIBILD for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS: Pregnancy: STRIBILD is Pregnancy Category B; however, there are no adequate and well-controlled studies in pregnant women. STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk.

Emtricitabine and tenofovir have been detected in human milk; it is not known if elvitegravir or cobicistat is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions and/or drug resistance in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD. Pediatric Use: Safety and effectiveness in children less than 18 years of age have not been established.

Geriatric Use: Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Caution should be exercised in the administration of STRIBILD in elderly patients.

Renal Impairment: STRIBILD should not be initiated in patients with CrCl <70 mL/min. STRIBILD should be discontinued if CrCl declines to <50 mL/min during treatment with STRIBILD. [See Warnings and Precautions, Adverse Reactions].]

Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. STRIBILD is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as no pharmacokinetic or safety data are available in these patients [See Dosage and Administration].]

OVERDOSAGE: If overdose occurs the patient must be monitored for evidence of toxicity. Treatment consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

203100-GS-002

October 2013

References: 1. STRIBILD [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013. 2. US Food and Drug Administration. Antiretroviral drugs used in the treatment of HIV infection. http://www. fda.gov/forconsumers/byaudience/forpatientadvocates/hivandaidsactivities/ucm118915.htm.

Accessed April 8, 2014. 3. Panel on Antiretroviral Guidelines for Adults and Adolescents.

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.

Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Updated May 1, 2014. Accessed May 8, 2014. 4. Zolopa A, Sax PE, DeJesus E, et al; for the GS-US-236-0102 Study Team. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/ emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. r 2013;63(1):96-100. 5. Rockstroh JK, DeJesus E, Henry K, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB) has durable efficacy and differentiated safety compared to atazanavir boosted by ritonavir plus emtricitabine/tenofovir DF in treatment-naïve HIV-1 infected patients: week 96 results. Poster presented at: Eleventh International Congress on Drug Therapy in HIV Infection; November 11-15, 2012; Glasgow, UK. Abstract #O424B.

GILEAD, the GILEAD Logo, STRIBILD, the STRIBILD Logo, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners. ©2014 Gilead Sciences, Inc. All rights reserved. STBP0223 06/14

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table of contents

13 17

Letter from the Editor

New Molecular Diagnostic Technologies: Opportunities For Infection Control?

Brian Currie, MD, MPH

34

Julia Garcia-Diaz, MD Arnab Ray, MD Karla Rivera Rivera, MD

Current Issues in and Approaches To Antimicrobial Resistance Ari Frenkel, MD Paul Cook, MD

23

47

Overview of the Management of Clostridium difficile Infections

Treatment Options in HIV

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The Changing HCV Landscape: Update on Diagnosis and Treatment Sonal Kumar, MD, MPH Ira M. Jacobson, MD

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The Accentuated Challenges Of Aging with HIV Kelly A. Gebo, MD Jennifer A. Schrack, PhD

Jonathan Z. Li, MD Paul E. Sax, MD

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Antimicrobial Stewardship: Current State of Affairs Lilian M. Abbo, MD Marissa Tysiak, PharmD

INFECTIOUS DISEASE SPECIAL EDITION 2014

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Start or Switch: Consider the possibilities For adults with no ARV treatment history and with HIV-1 RNA ≤100,000 copies/mL at the start of therapy or to replace current ARV therapy in certain stably suppressed adults with no history of virologic failure and no resistance to COMPLERA

INDICATION COMPLERA is indicated as a complete regimen for the treatment of HIV-1 infection in adults with no ARV treatment history and with HIV-1 RNA ≤100,000 copies/mL at the start of therapy; and in certain virologically suppressed (HIV-1 RNA <50 copies/mL) adults on a stable ARV regimen at the start of therapy to replace their current regimen, efficacy was established in patients who were virologically suppressed on a stable ritonavir-boosted protease inhibitor-containing regimen. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.

COMPLERA is not recommended for patients <18 years of age.

• Prescribing considerations in adults with no ARV treatment history: Virologic failure (HIV-1 RNA ≥50 copies/mL) was higher in subjects with baseline HIV-1 RNA >100,000 copies/mL

and in subjects with baseline CD4 cell count <200 cells/mm3 (regardless of baseline HIV-1 RNA levels). Compared to efavirenz, virologic failure in rilpivirine-treated subjects conferred a higher rate of overall resistance and cross-resistance to the NNRTI class and more subjects developed tenofovir and lamivudine/ emtricitabine associated resistance • Prescribing considerations in virologically suppressed adults: Patients must have no history of virologic failure, be stably suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months prior to switching therapy, currently be on their first or second ARV regimen prior to switching therapy, and have no current or past history of resistance to any component of COMPLERA

Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

ARV=antiretroviral; NNRTI=non-nucleoside reverse transcriptase inhibitor.

References: 1. COMPLERA Prescribing Information. Gilead Sciences, Inc; June 2014. 2. US Department of Health and Human Services, Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf. Accessed May 5, 2014.

DHHS-Recommended in adults with no ARV treatment history with pretreatment HIV-1 RNA <100,000 copies/mL and with CD4 count >200 cells/mm3.2

Visit complera.com/hcp

IMPORTANT SAFETY INFORMATION BOXED WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of COMPLERA, in combination with other antiretrovirals • COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, which are components of

COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted

Contraindications • Coadministration: COMPLERA should not be coadministered with drugs that induce CYP3A or increase gastric pH as this may lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class. Use of the following drugs with COMPLERA is contraindicated: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors (e.g., esomeprazole, lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole), systemic dexamethasone (>1 dose) and St. John’s wort

®

IMPORTANT SAFETY INFORMATION (CONT) Warnings and Precautions • New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir DF. In all patients, assess estimated creatinine clearance (CrCl) prior to initiating and during therapy. In patients at risk for renal dysfunction, additionally monitor serum phosphorus, urine glucose, and urine protein. Do not administer COMPLERA in patients with CrCl <50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent.

Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after initiation of high dose or multiple NSAIDs in patients with risk factors for renal dysfunction; consider alternatives to NSAIDs in these patients. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function • Drug interactions: Use COMPLERA with caution when given with drugs that may reduce the exposure of rilpivirine or when coadministered with a drug with known risk of Torsades de Pointes.

Supratherapeutic doses of rilpivirine have been shown to prolong the QTc interval of the electrocardiogram (ECG) in healthy subjects • Depressive disorders: The incidence of depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) reported in clinical trials (N=686) was 9% (most were mild or moderate in severity); and Grades 3 and 4 depressive disorders (regardless of causality) was 1%. Suicidal ideation was reported in 4 subjects and suicide attempt was reported in 2 subjects. Patients with severe depressive symptoms should seek immediate medical evaluation and the risks of continued therapy should be determined • Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity in patients without pre-existing hepatic disease or other identifiable risk factors. Patients with underlying hepatitis B or C, or those with marked elevations in liver-associated tests may be at increased risk. Appropriate laboratory testing and monitoring before and during therapy is recommended in patients with underlying hepatic disease or in patients with marked elevations in liver-associated tests prior to treatment initiation; consider testing and monitoring in patients without pre-existing hepatic dysfunction or other risk factors • Bone effects: Decreases in bone mineral density (BMD) and mineralization defects, including osteomalacia, have been seen in patients treated with tenofovir DF. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss. In patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms, hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered • Antiviral products: COMPLERA is a complete regimen for the treatment of HIV-1 infection. Do not coadminister with other antiretrovirals including products containing any of the same active components (unless needed for dose adjustment); products containing lamivudine; or with adefovir dipivoxil

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages.

• Fat redistribution and accumulation has been observed in patients receiving ARV therapy • Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable times to onset, has been reported

Adverse Reactions • In adults with no ARV treatment history: Common adverse reactions reported in clinical studies (incidence ≥2%, Grades 2-4) were depressive disorders (2%), insomnia (2%) and headache (2%) • In virologically suppressed adults: No new types of adverse reactions to COMPLERA were identified in stable, virologically suppressed patients switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% after switching to COMPLERA

Drug Interactions • CYP3A inducers: Drugs that induce CYP3A may decrease rilpivirine plasma concentrations which may lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class • CYP3A inhibitors: Drugs that inhibit CYP3A may increase rilpivirine plasma concentrations • Drugs increasing gastric pH may significantly decrease rilpivirine plasma concentrations and lead to loss of virologic response and possible resistance to COMPLERA or the NNRTI class – Use of proton pump inhibitors with COMPLERA is contraindicated – Antacids should be administered ≥2 hours before or ≥4 hours after COMPLERA – H2 receptor antagonists should be administered ≥12 hours before or ≥4 hours after COMPLERA • Drugs affecting renal function: Coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine and tenofovir • Prescribing information: Consult the full Prescribing Information for COMPLERA for more information on potentially significant drug interactions, including clinical comments

Pregnancy and Breastfeeding • Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if potential benefits justifies the potential risk. An Antiretroviral Pregnancy Registry has been established • Breastfeeding: Emtricitabine and tenofovir have been detected in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed

Dosage and Administration Adults: One tablet taken orally once daily with food.

Renal Impairment: Do not use in patients requiring dose reduction including in patients with estimated CrCl <50 mL/min.

Rifabutin coadministration: Additional rilpivirine 25 mg taken once daily with a meal is recommended.

®

COMPLERA A® (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of COMPLERA, in combination with other antiretrovirals [See Warnings and Precautions]. ] COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued emtricitabine or tenofovir DF, which are components of COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions]. ] INDICATIONS AND USAGE: COMPLERA is indicated as a complete regimen for the treatment of HIV-1 infection in adults with no antiretroviral (ARV) treatment history and with HIV-1 RNA ≤100,000 copies/mL at the start of therapy; and in certain virologically suppressed (HIV-1 RNA <50 copies/mL) adults on a stable ARV regimen at the start of therapy to replace their current regimen, efficacy was established in patients who were virologically suppressed on a stable ritonavir-boosted protease inhibitor-containing regimen. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. COMPLERA is not recommended for patients <18 years of age.

Prescribing considerations when initiating therapy with COMPLERA in adults with no ARV treatment history: • More rilpivirine-treated subjects with HIV-1 RNA >100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA ≤100,000 copies/mL. • Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count <200 cells/mm3 experienced virologic failure compared to rilpivirine-treated subjects with CD4+ cell count ≥200 cells/mm3.

• The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.

• More subjects treated with rilpivirine developed tenofovir and lamivudine/ emtricitabine associated resistance compared to efavirenz.

Prescribing considerations that should be met when replacing current ARV regimen with COMPLERA in virologically suppressed adults: • Patients should have no history of virologic failure.

• Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months prior to switching therapy.

• Patients should currently be on their first or second ARV regimen prior to switching therapy.

• Patients should have no current or past history of resistance to any component of COMPLERA. DOSAGE AND ADMINISTRATION: See Warnings and Precautions, Adverse Reactions,, and Use in Specific Populations s for additional information.

Adult Dosage: One tablet taken orally once daily with food.

Renal Impairment: Do not use in patients with estimated creatinine clearance (CrCl) <50 mL/min.

Rifabutin Coadministration: Additional rilpivirine 25 mg taken once daily with a meal during rifabutin coadministration.

CONTRAINDICATIONS: Coadministration: Do not use with drugs that induce CYP3A or increase gastric pH as significant decreases in rilpivirine plasma concentrations may occur leading to loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [See Drug Interactions].

• Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: rifampin, rifapentine • Proton pump inhibitors: esomeprazole, lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole • Systemic glucocorticoid: dexamethasone (>1 dose) • Herbal product: St. John’s wort WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of COMPLERA, in combination with other antiretrovirals. A majority of these cases have been in women.

Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with

no known risk factors. Treatment with COMPLERA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV: All patients with HIV-1 should be tested for chronic HBV before initiating ARV therapy. COMPLERA is not approved for the treatment of chronic HBV infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of COMPLERA. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment: Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF. Assess estimated CrCl in all patients prior to initiating therapy and as clinically appropriate during therapy with COMPLERA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated CrCl, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of COMPLERA, and periodically during COMPLERA therapy. COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high dose or multiple NSAIDS) [See Drug Interactions]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIVinfected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy.

Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Do not use COMPLERA in patients with estimated CrCl <50 mL/min.

Drug Interactions: Caution should be given when prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine or when coadministered with a drug with a known risk of Torsade de Pointes. In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram (ECG) [See Contraindications and Drug Interactions].

Depressive Disorders: Depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with rilpivirine. Through 96 weeks in Phase 3 trials (N=686), the incidence of depressive disorders (regardless of causality, severity) was 9% (most events were mild or moderate in severity), Grades 3 and 4 depressive disorders (regardless of causality) was 1%, and discontinuation due to depressive disorders was 1%; suicidal ideation was reported in 4 subjects and suicide attempt was reported in 2 subjects. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Hepatotoxicity: Hepatic adverse events have been reported with rilpivirine. Patients with underlying hepatitis B or C, or marked elevations in liver-associated tests prior to treatment may be at increased risk for worsening or development of liver-associated tests elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation.

Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors.

Bone Effects of Tenofovir DF: Bone mineral density (BMD):: In clinical trials in HIV-1 infected adults, tenofovir DF was associated with decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For more information, please consult the VIREAD (tenofovir DF) full Prescribing Information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Consider assessing BMD in patients with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.

Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected, appropriate consultation should be obtained. Mineralization defects:: Cases of osteomalacia associated with proximal renal tubulopathy manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF. Coadministration with Other Products: COMPLERA should not be administered concurrently with other products containing any of the same active components (emtricitabine, rilpivirine or tenofovir DF) unless needed for dose adjustment; with products containing lamivudine; or with adefovir dipivoxil.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving ARV therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome (IRS): IRS has been reported in patients treated with combination ARV therapy, including the components of COMPLERA. During the initial phase of combination ARV treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (e.g., Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

ADVERSE REACTIONS: See BOXED WARNING G and Warnings and Precautions s for additional serious adverse reactions.

In HIV-1 Infected Subjects with No ARV Treatment History: The safety assessment of rilpivirine, used in combination with other antiretrovirals, is based on the week 96 pooled data from two Phase 3 trials in ARV treatment-naive HIV-1 infected adults. A total of 686 subjects received rilpivirine in combination with other antiretrovirals as background regimen; 550 of whom received emtricitabine/ tenofovir DF. The median duration of exposure for subjects was 104 weeks.

Adverse Reactions: Treatment emergent adverse reactions (Grades 2-4) reported in ≥2% of subjects receiving rilpivirine + emtricitabine/tenofovir DF (N=550) through week 96 were: depressive disorders (2%; includes depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation), headache (2%), and insomnia (2%). Frequencies of adverse reactions are based on all Grades 2-4 treatment emergent adverse reactions assessed to be related to study drug. No new adverse reactions were identified between weeks 48 and 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population (for additional information, consult the Edurant [rilpivirine] full Prescribing Information). Two percent of subjects discontinued treatment with rilpivirine + emtricitabine/tenofovir DF due to adverse reactions (regardless of severity). The most common adverse reactions leading to discontinuation were psychiatric disorders (9 [1.6%] subjects); rash led to discontinuation in 1 (0.2%) subject. Rilpivirine adverse reactions:: Treatment emergent adverse reactions (≥Grade 2) occurring in <2% of subjects receiving rilpivirine (N=686) were (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.

Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 1, 2, 3, and 4, respectively) occurring in subjects receiving rilpivirine + emtricitabine/ tenofovir DF (N=550) through week 96 were: increased creatinine (6%, 1%, <1%, 0%), increased AST (16%, 4%, 2%, 1%), increased ALT (19%, 5%, 1%, 1%), increased total bilirubin (6%, 3%, 1%, 0%), increased fasting total cholesterol (14%, 6%, <1%, 0%), increased fasting LDL cholesterol (13%, 5%, 1%, 0%), and increased fasting triglycerides (0%, 1%, 1%, 0%).

Adrenal Function: Mean changes from baseline in basal cortisol and ACTH-stimulated cortisol at week 96 (N=686) were -19.1 nmol/L (95% CI: -30.9; -7.4) and +18.4 ± 8.36 nmol/L, respectively; both values were within normal range. Effects on adrenal function were comparable by background N(t)RTIs. No serious adverse reactions, deaths, or treatment discontinuations were attributed to adrenal insufficiency.

Serum Creatinine: Mean change from baseline in serum creatinine at week 96 (N=686) was 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL); most increases occurred within the first four weeks of treatment. Observed serum creatinine increases were similar among subjects with baseline mild or moderate renal impairment and subjects with baseline normal renal function; increases were comparable by background N(t)RTIs. No changes were considered to be clinically relevant and no subject discontinued treatment due to serum creatinine increases.

Serum Lipids: Mean changes from baseline in fasting serum lipids at week 96 were: total cholesterol: +2 mg/dL (N=430; baseline 162 mg/dL); HDL-cholesterol: +4 mg/ dL (N=429; baseline 42 mg/dL); LDL-cholesterol: -1 mg/dL (N=427; baseline 97 mg/ dL); and triglycerides: -14 mg/dL (N=430; baseline 123 mg/dL). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and week 96 values. Subjects receiving lipid lowering agents during treatment were excluded from these lipid analyses.

Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In patients coinfected with hepatitis B or C virus receiving rilpivirine, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection.

In Virologically Suppressed HIV-1 Infected Subjects: No new types of adverse reactions to COMPLERA were identified in stable, virologically suppressed subjects switching to COMPLERA from a regimen containing a ritonavirboosted protease inhibitor; however, the frequency of adverse reactions increased by 20% after switching to COMPLERA. Consult the respective full Prescribing Information for each individual component of COMPLERA for additional information regarding adverse reactions, including laboratory abnormalities and postmarketing events.

DRUG INTERACTIONS: See Contraindications s for additional serious drug interactions.

COMPLERA is a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretrovirals. Information regarding potential drug interactions with other antiretrovirals is not provided.

Drugs Inducing or Inhibiting CYP3A: Rilpivirine is primarily metabolized by CYP3A, thus drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine.

Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine leading to loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and

drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

Drugs Increasing Gastric pH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine leading to loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, which may increase the incidence of adverse reactions [See Warnings and Precautions].

QT Prolonging Drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

Established and Other Potentially Significant Drug Interactions: The drug interactions described are based on studies conducted with individual components of COMPLERA or are predicted drug interactions that may occur with COMPLERA; no drug interaction studies have been conducted using COMPLERA as a fixed-dose combination tablet. The list includes potentially significant interactions but is not all inclusive. For additional information, consult the Edurant, EMTRIVA (emtricitabine) or VIREAD full Prescribing Information. An alteration in dose or regimen may be recommended when the following drugs are coadministered with COMPLERA: • Antacids: aluminum, magnesium hydroxide, calcium carbonate. Antacids should be taken ≥2 hours before or ≥4 hours after COMPLERA. • Antimycobacterials: rifabutin. Give additional rilpivirine 25 mg once daily with a meal during rifabutin coadministration.

• Azole Antifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole.

No dose adjustment required; monitor for breakthrough fungal infections.

• H2-Receptor Antagonists: cimetidine, famotidine, nizatidine, ranitidine. H2-receptor antagonists should be taken ≥12 hours before or ≥4 hours after COMPLERA. • Macrolide/Ketolide Antibiotics: clarithromycin, erythromycin, telithromycin. Consider alternatives (e.g., azithromycin) when possible.

• Narcotic Analgesic: methadone. No dose adjustment required at therapy initiation; monitor during treatment; methadone maintenance dose may need adjustment.

Consult the full Prescribing Information prior to and during treatment with COMPLERA for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS: Pregnancy: COMPLERA is Pregnancy Category B; however, there are no adequate and well-controlled studies in pregnant women. COMPLERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry:: To monitor fetal outcomes of pregnant women exposed to COMPLERA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that rilpivirine and tenofovir are secreted in milk. Emtricitabine and tenofovir have been detected in human milk; it is not known if rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions and/or drug resistance in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMPLERA. Pediatric Use: COMPLERA is not recommended for patients <18 years of age because not all the individual components of COMPLERA have safety, efficacy and dosing recommendations available for all pediatric age groups.

Geriatric Use: Clinical studies of emtricitabine, rilpivirine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: COMPLERA should not be prescribed for patients with moderate, severe or end stage renal impairment (CrCl <50 mL/min) or patients who require dialysis [See Warnings and Precautions].

Hepatic Impairment: No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

COMPLERA has not been studied in patients with severe hepatic impairment (ChildPugh Class C).

OVERDOSAGE: If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with COMPLERA consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.

COMPLERA, EMTRIVA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

202123-GS-006 June 2014

COMPLERA, the COMPLERA Logo, EMTRIVA, GILEAD, the GILEAD Logo, GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other marks referenced herein are the property of their respective owners. ©2014 Gilead Sciences, Inc. All rights reserved. CPAP0139 7/14

Dear Readers: The producers of the police and legal procedural television series “Law & Order,” which completed its remarkable 20-year run in 2010, described the storylines for many of the show’s episodes as topical—or, as promotional spots for the program often blared, “ripped from the headlines.”

Infectious disease (ID) specialists, of course, could say the same about their work. Whether it’s the recent Ebola crisis in western Africa or the ongoing global fight against the spread of HIV/AIDS, the research and clinical work of ID physicians—and those who work with them—often is at the center of worldwide health concerns, and behind many of the headlines we read in newspapers every day.

In other words, dear readers, you do very special work.

Now in its 17th year (a pretty remarkable run in its own right), Infectious Disease Special Edition aims to serve as a resource for clinicians engaged in this very important field. Essentially, it is a vehicle that enables some of the leading minds in the ID arena—many of whom have been vital contributors to our mission for much if not all of our history—to share their insights and experience with the profession at large. They are the E is merely their platform. experts; IDSE

As managing editor, it is my honor and privilege to work with these leaders of the ID community. When I was asked to return after a 7-year absence, the opportunity to work with IDSE’s E authors made the decision a true no-brainer. In this, the publication’s 2014 issue, you will find review articles on topics ranging from HIV/ AIDS and Clostridium difficile infections to the issue of antimicrobial resistance and the best approaches for managing it. We also have a review of novel molecular diagnostic technologies as well as an expert commentary on antimicrobial stewardship.

In addition to our print publication, you also will find what we hope are valuable tools on our website, www. idse.net. Digital versions of review articles published herein are available on the site, as is access to exclusive news and clinical monographs, as well as other features.

At IDSE, E we know that it’s our readers making the headlines; we only strive to provide you with a little help along the way as you work to give some of the world’s most vulnerable populations a bit of good news for a change.

Thank you for reading and enjoy the issue.

Brian P. Dunleavy Managing Editor

EDITORIAL ADVISORY BOARD Brian Currie, MD, MPH Professor of Clinical Medicine Division of Infectious Diseases Albert Einstein College of Medicine Assistant Dean for Clinical Research Montefiore Medical Center New York, New York Julia Garcia-Diaz, MD Program Director Infectious Diseases Fellowship Program Ochsner Health System New Orleans, Louisiana

Jerome O. Klein, MD Professor of Pediatrics Boston University School of Medicine Boston Medical Center Boston, Massachusetts Harry W. Lampiris, MD Associate Professor of Clinical Medicine University of California at San Francisco Deputy Associate Chief of Staff San Francisco VA Medical Center San Francisco, California

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Paul E. Sax, MD Clinical Director, HIV Program Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts

Paul A. Volberding, MD Professor Department of Medicine Director of Research Global Health Sciences Director, AIDS Research Institute University of California at San Francisco San Francisco, California

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INFECTIOUS DISEASE SPECIAL EDITION 2014

13

WHEN

VIBATIV is the only once-daily bactericidal antibiotic with a dual mechanism of action indicated for infections due to MRSA1

K S I R MRSA E G R A L S M O O L

ncomycin molecule—

the re-engineered va — V TI BA VI th wi ep st xt ne Take the .U.S.: call for P.L when serious MRSA infections

2,3

against Gram-positive pathogens n tio ac l ida ric cte ba ro vit in nt ote hours4 24 er ov SA MR for C MI the 90 e ov evels of drug that remain ab nitoring1 mo l ve -le ug dr c uti pe ra the ut tho ser-friendly, once-daily dosing wi 1 als tri al nic cli ge lar in ed riz cte afety profile chara

P L U S

VIBATIV is the only once-daily bactericidal antibiotic indicated for the treatment of HABP/VABP due to MRSA INDICATION VIBATIV is indicated for the treatment of adult patients with hospitalacquired and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Staphylococcus aureus (including methicillin-susceptible and -resistant isolates). VIBATIV should be reserved for use when alternative treatments are not suitable.

VIBATIV is indicated for the treatment of adult patients with complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: • Staphylococcus aureus (including methicillin-susceptible and -resistant isolates) • Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or • Enterococcus faecalis (vancomycin-susceptible isolates only) Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative organisms.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to telavancin. VIBATIV may be initiated as empiric therapy before results of these tests are known. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VIBATIV and other antibacterial drugs, VIBATIV should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Available in two strengths: 250 mg and 750 mg1

IMPORTANT SAFETY INFORMATION Mortality Patients with pre-existing moderate/severe renal impairment (CrCl ≤50 mL/min) who were treated with VIBATIV for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia had increased mortality observed versus vancomycin. Use of VIBATIV in patients with preexisting moderate/severe renal impairment (CrCl ≤50 mL/min) should be considered only when the anticipated benefit to the patient outweighs the potential risk.

Nephrotoxicity New onset or worsening renal impairment occurred in patients who received VIBATIV. Renal adverse events were more likely to occur in patients with baseline comorbidities known to predispose patients to kidney dysfunction and in patients who received concomitant medications known to affect kidney function.

Monitor renal function in all patients receiving VIBATIV prior to initiation of treatment, during treatment, and at the end of therapy. If renal function decreases, the benefit of continuing VIBATIV versus discontinuing and initiating therapy with an alternative agent should be assessed.

Fetal Risk Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. Avoid use of VIBATIV during pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. Adverse developmental outcomes observed in three animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans. If not already pregnant, women of childbearing potential should use effective contraception during VIBATIV treatment.

Contraindication VIBATIV is contraindicated in patients with a known hypersensitivity to the drug.

Hypersensitivity Reactions Serious and potentially fatal hypersensitivity reactions, including anaphylactic reactions, may occur after first or subsequent doses. VIBATIV should be used with caution in patients with known hypersensitivity to vancomycin.

Geriatric Use Telavancin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group.

Infusion Related Reactions VIBATIV is a lipoglycopeptide antibacterial agent and should be administered over a period of 60 minutes to reduce the risk of infusion-related reactions.

Rapid intravenous infusions of the glycopeptide class of antimicrobial agents can cause “Red-man Syndrome”-like reactions including: flushing of the upper body, urticaria, pruritus, or rash.

For full Prescribing Information, including Boxed Warning and Medication Guide in the US, please visit www.VIBATIV.com.

References: 1. VIBATIV® (telavancin) Prescribing Information. South San Francisco, CA: Theravance, Inc; March 2014. 2. Draghi DC, et al. Comparative surveillance study of telavancin activity against recently collected Gram-positive clinical isolates from across the United States. Antimicrob Agents and Chemother. 2008;52:2383-2388. 3. Draghi DC, et al. In vitro activity of telavancin against recent Gram-positive clinical isolates: results of the 2004-05 Prospective European Surveillance Initiative. J Antimicrob Chemother. 2008;62:116-121. 4. Data on file. South San Francisco, CA: Theravance, Inc.

THERAVANCE®, the Cross/Star logo, VIBATIV® and the VIBATIV logo are registered trademarks of the Theravance Biopharma group of companies.

QTc Prolongation Caution is warranted when prescribing VIBATIV to patients taking drugs known to prolong the QT interval. In a study involving healthy volunteers, VIBATIV prolonged the QTc interval. Use of VIBATIV should be avoided in patients with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy.

Most Common Adverse Reactions The most common adverse reactions (greater than or equal to 10% of patients treated with VIBATIV) were taste disturbance, nausea, vomiting, and foamy urine.

VBT 00046-03

June 2014

VIBATIV VÂŽ (telavancin) for injection, for intravenous use Rx ONLY BRIEF SUMMARY. See package insert available at www.vibativ.com for full Prescribing Information, including Boxed Warning and Medication Guide.

INDICATIONS AND USAGE: VIBATIV is a lipoglycopeptide antibacterial drug indicated for the treatment of the following infections in adult patients caused by designated susceptible bacteria: â&#x20AC;˘ Complicated skin and skin structure infections (cSSSI) â&#x20AC;˘ Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Staphylococcus aureus. VIBATIV should be reserved for use when alternative treatments are not suitable.

CONTRAINDICATIONS: VIBATIV is contraindicated in patients with known hypersensitivity to telavancin.

WARNINGS: Patients with pre-existing moderate/severe renal impairment (CrCl Â&#x201D; mL/min) who were treated with VIBATIV for hospital-acTuired bacterial pneumonia/ ventilator-associated bacterial pneumonia had increased mortality observed versus vancomycin. Use of VIBATIV in patients with pre-existing moderate/severe renal impairment (CrCl Â&#x201D; mL/min) should be considered only when the anticipated beneĂ&#x20AC;t to the patient outweighs the potential risk.

Nephrotoxicity: New onset or worsening renal impairment has occurred. Monitor renal function in all patients.

Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. Avoid use of VIBATIV during pregnancy unless potential beneĂ&#x20AC;t to the patient outweighs potential risk to the fetus. Adverse developmental outcomes observed in 3 animal species at clinically relevant doses raise concerns about potential adverse developmental outcomes in humans.

WARNINGS AND PRECAUTIONS: Increased Mortality in Patients with HABP/ VABP and Pre existing Moderate to Severe Renal Impairment (CrCl Â&#x201D; mL/min): In the analysis of patients (classiÂżed by the treatment received) in the two combined HABP/VABP trials with pre-e[isting moderate/severe renal impairment (CrCl Â&#x201D; m// min) all-cause mortality within days of starting treatment was / ( ) in the VIBATIV group compared with / ( ) in the vancomycin group. All-cause mortality at 28 days in patients without pre-existing moderate/severe renal impairment (CrCl ! m//min) was 8 / ( ) in the VIBATIV group and 2/ ( 8 ) in the vancomycin group. Therefore VIBATIV use in patients with baseline CrCl Â&#x201D; m// min should be considered only when the anticipated beneÂżt to the patient outweighs the potential risk. Decreased Clinical Response in Patients with cSSSI and Pre-existing Moderate/Severe Renal Impairment (CrCl Â&#x201D; mL/min): In a subgroup analysis of the combined cSSSI trials, clinical cure rates in the VIBATIV-treated patients were lower in patients with baseline CrCl Â&#x201D; m//min compared with those with CrCl ! m// min. A decrease of this magnitude was not observed in vancomycin-treated patients.

Consider these data when selecting antibacterial therapy for use in patients with cSSSI and with baseline moderate/severe renal impairment. Nephrotoxicity: In both the HABP/ VABP trials and the cSSSI trials, renal adverse events were more likely to occur in patients with baseline comorbidities known to predispose patients to kidney dysfunction (pre-existing renal disease, diabetes mellitus, congestive heart failure, or hypertension).

The renal adverse event rates were also higher in patients who received concomitant medications known to affect kidney function (e.g., non-steroidal anti-inĂ&#x20AC;ammatory drugs, ACE inhibitors, and loop diuretics). Monitor renal function (i.e., serum creatinine, creatinine clearance) in all patients receiving VIBATIV. Values should be obtained prior to initiation of treatment, during treatment (at 8- to 2-hour intervals or more frequently, if clinically indicated), and at the end of therapy. If renal function decreases, the beneÂżt of continuing VIBATIV versus discontinuing and initiating therapy with an alternative agent should be assessed. In patients with renal dysfunction, accumulation of the solubilizer hydroxypropylbetacyclodextrin can occur. Pregnant Women and Women of Childbearing Potential: Avoid use of VIBATIV during pregnancy unless the potential beneÂżt to the patient outweighs the potential risk to the fetus. VIBATIV caused adverse developmental outcomes in animal species at clinically relevant doses. This raises concern about potential adverse developmental outcomes in humans. Women of childbearing potential should have a serum pregnancy test prior to administration of VIBATIV. If not already pregnant, women of childbearing potential should use effective contraception during VIBATIV treatment.

Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, may occur after Âżrst or subsequent doses. 'iscontinue VIBATIV at Âżrst sign of skin rash, or any other sign of hypersensitivity. Telavancin is a semi-synthetic derivative of vancomycin; it is unknown if patients with hypersensitivity reactions to vancomycin will experience cross-reactivity to telavancin. VIBATIV should be used with caution in patients with known hypersensitivity to vancomycin. Infusion-Related Reactions: VIBATIV is a lipoglycopeptide antibacterial agent and should be administered over a period of minutes to reduce the risk of infusion-related reactions. 5apid intravenous infusions of the glycopeptide class of antimicrobial agents can cause Âł5ed-man Syndrome´-like reactions including: Ă&#x20AC;ushing of the upper body, urticaria, pruritus, or rash.

Stopping or slowing the infusion may result in cessation of these reactions. Clostridium diIÂżFilH-Associated Diarrhea: &lostrLGL r uP GLIÂżcLle L -associated diarrhea (C'A') has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the Ă&#x20AC;ora of the colon and may L produces toxins A and B which contribute to permit overgrowth of C. GLIÂżcLle L . C. GLIÂżcLle the development of C'A'. Hypertoxin-producing strains of C. GLIÂżcLle L cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. C'A' must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because C'A' has been reported to occur more than 2 months after the administration of antibacterial agents. If C'A' is suspected or conÂżrmed, ongoing antibiotic use not directed against C. GLIÂżcLle L may need to be discontinued. Appropriate Ă&#x20AC;uid and electrolyte management, protein supplementation, antibiotic treatment of C. GLIÂżcLle L , and surgical evaluation should

be instituted as clinically indicated. Development of Drug-Resistant Bacteria: Prescribing VIBATIV in the absence of a proven or strongly suspected bacterial infection is unlikely to provide beneÂżt to the patient and increases the risk of the development of drug-resistant bacteria. As with other antibacterial drugs, use of VIBATIV may result in overgrowth of nonsusceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. QTc Prolongation: In a study involving healthy volunteers, doses of . and mg/kg of VIBATIV prolonged the QTc interval. Caution is warranted when prescribing VIBATIV to patients taking drugs known to prolong the QT interval. Patients with congenital long QT syndrome, known prolongation of the QTc interval, uncompensated heart failure, or severe left ventricular hypertrophy were not included in clinical trials of VIBATIV. Use of VIBATIV should be avoided in patients with these conditions. Coagulation Test Interference: Although telavancin does not interfere with coagulation, it interfered with certain tests used to monitor coagulation, when conducted using samples drawn to 8 hours after VIBATIV administration for patients being treated once every 2 hours. Blood samples for these coagulation tests should be collected as close as possible prior to a patientâ&#x20AC;&#x2122;s next dose of VIBATIV. Blood samples for coagulation tests unaffected by VIBATIV may be collected at any time. No evidence of increased bleeding risk has been observed in clinical trials with VIBATIV. Telavancin has no effect on platelet aggregation. Furthermore, no evidence of hypercoagulability has been seen, as healthy subMects receiving VIBATIV have normal levels of '-dimer and Âżbrin degradation products.

ADVERSE REACTIONS: In the cSSSI clinical trials, serious adverse events were reported in ( / 2 ) of patients treated with VIBATIV and most commonly included renal, respiratory, or cardiac events. Serious adverse events were reported in ( / 8) of vancomycin-treated patients, and most commonly included cardiac, respiratory, or infectious events. Treatment discontinuations due to adverse events occurred in 8 (72/929) of patients treated with VIBATIV, the most common events being nausea and rash (a each). Treatment discontinuations due to adverse events occurred in ( /9 8) of vancomycin-treated patients, the most common events being rash and pruritus (a each). The most common adverse events occurring in Â&#x2022; of VIBATIV-treated patients were taste disturbance, nausea, vomiting, and foamy urine. The following table displays the incidence of treatment-emergent adverse drug reactions reported in Â&#x2022;2 of patients treated with VIBATIV possibly related to the drug.

Body as a Whole 5igors 'igestive System Nausea Vomiting 'iarrhea Metabolic and Nutritional 'ecreased appetite Nervous System Taste disturbance* 5enal System Foamy urine

VIBATIV (N=929)

Vancomycin (N=938)

2

27

7

7 8

2

7

'escribed as a metallic or soapy taste.

In HABP/VABP clinical trials, serious adverse events were reported in of patients treated with VIBATIV and 2 of patients who received vancomycin. Treatment discontinuations due to adverse events occurred in 8 ( /7 ) of patients who received VIBATIV, the most common events being acute renal failure and electrocardiogram QTc interval prolonged (a each). Treatment discontinuations due to adverse events occurred in ( /7 2) of vancomycin-patients, the most common events being septic shock and multi-organ failure ( ). The following table displays the incidence of treatment-emergent adverse drug reactions reported in Â&#x2022; of HABP/VABP patients treated with VIBATIV possibly related to the drug.

VIBATIV (N= )

Vancomycin (N= 2)

Nausea

Vomiting 5enal Failure Acute

OVERDOSAGE: In the event of overdosage, VIBATIV should be discontinued and supportive care is advised with maintenance of glomerular Âżltration and careful monitoring of renal function. The clearance of telavancin by continuous venovenous hemoÂżltration (CVVH) has not been evaluated in a clinical study.

Manufactured by: Theravance Biopharma Antibiotics, Inc. Marketed by: Theravance Biopharma US, Inc. South San Francisco, CA 9 8

VBT - 2 -une 2

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Current Issues in and Approaches to Antimicrobial Resistance ARI FRENKEL, MD Infectious Disease Fellow East Carolina University Greenville, North Carolina

PAUL COOK, MD Chief, Division of Infectious Diseases East Carolina University Greenville, North Carolina Dr. Frenkel reports that he has no relevant financial interests to disclose. Dr. Cook reports that he has received grants and/ or research support from Gilead Sciences, Merck, and Pfizer; that he owns shares of Pfizer stock; and that he serves on the speakersâ&#x20AC;&#x2122; bureaus for Forest Laboratories and Merck.

I

t is now well known that the use and

overuse of antibiotics has resulted

in increasing resistance by causing

breeding of microorganisms that are no longer susceptible to available antimicrobial agents.1 In 2010, health care providers in the United States prescribed 258 million courses of antibiotics in the outpatient setting; this translates into 833 prescriptions per 1,000 persons, and these numbers do not include the use of these drugs in hospitalized patients.2

W W W. I D S E . N E T

It is estimated that up to 50% of all antibiotics prescribed in the United States in acute care hospitals are improperly prescribed or needless.3 Annually, more than 2 million individuals are infected with antibiotic-resistant organisms.4 These patients are at increased risk for mortality and morbidity as well as extended hospitalization, and increased health care costs.5 The Centers for Disease Control and Prevention (CDC) estimates that in the United States alone, more than 23,000 people die as a result of antibiotic-resistant infections each year.4 The cost of antimicrobial resistance has been estimated to exceed $20 billion.6,7 As a result, the CDC now classifies antimicrobial resistance as one of the most serious health threats worldwide.4 With advancements in areas such as chemotherapy for cancer, transplant medicine, dialysis, and immunomodulating treatments for autoimmune diseases, the need for effective antimicrobial agents has become even more crucial. Health care providers often are left with no choice but to treat with drugs that are frequently more expensive, more toxic, and less effective.4 Therefore, it is essential to have mechanisms in place to reduce the unnecessary use of antibiotics as well as the duration of use in patients who require treatment.

INFECTIOUS DISEASE SPECIAL EDITION 2014

17

Table 1. Summary of CDC Antimicrobial Resistance Threat Levels Urgent Threats

Serious Threats

Clostridium difficile

Acinetobacter

ESBLs

Non-typhoidal Salmonella

MRSA

VRSA

Concerning Threats

CRE

Campylobacter

VRE

Salmonella typhi

Streptococcus pneumoniae

Group A streptococcus

Gonorrhoeae

Candida

Pseudomonas aeruginosa

Shigella

Tuberculosis

Group B streptococcus

CDC, Centers for Disease Control and Prevention; CRE, carbapenem-resistant Enterobacteriaceae; ESBLs, extended-spectrum β-lactamases; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococci; VRSA, vancomycin-resistant Staphylococcus aureus Adapted p from referen reference nce 4.

At present, the CDC places resistant bacterial organisms into 3 categories: urgent, serious, and concerning (Table 1). Each category assigns a “hazard level” of importance to the threat. An urgent threat refers to a high consequence of antibiotic resistance, which poses a significant threat to patients and has the potential to become a public health concern. A serious threat can also become an urgent threat, but frequently there are antimicrobial therapeutic options available. A concerning threat refers to a low risk for resistance, but it is recommended that bacteria in this category be monitored closely.4

Resistance in Gram-Negative Bacteria Resistance of bacteria to antibiotics occurs in a variety of ways. A common mechanism of resistance is production of β-lactamases, which are enzymes that hydrolyze the β-lactam ring of penicillins, cephalosporins, and carbapenems, thereby rendering the drugs inactive.8 Although antibiotic resistance can occur in both gram-positive and gram-negative bacteria (GNB), the resistance mechanisms are much more complicated in gram-negative organisms. GNBs such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, tend to be highly resistant to antimicrobial agents. In fact, these bacteria can become resistant to nearly all antibiotics. The most concerning gram-negative infections are health care–associated, as these tend to be the most resistant; this is of particular concern in the ICU, where some of the highest rates of multidrug-resistant (MDR) GNBs are found.8 Indeed, patients in the ICU often develop colonization with MDR organisms that then make their way to the long-term care facilities and even into the community.

This phenomenon can occur when ICU patients circulate through acute and chronic health care facilities. Multidrug resistance is defined as resistance by the organism to more than 1 agent from 3 or more antimicrobial categories. When an organism is resistant to more than 1 agent in all but 2 categories, it is referred to as extreme drug resistance. Finally, when an organism is resistant to all antibiotics, it is referred to as being pan-drug resistant.8,9

18

W W W. I D S E . N E T

The clinically important β-lactamases in gram-negative organisms include AmpC, extended-spectrum β-lactamases (ESBL), and carbapenemases (Table 2).10 Enterobacterr and Citrobacterr species commonly possess AmpC-type β-lactamases. These organisms are typically resistant to first-, second-, and third-generation cephalosporins. The AmpC C gene is chromosomal in Enterobacterr and Citrobacterr and is inducible by β-lactams. The AmpC C gene is poorly expressed or not expressed in Escherichia colii and Klebsiella species, respectively, but the gene can be acquired from a plasmid of another organism, thus giving it the same phenotype as Enterobacter. The carbapenems are the most reliable drugs for these organisms, although cefepime, piperacillin/tazobactam, aminoglycosides, trimethoprim/sulfamethoxazole, and tigecycline may also be effective.10 ESBL-producing bacteria have the ability to hydrolyze penicillins, cephalosporins, and monobactams. Fortunately, these enzymes have no effect on carbapenems, which are the drugs of choice for such infections. These ESBL-producing organisms often carry genes on plasmids that make them resistant to other classes of antibiotics such as aminoglycosides and fluoroquinolones.10 Carbapenemase-producing organisms are increasingly being recognized in Enterobacteriaceae, most commonly K. pneumoniae, and are designated carbapenemase-resistant Enterobacteriaceae (CRE).11 The carbapenemases are a diverse group of β-lactamases; the common types are designated serine carbapenemases (classes A, C, and D) and metallo-β-lactamases (class B), so-called because of the critical importance of zinc ion to β-lactamase activity. The latter class includes the New Delhi metallo-β-lactamase (NDM-1). Because carbapenemase genes are located on plasmids, there is the potential for rapid transfer of the genetic material to other organisms, including other species and P. aeruginosa. Also, cotransfer of other resistance genes from the same plasmid is common, making these organisms resistant to all β-lactams, aminoglycosides, fluoroquinolones, and tetracyclines.11

Table 2. Summary of Clinically Relevant β-Lactamases in Gram-Negative Bacteria Enterobacteriaceae

Pseudomonas aeruginosa

Acinetobacter

AmpC β-lactamases

ESBL

Carbapenemases

DNA gyrase/ topoisomerase mutations

Aminoglycosidemodifying enzymes

Multidrug efflux pumps

Porin mutations

Altered penicillinbinding protein

Staphylococcus aureus

Penicillinase ESBL, extended-spectrum β-lactamase Adapted from references 9-12.

Ineffective binding of β-lactams to penicillin-binding protein (PBP) 2a (a mutated form of PBP2) is responsible for the resistance of methicillin-resistant (MRSA).

Ceftaroline, a fifth-generation cephalosporin, is the only commercially available β-lactam with activity against MRSA.12 DNA gyrase and topoisomerase mutations lead to decreased susceptibility to fluoroquinolones. Reduced susceptibility to fluoroquinolones also may be due to removal of the drug from the cell via efflux pumps.13,14 Efflux pumps are present in many bacteria and are responsible for removal of a variety of substances, including certain antimicrobial agents from the cell.

Upregulation of efflux pumps is a common mechanism of resistance of both P. aeruginosa and A. baumanniii to carbapenems, particularly meropenem and doripenem, and to fluoroquinolones. Other forms of resistance seen with P. aeruginosa include aminoglycoside-modifying enzymes, and metallo-β-lactamases.13-15 Finally, porins are outer membrane protein channels that allow certain substances, including some antibiotics, to penetrate the bacterial cell membrane and wall.

Downregulation of the outer membrane proteins results in resistance of the organism to the drug (eg, imipenemresistant P. aeruginosa). It is not uncommon for phenotypic resistance to certain antibiotics to be due to a variety of mechanisms, including carbapenemase activity in the presence of decreased expression of porins.15,16

common MDR organisms. Treatment of MDR organisms begins with broad-spectrum antibiotics for the suspected organism.17 Empiric antibiotic therapy should be based on institution-specific antibiograms. Once an organism is identified and susceptibilities are available, antibiotics can be streamlined.17 In certain situations, the only effective antibiotics are highly toxic drugs such as colistin.18 In patients with MDR organisms or with CRE, colistin is frequently used in combination with a carbapenem such as meropenem. The effectiveness of treatment in this scenario depends on the site of infection, control of the source of infection (eg, drainage of an abscess), and type of resistant organism. Host factors, including immunosuppression, diabetes, renal function, and age are major determinants of patient outcomes.17,18 There are investigational agents with activity against β-lactamases, including carbapenemases. One of the more promising drugs is avibactam, which has been used in combination with ceftazidime (Novexel, Forest).

Avibactam has good activity against the class A, C, and D carbapenemases, but no activity against the class B metallo-β-lactamases (eg, NDM-1).19 Therefore, it is important for microbiology laboratories to be able to identify an organism as one with carbapenemase activity, and also to determine which class of carbapenemase is present.

Treatment of MDR Organisms

Preventing Resistance

Table 3 illustrates major mechanisms of resistance and the common resistant patterns seen with the more

Preventing the development and spread of resistant organisms is a difficult and multidisciplinary task that

INFECTIOUS DISEASE SPECIAL EDITION 2014

19

Table 3. Recommended Treatment of MDR Organisms Type of Resistance

Common Organisms

Recommended Treatment

Comments

AmpC β-lactamase

Enterobacter cloacae and other Enterobacteriaceae Pseudomonas aeruginosa

Any carbapenem or cefepime (Maxipime IV, Hospira)

TMP-SMX, quinolone, tigecycline also may be effective

ESBL

Klebsiella pneumoniae and other Enterobacteriaceae

Any carbapenem

TMP-SMX, quinolone, tigecycline also may be effective

Carbapenemase

K. pneumoniae and other Enterobacteriaceae

Meropenem or tigecycline (Tygacil, Pfizer) + polymyxin E (colistin)

Rifampin plus colistin also may be effective

Alteration of penicillinbinding protein

MRSA

Vancomycin

Daptomycin, linezolid, TMP-SMX, ceftaroline are alternatives

Mutation of DNA gyrase and topoisomerase

Enterococcus faecium (VRE)

Linezolid (Zyvox, Pfizer) or daptomycin (Cubicin, Cubist)

Tigecycline may be an alternative agent

Decreased permeability plus increased efflux plus carbapenemases

P. aeruginosa Acinetobacter baumannii

Colistin

Tigecycline may be effective against certain strains of A. baumannii

Aminoglycoside-modifying enzymes

P. aeruginosa, A. baumannii

Meropenem (Merrem IV, AstraZeneca) or imipenem (Primaxin IV, Merck) or piperacillin/tazobactam (Zosyn, Pfizer) or cefepime

ESBL, extended-spectrum β-lactamase; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; TMP-SMX, trimethoprim/sulfamethoxazole; VRE, vancomycin-resistant enterococci Adapted from references 17 and 18.

involves both infection control and antimicrobial stewardship (see commentary, page 76). Effective infection control programs limit the spread of resistant organisms through monitoring and surveillance. Antimicrobial stewardship programs (ASPs) improve the way in which antibiotics are used by shortening the duration of antibiotic treatment, limiting the use of broad-spectrum agents, and monitoring the appropriateness of antibiotic use.

The CDC has implemented the Healthcare-Associated Infections Projects. This program involves a network of state health departments and their academic medical centers. The program gathers information on antibiotic resistance and tracks important information such as the number and frequency of infections, and those people at risk for the infection. Current programs include Infection Tracking, Candida Bloodstream Infections, and Antibiotic Use Prevalence Survey. Other programs include Active Bacterial Core Surveillance, and Healthcare-Associated Infections–Community Interface. Additionally, the CDC’s national Healthcare Safety network is an electronic reporting system that enables

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hospitals to report infections, antibiotic use, and resistance.4 The information obtained by these programs provides insight and useful information on preventing the spread of resistant infections. It also allows facilities to aim at particular areas of interest and make needed improvements.

ASPs, meanwhile, were designed to improve antibiotic use. These programs focus on prescribing the correct antibiotics at the correct dose and reducing the duration of antibiotics when longer durations are no longer beneficial. These programs also reduce the rates of infections with resistant organisms and with C. difficile infection.20,21 Additionally, these programs have proven to reduce treatment failures and improve patient safety.22,23 Currently, the CDC recommends that all acute care hospitals set up an ASP.24 For an ASP to function properly, it needs to have financial support, drug expertise via dedicated pharmacists, the ability to implement recommendations, a system to monitor the use of antibiotics and resistant organisms, and the ability to educate others on optimal antibiotic use. Effective ASPs demand close working

relationships with infectious diseases, pharmacy, the microbiology laboratory, quality improvement, information technology, clinicians, and nurses.

ASPs often institute policies that instruct prescribers on the recommended and appropriate dose, duration, and indication for antibiotics. Ideally, this information is made available to all prescribers and is based on national guidelines. Prior authorization often is required for antimicrobial agents that have a broad spectrum of activity, and when there is a particular toxicity or side effect associated with the antibiotic. ASPs often audit charts to assure compliance with the regulations that have been implemented.22,24 Although the primary focus of antimicrobial stewardship is to assure appropriate use of antibiotics, ASPs also save money. In a study at the University of Maryland, an ASP saved $17 million over an 8-year period.25 Another means of preventing overuse of antibiotics and, as a result, the development of antibiotic-resistant organisms is by appropriate vaccination. Pneumococcal vaccine has been proven effective as a way to reduce antibiotic-resistant Streptococcus pneumoniae.26 There are 2 vaccines: the 23-valent polysaccharide vaccine (Pneumovax, Merck) and the 13-valent conjugate vaccine (Prevnar 13, Pfizer). It is clear that these vaccines are underused at present. Vaccination of at-risk populations should help reduce antibiotic use.

Summary The effect of antibiotics on the course of medicine has been enormous. Ironically, antibiotic overuse has led to increased resistance, and increased morbidity, mortality, hospital length of stay, and cost. Discovery of new drugs will be important in the fight against antibiotic resistance. Programs such as infection control and ASPs are critical to prevent or reduce the growing problem of antibiotic resistance.

References 1.

Huttner A, Harbarth S, Carlet J, et al. Antimicrobial resistance: a global view from the 2013 World Healthcare-Associated Infections Forum. Antimicrob Resist Infect Control. 2013;2(1):31.

2. Hicks LA, Taylor TH Jr, Hunkler RJ. US outpatient antibiotic prescribing, 2010. N Engl J Med. 2013;368(15):1461-1462.

3. Camins BC, King MD, Wells JB, et al. Impact of an antimicrobial utilization program on antimicrobial use at a large teaching hospital: a randomized controlled trial. Infect Control Hosp Epidemiol.

2009;30(10):931-938.

4. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed June 30, 2014.

5. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis. 2006;42(suppl 2):S82-S89.

6. Alliance for the Prudent Use of Antibiotics. The cost of antibiotic resistance to US families and the health care system. http://www. tufts.edu/med/apua/consumers/personal_home_5_1451036133. pdf. Accessed July 1, 2014.

7. Roberts RR, Hota B, Ahmad I, et al. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching

hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49(8):1175-1184.

8. Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care.

2011;1:47.

9. Nicasio AM, Kuti JL, Nicolau DP. The current state of multidrugresistant gram-negative bacilli in North America. Pharmacotherapy.

2008;28(2):235-249.

10. Kanj SS, Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum beta-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa. Mayo Clin Proc. 2011;86(3):250-259.

11. Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve Clin J Med. 2013;80(4):225-233.

12. Llarrull LI, Fisher JF, Mobashery S. Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new beta-lactams that meet the challenge. Antimicrob Agents Chemother. 2009;53(10):4051-4063.

13. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005;41(suppl 2):S120-S126.

14. Hooper DC. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis. 2000;31(suppl 2):S24-S28.

15. Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis. 2006;43(suppl 2):S49-S56.

16. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev. 2009;22(4):582-610.

17. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012;25(3):450-470.

18. Dhariwal AK, Tullu MS. Colistin: re-emergence of the “forgotten” antimicrobial agent. J Postgrad Med. 2013;59(3):208-215.

19. Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/Ð-lactamase inhibitor combination. Drugs.

2013;73(2):159-177.

20. Diaz-Granados CA. Prospective audit for antimicrobial stewardship in intensive care: impact on resistance and clinical outcomes. Am J Infect Control. 2012;40(6):526-529.

21. Elligsen M, Walker SA, Pinto R, et al. Audit and feedback to reduce broad-spectrum antibiotic use among intensive care unit patients: a controlled interrupted time series analysis. Infect Control Hosp Epidemiol. 2012;33(4):354-361.

22. Nowak MA, Nelson RE, Breidenbach JL, et al. Clinical and economic outcomes of a prospective antimicrobial stewardship program. Am J Health Syst Pharm. 2012;69(17):1500-1508.

23. Kaki R, Elligsen M, Walker S, et al. Impact of antimicrobial stewardship in critical care: a systematic review. J Antimicrob Chemother.

2011;66(6):1223-1230.

24. Fridkin S, Baggs J, Fagan R, et al; Centers for Disease Control and Prevention (CDC). Vital signs: improving antibiotic use among hospitalized patients. MMWR Morb Mortal Wkly Rep. 2014;63(9):194-200.

25. Centers for Disease Control and Prevention. Antibiotic stewardship—the ultimate return on investment. http://www.cdc.gov/ getsmart/healthcare/learn-from-others/factsheets/antibiotic-use. html. Accessed July 1, 2014.

26. Alicino C, Barberis I, Orsi A, et al. Pneumococcal vaccination strategies in adult population: perspectives with the pneumococcal 13-valent polysaccharide conjugate vaccine. Minerva Med. 2014;105(1):89-97.

INFECTIOUS DISEASE SPECIAL EDITION 2014

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New Molecular Diagnostic Technologies: Opportunities for Infection Control?

BRIAN CURRIE, MD, MPH Vice President, Medical Research Division of Infectious Diseases Montefiore Medical Center Assistant Dean for Clinical Research at Montefiore Medical Center Professor of Clinical Medicine Albert Einstein College of Medicine Bronx, NY Dr. Currie reported that he has no relevant financial interests to disclose.

T

he introduction of new molecular technologies into the clinical microbiology setting is transforming clinical diagnostic testing and

laboratory operations. The rapid adoption of these technologies

is providing microbiological diagnostic information with turnaround times measured in hours rather than days, as with traditional, culturebased techniques. An increasing body of information is already demonstrating that the earlier availability of actionable diagnostic bacterial and viral testing results can improve patient outcomes.

Available molecular diagnostic technologies now include nucleic acid amplification, mass spectrometry (MS), and next-generation sequencing (NGS)–based approaches. Increasingly, many laboratories are evaluating their operations to identify opportunities to employ molecular testing approaches and to potentially reduce or limit their current reliance on high-cost, labor-intensive, culture-based diagnostic testing to only those applications where it is deemed necessary.1-4 As clinical microbiologists explore and define the balance between molecular diagnostic testing and culture-based techniques, antibiotic stewardship, infection control, and public health practitioners are also experimenting with

W W W. I D S E . N E T

ways these technologies can affect their work. This article will focus on how these new molecular-based tests are being applied to infection control practice. It will introduce each of these options sequentially, highlight some commercially available assays in each category— with a bias toward FDA-approved tests—and provide some evidence for how infection control practitioners have successfully implemented them into their practice.

Nucleic Acid Amplification Approaches Nucleic acid amplification–based diagnostic testing was the first molecular technology to be applied to clinical laboratory operations, and it has the longest track

INFECTIOUS DISEASE SPECIAL EDITION 2014

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record of application to infection control practice. The technology continues to be best exemplified by the introduction of real-time multiplex polymerase chain reaction (PCR) assays that have demonstrated markedly superior sensitivity and specificity for detection of targeted pathogens compared with culture techniques or nonmolecular antigen tests.3,5 When optimized to run from direct swab samples without sample pre-preparation or DNA extraction, they offer turnaround times of 1 to 1.5 hours. Coupled with the development of highthroughput platforms capable of running multiple different assays simultaneously, these approaches began to represent attractive alternatives for clinical microbiology laboratories to use in the diagnosis of both bacterial and viral infections.

Early in the introduction of these assays, infection control practitioners quickly identified that their use could profoundly affect the ability to successfully identify and rapidly isolate potentially infectious patients.

The attributes of these assays provided support for point-of-care (POC) decision making for newly admitted and hospitalized patients, as clinically indicated.

Not only could POC decision making optimize the isolation of patients who require it, it could also prevent the

unnecessary isolation of patients who do not, reducing the costs associated with isolation and optimizing the use of relatively scarce resources, such as singlepatient isolation rooms and antiviral drugs. Additionally, these assays also represented a way to rapidly identify patients who are asymptomatically colonized with targeted organisms, thus greatly facilitating the conduct of hospital-based prevalence surveys and active surveillance programs designed to reduce the prevalence of targeted organisms.

Commercially available assays initially focused on the detection of the etiologies of most hospitalacquired infections with individually tailored assays for specific pathogens, but available products have quickly expanded to include symptom-based panels (ie, potential detection of any of the most common infectious causes of diarrhea or upper respiratory symptoms) or panels that screen for asymptomatic carriage of any number of multidrug-resistant (MDR) nosocomial bacteria that could potentially be associated with rectal colonization of hospitalized patients. To accommodate the needs associated with newly emerging pathogens such as carbapenemase-producing Klebsiella pneumoniae (carbapenem-resistant Enterobacteriaceae

Table 1. FDA-Approved Molecular Diagnostic Tests for Nosocomial Pathogens Device, Manufacturer

Assay Type

Sample Type

Target Pathogen

Turnaround Time

HighThroughput Platform

BD GeneOhm BD Diagnostics

Real-time PCR

Direct swab

C. difficile, MRSA, S. aureus, VRE

1.5 h

Yes

GeneXpert Cepheid

Real-time PCR

Direct swab

C. difficile, MRSA, S. aureus, VRE

1h

Yes

Meridian Illumigene Meridian Bioscience

Isothermic DNA amplification

Direct swab

C. difficle

1h

No

Prodesse ProGastro Prodesse

Real-time PCR

Direct swab Sample requires pre-preparation DNA extraction

C. difficle

3-4 h

No

Nuclisens Easy Q bioMĂŠrieux

Real-time PCR

Direct swab Sample requires pre-preparation DNA extraction

MRSA

2h

No

Roche LightCyler MRSA Advanced Test Roche Molecular Systems

Real-time PCR

Direct swab

MRSA

2h

No

FilmArray Biofire

Real-time PCR

Direct swab

C. difficle via panel

1h

No

C. difficle, Clostridium difficle; MRSA, methicillin-resistant Staphylococcus aureus; PCR, polymerase chain reaction; VRE, vancomycin-resistant enterococci

24

W W W. I D S E . N E T

[CRE]), new assays are being developed.

Table 1 summarizes the characteristics of a number of commercially available, FDA-approved, real-time PCR products that have focused on the detection of common nosocomial bacterial pathogens. FDA-approved assays are available for Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile. The BD GeneOhm and GeneXpert devices continue to be the most commonly deployed real-time PCR platforms because they work from direct swab samples, have a broader library of available assays, and are available as high-throughput platforms. Currently available kits for the detection of gram-negative nosocomial pathogens remain somewhat limited due in large part to the fact that gram-negative resistance gene targets are much harder to characterize.3,5-7 Given the emergence of CRE as a significant public health threat, and the pressing need for an accurate diagnostic test, manufacturers have focused on the development of real-time CRE PCR assays.3,7 CRE carbapenem resistance is caused by a complex group of genes—KPC, NDM, OXA, VIM, and IMP— all of which encode for carbapenemases.3,7 These genes share less than 60% sequence homology with each other, and numerous genetic variants occur within each group. They present a significant challenge for the development of real-time CRE PCR assays.3,7 Despite these obstacles, a number of assays are currently commercially available in the United States and Europe, on a research use-only basis (Table 2). All are optimized to use direct patient swab samples with rapid turnaround times of 50 to 120 minutes. Preliminary performance data suggests that all tests have been able to detect their stated targets with high sensitivity and specificity.8-13 Only 2 of the assays are available for use in the United States—the BD MAX CRE assay, which has FDA research use-only status, and the Acuitas MDRO Gene Test, which is only available via a company-owned central laboratory that is Clinical Laboratory Improvement Amendment approved and offers 24-hour turnaround.

Still, the application of CRE-specific, multiplex realtime PCR assays as infection control tools has been established and these efforts are quite illustrative of how this technology can potentially affect practice.

Although they are primarily based on the use of “homegrown” applications or prototype assays to date, these technologies have been used by infection control practitioners for sentinel surveillance and periodic largescale, hospital-wide prevalence surveys. Demonstration projects have explored the use of these assays for POC rapid screening of emergency room patients who are about to be admitted to the hospital for asymptomatic CRE rectal colonization.14 Coupled with rapid institution of contact isolation precautions, this approach may prove effective in addressing the significant influx of CRE-colonized patients from outside acute and chronic care facilities in areas already endemic for CRE. Perhaps most significantly, these assays have been used to

successfully drive active surveillance programs for CRE, which trigger rapid initiation of contact isolation precautions for all CRE-positive patients. This approach is effective in reducing the prevalence of CRE in individual hospital units and across institutions. When applied across all ICUs in a New York-based health care system, this approach resulted in a sustainable 52.7% reduction in CRE prevalence.15 A similar approach has been demonstrated to contain a hospital-wide CRE outbreak.16 Although these results are quite promising, widespread adoption of active surveillance strategies for CRE, or for any MDR nosocomial pathogens for that matter, will continue to depend on the extent to which these technologies are accepted by clinical microbiology laboratories. The increased cost of testing, the limited capacity of most laboratories to run the assays, and the current lack of FDA-approved products continue to serve as barriers to laboratory implementation.

Mass Spectrometry Approaches Mass spectrometry applications for bacterial identification were first reported in 1975, and are based on the fact that small molecules can be harvested from lyophilized bacteria that produce distinct MS “signatures,” enabling taxonomic distinction of some bacteria.2 However, it was not until the later development of matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) that the characterization of macromolecules became feasible. Subsequent work has established that application of the technique

Table 2. Real-Time CRE PCR Assays in Development Assay Name/ Manufacturer

Target Genes

BD MAX CRE RUO assay KPC, NDM OXA BD Diagnostics Acuita MDRO Gene Test OpGen

KPC, NDM, OXA VIM, IMP, also detects CTX-M, Van A

NuclisSENS Easy Q KPC Test bioMérieux

KPC C only

Xpert Carba–R Cepheid

KPC, NDM, VIM, OXA, IMP

Check-MDR Carba test Check-Points

KPC, NDM, OXA, VIM, IMP

eazyplex SuperBug CRE Amplex

KPC, NDM, OXA, VIM

CRE, carbapenem-resistant Enterobacteriaceae; PCR, C , po polymerase y e ase c chain a reaction eact o

INFECTIOUS DISEASE SPECIAL EDITION 2014

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Spectrum

Spec ctrum created

Detector

Dete ection

Vacuum Flight Tube

Sepa aration: TOF (no electric e field)

Laser

Acce eleration through electtrostatic field

Crystalized matrix with an nalytes Matrrix-assisted laser deso orption ionization

Figure. Schematic of MALDI-TOF MS process.

MALDI-TOF MS, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

to whole bacterial cells can produce characteristic and reproducible spectra, largely based on proteins used to reliably identify bacteria to the genus and species levels within minutes.2,17 The MALDI-TOF MS process is summarized in the Figure. Microbial samples are deposited on a target plate and a matrix solution that crystalizes with the sample and lyses the cells is added. The samples are then vaporized and ionized by short laser bursts. Ionized particles pass through an electrostatic field and are accelerated through a vacuum. The time it takes for each particle to reach a detector, the time of flight, depends on the mass and charge of the particle and is used to create a spectral profile. Identification of the organism is accomplished with software that automatically compares the obtained profile with a reference library and turnaround time is measured in minutes.2,17,18

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In general, MALDI-TOF MS has been demonstrated to outperform traditional culture techniques for identification, and is extremely rapid.18 Two MALDI-TOF systems are commercially available—the MALDI Biotyper (Brucker Daltonics) and the VITEK MS (bioMérieux). The bioMérieux product was approved by the FDA in 2013 and the MALDI Biotyper was approved by the FDA for research use only in 2014.

Published literature suggests that both systems have comparable performance characteristics.19 Although the systems present a significant initial outlay for the cost of equipment, subsequent analysis of samples is very inexpensive.2,3 Studies have demonstrated that this technology can be applied directly to positive blood cultures and can be used to optimize appropriate antibiotic therapy.2,18,21-24 Additional protocols seek to optimize the direct application to urine samples without preculture.2,24

The use of MALDI-TOF MS for the detection of antibiotic resistance is currently an area of intense investigation.2,20,24,25 Several different types of assays are in development for the detection of MDR bacteria. One approach is to analyze drug metabolites via MS after bacteria are subjected to short incubation in the presence of antibiotics.24,25 A second approach incorporates incubation of samples in stable isotopes of carbon and nitrogen and the presence of antibiotics and determines drug resistance by the characteristic shift in profile peaks.20 A third approach seeks to identify enzymes related to antibiotic resistance via direct detection of their signature MS peaks.25 Protocols for MRSA, VRE, and β-lactamases, including the carbapenemases of CRE, are in development and require further validation.3,25 There is also interest in the use of MALDI-TOF MS for strain typing of bacteria as an epidemiologic tool to assist infection control investigations.2,24,26 Successful application of MALDI-TOF MS for bacterial strain typing remains problematic, and it has been argued that the current technology is not capable of providing the level of resolution necessary to accomplish the task.2,24 Conversely, it has been suggested that strict adherence to sample preparation to reduce MALDI-TOF MS profile variations that are attributed to differences in sample culture conditions; improved lysis of samples to provide enhanced detection of minor peaks in generated profiles currently missed; enhanced libraries to improve resolution; greater inclusion of other nonprotein macromolecules into the MS analysis; enhanced use of biometrics-enabled analytic tools; and more detailed evaluation of specific profile peaks may yet allow for bacterial strain typing.26,27 Even if achievable, there appears to be consensus that strain-typing capability will only be bacterium-specific.26 Despite these obstacles, MALDI-TOF MS applications are useful strain-typing tools in the investigation of a VRE outbreak and for a Streptococcus pneumoniae conjunctivitis outbreak.28,29 However, these applications required complex sample preparation and the creation of specific novel spectral libraries.

Given the requirement for pure culture samples for analysis and the current capacity of existing commercially available equipment, the primary affect of MALDITOF MS on infection control and hospital epidemiology practice will result from the earlier identification of patients with clinical infections caused by targeted nosocomial pathogens and more timely institution of isolation protocols. In the near future, this capability may be enhanced to include earlier identification of clinical isolates of MDR nosocomial pathogens. Future investigations may provide for the development of some species-specific strain-typing technology, but it is still not clear how and if they would become integrated into clinical microbiology laboratory operations. Because MALDI-TOF MS cannot be optimized to run directly from patient samples, other than blood or urine, it subsequently will not have utility as a tool for real-time active surveillance.

Next-Generation Sequencing Approaches Nucleic acid sequencing approaches have rapidly evolved from first-generation capillary electrophoresis-based Sanger methods with the application of NGS technology.1,29,30 Contrary to prior approaches to wholegenome sequencing, NGS approaches include fragmenting DNA into libraries of smaller segments that are then subjected to massively parallel sequencing. The subsequent shorter “reads” are then reassembled using a known reference genome as a scaffold (resequencing) or by using overlapping regions (de novo assembly). The approach has revolutionized whole-genome sequencing by providing rapid high-throughput results at a relatively low cost. Initially applied to human genomic targets, the process is being adapted for use in the clinical microbiology laboratory for bacterial speciation, identification of antibiotic resistance, and as a bacterial strain-typing method in support of epidemiologic investigations.1,30-32 Current commercially available, widely used sequencing products are summarized in Table 3, and notably, now include 3 lower-cost benchtop options.

Adapting NGS to bacterial strain typing presents several challenges. First, there are only a limited number of reference genomes available, so de novo assembly frequently is required. Shorter read lengths can result in a higher number of sequence gaps and can effect data quality. Some NGS platforms offer pairedend sequencing protocols, which allows sequencing to progress from both ends of a DNA fragment and results in enhanced alignment of the reads. This problem has also been addressed by the use of publicly available short-read software algorithms that can provide enhanced assembly. A third option is the use of targeted sequencing, where only a subset of genes or defined regions of interest are sequenced.1 Both resequencing and targeted sequencing will require the creation of comparative genome libraries by laboratory staff.

Table 3. Commercially Available NGS Platforms Illumina Platform (Illumina) 454 genome sequencer (Roche Applied Science) SOLiD platform (Life Technologies) Benchtop applications MiSeq (Illumina) Ion Torrent platforms (Life Technologies) Micro SEQ (Life Technologies) NGS, next-generation sequencing

INFECTIOUS DISEASE SPECIAL EDITION 2014

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Next-generation sequencing has demonstrated utility as a strain-typing tool in support of outbreak investigations at institutions with exceptional laboratory support. NGS was used to investigate recurrent episodes of MRSA colonization of infants in a neonatal ICU (NICU) over a 6-month period.33,34 The investigation was able to demonstrate MRSA transmission in the NICU, as well as between mothers in a postnatal ward and in the community. MRSA carriage by a staff member was ultimately identified as the source of the prolonged outbreak in the NICU. Similarly, whole-genome sequencing was used as a key adjunct epidemiologic tool during an investigation of a prolonged hospital outbreak of CRE that persisted despite initiation of enhanced infection control interventions.35 Data from the analysis was able to reconstruct a transmission map that established 3 different lines of patient-to-patient CRE transmission that emanated from a single known CRE-infected patient who had been discharged 3 weeks before the hospital identified the first clinical case of the outbreak. The analysis provided actionable insights that were used to facilitate subsequent control of nosocomial transmission.

Whole-genome sequencing was used during another hospital-wide CRE outbreak investigation to characterize infection chains occurring in the surgical ICU.16 Analysis was able to establish that transmission was not related to staff colonization. An additional investigation used whole-genome sequencing as a strain-typing tool to evaluate 1,223 cases of C. difficile infection over a 5-year period from a single community.36 Analysis was able to establish that patient-to-patient transmission only accounted for slightly more than one-third of the cases. A large proportion of infections involved genetically unique strains, suggesting exposure to asymptomatic human or environmental sources as the etiology of these infections. The authors concluded that the use of rapid benchtop sequencing could provide nearly realtime C. difficile strain typing and could prove to be an important adjunct tool for institutional infection control practices.

Although NGS whole-genome sequencing shows great promise as an adjunct infection control tool for epidemiologic investigations, it is currently restricted to those institutions that have access to exceptional laboratory support far beyond the current capability of most clinical microbiology laboratories. Even in these settings, it has been difficult to take full advantage of the near real-time capability of the technology.

Given the exponential explosion of genome sequencing technology in the past 5 years, it is not unreasonable to expect that low-cost benchtop NGS whole-genome sequencing platforms will be optimized for clinical laboratory use in the near future. The routine availability of near real-time strain typing will profoundly influence infection control practice.

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Summary The past several years have seen the introduction of significant molecular-based diagnostic technologies into the clinical microbiology laboratory. Options for real-time PCR testing have expanded to include syndromic and gene-resistance panels, new assays are being developed for newly emergent pathogens, such as CRE, and high-throughput platforms have been introduced. MALDI-TOF MS and NGS platforms have been introduced and are increasingly being adopted by clinical microbiologists and reference laboratories.

Although designed and marketed primarily as diagnostic tools, antibiotic stewardship, infection control, and public health practitioners are already experimenting with how these technologies can improve their practice.

The infection control literature now includes an expanding portfolio of reports describing successful use of both real-time PCR testing and NGS as adjunct tools for hospital epidemiology. Real-time PCR testing continues to represent an alternative tool for POC screening to optimize initiation of isolation protocols and to drive effective active surveillance intervention strategies. It is also an attractive tool for rapid surveillance surveys. NGS is an effective near real-time bacterial strain-typing tool for the investigation of outbreaks. However, continued development of NGS technologies will be necessary to incorporate them into routine clinical microbiology laboratory operations. The utility of MALDI-TOF MS as an infection control tool remains uncertain.

There are significant barriers to adoption of real-time PCR testing and NGS technologies. Both are currently associated with a relatively high cost per sample analyzed. Although real-time PCR has largely been optimized for clinical microbiology use, NGS applications will need to become less complex. The widespread adoption and availability of these technologies for infection control use is also largely dependent on their appeal and acceptability to clinical laboratories for application to routine diagnostic testing. For instance, it is still not clear how NGS will find a niche in the clinical diagnostic arena. Alternatively, some medical centers may elect to support the use of these technologies for infection control activities, independent of their utility as clinical diagnostic tools. Continued research in the infection control arena demonstrating high-impact results from access to real-time PCR and NGS may facilitate this process.

References 1.

Kirkup BC, Mahlen S, Kallstrom G. Future-generation sequencing and clinical microbiology. Clin Lab Med. 2013;33(3):685-704.

2. Dingle TC. Butler-Wu SM. MALDI-TOF mass spectrometry for microorganism identification. Clin Lab Med. 2013;33(3):589-609.

3. Hrabak J, Chudackova E, Papagiannitis CC. Detection of carbapenemases in Enterobacteriaceae: a challenge for diagnostic microbological laboratories. Clin Microbiol Infect. 2014 May 22.

[Epub ahead of print].

4. Hondinka RL, Kaiser L. Is the era of viral culture over in the clinical microbiology laboratory? J Clin Microbiol. 2013;51(1):4-8.

5. Currie B. Impact of molecular diagnostics on infection control.

IDSE. 2011;14:11-15.

6. Tuite N, Reddington K, Barry T, et al. Rapid nucleic acid diagnostics for the detection of antimicrobial resistance in gram-negative bacteria: is it time for a paradigm shift? J Antimicrob Chemother.

2014;69(7):1729-1793.

7. Currie B. The emergence of carbapenemase-producing Enterobacteriaceae. IDSE. 2012;15:9-13.

8. Roger-Dalbert C, Labourdette R, Brochu V, et al. First clinical evaluation of the BD MAX CRE RUO Assay on rectal swabs from intensive care unit patients. Paper presented at: 23rd meeting of the European Society of Clinical Microbiology and Infectious Diseases; April 27-30, 2013; Berlin, Germany.

9. Kaase M, Kaminski A, Pfenningwirth N, et al. Validation of a rapid molecular assay (eazyplex Superbug) for frequently occurring carabapenemase genes in Enterobacteriaceae. Paper presented at: 24th meeting of the European Society of Clinical Microbiology and Infectious Diseases; May 10-13, 2014; Barcelona Spain.

10. Spanu T, Fiori B, D’Inzeo T, et al. Evaluation of the new NucliSENS EasyQ KPC test for rapid detection of Klebsiella pneumoniae carbapenemase genes (blakpc). J Clin Microbiol. 2012;50(8):2783-2785.

11. Cuzon G, Naas T, Bogaerts P, et al. Probe litigation and real-time detection of KPC, OXA-48, VIM, IMP, and NDM carbapenemase genes. Diagn Microbiol Infect Dis. 2013;76(4):502-505.

12. Kersey RK, Rockweiler TJ, Quan J, et al. Determining analytical specificity of the Acuitas MDRO Gene Test by comparing detected genotypes to antibiograms for a large set of multidrug-resistant organisms harboring KPC, NDM, VIM, IMP, OXA, CTX-M and/or Van A resistance gene families. Paper presented at: 54th annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 5-9, 2014; Washington, DC. Abstract 892.

13. Tenover FC, Canton R, Kop J, et al. Detection of colonization by carbapenemase—producing gram negative bacilli in patients by use of the Xpert MDRO assay. J Clin Microbiol.

2013;51(11):3780-3787.

14. Burton NE, Aguirre D, Leung S, et al. Screening for colonization with Klebsiella pneumoniae carbapenmase producing Enterobacteriaceae in the emergency department of a NYC medical center using a prototype multiplex PCR assay. Paper presented at: ID Week 2012; October 17-21, 2012; San Diego, CA. Abstract 1422.

15. Burton NE, Aguirre D, Leung S, et al. PCR based active surveillance for carbapenem-resistant Klebsiella pneumoniae (KPC) colonization with rapid initiation of contact isolation achieved significant reduction in KPC colonization prevalence in the ICUs of a NYC medical center. Paper presented at: ID Week 2012; October 17-21, 2012; San Diego, CA. Abstract 686.

16. Lippmann N, Lubbert C, Kaiser T, et al. Clinical epidemiology of Klebsiella pneumoniae carbapenemases. Lancet.

2014;14(4):271-272.

20. Demirev PA, Hagan NS, Antoine MD, et al. Establishing drug resistance in microorganisms by mass spectrometry. J Am Soc Mass Spectrom. 2013;24(8):1194-1201.

21. Idelevich EA, Schüle I, Grünastel B, et al. Rapid identification of microorganisms from positive blood cultures by MALDI-TOF mass spectrometry subsequent to very short-term incubation on solid medium. Clin Microbiol Infect. 2014 Apr 3. [Epub ahead of print] 22. Spanu T, De Carolis E, Fiore B, et al. Evaluation of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry in comparison to rpoB gene sequencing for species identification of bloodstream infection staphylococcal isolates. Clin Microbiol Infect. 2011;17(1):44-49.

23. Kothari A, Morgan M, Haake DA. Emerging technologies for rapid identification of bloodstream pathogens. Clin Infect Dis. 2014;59(2):272-278.

24. DeMarco ML, Ford BA. Beyond identification-emerging and future uses for MALDI-TOF mass spectrometry in the clinical microbiology laboratory. Clin Lab Med.2013;33(3):611-628.

25. Hrabak JE, Chudackova E, Walkova R. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry for detection of antibiotic resistance mechanisms: from research to routine diagnosis. Clin Microbiol Rev. 2013;26(1):103-114.

26. Sandrin TR, Goldstein JE, Schumaker S. MALDI-TOF MS profiling of bacteria at the strain level: a review. Mass Spectrum Rev. 2013;32(3):188-217.

27. Golstein JE, Zhang L, Borror CM, et al. Culture conditions and sample preparation methods affect spectrum quality and reproducibility during profiling of Staphylococcus aureus with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Lett Appl Microbiol. 2013;57(2):144-150.

28. Griffin PM, Price GR, Schooneveldt JM, et al. Use of matrix-assisted laser desorption ionization-time of flight mass spectrometry to identify vancomycin-resistant Enterococcii and investigate the epidemiology of an outbreak. J Clin Microbiol. 2012;50(9):2918-2931.

29. Williamson YM, Maura H, Woofit AR, et al. Differentiation of Streptococcus pneumoniae conjunctivitis outbreak isolates by matrix-assisted laser desorption-time of flight mass spectrometry.

Appl Environ Microbiol. 2008;74(19):5891-5897.

30. MacCannell D. Bacterial strain typing. Clin Lab Med. 2013;33(3): 629-650.

31. Gardy J L. Investigation of disease outbreaks with genome sequencing. Lancet Infect Dis. 2013;13(2):101-102.

32. Diep BA. Whole-genome sequencing for outbreak investigations.

Lancet Infect Dis. 2013; 13(2):130-136.

33. Price JR, Didelot X, Crook DW, et al. Whole genome sequencing in the prevention and control of Staphylococcus aureus infection.

J Hosp Infect. 2013;83(1):14-21.

17. Sandrin TR, Demirev PA. Using mass spectrometry to identify and characterize bacteria. Microbe. 2014;9(1):23-29.

34. Harris SR, Cartwright EJ, Torok ME, et al. Whole genome sequencing may be key to abating hospital-based methicillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect Dis. 2013;13(5): 1079-1080.

18. Dubois D, Grare M, Prere M, et al. Performances of the Vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry system for rapid identification of bacteria in routine clinical microbiology. J Clin Microbiol. 2012;50(8):2568-2576.

35. Snitkin ES, Zelazny AM, Thomas PJ, et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole genome sequencing. Sci Transl Med. 2012;4(148):148ra116.

19. Carbonnelle E, Grohs P, Jacquier H, et al. Robustness of two MALDI-TOF mass spectrometry systems for bacterial identification.

J Micrbial Methods. 2012;89(2):133-136.

36. Eyre DW, Cule ML, Wilson DJ, et al. Diverse sources of C. difficle infection identified on whole-genome sequencing. N Eng J Med. 2013;369(13):1195-1205.

INFECTIOUS DISEASE SPECIAL EDITION 2014

29

Mul e op O commitment.

Discover One by Gilead â&#x20AC;&#x201D; our commitment to providing a range of therapies and ongoing support for your treatment decisions.

Please see Brief Summaries of full Prescribing Information for STRIBILD and COMPLERA, including BOXED WARNINGS, on the following pages.

STRIBILD ® (elvitegravir 150 mg/cobicistat 150 mg/ emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief summary of full Prescribing Information.

See full Prescribing Information. Rx only.

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of STRIBILD, in combination with other antiretrovirals [See Warnings and Precautions].]

STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued emtricitabine or tenofovir DF, which are components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions].]

INDICATIONS AND USAGE: STRIBILD is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naive.

DOSAGE AND ADMINISTRATION: See Warnings and Precautions, Adverse Reactions, and Use in Specific Populationss for additional information.

Adult Dosage: One tablet taken orally once daily with food.

Renal Impairment: Do not initiate in patients with estimated creatinine clearance (CrCl) <70 mL/min. Discontinue if CrCl declines to <50 mL/min during treatment.

Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B).

No data are available regarding use in patients with severe hepatic impairment (Child-Pugh Class C). STRIBILD is not recommended for patients with severe hepatic impairment.

Testing Prior to Initiation: Test patients for HBV infection and document CrCl, urine glucose, and urine protein.

CONTRAINDICATIONS: Coadministration: Do not use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening adverse events, or with drugs that strongly induce CYP3A as this may decrease STRIBILD plasma concentrations leading to a loss of efficacy and possible resistance to STRIBILD [See Drug Interactions]: • Alpha 1-adrenoreceptor antagonist: alfuzosin. Potential for hypotension.

• Antimycobacterial: rifampin. May lead to a loss of efficacy and possible resistance.

• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine.

Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

• GI motility agents: cisapride. Potential for cardiac arrhythmias.

• Herbal products: St. John’s wort. May lead to a loss of efficacy and possible resistance.

• HMG CoA reductase inhibitors: lovastatin, simvastatin. Potential for myopathy, including rhabdomyolysis.

• Neuroleptics: pimozide. Potential for cardiac arrhythmias.

• PDE-5 inhibitors: sildenafil when dosed as REVATIO for the treatment of pulmonary arterial hypertension. Increased potential for sildenafil-associated adverse events (visual disturbances, hypotension, priapism, and syncope).

• Sedative/hypnotics: orally administered midazolam, triazolam.

Potential for prolonged or increased sedation or respiratory depression.

WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals.

A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV: All patients with HIV-1 should be tested for chronic HBV infection before initiating antiretroviral therapy. STRIBILD is not approved for the treatment

of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment: Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF and with STRIBILD. In clinical trials through 96 weeks, 10 (1.4%) subjects in the STRIBILD group (N=701) and 2 (0.3%) subjects in the combined comparator groups (N=707) discontinued study drug due to a renal adverse reaction. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to 0 in the comparator groups. Two of these 4 subjects had renal impairment (CrCl <70 mL/min) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation. Renal replacement therapy was not required. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Drug Interactions]. ] Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function. Monitoring:: CrCl, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Do not initiate in patients with CrCl <70 mL/min.

Routinely monitor CrCl, urine glucose, and urine protein during therapy in all patients. Additionally monitor serum phosphorus in patients at risk for renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in CrCl without affecting renal glomerular function [See Adverse Reactions], ] patients with a confirmed increase in serum creatinine of >0.4 mg/dL from baseline should be closely monitored for renal safety. Discontinue STRIBILD if CrCl declines to <50 mL/min.

Use with Other Antiretroviral Products: STRIBILD is a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended. Do not coadminister with products containing any of the same active components; with products containing lamivudine; with products containing ritonavir; or with adefovir dipivoxil.

Bone Effects of tenofovir DF: Bone Mineral Density (BMD):: In clinical trials in HIV-1 infected adults, tenofovir DF was associated with decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For additional information, consult the VIREAD (tenofovir DF) full Prescribing Information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Consider assessing BMD in patients with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial.

If bone abnormalities are suspected appropriate consultation should be obtained. Mineralization Defects:: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF. [See Adverse Reactions] Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome (IRS): IRS has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (e.g., Graves’ disease, polymyositis, and Guillain-Barre syndrome) have been reported to occur in the setting of immune

reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

ADVERSE REACTIONS: See BOXED WARNING G and Warnings and Precautionss for additional serious adverse reactions. The safety assessment of STRIBILD is based on pooled data from two Phase 3 trials in antiretroviral treatmentnaive HIV-1 infected adults. A total of 701 subjects received STRIBILD once daily for at least 96 weeks. 4.6% of subjects discontinued STRIBILD due to adverse events, regardless of severity.

Adverse Reactions: Treatment emergent adverse reactions (all grades) reported in ≥5% of subjects receiving STRIBILD (N=701) through week 96 were: nausea (16%), diarrhea (12%), abnormal dreams (9%), and headache (7%). Frequencies are based on all treatment emergent adverse reactions attributed to study drugs. See Warnings and Precautionss for more information on renal adverse reactions.

Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 3-4) occurring in ≥2% of subjects receiving STRIBILD (N=701) through 96 weeks were: creatine kinase ≥10.0x ULN (7%); urine RBC (hematuria) >75 RBC/HPF (3%); amylase >2.0x ULN (3%); and AST >5.0x ULN (2%). For subjects with serum amylase >1.5x ULN, lipase test was performed; increased lipase (Grades 3-4) occurring in STRIBILD (N=61) was 15%. Proteinuria (all grades) occurred in 46% of subjects receiving STRIBILD. Cobicistat has been shown to decrease CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function; decreases in CrCl occurred early in treatment with STRIBILD after which they stabilized. Mean ±SD changes after 96 weeks of treatment were: serum creatinine, 0.13 ±0.13 mg/dL; and eGFR by Cockcroft-Gault, -13.2 ±15.7 mL/min. Elevation in serum creatinine (all grades) occurred in 10% of subjects. BMD was assessed

by DEXA in a non-random subset; mean decreases in BMD from baseline to Week 96 in the STRIBILD group (N=47) were comparable to the comparator group at the lumbar spine (-2.0%) and the hip (-3.2%).

Bone fractures occurred in 14 subjects (2.0%) in the STRIBILD group.

Serum Lipids: In clinical trials, 11% of subjects receiving STRIBILD were on lipid lowering agents at baseline; through Week 96, an additional 8% of subjects were started on lipid lowering agents. Mean changes from baseline in fasting serum lipids in subjects receiving STRIBILD (N=701) through 96 weeks were: total cholesterol: week 96 change +12 (N=571; baseline 166 mg/dL); HDL-cholesterol: week 96 change +7 (N=571; baseline 43 mg/dL); LDL-cholesterol: week 96 change +12 (N=572; baseline 100 mg/dL); triglycerides: week 96 change +8 (N=571; baseline 122 mg/dL). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.

Consult the respective full Prescribing Information for each available individual component of STRIBILD for additional information regarding adverse reactions, including laboratory abnormalities and postmarketing events.

DRUG INTERACTIONS: See Contraindicationss for additional serious drug interactions.

STRIBILD is a complete regimen for the treatment of HIV-1 infection. STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection.

Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.

Potential for STRIBILD to Affect Other Drugs: Cobicistat is an inhibitor of CYP3A and CYP2D6 and the transporters p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the concentrations of CYP2C9 substrates.

Potential for Other Drugs to Affect STRIBILD: Elvitegravir and cobicistat are metabolized by CYP3A. Cobicistat is also metabolized to a minor extent by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased concentrations of cobicistat and elvitegravir, which may lead to loss of efficacy and development of resistance.

Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the concentration of cobicistat.

Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, which may increase the incidence of adverse reactions [see Warnings and Precautions]. ] Established and Other Potentially Significant Interactions: The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD. The list includes potentially significant interactions but is not all inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with STRIBILD: • Acid Reducing Agents: antacids. Separate STRIBILD and antacid administration by at least 2 hours.

• Antiarrhythmics: amiodarone, bepridil, digoxin, disopyramide, flecainide, systemic lidocaine mexiletine, propafenone, quinidine.

Caution warranted and therapeutic concentration monitoring recommended.

STRIBILD® (elvitegravir 150 mg/cobicistat 150 mg/ emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief summary (cont) t • Antibacterials: clarithromycin, telithromycin. Clarithromycin: no dose adjustment required for patients with CrCl ≥60 ml/min; the dose should be reduced by 50% for patients with CrCl between 50 and 60 mL/min. Telithromycin: concentrations of telithromycin and/or cobicistat may be increased.

• Anticoagulants: warfarin. International normalized ratio (INR) monitoring recommended.

• Anticonvulsants: carbamazepine, oxcarbazepine phenobarbital, phenytoin, clonazepam, ethosuximide. Phenobarbital, phenytoin, carbamazepine, and oxcarbazepine: may lead to loss of efficacy and possible resistance to STRIBILD. Alternative anticonvulsants should be considered. Clonazepam and ethosuximide: clinical monitoring recommended.

• Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs), Tricyclic Antidepressants (TCAs), trazodone. Dose titration of the antidepressant and monitoring for antidepressant response recommended.

• Antifungals: itraconazole, ketoconazole, voriconazole. Ketoconazole and itraconazole: the maximum daily dose should not exceed 200 mg/day. Voriconazole: an assessment of benefit/risk ratio is recommended to justify use.

• Anti-gout: colchicine. Do not coadminister in patients with renal or hepatic impairment. For other patients, modify the dose and/or regimen as described in the full PI for STRIBILD. • Antimycobacterials: rifabutin, rifapentine. May lead to loss of efficacy and possible resistance to STRIBILD. Coadministration not recommended.

• Beta-Blockers: metoprolol, timolol. Clinical monitoring recommended and a dose decrease of the beta blocker may be necessary.

• Calcium Channel Blockers: amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil. Caution warranted and clinical monitoring recommended.

• Corticosteroids (Systemic): dexamethasone. May lead to loss of efficacy and possible resistance to STRIBILD. • Corticosteroids (Inhaled/Nasal): fluticasone. Alternative corticosteroids should be considered, particularly for long term use.

• Endothelin Receptor Antagonists: bosentan. Discontinue bosentan at least 36 hours prior to initiating STRIBILD. For patients taking STRIBILD for at least 10 days, start or resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.

• HMG CoA Reductase Inhibitors: atorvastatin. Initiate with the lowest starting dose and titrate carefully while monitoring for safety.

• Hormonal Contraceptives: norgestimate/ethinyl estradiol.

Coadministration with STRIBILD resulted in decreased plasma concentrations of ethinyl estradiol and an increase in norgestimate.

The effects of increased progesterone exposure are not fully known.

The potential risks and benefits of coadministration should be considered, particularly in women who have risk factors for progesterone exposure. Alternative (non hormonal) methods of contraception can be considered.

• Immunosuppressants: cyclosporine, rapamycin, sirolimus, tacrolimus. Therapeutic monitoring recommended.

• Narcotic Analgesics: buprenorphine, naloxone. Closely monitor for sedation and cognitive effects.

• Inhaled Beta Agonist: salmeterol. Coadministration not recommended due to the increased risk of salmeterol cardiovascular adverse events, including QT prolongation, palpitations, and sinus tachycardia.

• Neuroleptics: perphenazine, risperidone, thioridazine. Decrease in dose of the neuroleptic may be needed.

• Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil, tadalafil, vardenafil. Dosage for erectile dysfunction:: sildenafil, a single dose not exceeding 25 mg in 48 hours; vardenafil, a single dose not exceeding 2.5 mg in 72 hours; tadalafil, a single dose not exceeding 10 mg in 72 hours; increase monitoring for PDE-5 associated adverse reactions. Dosage for pulmonary arterial hypertension (PAH):: tadalafil: stop tadalafil at least 24 hours prior to initiating STRIBILD; start or resume at 20 mg once daily in patients receiving STRIBILD for at least 1 week and increase to 40 mg once daily based on individual tolerability.

• Sedative/hypnotics: Benzodiazepines. Parenteral midazolam: coadministration should be done in a setting ensuring close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation; dose reduction should be considered, especially if more than a single dose is administered. Other sedative/hypnotics: dose reduction may be necessary and clinical monitoring recommended.

Consult the full PI prior to and during treatment with STRIBILD for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS: Pregnancy: STRIBILD is Pregnancy Category B; however, there are no adequate and well-controlled studies in pregnant women.

STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry:: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established.

Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. Emtricitabine and tenofovir have been detected in human milk; it is not known if elvitegravir or cobicistat is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions and/or drug resistance in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD. Pediatric Use: Safety and effectiveness in children less than 18 years of age have not been established.

Geriatric Use: Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Caution should be exercised in the administration of STRIBILD in elderly patients.

Renal Impairment: STRIBILD should not be initiated in patients with CrCl <70 mL/min. STRIBILD should be discontinued if CrCl declines to <50 mL/min during treatment with STRIBILD. [See Warnings and Precautions, Adverse Reactions]. ] Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. STRIBILD is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) as no pharmacokinetic or safety data are available in these patients [See Dosage and Administration]. ] OVERDOSAGE: If overdose occurs the patient must be monitored for evidence of toxicity. Treatment consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

203100-GS-002 October 2013

COMPLERA® (emtricitabine 200 mg, rilpivirine 25 mg, tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief Summary of full Prescribing Information. See full Prescribing Information. Rx Only.

WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (tenofovir DF), a component of COMPLERA, in combination with other antiretrovirals [See Warnings and Precautions].]

COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued emtricitabine or tenofovir DF, which are components of COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions].]

INDICATIONS AND USAGE: COMPLERA is indicated as a complete regimen for the treatment of HIV-1 infection in adults with no antiretroviral (ARV) treatment history and with HIV-1 RNA ≤100,000 copies/mL at the start of therapy; and in certain virologically suppressed (HIV-1 RNA <50 copies/mL) adults on a stable ARV regimen at the start of therapy to replace their current regimen, efficacy was established in patients who were virologically suppressed on a stable ritonavirboosted protease inhibitor-containing regimen. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. COMPLERA is not recommended for patients <18 years of age.

Prescribing considerations when initiating therapy with COMPLERA in adults with no ARV treatment history: • More rilpivirine-treated subjects with HIV-1 RNA >100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA ≤100,000 copies/mL. • Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count <200 cells/mm3 experienced virologic failure compared to rilpivirine-treated subjects with CD4+ cell count ≥200 cells/mm3.

• The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and crossresistance to the NNRTI class compared to efavirenz.

• More subjects treated with rilpivirine developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz.

Prescribing considerations that should be met when replacing current ARV regimen with COMPLERA in virologically suppressed adults: • Patients should have no history of virologic failure.

• Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months prior to switching therapy.

• Patients should currently be on their first or second ARV regimen prior to switching therapy.

• Patients should have no current or past history of resistance to any component of COMPLERA. DOSAGE AND ADMINISTRATION: See Warnings and Precautions, Adverse Reactions, and Use in Specific Populationss for additional information.

Adult Dosage: One tablet taken orally once daily with food.

Renal Impairment: Do not use in patients with estimated creatinine clearance (CrCl) <50 mL/min.

Rifabutin Coadministration: Additional rilpivirine 25 mg taken once daily with a meal during rifabutin coadministration.

CONTRAINDICATIONS: Coadministration: Do not use with drugs that induce CYP3A or increase gastric pH as significant decreases in rilpivirine plasma concentrations may occur leading to loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [See Drug Interactions]. ] • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: rifampin, rifapentine • Proton pump inhibitors: esomeprazole, lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole • Systemic glucocorticoid: dexamethasone (>1 dose) • Herbal product: St. John’s wort WARNINGS AND PRECAUTIONS: Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of COMPLERA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with COMPLERA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients Coinfected with HIV-1 and HBV: All patients with HIV-1 should be tested for chronic HBV before initiating ARV therapy.

COMPLERA is not approved for the treatment of chronic HBV infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of COMPLERA. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment: Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF. Assess estimated CrCl in all patients prior to initiating therapy and as clinically appropriate during therapy with COMPLERA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated CrCl, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of COMPLERA, and periodically during COMPLERA therapy. COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high dose or multiple NSAIDS) [See Drug Interactions]. ] Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Do not use COMPLERA in patients with estimated CrCl <50 mL/min.

Drug Interactions: Caution should be given when prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine or when coadministered with a drug with a known risk of Torsade de Pointes. In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown

to prolong the QTc interval of the electrocardiogram (ECG) [See Contraindications and Drug Interactions]. ] Depressive Disorders: Depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with rilpivirine. Through 96 weeks in Phase 3 trials (N=686), the incidence of depressive disorders (regardless of causality, severity) was 9% (most events were mild or moderate in severity), Grades 3 and 4 depressive disorders (regardless of causality) was 1%, and discontinuation due to depressive disorders was 1%; suicidal ideation was reported in 4 subjects and suicide attempt was reported in 2 subjects. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Hepatotoxicity: Hepatic adverse events have been reported with rilpivirine. Patients with underlying hepatitis B or C, or marked elevations in liver-associated tests prior to treatment may be at increased risk for worsening or development of liver-associated tests elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liverassociated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.

Bone Effects of Tenofovir DF: Bone mineral density (BMD):: In clinical trials in HIV-1 infected adults, tenofovir DF was associated with decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For more information, please consult the VIREAD (tenofovir DF) full Prescribing Information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Consider assessing BMD in patients with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected, appropriate consultation should be obtained. Mineralization defects:: Cases of osteomalacia associated with proximal renal tubulopathy manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF. Coadministration with Other Products: COMPLERA should not be administered concurrently with other products containing any of the same active components (emtricitabine, rilpivirine or tenofovir DF) unless needed for dose adjustment; with products containing lamivudine; or with adefovir dipivoxil.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving ARV therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.

Immune Reconstitution Syndrome (IRS): IRS has been reported in patients treated with combination ARV therapy, including the components of COMPLERA. During the initial phase of combination ARV treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (e.g., Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

ADVERSE REACTIONS: See BOXED WARNING G and Warnings and Precautionss for additional serious adverse reactions.

In HIV-1 Infected Subjects with No ARV Treatment History: The safety assessment of rilpivirine, used in combination with other antiretrovirals, is based on the week 96 pooled data from two Phase 3 trials in ARV treatment-naive HIV-1 infected adults. A total of 686 subjects received rilpivirine in combination with other antiretrovirals as background regimen; 550 of whom received emtricitabine/tenofovir DF. The median duration of exposure for subjects was 104 weeks.

Adverse Reactions: Treatment emergent adverse reactions (Grades 2-4) reported in ≥2% of subjects receiving rilpivirine + emtricitabine/tenofovir DF (N=550) through week 96 were: depressive disorders (2%; includes depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation), headache (2%), and insomnia (2%). Frequencies of adverse reactions are based on all Grades 2-4 treatment emergent adverse reactions assessed to be related to study drug. No new adverse reactions were identified between

weeks 48 and 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population (for additional information, consult the Edurant [rilpivirine] full Prescribing Information). Two percent of subjects discontinued treatment with rilpivirine + emtricitabine/tenofovir DF due to adverse reactions (regardless of severity). The most common adverse reactions leading to discontinuation were psychiatric disorders (9 [1.6%] subjects); rash led to discontinuation in 1 (0.2%) subject. Rilpivirine adverse reactions:: Treatment emergent adverse reactions (≥Grade 2) occurring in <2% of subjects receiving rilpivirine (N=686) were (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.

Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 1, 2, 3, and 4, respectively) occurring in subjects receiving rilpivirine + emtricitabine/tenofovir DF (N=550) through week 96 were: increased creatinine (6%, 1%, <1%, 0%), increased AST (16%, 4%, 2%, 1%), increased ALT (19%, 5%, 1%, 1%), increased total bilirubin (6%, 3%, 1%, 0%), increased fasting total cholesterol (14%, 6%, <1%, 0%), increased fasting LDL cholesterol (13%, 5%, 1%, 0%), and increased fasting triglycerides (0%, 1%, 1%, 0%).

Adrenal Function: Mean changes from baseline in basal cortisol and ACTH-stimulated cortisol at week 96 (N=686) were -19.1 nmol/L (95% CI: -30.9; -7.4) and +18.4 ± 8.36 nmol/L, respectively; both values were within normal range. Effects on adrenal function were comparable by background N(t)RTIs. No serious adverse reactions, deaths, or treatment discontinuations were attributed to adrenal insufficiency.

Serum Creatinine: Mean change from baseline in serum creatinine at week 96 (N=686) was 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL); most increases occurred within the first four weeks of treatment.

Observed serum creatinine increases were similar among subjects with baseline mild or moderate renal impairment and subjects with baseline normal renal function; increases were comparable by background N(t)RTIs. No changes were considered to be clinically relevant and no subject discontinued treatment due to serum creatinine increases.

Serum Lipids: Mean changes from baseline in fasting serum lipids at week 96 were: total cholesterol: +2 mg/dL (N=430; baseline 162 mg/dL); HDL-cholesterol: +4 mg/dL (N=429; baseline 42 mg/dL); LDLcholesterol: -1 mg/dL (N=427; baseline 97 mg/dL); and triglycerides: -14 mg/dL (N=430; baseline 123 mg/dL). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and week 96 values. Subjects receiving lipid lowering agents during treatment were excluded from these lipid analyses.

Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In patients coinfected with hepatitis B or C virus receiving rilpivirine, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection.

In Virologically Suppressed HIV-1 Infected Subjects: No new types of adverse reactions to COMPLERA were identified in stable, virologically suppressed subjects switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% after switching to COMPLERA. Consult the respective full Prescribing Information for each individual component of COMPLERA for additional information regarding adverse reactions, including laboratory abnormalities and postmarketing events.

DRUG INTERACTIONS: See Contraindicationss for additional serious drug interactions.

COMPLERA is a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretrovirals. Information regarding potential drug interactions with other antiretrovirals is not provided.

Drugs Inducing or Inhibiting CYP3A: Rilpivirine is primarily metabolized by CYP3A, thus drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine leading to loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

Drugs Increasing Gastric pH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine leading to loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and other renally eliminated drugs, which may increase the incidence of adverse reactions [See Warnings and Precautions]. ] QT Prolonging Drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the

ECG. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

Established and Other Potentially Significant Drug Interactions: The drug interactions described are based on studies conducted with individual components of COMPLERA or are predicted drug interactions that may occur with COMPLERA; no drug interaction studies have been conducted using COMPLERA as a fixed-dose combination tablet.

The list includes potentially significant interactions but is not all inclusive. For additional information, consult the Edurant, EMTRIVA (emtricitabine) or VIREAD full Prescribing Information. An alteration in dose or regimen may be recommended when the following drugs are coadministered with COMPLERA: • Antacids: aluminum, magnesium hydroxide, calcium carbonate.

Antacids should be taken ≥2 hours before or ≥4 hours after COMPLERA. • Antimycobacterials: rifabutin. Give additional rilpivirine 25 mg once daily with a meal during rifabutin coadministration.

• Azole Antifungals: fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole. No dose adjustment required; monitor for breakthrough fungal infections.

• H2-Receptor Antagonists: cimetidine, famotidine, nizatidine, ranitidine. H2 -receptor antagonists should be taken ≥12 hours before or ≥4 hours after COMPLERA. • Macrolide/Ketolide Antibiotics: clarithromycin, erythromycin, telithromycin. Consider alternatives (e.g., azithromycin) when possible.

• Narcotic Analgesic: methadone. No dose adjustment required at therapy initiation; monitor during treatment; methadone maintenance dose may need adjustment.

Consult the full Prescribing Information prior to and during treatment with COMPLERA for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS: Pregnancy: COMPLERA is Pregnancy Category B; however, there are no adequate and well-controlled studies in pregnant women. COMPLERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry:: To monitor fetal outcomes of pregnant women exposed to COMPLERA, an Antiretroviral Pregnancy Registry has been established.

Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that rilpivirine and tenofovir are secreted in milk. Emtricitabine and tenofovir have been detected in human milk; it is not known if rilpivirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions and/or drug resistance in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMPLERA. Pediatric Use: COMPLERA is not recommended for patients <18 years of age because not all the individual components of COMPLERA have safety, efficacy and dosing recommendations available for all pediatric age groups.

Geriatric Use: Clinical studies of emtricitabine, rilpivirine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: COMPLERA should not be prescribed for patients with moderate, severe or end stage renal impairment (CrCl <50 mL/min) or patients who require dialysis [See Warnings and Precautions]. ] Hepatic Impairment: No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. COMPLERA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

OVERDOSAGE: If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with COMPLERA consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.

COMPLERA, EMTRIVA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

202123-GS-006 June 2014

COMPLERA, the COMPLERA Logo, EMTRIVA, GILEAD, the GILEAD Logo, GSI, HEPSERA, STRIBILD, the STRIBILD Logo, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. ©2014 Gilead Sciences, Inc. All rights reserved. PTFP0071 08/14

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Treatment Options in HIV JONATHAN Z. LI, MD Division of Infectious Diseases Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts

PAUL E. SAX, MD Division of Infectious Diseases Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Dr. Li disclosed that he serves as a consultant for Seracare Life Sciences and TherapyEdge; Dr. Sax disclosed that he serves as a consultant for AbbieView, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmith hKline, Janssen, Merck, and ViiV, and that he has received d grants and/or research support (funds paid directly to insstitution) from SmithKline.

Bristol-Myers Squibb, Gilead Sciences, and GlaxoS

I

n its 2014 guidelines update, the US Department of Health and Human

Services (DHHS) reiterated its broad recommendations to treat all patients with HIV and expanded its list of recommended antiretroviral

regimens. This review discusses some important considerations from both the DHHS and International AIDS Society-USA (IAS-USA) guidelines, along with summaries of recent key studies that are relevant to clinical practice.

When To Initiate ART The latest update to the 2014 DHHS guidelines upholds many of the recommendations of the previous version. The document states: “Antiretroviral therapy (ART) is recommended for alll HIV-infected individuals to reduce the risk of disease progression. The strength and evidence for this recommendation vary by pretreatment CD4 cell count. … ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.”1 The following CD4 thresholds, with ratings of the recommendation and strength of the evidence related to preventing disease progression, are still listed as follows1:

34

W W W. I D S E . N E T

• CD4 count <350 cells/mm3 (AI) • CD4 count 350 to 500 cells/mm3 (AII) • CD4 count >500 cells/mm3 (BIII) (Rating of Recommendations: A, Strong; B, Moderate; C, Optional. Rating of Evidence: I, data from randomized controlled trials; II, data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III, expert opinion.)

Similarly, the 2014 International AIDS Society-USA (IAS-USA) guidelines state: “ART is recommended regardless of CD4 cell count.”2 The reasons for the recommendation to treat all individuals with HIV have been accumulating over the past

several years. First, evidence increasingly has suggested that CD4 nadir—not just the absolute CD4 cell count—may predict certain adverse outcomes, such as risk for cardiovascular disease or the development of neurocognitive dysfunction. Second, there is an increased appreciation for the adverse effect of cumulative viral replication over time. In one cohort analysis, “viremia copy-years”—a product of both the height of the viral load and the duration of viremia—was a stronger predictor of survival than cross-sectional CD4 cell count.3 Third, some studies have shown that initiating therapy at CD4 counts greater than 500 cells/mm3 results in improved survival rates compared with lower values. One recent study demonstrated that patients treated at this CD4 threshold had survival rates comparable to those of uninfected individuals.4 Fourth, and perhaps most importantly, HPTN (HIV Prevention Trials Network) 052 demonstrated that ART strongly reduced the risk for HIV transmission while also providing clinical benefits.5 The study enrolled 1,753 serodiscordant couples; the HIV-infected partners lacked symptoms and had a CD4 count between 350 and 550 cells/mm3. Participants were randomized to either begin ART or defer therapy until their CD4 count fell to 250 cells/mm3. However, an independent data safety and monitoring board found that 28 studyrelated HIV infections occurred in the deferred therapy group compared with only 1 new infection in the ART arm (which led to early discontinuation of this study).

Additionally, early initiation of ART delayed the time to AIDS events and decreased the incidence of clinical events.6 The results of HPTN 052 have had a profound effect on the uptake of ART within certain communities. In 2010, the San Francisco Department of Public Health recommended treatment for all individuals once HIV is diagnosed to reduce disease incidence. Local investigators subsequently reported that a significantly higher proportion of patients with a CD4 count greater than 500 cells/mm3 are initiating ART.7 In clinical practice, we have found that informing patients that ART reduces the risk for HIV transmission ultimately serves as a strong motivator for their decision to start therapy, even for those with high CD4 cell counts. Although the results of HPTN 052 are impressive, clinicians nonetheless should continue to recommend safe sexual practices to their patients because intermittent viral shedding in genital secretions even during effective ART is well documented.8,9 Because some transmissions may occur outside of established couples (these were well documented in HPTN 052), certain seronegative, high-risk individuals may be candidates for preexposure prophylaxis (PrEP) with coformulated tenofovir/emtricitabine (Truvada, Gilead; TDF/FTC). The 2014 guidelines from the US Public Health Service now recommend daily oral PrEP for all high-risk, sexually active adults and injection drug users, once concurrent HIV infection has been excluded.10 The importance of adherence to PrEP was underscored by

the results of the VOICE (Vaginal and Oral Interventions to Control the Epidemic) study, which failed to show efficacy for PrEP in African women.11 However, blood sample analyses revealed that less than one-third of participants were taking their medications as directed.

Importantly, the DHHS guidelines do provide practitioners with the option to defer therapy in certain individuals. Specifically, the guidelines state: “Patients may choose to postpone therapy, and providers, on a caseby-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.”1 Evidence for the benefits of ART is much stronger for patients with low CD4 cell counts, so treatment may be deferred in asymptomatic individuals with CD4 counts greater than 500 cells/mm3 who are not ready to begin ART. Additionally, it should be noted that guidelines from the European AIDS Clinical Society do not recommend treatment in patients with CD4 counts greater than 500 cells/mm3, citing the absence of controlled clinical trials documenting any benefit.12 Of particular interest for this patient population is the ongoing multinational, randomized START (Strategic Timing of Antiretroviral Treatment) study, an investigation of when to initiate ART.13 For this study, 4,000 treatment-naive individuals with CD4 counts greater than 500 cells/mm3 are being enrolled and randomized to either start ART or defer treatment until their CD4 count falls below 350 cells/mm3 (or symptoms of AIDS are observed). Important end points include HIV and non–HIV-related complications. The latter are of particular interest because effective ART and a relatively high CD4 count should result in an extremely low incidence of HIV-related complications. Furthermore, HIV pathogenesis studies suggest that ongoing viral replication is associated with increased immune activation and inflammation, both of which may lead to an increased risk for non–HIV-related complications.14,15 The management of individuals recently infected with HIV has long been controversial. In the current DHHS guidelines, the term early HIV infection is used to encompass both those who have acute symptomatic disease with high viral replication (and often negative antibody) as well as those infected within the previous 6 months.1 One recently published article provided strong evidence that therapy during acute infection—the earlier the better—leads to a higher likelihood of maintaining a normal CD4 cell count.16 Moreover, the study confirmed previous data that CD4 cell counts decline relatively quickly in these patients if they are not treated, reaching commonly used CD4 thresholds for treatment fairly quickly (ie, within 12-18 months). A second study demonstrated that the earlier ART is initiated after infection, the lower the level of HIV in the viral reservoir.17 Patients with low viral burdens could be ideal candidates for HIV cure strategies.

In summary, the bulk of evidence now favors the treatment of acute HIV infection with indefinite ART, which already is implied in current treatment guidelines.1,2 Clinicians should remember to order a

INFECTIOUS DISEASE SPECIAL EDITION 2014

35

resistance genotype before beginning therapy, and initial strategies should consist of a boosted protease inhibitor (PI)-based regimen, because transmission of highly PI-resistant virus is extremely rare; an integrase inhibitor-based regimen also would be reasonable for this same reason.

What Treatment To Start The option to begin ART earlier would not have been possible were it not for the development of the current generation of safer therapies, which are less prone to option-limiting resistance (Table 1). In the past, clinicians’ attempts at aggressive treatment were plagued by the unanticipated toxicity of ART options, which was characterized by high rates of metabolic and morphologic complications. Importantly, the most toxic of these early agents—in particular, stavudine (Zerit, Bristol-Myers Squibb), didanosine (Videx, Bristol-Myers Squibb), indinavir (Crixivan, Merck), and nelfinavir—are no longer widely used in the developed world; thus, these complications have become rare (although a recent uncontrolled study suggested that even today, lipoatrophy remains prevalent among patients on treatment).18 Longitudinal studies of the recent treatment era have reported unprecedented levels of virologic suppression for patients undergoing therapy. Treatment results observed in clinical practice now are comparable to those reported in clinical trials,19 even in difficult-to-treat patient populations.20,21 Additionally, treatment changes due to toxicity have dramatically decreased over time.22 Not surprisingly, increased rates of treatment success have been accompanied by a dramatic decrease in the incidence of both treatment failure and drug resistance; furthermore, the increased number of options for treatment-experienced patients has translated into rates of virologic suppression similar to those observed in treatment-naive patients.23 In the 2014 DHHS guidelines, the list of recommended ART regimens has been both expanded and simplified.1 Instead of establishing a “preferred” class of ART, the DHHS now refers to “recommended” regimens, 7 of which are recommended for all patients, regardless of pre-ART viral load or CD4 cell count, and 3 of which are recommended only for individuals with HIV RNA less than 100,000 copies/mL (Table 2).

In addition to the 4 initial regimens that were part of the preferred regimen from prior years—TDF/FTC with either efavirenz (Sustiva, Bristol-Myers Squibb; EFV), atazanavir (Reyataz, Bristol-Myers Squibb; ATV)/ritonavir (Norvir, AbbVie; r), darunavir (Prezista, Janssen; DRV)/r, or raltegravir (Isentress, Merck; RAL)—3 additional regimens are now recommended for individuals with any viral load. These include dolutegravir (Tivicay, Viiv/GlaxoSmithKline; DTG) with either abacavir (Ziagen, Viiv; ABC)/lamivudine (Epivir, Viiv; 3TC) or TDF/FTC, and the single-pill regimen of TDF/FTC plus elvitegravir (Stribild, Gilead; EVG) and the pharmacokinetic booster cobicistat (various; COBI).1

36

W W W. I D S E . N E T

DOLUTEGRAVIR-BASED REGIMENS DTG is the most recently approved antiretroviral and has been studied in both treatment-naive and treatment-experienced patients. In an open-label, Phase II study, DTG was comparable to EFV at weeks 48 and 96 when combined with 2 nucleoside reverse transcriptase inhibitors (NRTIs).24,25 Additionally, 3 Phase III clinical trials in treatment-naive patients also have been conducted. In the first, DTG was noninferior to RAL in combination with 2 NRTIs.26 The SINGLE trial, a randomized double-blind study, compared ABC/3TC plus DTG with TDF/FTC/EFV. The results showed that the ABC/3TC plus DTG arm was superior to TDF/FTC/ EFV.27 In the FLAMINGO study, DTG was also found superior to DRV/r.28 The superiority of DTG in both of these trials was largely due to improved tolerability and a higher rate of drug discontinuation in the comparator arm. Another important feature of DTG is its high barrier to resistance as DTG retains activity against some viruses resistant to both RAL and EVG, and treatment-emergent resistance rarely occurs, even in those with virologic failure. The results from small studies that administered twice-daily DTG to this very difficult-to-treat patient population with highly resistant virus have been encouraging.29 In August 2013, the FDA approved DTG for use in combination regimens in treatment-naive and treatment-experienced patients.

Single-tablet formulations of DTG with ABC/3TC are in development.

TENOFOVIR/EMTRICITABINE-BASED REGIMENS Two pivotal Phase III studies have compared TDF/ FTC/EVG/COBI with currently approved regimens that are recommended for initial ART; the results of these trials were instrumental in the FDA’s approval of the regimen for use in treatment-naive patients in 2012.30,31 In a randomized, double-blind placebo-controlled study, 700 treatment-naive patients were assigned to receive either TDF/FTC/EVG/COBI or coformulated TDF/FTC/EFV, plus matching placebos.30 At week 48, rates of virologic suppression were 88% for the TDF/ FTC/EVG/COBI patients versus 84% for the TDF/ FTC/EFV arm, which met the study protocol criteria for noninferiority. There was significantly more nausea observed in those who received TDF/FTC/EVG/ COBI but significantly more incidents of rash and central nervous system (CNS) side effects were observed in those treated with TDF/FTC/EFV. A separate, similarly designed study compared TDF/FTC/EVG/COBI with TDF/FTC plus ATV/r.31 At week 48, rates of virologic suppression were 90% for TDF/FTC/EVG/COBI versus 87% for the TDF/FTC plus ATV/r arm, which also met the protocol’s criteria for noninferiority. Side-effect profiles between the 2 regimens were quite similar, with the exception of a higher rate of jaundice experienced by those receiving TDF/FTC plus ATV/r. Week 96 results from these studies demonstrated that treatment responses to TDF/FTC/EVG/COBI were maintained, with no unanticipated adverse events.32

Table 1.

Generic Name (Brand Name/Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

300-mg tablets 20-mg/mL oral solution

300 mg bid or 600 mg qd

None

600/300-mg tablets

1 tablet qd

None

300-/150-/300-mg tablets

1 tablet bid

None

125-, 200-, 250-, 400mg enteric-coated capsules 10-mg/mL oral solution

Delayed-release capsule: <60 kg: 250 mg qd ≥60 kg: 400 mg qd With tenofovir [TDF]: <60 kg: 200 mg qd ≥60 kg: 250 mg qd Note: Preferred oral solution dosing is bid; total daily dose divided

Should be administered on an empty stomach at least 30 min before or 2 h after meal

NRTIs Abacavir sulfate [ABC] (Ziagen, GlaxoSmithKline)a

Abacavir sulfate/ lamivudine (Epzicom, GlaxoSmithKline)

Abacavir sulfate/ lamivudine/zidovudine (Trizivir, GlaxoSmithKline)

Didanosine [ddl] (Videx/Videx EC, Bristol-Myers Squibb Oncology/Immunology)a

Emtricitabine [FTC]

200-mg capsules 1 capsule qd 10-mg/mL oral solution 240 mg (24 mL) PO qd

None

150-, 300-mg tablets; 150 mg bid or 300 mg qd 10-mg/mL oral solution

None

(Epivir, GlaxoSmithKline)a

Lamivudine/zidovudine

150-/300-mg tablets

1 tablet bid

None

15-, 20-, 30-, 40-mg capsules 1-mg/mL oral solution

<60 kg: 30 mg bid ≥60 kg: 40 mg bid Note: WHO recommends 30 mg bid dosing regardless of body weight

None

300-mg tablets

1 tablet qd

None

300-/200-mg tablets

1 tablet qd

None

(Emtriva, Gilead Sciences)

Lamivudine [3TC]

(Combivir, GlaxoSmithKline)a

Stavudine [d4T] (Zerit, Bristol-Myers Squibb Oncology/Immunology)

Tenofovir disoproxil fumarate (Viread, Gilead Sciences)

Tenofovir disoproxil fumarate/emtricitabine (Truvada, Gilead Sciences)

Zidovudine [ZDV] (Retrovir, GlaxoSmithKline)

100-mg capsules 200 mg tid or 300 mg bid 300-mg tablets 10-mg/mL oral solution 10-mg/mL IV solution

None

100-, 200-mg tablets

400 mg tid (100-mg tablets can be dispersed in water; 200-mg tablets should be taken intact)

Separate dosing from antacids by 1 h with or without food

50-, 200-mg capsules 600-mg tablets

600 mg qd (at bedtime)

Take on empty stomach at bedtime to reduce side effects

NNRTIsb Delavirdine mesylate [DLV] (Rescriptor, Pfizer)

Efavirenz [EFV] (Sustiva, Bristol-Myers Squibb)

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Table 1.

Generic Name (Brand Name/Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

100-mg tablets

200 mg bid

Take after full meal

Immediate-release: 200-mg tablets 50 mg/5-mL oral suspension Extended-release: 400-mg tablets

Immediate-release: 200 mg qd x 2 wk then 200 mg bid Extended-release: NVP-naive: 200-mg immediate-release tablets qd x 2 wk, then 400 mg extendedrelease qd NVP-experienced: 400-mg tablet qd

None

25-mg tablets

25 mg qd

Take with a meal

100-, 150-, 200-, 300mg capsules

Treatment-naive patients only: 400 mg qd or 300 mg + 100 mg of ritonavir [RTV] qd Treatment-experienced patients or with TDF: Treatment-naive patients in combination with EFV: 400 mg + 100 mg of RTV qd

Take with food

75-, 150-, 600-, 800mg tablets

Treatment-experienced patients: 600 mg bid + 100 mg RTV bid Treatment-naive patients: 800 mg qd + RTV 100 mg qd (Unboosted DRV is not recommended)

Take with food

700-mg tablet

Treatment-naive patients: 1,400 mg bid 700 mg bid + 100 mg RTV bid or 1,400 mg qd + 200 mg or 100 mg RTV PI-experienced: 700 mg bid + 100 mg RTV bid Coadministration with EFV (recommended): 700 mg + 100 mg RTV bid 1,400 mg + 300 mg RTV qd

None

NNRTIs Etravirine [ETV] (Intelence, Tibotec)

Nevirapine [NVP] (Viramune and Viramune XR, Boehringer Ingelheim)a

Rilpivirine [RPV] (Edurant, Tibotec) PIsc Atazanavir sulfate [ATV] (Reyataz, Bristol-Myers Squibb)

Darunavir ethanolate [DRV] (Prezista, Tibotec)

Fosamprenavir [FPV] (Lexiva, GlaxoSmithKline/Vertex)

38

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Table 1. Overview of Current Antiretroviral Agents Generic Name (Brand Name/Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

100-, 200-, 333-, 400mg capsules

800 mg q8h 800 mg + 100 mg or 200 mg RTV bid

Unboosted: Take 1 h before or 2 h after meals; may take with skim milk/low-fat meal Boosted: Take with or without food Separate dosing from ddl by 1 h

200-/50-mg tablet 400-/100-mg per 5 mL oral solution

2 tablets bid or 5 mL bid 4 tablets qd or 10 mL qd Note: Once-daily dosing recommended ONLY for treatment-naive patients.

Not for use in combination with EFV, NVP, FPV, or nelfinavir [NFV].

Treatment-experienced patients and in combination with EFV or NVP: 3 tablets bid or 6.7-mL oral solution bid

Tablets: None Oral: Take with food

250-, 625-mg tablets 50-mg/g oral powder

750 mg tid or 1,250 mg bid

Take with food to improve absorption; also can be dissolved in water

100-mg capsules or tablets 80-mg/mL oral solution

600 mg bid (when used as only PI) 100-400 mg qd in 1 to 2 divided doses as pharmacokinetic booster for other PIs

Take with food or up to 2 h after a meal to improve tolerability

(Invirase, Roche)

200-mg capsules 500-mg tablets

1,000 mg + 100 mg RTV bid (Unboosted SQV is not recommended)

Take within 2 h of full meal

Tipranavir [TPV]

250-mg capsules

500 mg + 200 mg RTV bid (Unboosted TPV is not recommended)

Take with food

Injectable (lyophilized powder): Each singleuse vial contains 108 mg of T-20 to be reconstituted with 1.1 mL of sterile water to deliver approximately 90 mg/mL

90 mg (1 mL) sc bid Administered subcutaneously into upper arm, anterior thigh, or abdomen

None

PIsc Indinavir sulfate [IDV] (Crixivan, Merck)

Lopinavir/ritonavir [LPV/r] (Kaletra, Abbott)

Nelfinavir mesylate (Viracept, Pfizer)

Ritonavir (Norvir, Abbott)

Saquinavir mesylate [SQV]

(Aptivus, Boehringer Ingelheim)

Fusion Inhibitors Enfuvirtide [T-20] (Fuzeon, Roche/Trimeris)

INFECTIOUS DISEASE SPECIAL EDITION 2014

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Table 1. Overview of Current Antiretroviral Agents Generic Name (Brand Name/Manufacturer)

Formulation

Recommended Adult Dosing

Food Effect

150 mg bid when administered with strong CYP3A inhibitors 300 mg bid when administered with T-20, TPV, RTV, NVP, and weak CYP3A inhibitors 600 mg bid when administered with CYP3A inducers (eg, EFV, ETV, rifampin) and without CYP3A inhibitors

None

400-mg tablets

1 tablet bid

Take with or without food

50-mg tablets

1 tablet qd 1 tablet bid for patients with resistance to integrase inhibitors

Take with or without food

600-/200-/300-mg combination tablet

1 tablet qd

Take on empty stomach; dosing at bedtime may improve tolerability of nervous system symptoms

Emtricitabine/ 200-/25-/300-mg rilpivirine/tenofovir combination tablet disoproxil fumarate (Complera, Gilead Sciences/ Janssen Therapeutics)

1 tablet qd

Take with a meal

Emtricitabine/ tenofovir/elvitegravir/ cobicistat (Stribild, Gilead Sciences)

1 tablet qd

Take with food

CCR5 co-receptor antagonists Maraviroc (Selzentry, ViiV Healthcare/ GlaxoSmithKline)

150-, 300-mg tablets

Integrase strand transfer inhibitors Raltegravir (Isentress, Merck)

Dolutegravir [DTG] (Tivicay, ViiV Healthcare/ GlaxoSmithKline) Combination regimens Efavirenz/emtricitabine/ tenofovir disoproxil fumarate (Atripla, Gilead Sciences/ Bristol-Myers Squibb)

300-/200-/150-/150mg combination tablet

bid, twice daily; CYP, cytochrome P450; ddI, didanosine; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PO, orally; qd, once daily; sc, subcutaneous; tid, 3 times daily; WHO, World Health Organization a

Generic formulations are also available.

b

During clinical trials, NNRTIs were discontinued because of rash in 7% of NVP-treated patients, 4.3% of DLV-treated patients, 1.7% of EFV-treated patients, and 2% of ETV-treated patients. Rare cases of Stevens-Johnson syndrome have been reported with the use of all 3 NNRTIs; the highest incidence was observed with NVP use. c

Cases of worsening glycemic control in patients with preexisting diabetes and cases of new-onset diabetes, including diabetic ketoacidosis, have been reported with the use of all PIs. Patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risk for cardiovascular events and pancreatitis. Interventions can include dietary modification, lipid-lowering modification or agents, or discontinuation of PIs.

40

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Table 2. DHHS Antiretroviral Regimens Recommended for Treatment-Naive Patients Recommended Regimens for All Patients

Recommended Regimens for Patients With HIV RNA <100,000 copies/mL

NNRTI-based (1 NNRTI + 2 NRTIs)

EFV Va + TDFb + FTCc

EFV Va + ABCd/3TCc RPV Ve/TDFb/FTCc

PI-based (1 PI + 2 NRTIs)

ATV/rf + TDFb + FTCc DRV/r (qd) + TDFb + FTCc

ATV/rf + ABCd/3TCc

InSTI-based (1 InSTI + 2 NRTIs)

DTG + TDFb/FTCc DTG + ABCd/3TCc EVGh/COBIi/ TDFb/FTCc RAL + TDFb/FTCc

Regimen

Alternative Regimens

DRV/r + ABCd/3TCc LPV/rg (qd or bid) + ABCd/3TCc or TDFb/FTCc RAL + ABCd/3TCc

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; bid, twice daily; CCR5, chemokine receptor 5; COBI, cobicistat; CrCl, creatinine clearance; ddI, didanosine; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; HLA, human leukocyte antigen; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; qd, once daily; /r, ritonavir-boosted; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir a

EFV should not be used during the first trimester of pregnancy, in those trying to conceive, or in those not using effective contraception.

b

TDF should be used with caution in patients with renal insufficiency.

c

3TC may substitute for FTC or vice versa.

d

ABC should not be used in patients who test positive for HLA-B*57011 and should be used with caution in patients at high risk for cardiovascular disease or with pretreatment HIV RNA >100,000 copies/mL. e

RPV is not recommended in patients with pretreatment HIV RNA >100,000 copies/mL. Virologic failure is more common in patients with pretreatment CD4 counts of <200 cells/mm3 who are treated with RPV + 2 NRTIs. f

ATV/r should not be used in patients who require >20 mg omeprazole per day and is generally preferred over ATV. Unboosted ATV may be used when ritonavir boosting is not possible. g

LPV/r qd is not recommended for pregnant women; LPV/r (bid) + ZDV/3TC is the preferred regimen for use in pregnant women.

h

EVG/COBI/TDF/FTC should not be started in patients with an estimated CrCl <70 mL/min and should be changed to an alternative regimen if the patientâ&#x20AC;&#x2122;s CrCl falls below 50 mL/min. EVG/COBI/TDF/FTC should not be used with other antiretroviral drugs or with nephrotoxic drugs. i

COBI is a potent cytochrome P450 3A inhibitor. It can increase the concentration of other drugs metabolized by this pathway. Refer to the DHHS guidelines for information about interactions with concomitantly administered drugs.

Adapted dapted from o reference e e e ce 1.

An important practical consideration for TDF/FTC/ EVG/COBI is that it should not be used in patients with an estimated glomerular filtration rate (GFR) less than 70; furthermore, it also should be avoided in regimens that contain HIV PIs, as there is a 3-way interaction between EVG, COBI, and HIV PIs. COBI is known to inhibit the tubular secretion of creatinine, thus patients treated with this drug show small increases in serum creatinine levels. Studies have demonstrated that this effect does not result in an actual decrease in the GFR, and hence this likely is a benign effect.33 Nonetheless, clinicians do need to be vigilant for TDF-related tubular toxicity, which occurred in 1% of patients treated with TDF/FTC/EVG/COBI; such toxicity may be manifested by a greater increase in serum creatinine, proteinuria, or glycosuria, any of which should prompt discontinuation of TDF.30,31 COBI as a stand-alone pharmacokinetic booster is currently undergoing FDA review.

OTHER REGIMENS Three regimens are recommended only for individuals with viral load less than 100,000 HIV RNA copies/ mL. These include ABC/3TC with either EFV or ATV/r, as well as the coformulated rilpivirine (Edurant, Janssen; RPV)/TDF/FTC. In the ACTG (AIDS Clinical Trials Group) A5202 study, more than 1,800 participants were randomized to receive either ABC/3TC or TDF/FTC in combination with either EFV or ATV/r.34 Rates of virologic failure were significantly higher for participants with HIV RNA of at least 100,000 copies/mL treated using an ABC/3TC-containing regimen. Data indicate that individuals should be screened for the HLA-B*57011 genotype before an ABC-containing regimen is initiated as the absence of this allele is associated with a significantly reduced risk for ABC hypersensitivity syndrome.35 The single-pill regimen of TDF/TFC plus RPV has been evaluated in several large Phase III studies.36-38 The

INFECTIOUS DISEASE SPECIAL EDITION 2014

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Table 3. Initial Antiretroviral Regimens From the IAS–USA Regimen

NNRTI plus NRTIs

Recommended Regimens

Alternative Regimensa

Comments

EFV/TDF/FTC

NVP plus TDF/FTC (or ABC/3TC)

Severe hepatotoxicity and rash with NVP are more common when CD4 cell count is >350 cells/mm3 in women and >400 cells/mm3 in men

DRV/r plus TDF/FTC

DRV plus ABC/3TC

ATV/r plus TDF/FTC

LPV/r plus plus 2 NRTIs

ATZ is associated with nephrolithiasis, cholelithiasis, and chronic kidney injury

ATV/r plus ABC/3TCe

ATV/r/COBI plus 2 NRTIs

RAL plus TDF/FTC

RAL plus ABC/3TC

EFV plus ABC/3TCb,c RPV/TDF/FTC or RPV plus ABC/3TC

PI/r plus NRTIsd

RAL is administered twice daily

DTG/TDF/FTC InSTI plus NRTIs DTG/ABC/3TC EVG/COBI/TDF/FTC 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; HLA, human leukocyte antigen; IAS–USA, International Antiviral Society–USA; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; /r, ritonavir-boosted; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine a

ZDV/3TC is an alternative component for all 3 regimens, but the toxicity of ZDV reduces its utility.

b

In HLA-B*5701–negative patients with baseline plasma viremia <100,000 copies/mL.

c

Consider avoiding the use of ABC or LPV/r in patients at risk for or who have cardiovascular disease.

d

HLA-B*57011 screening is recommended to reduce the risk for hypersensitivity reactions.

e

Use in patients with plasma HIV-1 RNA <100,000 copies/mL.

Adapted from reference 2.

overall results of these trials showed that RPV was noninferior to EFV. However, patients in these studies were more likely to experience virologic failure with RPV than with EFV (with possible selection of cross-resistance to etravirine [Intelence, Janssen]), especially if their baseline viral load was greater than 100,000 copies/ mL. The lower efficacy of RPV was compensated by its improved safety and tolerability profile (in particular, a lower incidence of rash and CNS side effects) compared with EFV; lipid changes also favored RPV. When prescribing RPV, clinicians need to remind patients of the importance of taking the medication with a full meal and to avoid the concomitant use of proton pump inhibitors. These are essential measures to ensure the drug is fully absorbed.

ALTERNATIVE REGIMENS Finally, the list of alternative regimens in the DHHS guidelines has been simplified to 4 combinations that are considered effective and tolerable, but have potential disadvantages or less data for their use when compared with the recommended regimens. For example, ritonavir-boosted lopinavir (Kaletra, AbbVie; LPV/r) is still considered a preferred PI in certain situations (eg, pregnant HIV-infected women), but the greater risk

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W W W. I D S E . N E T

for adverse events, need for a higher RTV dose, and pill burden limit its usefulness.1 Some of the drugs that no longer appear as part of an “alternative” regimen include zidovudine (Retrovir, Viiv; ZDV, AZT), nevirapine (Viramune, Boehringer Ingelheim; NVP), saquinavir (Invirase, Genentech; SQV), fosamprenavir (Lexiva, Viiv; FPV), and maraviroc (Selzentry, Viiv; MVC).

Tables 3 and 4 summarize the IAS-USA recommendations for treatment-naive and special populations.

New and Investigational Strategies for Treatment In an abstract presentation at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI), Raffi et al presented the results of a Phase III, randomized, open-label study of RAL versus TDF/FTC, both combined with DRV/r.39 Overall, the RAL arm was found to be noninferior to the TDF/FTC arm. However, the RAL and DRV/r regimen appeared to perform less well for participants with CD4 cell counts less than 200 cells/mm3 or HIV RNA of at least 100,000 copies/mL. A separate abstract presented at the 2014 CROI meeting highlighted the results of the Phase IIb LATTE study of a 2-drug maintenance regimen of rilpivirine with GSK744 (GlaxoSmithKline), a novel integrase

Table 4. Initial Regimens for Use in Special Circumstances From the IAS–USA

PI/r plus InSTI (NRTI-sparing)

Regimen

Comments

DRV/r plus RAL

RAL taken twice daily, DRV/r taken once daily.

DRV/r plus RAL less effective at CD4 cell counts of <200/mcL and possibly HIV-1 RNA >100,000 copies/ mL; LPV/r plus RAL taken twice daily

LPV/r plus RAL LPV/r plus 3TC

3TC, lamivudine; DRV, darunavir; IAS–USA, International Antiviral Society–USA; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; /r, ritonavir-boosted; RAL, raltegravir Adapted dapted from o reference e e e ce 2.

inhibitor.40 Used as a maintenance regimen after initial virologic suppression, the oral regimen of rilpivirine and GSK744 was well tolerated and demonstrated to be as effective as the standard regimen of EFV plus 2 NRTIs. The significance of these results is that it supports the continued development of rilpivirine and GSK744 as long-acting injectable drugs for maintenance treatment of HIV. Another promising investigational antiretroviral agent currently in development is tenofovir alafenamide fumarate (GS7340, Gilead; TAF), a prodrug form of TDF. This agent achieves very high intracellular concentrations of TDF with corresponding low plasma levels. As a result, much lower doses of TAF are required to achieve antiviral activity that is comparable to TDF, as shown in a recent Phase II study that compared TDF/FTC/EVG/ COBI with TAF/FTC/EVG/COBI.41 Encouragingly, TAF had significantly less negative effects on serum creatinine levels and bone mineral density. Single-tablet regimens of TAF/FTC/EVG/COBI and TAF/FTC/DRV/COBI are in development.

References 1.

Panel on Antiretroviral Guidelines for Adults and Adolescents.

Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents— May 1, 2014. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf. Accessed July 1, 2014.

2. Günthard HF, Aberg JA, Eron JJ, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel. JAMA. 2014;312(4):410-425.

3. Mugavero MJ, Napravnik S, Cole SR, et al. Viremia copy-years predicts mortality among treatment-naive HIV-infected patients initiating antiretroviral therapy. Clin Infect Dis. 2011;53(9):927-935.

4. Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population.

AIDS. 2013;27(6):973-979.

5. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493-505.

6. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis. 2014;14(4):281-290.

7. Hsu LC, Truong HH, Vittinghoff E, et al. Trends in early initiation of antiretroviral therapy and characteristics of persons with HIV initiating therapy in San Francisco, 2007-2011. J Infect Dis. 2014;209(9):1310-1314.

8. Lambert-Niclot S, Tubiana R, Beaudoux C, et al. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma on a 2002-2011 survey. AIDS. 2012;26(8):971-975.

9. Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS. 2012;26(12):1535-1543.

10. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States—2014 clinical practice guideline. http://stacks.cdc.gov/view/cdc/23109/cdc_23109_DS1. pdf. Accessed May 23, 2014.

11. Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofovir/emtricitabine or vaginal tenofovir gel in the VOICE study (MTN 003). Presented at: 20th Conference on Retroviruses and Opportunistic Infections.

Atlanta, GA; March 3-6, 2013. Abstract 26LB. 12. European AIDS Clinical Society. Guidelines Version 7.0, October 2013. http://eacsociety.org/Portals/0/Guidelines_Online_131014. pdf. Accessed May 18, 2014.

13. University of Minnesota Clinical and Translational Science Institute. Strategic timing of antiretroviral treatment (START). http:// clinicaltrials.gov/ct2/show/NCT00867048?term=START&rank=1.

Accessed May 18, 2014.

14. Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197(1):126-133.

15. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.

16. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368(3):218-230.

17. Ananworanich J, Vandergeeten C, Chomchey N, et al. Early ART intervention restricts the seeding of the HIV reservoir in long-lived central memory CD4 T cells. Presented at: 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA; March 3-6, 2013. Abstract 47.

18. Leclercq P, Goujard C, Duracinsky M, et al. High prevalence and impact on the quality of life of facial lipoatrophy and other abnormalities in fat tissue distribution in HIV-infected patients treated with antiretroviral therapy. AIDS Res Hum Retroviruses.

2013;29(5):761-768.

INFECTIOUS DISEASE SPECIAL EDITION 2014

43

19. Gill VS, Lima VD, Zhang W, et al. Improved virological outcomes in British Columbia concomitant with decreasing incidence of HIV type 1 drug resistance detection. Clin Infect Dis. 2010;50(1):98-105.

20. Moore RD, Bartlett JG. Dramatic decline in the HIV-1 RNA level over calendar time in a large urban HIV practice. Clin Infect Dis. 2011;53(6):600-604.

21. Sax PE. Antiretroviral therapy: now â&#x20AC;&#x153;it just works.â&#x20AC;? Clin Infect Dis. 2011;53(6):605-608.

22. Helleberg M, Kronborg G, Larsen CS, et al. Decreasing rate of multiple treatment modifications among individuals who initiated antiretroviral therapy in 1997-2009 in the Danish HIV Cohort Study.

Antivir Ther. 2012 [Epub ahead of print].

23. Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrugresistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis. 2009;49(9):1441-1449.

24. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2011;12(2):111-118.

25. Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS. 2013;27(11):1771-1778.

26. Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381(9868):735-743.

27. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-1818.

28. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014; 383(9936):2222-2231.

29. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2012;207(5):740-748.

30. Sax PE, DeJesus E, Mills A, et al. Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439-2448.

31. DeJesus E, Rockstroh JK, Henry K, et al. Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus

44

W W W. I D S E . N E T

ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet.

2012;379(9835):2429-2438.

32. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate versus efavirenz/emtricitabine/ tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr.

2013;63(1):96-100.

33. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61(1):32-40.

34. Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir DF/emtricitabine as part of combination regimens for initial treatment of HIV: final results. J Infect Dis. 2011;204(8):1191-1201.

35. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579.

36. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 doubleblind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr. 2012;60(1):33-42.

37. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial.

Lancet. 2011;378(9787):229-237.

38. Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS. 2014;28(7):989-997.

39. Raffi F, Babiker A, Richert L, et al. First-line raltegravir (RAL) + darunavir/ritonavir (DRV/r) is non-inferior to tenofovir/emtricitabine (TDF/FTC) + DRV/r: the NEAT 001/ANRS 143 randomised trial. Presented at: Conference on Retroviruses and Opportunistic Infections. Boston, MA; March 3-6, 2014. Abstract 84LB. 40. Margolis D, Brinson C, Eron J, et al. 744 and rilpivirine as two-drug oral maintenance therapy: LAI116482 (LATTE) week 48 results.

Presented at: Conference on Retroviruses and Opportunistic Infections. Boston, MA; March 3-6, 2014. Abstract 91LB. 41. Markowitz M, Zolopa A, Squires K, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother.

2014;69(5):1362-1369.

DIFICID ® (fidaxomicin) tablets, for oral use BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for Full Prescribing Information.

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID® and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused

by Clostridium difficile.

Clostridium difficile-Associated Diarrhea DIFICID is a macrolide antibacterial drug indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD).

CONTRAINDICATIONS Hypersensitivity to fidaxomicin.

WARNINGS AND PRECAUTIONS Not for Systemic Infections Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.

Hypersensitivity Reactions Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted. Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.

Development of Drug-Resistant Bacteria Prescribing DIFICID in the absence of a proven or strongly suspected C. difficilee infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice. The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.

Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.

Selected Adverse Reactions with an Incidence of ≥2% Reported in DIFICID Patients in Controlled Trials DIFICID (N=564)

Vancomycin (N=583)

n (%)

n (%)

Anemia

14 (2%)

12 (2%)

Neutropenia

14 (2%)

6 (1%)

System Organ Class Preferred Term

Metabolism and Nutrition Disorders:: hyperglycemia, metabolic acidosis Skin and Subcutaneous Tissue Disorders:: drug eruption, pruritus, rash Post Marketing Experience Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.

Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and rabbits by the intravenous route at doses up to 12.6 and 7 mg/kg, respectively.

The plasma exposures (AUC0-t) at these doses were approximately 200- and 66-fold that in humans, respectively, and have revealed no evidence of harm to the fetus due to fidaxomicin. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers It is not known whether fidaxomicin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DIFICID is administered to a nursing woman.

Pediatric Use The safety and effectiveness of DIFICID in patients <18 years of age have not been established.

Geriatric Use Of the total number of patients in controlled trials of DIFICID, 50% were 65 years of age and over, while 31% were 75 and over. No overall differences in safety or effectiveness of fidaxomicin compared to vancomycin were observed between these subjects and younger subjects.

In controlled trials, elderly patients (≥65 years of age) had higher plasma concentrations of fidaxomicin and its main metabolite, OP-1118, versus non-elderly patients (<65 years of age). However, greater exposures in elderly patients were not considered to be clinically significant. No dose adjustment is recommended for elderly patients.

OVERDOSAGE No cases of acute overdose have been reported in humans. No drug-related adverse effects were seen in dogs dosed with fidaxomicin tablets at 9600 mg/day (over 100 times the human dose, scaled by weight) for 3 months.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility Long-term carcinogenicity studies have not been conducted to evaluate the carcinogenic potential of fidaxomicin.

Neither fidaxomicin nor OP-1118 was mutagenic in the Ames assay.

Fidaxomicin was also negative in the rat micronucleus assay. However, fidaxomicin was clastogenic in Chinese hamster ovary cells.

Fidaxomicin did not affect the fertility of male and female rats at intravenous doses of 6.3 mg/kg. The exposure (AUC0-t) was approximately 100 times that in humans.

Blood and Lymphatic System Disorders

Distributed by:

Gastrointestinal Disorders Nausea

62 (11%)

66 (11%)

Vomiting

41 (7%)

37 (6%)

Abdominal Pain

33 (6%)

23 (4%)

Gastrointestinal Hemorrhage

20 (4%)

12 (2%)

The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials: Gastrointestinal Disorders:: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon Investigations:: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count

Cubist Pharmaceuticals U.S. Lexington, MA 02421 USA Made in Canada.

DIFICID® is a registered trademark of Cubist Pharmaceuticals in the United States. ©2014 Cubist Pharmaceuticals. All rights reserved.

Revised: April 2014 DIF-0161-1

In adult patients with Clostridium difficile-associated diarrhea (CDAD)

DIFICID® (fidaxomicin) tablets demonstrated comparable clinical response at 10 days and superior sustained clinical response through 25 days beyond the end of treatment vs vancomycin1* DIFICID (n=542) was studied vs vancomycin (n=563) in two large Phase 3 CDAD trials (N=1105)1 Outcomes of treatment with DIFICID1 100

88% 86%

DIFICID 200 mg twice daily (n=542) vancomycin 125 mg four times daily (n=563)

PATIENTS (%)

80

71% 57%

60

40

20

0

CLINICAL RESPONSE

SUSTAINED CLINICAL RESPONSE

Primary endpoint: clinical response at the end of 10-day treatment.1 Sustained clinical response: initial clinical response at 10 days + survival without proven or suspected CDAD recurrence at 25 days post treatment end.1 Study description: two Phase 3, randomized, double-blind, non-inferiority studies (N=1105) comparing the efficacy and safety of oral DIFICID 200 mg twice daily versus oral vancomycin 125 mg four times daily for 10 days in the treatment of adults (aged ≥18 years) with CDAD (defined by >3 unformed bowel movements in the 24 hours before randomization and presence of either C. difficile toxin A or B in the stool within 48 hours of randomization). Enrolled patients received no more than 24 hours of pretreatment with vancomycin or metronidazole and had either no prior CDAD history or only one prior CDAD episode in the past 3 months. Subjects with life-threatening/fulminant infection, hypotension, septic shock, peritoneal signs, significant dehydration, or toxic megacolon were excluded.1

Efficacy measured only at days 10 and 35.1

DIFICID was associated with a lower rate of CDAD recurrence vs vancomycin at 25 days post treatment end as measured by sustained clinical response (14% [67/474] vs 26% [127/488])2,3 Since clinical success at the end of treatment and mortality rates were similar across treatment arms (approximately 6% in each group), differences in sustained clinical response were due to lower rates of proven or suspected CDAD during the follow-up period in DIFICID patients1 In patients infected with a BI isolate, DIFICID did not demonstrate superiority in sustained clinical response when compared with vancomycin1

Indications and Usage DIFICID is a macrolide antibacterial drug indicated in adults ≥18 years of age for treatment of Clostridium difficileassociated diarrhea (CDAD) To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile

Important Safety Information DIFICID is contraindicated in patients with hypersensitivity to fidaxomicin DIFICID should not be used for systemic infections Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria The most common adverse reactions reported in clinical trials are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%)

Please see brief summary of full Prescribing Information for DIFICID on adjacent page.

For more information about DIFICID and the AccessDIFICID™ patient access support program, please visit DIFICID.com or call 844-CUBIST-CARES (844 -282-4782) (M-F, 8 AM-8 PM; SAT, 9 AM-1PM, ET) *Confidence interval was derived using Wilson’s score method. Approximately 5% to 9% of the data in each trial and treatment arm were missing sustained response data and were imputed using a multiple imputation method.1 References: 1. DIFICID [package insert]. Lexington, MA: Cubist Pharmaceuticals; April 2014. 2. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.003. June 17, 2010. Optimer Pharmaceuticals, Inc. 3. Data on file. A multinational, multicenter, double-blind, randomized, parallel-group study to compare the safety and efficacy of 200 mg PAR-101 taken q12h with 125 mg vancomycin taken q6h for ten days in subjects with Clostridium difficile-associated diarrhea. Clinical study report 101.1.C.004. June 4, 2010. Optimer Pharmaceuticals, Inc.

www.cubist.com ©2014 Cubist Pharmaceuticals DIF-0136-1 September 2014 DIFICID® and AccessDIFICIDTM are trademarks of Cubist Pharmaceuticals.

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Overview of the Management Of Clostridium difficile Infections JULIA GARCIA-DIAZ, MD, MSC, FIDSA Program Director, Infectious Disease Fellowship Program Ochsner Clinic Associate Professor University of Queensland/Ochsner School Clinical Associate Professor of Medicine Tulane University New Orleans, Louisiana

ARNAB RAY, MD Gastroenterologist Ochsner Clinic New Orleans, Louisiana

KARLA RIVERA RIVERA, MD Infectious Disease Fellow Ochsner Clinic New Orleans, Louisiana

C

Drs. Ray and Rivera Rivera report that they have no relevant financial interests to disclose. Dr. Garcia-Diaz reports that she has received grant and/or research support for pharmaceutical trials from Astellas, Cubist, GlaxoSmithKline, and Sanofi-Aventis, and that she serves on the speakerâ&#x20AC;&#x2122;s bureau at Astellas.

lostridium difficile infection (CDI), a common cause of infectious diarrhea, has become increasingly prevalent in the acute care setting.1 CDI is associated with increased

morbidity and more recently with increased mortality,2,3 and it has

surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the leading cause of hospital-acquired infections (HAIs).2,4 CDI also increases hospital length of stay (LOS) and care costs. A well-known cause of antibiotic-associated diarrhea, it is estimated to account for 15% to 25% of all diarrheal episodes.2 No longer only associated with health care facilities, C. difficile infections are now an emerging threat in the community.

Epidemiology C. difficile is responsible for 12% of all HAIs in 10 geographically diverse states (Figure 1). This translated to an estimated 80,400 cases of hospital-onset infections.5,6 The Centers for Disease Control and Prevention (CDC) national and state HAI progress report

W W W. I D S E . N E T

estimated that there were 107,700 hospital-onset CDIs nationwide in 2011 (the most recently reported data from 2012 showed a 2% decline in reported cases).4 Once thought to have a low attributable mortality rate, recent data has estimated CDI mortality to be 6.9% at 30 days after diagnosis and 16.7% at 1 year.6 The infection accounts for approximately 14,000 deaths annually, and there was a 400% increase in CDI-related deaths from 2000 to 2007, with most deaths occurring in older individuals.7,8 It is estimated that half of all CDIs occur in people younger than age 65 years. However, 90% of CDIrelated deaths occur in those who are 65 and older.

INFECTIOUS DISEASE SPECIAL EDITION 2014

47

Barrier precautions and environmental cleaning

STOP ACQUISITION OF TOXIGENIC C. DIFFICILE STRAIN (ingestion of spores)

UNNECESSARY ANTIMICROBIAL USE ACQUISITION OF C. DIFFICILE

C. DIFFICILE E INFECTION (community-acquired)

ASYMPTOMATIC C. DIFFICILE COLONIZATION

Vaccines (if risk factors), monoclonal antibodies

HOSPITALIZATION

ANTIMICROBIALS (alter the gut microbiome)

Restore gut flora or colonize with nontoxigenic C. difficile

ANTIBIOTIC TREATMENT (minimize disruption of gut flora) +/• Vaccines (boost immunity) • Monoclonal antibodies (passive immunity) • Nontoxigenic C. difficile

CDI (mild, moderate, severe; first episode, recurrence)

FECAL MICROBIOTA TRANSPLANTATION

Figure 1. Overview of the current hospital epidemiology and management strategies to prevent and treat CDI. CDI, Clostridium difficile infection Note: Prevention and treatment strategies are designated by green arrows.

Adapted from Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis. 2010;51(11):1306-1313.

Furthermore, about 25% show initial symptoms in the hospital versus 75% in nursing homes, doctors’ offices, and clinics; hence, 94% of all CDIs are linked to medical care.8 Not only is this a concern for patient safety, it is also a concern for health care costs nationwide, which indirectly affect patient care. Scott demonstrated an average attributable per-patient cost of $9,124 for CDI, higher than catheter-associated urinary tract infections, which occurred at a higher rate at the time of the study.9 This translates to approximately $1 billion in extra health care costs annually. Yet, others have estimated the cost for CDI treatment to be as high as $4.9 billion in the acute care setting.10 Although once thought to be strictly an HAI, there is an increasing number of community-acquired C. difficile infections (CaCDI). Some reports estimate that 30% to 40% of all CDI cases are CaCDI.11,12 Of note, Khanna et al demonstrated that 22% of patients had no antibiotic exposure in the 90 days before the onset of CaCDI.12

48

Pathogenesis of Hypervirulent Strains As the rates of CDI increased in 2000, the North American Pulsed Field type 1 strain (NAP1), or PCR ribotype 027 emerged; this strain was responsible for the Pittsburgh, Atlanta, and Montreal CDI outbreaks.2 This strain has increased production of the classic A (enterotoxin; 16-fold) and B (cytotoxin; 23-fold) toxins, and also an additional binary toxin currently under study; the latter is associated with a more severe diarrheal illness. It is also inherently resistant to fluoroquinolone (FQ) antibiotics, likely secondary to their increasing and widespread use.

Although FQs are not recommended for the treatment of CDI, their use is an important epidemiologic risk factor for the spread within health care facilities. Metronidazole (various) is the current recommended choice for mild to moderate disease and those with NAP1 infections see high failure rates,13 thought to be secondary to the severity of the disease, low concentration levels in the fecal material, and poor tolerance. The NAP1 or

Table 1. Treatment Options for Clostridium difficile Infection FDA-Approved

Off-Label Options

New Drugs in Development

Biotherapeutics

Metronidazole

Rifaximin (Xifaxan, Salix)

LFF571 (Novartis)

Fecal microbiota transplantation

Vancomycin

Nitazoxanide

Surotomycin (CB-183, 315, Cubist)

VP20621 (ViroPharma)

Fidaxomicin (Dificid, Cubist)

Tigecycline (Tygacil, Pfizer)

SMT 19969 (Summit)

Probiotics

Cadazolid (ACT-179811, Actelion) Oritavancin (LY333328, The Medicines Company) Cholate meta-benzene sulfonic derivative

ribotype 027 strains were associated with an increase in recurrences and a more complicated clinical course, therefore higher morbidity and mortality rates.14 Another strain sharing hypervirulence is C. difficile PCR ribotype 078. Keel et al demonstrated that this was the most commonly isolated strain in swine and calves.15 Also frequently found in meat products, ribotype 078 is a possible risk factor for animal-to-human transmission, as well as a source for CaCDI.15 In the United States, ribotype 078 is reported to be the third most commonly isolated strain in CaCDI.16 It shares toxin A and B production as well as a binary toxin.

In general, CaCDI may present with a more severe infection; patients are less likely to receive antibiotics and more likely to be younger and have a greater proportion of PCR ribotype 078 than those with CDI acquired in a hospital setting.17 More vigilance is required to detect these cases in the community which may not present with the traditional predisposing factors.

also had higher rates of infection in patients age 65 years and older who had been admitted to an inpatient hospital setting, had any underlying disorder, and had a history of exposure to antibiotic therapy.14 However, although Brown et al found use of tetracyclines and penicillins related to lower risk for CDI,18 Keessen et al found that clindamycin (various) exposure was also a major risk factor, in addition to exposure to cephalosporins and FQs, specifically for CDI due to ribotype 078.19 Yet another study showed that in addition to the aforementioned risk factors, hospital LOS was a risk factor for colonization with C. difficile leading to CDI.20 Additional studies have highlighted treatment with PPIs as a novel risk factor for CaCDI in military active duty personnel (this study also revealed higher morbidity and mortality rates among older individuals plus those once considered low-risk groups for CaCDI, including community dwellers, pregnant women, and children).21

Risk Factors

Treatment Approaches

As the leading cause of HAIs, there is a need for understanding risk factors associated with CDI. The CDC has confirmed advanced age (â&#x2030;Ľ65) and antibiotic exposure as risk factors for CDI and CaCDI primary and recurrent infections.8 Multiple meta-analyses have confirmed older age, continued antibiotic exposure, and concomitant use of H2 blockers and proton pump inhibitors (PPIs) as risk factors for recurrent CDI as well as comorbid conditions, previous CDI recurrence, CDI acquired in the hospital setting, and prolonged hospital LOS.18 Although it is generally agreed that exposure to certain antibiotics (particularly FQs) increases the risk for CDIs, there has been some conflicting data as to what classes of drugs yield the greatest risk. Goorhuis et al, for example, found FQ treatment to be an independent risk factor for CDI due to ribotype 078. Ribotype 027

In general, strategies for treatment should be tailored according to the patientâ&#x20AC;&#x2122;s age and underlying comorbidities (Table 1).

FDA-Approved Options METRONIDAZOLE

AND

VANCOMYCIN

Metronidazole is a nitroimidazole with broad activity against anaerobic bacteria, including C. difficile. It is currently recommended as the drug of choice for mild to moderate CDI.22 Vancomycin is a glycopeptide that is not absorbed when given orally. Vancomycin is currently recommended for the first episode of moderate to severe CDI or in cases of metronidazole therapy failure or potentially life-threatening CDI.22 Although early studies demonstrated similar efficacy between the 2 agents,23 studies since 2004 have shown

INFECTIOUS DISEASE SPECIAL EDITION 2014

49

an increased rate of treatment failures associated with metronidazole (16%-38%), whereas vancomycin failures remained the same (1%-6%).24 Zar et al was the first study to compare the drugs directly, in a prospective manner, in the treatment of C. difficile-associated diarrhea (CDAD). Among the patients with mild CDAD, treatment with metronidazole or vancomycin resulted in clinical cure in 90% and 98% of the patients, respectively (P=0.36). The critical results from this study were that among the patients with severe CDAD, clinical cure was 76% for metronidazole and 97% for vancomycin (P=0.02). Recurrence rates were similar (15% and 14%) between the 2 groups.24 Oral metronidazole is completely absorbed in the gastrointestinal tract but fecal penetration is poor, leading to low luminal concentrations (range 0.8-24 mcg/g; the susceptible range is 0.2-2.0 mcg/mL). Additionally, IV metronidazole has been shown inferior (P<0.001) to both oral metronidazole and oral vancomycin.25

FIDAXOMICIN Fidaxomicin (FDX; Dificid, Cubist) is the most recent CDI treatment to receive FDA approval. It is a macrocyclic antibiotic that is highly active against C. difficile (MIC90, 0.25 mcg/mL), including the epidemic strain.

Results from 8 in vitro studies comprising 1,323 C. difficile isolates showed the minimum inhibitory concentration (MIC) range of FDX to be greater than 0.001 to 1 mcg/mL, with a MIC90 of 0.5 mcg/mL. No resistant isolate has been reported, although a single strain was recovered from a cured patient who had an elevated MIC of 16 mcg/mL at the time of recurrence.26 In the pivotal trial of FDX versus vancomycin, clinical cure rates were similar and FDX was noninferior to vancomycin (92.1% and 89.8%, respectively). However, patients treated with FDX had lower recurrence (13.3% vs 24%; P=0.004).27 Additionally, data from the 2 Phase III trials showed that FDX, when administered concomitantly with other antibiotics, has a higher cure rate (46 of 51 [90.2%]) than vancomycin (33 of 45 [73.3%]; P=0.031) and that overall treatment with FDX compared with vancomycin was associated with lower recurrence rates (16.9% vs 29.2%; P=0.048).28 The lower recurrence rates associated with FDX may be due to the drug’s ability to preserve the normal gut microbiome and completely resolve the underlying CDI pathogen, or both. A randomized clinical trial assessed the microflora-sparing properties of FDX by examining fecal samples for quantitative cultures for C. difficile and cytotoxin B fecal filtrate concentrations against normal microbiota.

FDX and vancomycin rapidly killed C. difficile and neutralized toxin; however, FDX preserved the microbiome during and after CDI treatment.27

Other Options Because results with currently available treatments have been suboptimal—with high rates of recurrence— new modalities and treatments have been pursued.

50

W W W. I D S E . N E T

RIFAXIMIN Rifaximin (Xifaxan, Salix) is a semisynthetic derivative of rifamycin approved for the treatment of traveler’s diarrhea; it is also used off label for irritable bowel syndrome and hepatic encephalopathy. It has in vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria. After 3 days of therapy, the fecal level of the drug reaches 8,000 mcg/g.29 C. difficile resistance to rifampin (a surrogate for rifaximin) has been observed in several studies. The prevalence of rifampin resistance among 470 C. difficile isolates from a large teaching hospital was analyzed and was observed in 173 patients (36.8%), including 167 of 205 (81.5%) with epidemic clone (BI/ NAP1) isolates (P<0.001). Of 8 patients who were exposed to rifamycin, 7 had rifampin-resistant C. difficile compared with 166 of 462 unexposed patients (relative risk, 2.4).30 In an open-label trial, 8 of 13 enrolled patients received rifaximin; all patients reported symptom resolution; 7 had no relapse at follow-up (median 162 days).31 Overall, more attention has been given to use of rifaximin as a “chaser” rather than as first-line therapy. In one study, for example, patients were given rifaximin versus placebo immediately after finishing standard anti-CDI antibiotics. CDI recurrence was lower in the rifaximin arm versus placebo (15% vs 31%; P=0.11).32 A randomized placebo-controlled trial testing the hypothesis that rifaximin given in a decreasing dose over 4 weeks after successful CDI treatment will reduce relapse is currently ongoing.

NITAZOXANIDE Nitazoxanide (NTZ) is a synthetic nitrothiazole benzamide approved for the treatment of Cryptosporidium and Giardia species. It has excellent in vitro activity against C. difficile with an MIC90 of 0.125 mcg/ mL. A prospective, randomized, double-blind study compared NTZ (7 and 10 days) with metronidazole (10 days) in hospitalized patients with C. difficile colitis. Response rate at 1 month for metronidazole was 57.6% compared with 65.8% (7 days) and 74.3% (10 days; P=0.34) for NTZ.33 In another study, patients who had failed metronidazole treatment were given NTZ; 74% responded, although 7 later had recurrent disease (54% cure rate).

Three who initially failed and 1 who had recurrent disease were retreated with NTZ and responded, yielding an aggregate cure rate of 66% in this difficult-to-treat patient population.34 No clinical trials are currently ongoing.

TIGECYCLINE Tigecycline (Tygacil, Pfizer) has activity against a broad spectrum of gram-positive and gram-negative aerobes and anaerobes, including C. difficile (MIC90 of 0.06-0.25 mcg/mL).35 Multiple case reports and small case series using IV tigecycline as adjunctive therapy to other treatment options for severe, refractory CDI in

critically ill patients have reported some success. A prospective clinical trial assessing the safety of tigecycline added to standard oral therapy (vancomycin or metronidazole) was completed recently and results are pending.

New Drugs in Development LFF571 LFF571 (Novartis) is a novel semisynthetic thiopeptide antibiotic with potent activity against a variety of gram-positive pathogens, including C. difficile. In a hamster model, LFF571 was more efficacious and had fewer recurrences than vancomycin.36 A study investigating the safety and pharmacokinetics of single- and multiple-ascending oral doses in healthy individuals reported that the drug was generally safe and well tolerated.37 A Phase II study of the safety and efficacy of multiple daily dosing of oral LFF571 in patients with moderate CDIs was completed recently and data is pending.

SUROTOMYCIN Surotomycin (CB-183,315, Cubist) is an orally available lipopeptide antibiotic that is structurally related to daptomycin.38 Surotomycin has shown good potency against C. difficile isolates (including 027/NAP1/BI isolates) as well as those with high MICs to metronidazole, moxifloxacin, and vancomycin. It lacks activity against Enterobacteriaceae and species of the Bacteroides group (MIC90 >8,192 mcg/mL); this suggests that this compound will minimize disruption and lead to rapid recovery of the normal gut flora.39,40 Surotomycin has successfully completed a Phase II trial in patients with CDI. It also showed better sustained cure rates than vancomycin as well as reduction and delay in recurrence (17% for surotomycin vs 36% vancomycin) of CDAD episodes.38 Phase III trials are ongoing.

SMT 19969 SMT 19969 (Summit) is a bis-benzimidazole tetrahydrate compound that has demonstrated potent activity against C. difficile isolates with MIC90 values 2-, 8-, and 16-fold lower than FDX, metronidazole, and vancomycin, respectively. SMT 19969 has shown limited activity against gram-positive and gram-negative anaerobes, including Bacteroides species, Bifidobacterium species, and others (with the exception of Clostridia). This suggests that SMT 19969 would have minimal disruption in the gut flora and preservation of the normal gut microbiome.41,42 SMT 19969 was safe and well tolerated at all dosages in the recent Phase I trial.41 A Phase II trial is ongoing.

CADAZOLID Cadazolid (CDZ; ACT-179811, Actelion) is a new quinolonyl-oxazolidinone with structural elements of the oxazolidinone as well as the quinolone class. It is a strong inhibitor of C. difficile protein synthesis that leads to the suppression of toxin and spore formation.

A recent study showed CDZ was active against all (including linezolid- and moxifloxacin-resistant) C. difficile strains (MIC90 0.125, range 0.03-0.25 mg/L). The CDZ geometric mean MIC was 152-, 16-, 9-, and 7-fold lower than those of moxifloxacin, linezolid, metronidazole, and vancomycin, respectively. CDZ levels persisted at 50- to 100-fold supra MIC for 14 days after dosing. Inhibition of gut microflora was limited with the exception of bifidobacteria; Bacteroides fragilis group and Lactobacillus species counts were not affected.43 In Phase I trials, CDZ was well tolerated and systemic exposure was low. Most of the compound was recovered unchanged in the feces, resulting in high concentrations in the colon.44 A Phase II study evaluated the efficacy, safety, and tolerability of CDZ in patients with CDAD. The results of this study indicate that the cure rates for all twice-daily doses of CDZ (76.5% [250 mg]; 80% [500 mg]; 68.4% [1,000 mg]) were similar to or better than those for vancomycin (68.2%). Recurrence rates were lower for all twice-daily doses of CDZ (18.2% [250 mg]; 25% [500 mg]; 22.2% [1,000 mg]) compared with vancomycin (50%).45 Phase III clinical trials are underway.

ORITAVANCIN Oritavancin (ORI; LY333328, The Medicines Company) is a lipoglycopeptide with activity against C. difficile. In vitro, it was found to be at least 4-fold more potent than vancomycin against C. difficile strains tested.46 When tested for the treatment of PCR ribotype 027 in a human gut model, it was found that both ORI and vancomycin were effective in treating CDI, but only ORI appeared active against spore forms of C. difficile. Overall, ORI therapy may be more effective in treating CDI than vancomycin because it may prevent recrudescence of C. difficile spores.47 In a simulated CDI human gut model, Chilton et al demonstrated that ORI short-course therapy (4-day) might be an effective CDI treatment.48 More recently this same group showed that ORI might adhere to spores, potentially causing early inhibition of germinated cells and preventing subsequent vegetative outgrowth and spore recovery. Again, this may prevent some recurrences of CDI that are due to germination of residual spores after antibiotic therapy.49 Despite all the information thus far available, no clinical trials are ongoing.

CAMSA Cholate meta-benzene sulfonic derivative (CamSA) is a bile salt analog that inhibits C. difficile spore germination in vitro. Howerton et al infected mice with massive inocula of C. difficile spores and treated them with different concentrations of CamSA. A single 50-mg/ kg dose of CamSA prevented CDI without any toxicity.

This is a novel approach and would add to the treatment of CDI without compromising the microbiota in these patients.50 CamSAâ&#x20AC;&#x2122;s in vitro stability, distribution, and cytotoxicity are currently being characterized.

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MONOCLONAL ANTIBODIES

Biotherapeutics

250 Simpson’s Reciprocal Index

MK-3415A (Merck) is a combination of monoclonal antibodies (mAbs) to C. difficile toxin A (MK-3415) and toxin B (MK-6072). A Phase II study showed favorable results when C. difficile human mAbs were administered to patients with C. difficile infection after being treated with metronidazole or vancomycin. This clinical trial showed significant reduction in the rate of recurrence of C. difficile among patients treated with the mAbs (7% vs 25%; P<0.001). The recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06); among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively (P=0.006).51 Phase III trials are ongoing.

200 150 100 50 0 Donors

FECAL MICROBIOTA TRANSPLANTATION There has been a lot of attention surrounding the success of fecal microbiota transplantation (FMT) in the treatment of recurrent CDI. To date, numerous studies have shown superior efficacy of FMT over traditional antibiotics.

The landmark study published by van Nood et al randomized patients with recurrent CDI to FMT via nasoduodenal infusion, vancomycin, and vancomycin with bowel lavage. The study was halted at interim analysis because the FMT arm showed a superior success rate (81%) compared with the vancomycin (31%) and vancomycin with bowel lavage arms (23%). Two of the 3 treatment failures in the FMT arm resolved with a second infusion from a different donor, bringing the overall success rate to 93.75%.52 This is consistent with meta-analyses of the success rate of FMT for CDI worldwide, which is 91%, regardless of the route of administration.53 Additionally, after the donor-feces infusion, patients showed an increased fecal bacterial diversity very much similar to the donors (Figure 2). In 8 patients from whom samples were available, the diversity of fecal microbiota could not be distinguished from that of the donors during the follow-up period.52 Although concerns have been raised regarding the safety of FMT, numerous literature reviews have reported no serious adverse events (AEs) or infectious transmissions directly attributable to FMT.54 There are, however, legitimate concerns regarding the safety of FMT in patients with compromised immune systems.

Immunocompromised patients seem to be at increased risk for developing recurrent CDI due to repeated antibiotic treatment, prolonged hospital LOS, and decreased ability to eradicate the infection. A multicenter retrospective study of FMT in 75 immunocompromised adults found similar efficacy (89%) to other studies and no infectious complications directly attributable to FMT, with follow-up to 11 months. Patients included were solid organ transplants, HIV/AIDS, patients undergoing chemotherapy, and those receiving immunosuppressive

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Patients before Patients after infusion infusion

Figure 2. Microbial diversity in patients before and after infusion of donor feces compared with diversity in healthy donors.

Adapted from reference 52.

treatment for inflammatory bowel disease.55 Cost is also an issue with FMT. An analysis of FMT versus vancomycin for recurrent CDI found that FMT had an incremental cost-effectiveness ratio of $17,016 relative to vancomycin. More specifically, FMT via colonoscopy was felt to be the most cost-effective route of administration compared with duodenal infusion or enema.56 FMT has proven to be safe and efficacious, but it remains a time-consuming and nonstandard process.

Although the major gastrointestinal societies and the Infectious Diseases Society of America released a joint statement on donor screening guidelines in July 2013, the recommendations are not evidence-based.57 Finding and screening a donor can be a time-consuming, expensive, and embarrassing process for the patient.

In the inpatient setting with a critically ill patient, there is not always time to properly identify and screen a donor.

Multiple techniques have been developed to try to work around these inherent difficulties in an attempt to standardize and speed up treatment, including frozen stool protocols and open-access stool banks.

In frozen stool protocols, donor stool is blended, filtered, and then processed with glycerol before freezing at –80°C for later usage. Before use in FMT, the frozen slurry is thawed in an ice bath. A series of 43 patients treated with the frozen protocol showed an 86% treatment success rate, but it should be noted that 30% of the patients had underlying inflammatory bowel disease.58 More recently, Youngster et al conducted an open-label, randomized, controlled pilot study using

Table 2. Clostridium difficile Vaccines and Immunologics Product

Antigen

Formulation

Clinically trials

ACAM-CDIFF Vaccine (Sanofi Pasteur)

Formalin inactivated toxins A and B from VPI 10463

+/- alum-adjuvant IM injections 0, 7, and 28-30

Phase I volunteer safety and immune response Phase II for CDI Phase II for CDI prevention (ongoing)

Intercell IC84 Vaccine

Recombinant fusion protein of toxin A and B binding regions

+/- aluminum salt adjuvant IM injection days 0, 7, and 21

Phase I volunteer safety and immune response

Clostridium difficile vaccine (Pfizer)

Molecularly and chemically inactivated toxins A and B

Vaccine with or without unnamed adjuvant, 3 ascending doses

Phase I volunteer safety and immune response

Monoclonal antibodies: MK-6072 & MK-3415A (Merck)

Monoclonals targeting toxin binding epitopes

Human monoclonal antibody Two Phase III clinical trials IV

frozen inoculum from unrelated donors.59 Overall cure rate was 90% at 8 weeks.

North York General Hospital in Toronto, Canada, has begun offering patients the option to bank their own stool before hospital admission in the event they become infected with hospital-acquired CDI. This approach offers the advantages of not requiring a donor or screening testing. This program is a pilot study and no efficacy data is available yet.60 Open Biome, meanwhile, is a nonprofit “stool bank” developed at Massachusetts Institute of Technology in Cambridge. A selected few “healthy donors” have undergone extensive screening for common infectious diseases beyond the consensus screening guidelines, and serially collected and frozen the stool, making it commercially available for hospitals. Anecdotal reports thus far have been positive, and data collection is currently underway to publish safety and efficacy data.

There is concern from the FDA regarding oversight and regulation of “stool banks,” although Open Biome operates under an institutional review board.

The ultimate goal is to remove the “fecal” from FMT, and this may be accomplished via stool substitute transplant therapy. Queen’s University in Canada has successfully reproduced 33 purified intestinal bacterial cultures under anaerobic conditions into a synthetic mixture, which was then instilled into the colons of 2 patients with recurrent CDI due to a hypervirulent ribotype 078 strain. Both patients had resumption of normal bowel habits within 3 days with durability of cure at 6 months.61 The “holy grail” of FMT is to develop a pill that would reconstitute the colonic microbiome and eradicate C. difficile. Louie presented a pilot series of 31 patients treated with 24 to 34 pills of fecally derived bacteria covered in gelatin to survive gastric acid and deliver the contents to the colon; 30 of 31 patients enrolled were cured with no significant AEs noted.62

VP20621 VP20621 (ViroPharma), spores of nontoxigenic C. difficile (NTCD) strain M3, have been shown to be protective against challenge with toxigenic strains in hamsters.63 Human administration and colonization by VP20621 may prevent primary CDI or recurrent CDI. Phase I clinical safety testing was completed in 2010.

Healthy adults received single or multiple doses of an oral suspension of VP20621 or placebo. All doses were well tolerated, and no serious AEs were reported and no discontinuation due to AEs occurred. Participants did not experience diarrhea or change in bowel habits.

Persistent colonization with VP20621 was detected in stools on days 21 to 28 in 44% of participants. VP20621 was able to colonize the gastrointestinal tracts of those pretreated with vancomycin.64 A Phase II clinical trial in recurrent CDI is underway.

PROBIOTICS A Cochrane meta-analysis of 31 randomized studies and 4,492 participants concluded that taking probiotics with antibiotics reduced the risk for developing CDAD by 64%. The use of probiotics appeared to be safe and effective in patients who were not immunocompromised.65 There are a number of clinical trials currently ongoing to determine the role of probiotics in the prevention of CDI and/or CDI recurrence.

Vaccines The only currently available antibody treatment for CDI is pooled intravenous immunoglobulin (IVIG); IVIG preparations contain neutralizing levels of IgG antibody to toxin A and B. To date, no studies have provided conclusive evidence for any clinical benefit of IVIG. Active immunization rather than passive is appealing, as this would confer durable protection against CDI. Vaccines for CDI have been in development for more than 2 decades. Torres et al showed that a formalin-inactivated

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C. difficile culture filtrate protected hamsters when given by nasal, intraperitoneal, and subcutaneous routes.66 Currently there are 3 vaccines in clinical development. ACAM-CDIFF (Sanofi-Pasteur) is a mixture of formalin-inactivated toxin A and B that is given 3 times IM. The vaccine has been shown to be safe, well tolerated, and immunogenic in healthy adults. Phase II trials have been completed in the therapeutic setting and additional trials in the prophylactic setting are ongoing.

Due to the fact that the vaccine addresses an important unmet medical need, ACAM-CDIFF has been fasttracked by the FDA.67 A second injectable vaccine, IC84, is a subunit recombinant protein vaccine consisting of 2 truncated toxins A and B from C. difficile. IC84 has undergone Phase I safety and immunogenicity testing in volunteer subjects and also has been shown to be highly immunogenic in elderly subjects.68 In addition, a vaccine derived from molecularly and chemically inactivated toxins A and B is currently undergoing Phase I clinical trials.

Conclusion The incidence of CDI has increased dramatically over the past 2 decades and we have seen the emergence of epidemic strains with new resistance patterns, which have resulted in high morbidity and mortality.

Despite the treatment advances in recent years, several challenges are still present: appropriate treatment of severe complicated/fulminant CDI; the management of CDI recurrence; proper management of repeat episodes and the BI/NAP1/027 strain; and, lastly, the role of vaccines, immunologics, and other biotherapeutics. The use of biotherapeutics to restore normal flora seems a novel and successful approach.

There is a great need to continue to explore and develop new agents in the antimicrobial arena that spare the normal flora and perhaps most of all, avoid using antimicrobials altogether, whenever possible.

References 1.

Centers for Disease Control and Prevention. MMWR quickstats: rates of Clostridium difficile infection among hospitalized patients aged >65 years by age group—National Hospital Discharge Survey, United States, 1996-2009. CDC. 2011;60(34):1153-1185.

2. Centers for Disease Control and Prevention. Clostridium difficile FAQs (online). http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_ faqs_HCP.html. Accessed July 1, 2014.

3. Virginia Department of Health. Clostridium difficile (C. difficile) infections. http://www.vdh.virginia.gov/epidemiology/surveillance/ hai/cdiff.htm#Citation2.

4. Arnold K, Avery L, Bennett R, et al. National and state healthcareassociated infections progress report. http://www.cdc.gov/HAI/ pdfs/progress-report/hai-progress-report.pdf.

5. Magill SS, Edwards JR, Bamberg W, et al. Multistate point-prevalence survey of health care-associated infections. N Engl J Med. 2014:370(13):1198-1208.

program—healthcare-associated infections community interface activity. http://www.cdc.gov/hai/eip/pdf/Cdiff-factsheet.pdf.

8. Centers for Disease Control and Prevention. CDC vitalsigns. http:// www.cdc.gov/vitalsigns/pdf/2012-03-vitalsigns.pdf.

9. Scott RD. The direct medical costs of healthcare-associated infections in US hospitals and the benefits of prevention. http://www.cdc.gov/hai/pdfs/hai/scott_costpaper.pdf.

10. Dubberke ER, Olsen MA. Burden of Clostridium difficile on the healthcare system. Clin Infect Dis. 2012;55(suppl 2):S88-S92.

11. Leffler DA, Lamont JT. Editorial: Not so nosocomial anymore: the growing threat of community-acquired Clostridium difficile. Am J Gastroenterol. 2012;107(1):96-98.

12. Khanna S, Pardi DS, Aronson SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol. 2012;107(1):89-95.

13. Kuijper EJ, Wilcox MH. Decreased effectiveness of metronidazole for the treatment of Clostridium difficile infection. Clin Infect Dis. 2008;47(1):63-65.

14. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58(10):1394-1400.

15. Keel K, Brazier JS, Post KW, Weese S, Songer JG. Prevalence of PCR ribotypes among Clostridium difficile isolates from pigs, calves, and other species. J Clin Microbiol. 2007;45(6):1963-1964.

16. Goorhuis A, Debast S, van Leengoed L, et al. Clostridium difficile PCR ribotype 078: an emerging strain in humans and pigs? J Clin Microbiol. 2008;46(3):1157.

17. Rupnik M, Widmer A, Zimmermann O, et al. Clostridium difficile toxinotype V, ribotype 078, in animals and humans. J Clin Microbiol. 2008;46(6):2146.

18. Brown KA, Khanafer N, Daneman N, et al. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57(5):2326-2332.

19. Keessen E, Hensgens M, Spigaglia P. Antimicrobial susceptibility profiles of human and piglet Clostridium difficile PCR-ribotype 078. Antimicrob Resist Infect Control. 2013;2:14.

20. Eyre DW, Walker AS, Wyllie D, et al. Predictors of first recurrence of Clostridium difficile infection: implications for initial management. Clin Infect Dis. 2012;55(suppl 2):S77-S87.

21. Gutiérrez R, Riddle M, Porter K. Epidemiology of Clostridium difficile infection among active duty United States military personnel (1998-2010). BMC Infect Dis. 2013;13:609.

22. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.

23. Teasley DG, Gerding DN, Olson MM, et al. Prospective randomised trial of metronidazole versus vancomycin for Clostridium-difficileassociated diarrhoea and colitis. Lancet. 1983;2(8358):1043-1046.

24. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45(3):302-307.

25. Wenisch C, Parschalk B, Hasenhündl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22(5):813-818.

26. Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother.

2013;57(10):4872-4876.

27. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

6. Dubberke ER. Strategies to prevent Clostridium difficile infections in acute care hospitals. Infect Control Hosp Epidemiol.

2014;35(6):628-645.

28. Mullane KM, Miller MA, Weiss K, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis. 2011;53(5):440-447.

7. Centers for Disease Control and Prevention. Investigating Clostridium difficile infections across the US—emerging infections

29. Adachi JA, DuPont HL. Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis. 2006;42(4):541-547.

54

W W W. I D S E . N E T

30. Curry SR, Marsh JW, Shutt KA, et al. High frequency of rifampin resistance identified in an epidemic Clostridium difficile clone from a large teaching hospital. Clin Infect Dis. 2009;48(4):425-429.

31. Rubin DT, Sohi S, Glathar M, et al. Rifaximin Is effective for the treatment of Clostridium difficile-associated diarrhea: results of an open-label pilot study. Gastroenterol Res Pract. 2011;2011:106978.

32. Garey KW, Ghantoji SS, Shah DN, et al. A randomized, double-blind, placebo-controlled pilot study to assess the ability of rifaximin to prevent recurrent diarrhoea in patients with Clostridium difficile infection. J Antimicrob Chemother.

2011;66(12):2850-2855.

33. Musher DM, Logan N, Bressler AM, et al. Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study. Clin Infect Dis. 2009;48(4):e41-e46.

34. Musher DM, Logan N, Mehendiratta V, et al. Clostridium difficile colitis that fails conventional metronidazole therapy: response to nitazoxanide. J Antimicrob Chemother. 2007;59(4):705-710.

35. Hecht DW, Galang MA, Sambol SP, et al. In vitro activities of 15 antimicrobial agents against 110 toxigenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother. 2007;51(8):2716-2719.

36. Trzasko A, Leeds JA, Praestgaard J, et al. Efficacy of LFF571 in a hamster model of Clostridium difficile infection. Antimicrob Agents Chemother. 2012;56(8):4459-4462.

37. Ting LS, Praestgaard J, Grunenberg N, et al. A first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob Agents Chemother.

2012;56(11):5946-5951.

38. Mascio CT, Chesnel L, Thorne G, et al. Surotomycin demonstrates low in vitro frequency of resistance and rapid bactericidal activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium. Antimicrob Agents Chemother. 2014;58(7):3976-3982.

39. Citron DM, Tyrrell KL, Merriam CV, et al. In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of Clostridium difficile, 445 other intestinal anaerobes, and 56 Enterobacteriaceae species. Antimicrob Agents Chemother.

2012;56(3):1613-1615.

40. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of surotomycin in an in vitro gut model of Clostridium difficile infection.

J Antimicrob Chemother. 2014 May 9. [Epub ahead of print].

41. Vickers R, Robinson N, Best E, et al. SMT19969 for Clostridium difficile infection (CDI): Phase I study investigating safety and pharmacokinetics in healthy male subjects. Presented at the 53rd Interscience Conference Antimicrobial Agents and Chemotherapy.

Denver, CO: September 10-13, 2013. Abstract F-626.

42. Vickers R, Tinsley J, Storer R, et al. SMT-19969–a novel antibiotic for C. difficile infection: C. difficile growth inhibition, spectrum and resistance development. Presented at the 51st Interscience Conference Antimicrobial Agents and Chemotherapy. Chicago, IL: September 17-20, 2011. Abstract B-1194.

43. Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother. 2014;69(3):697-705.

44. Baldoni D, Gutierrez M, Timmer W, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses. J Antimicrob Chemother.

2014;69(3):706-714.

45. Locher HH, Seiler P, Chen X, et al. In vitro and in vivo antibacterial evaluation of cadazolid, a new antibiotic for treatment of Clostridium difficile infections. Antimicrob Agents Chemother.

2014;58(2):892-900.

46. O’Connor R, Baines SD, Freeman J, et al. In vitro susceptibility of genotypically distinct and clonal Clostridium difficile strains to oritavancin. J Antimicrob Chemother. 2008;62(4):762-765.

47. Baines SD, O’Connor R, Saxton K, et al. Comparison of oritavancin versus vancomycin as treatments for clindamycin-induced Clostridium difficile PCR ribotype 027 infection in a human gut model.

J Antimicrob Chemother. 2008;62(5):1078-1085.

48. Chilton CH, Freeman J, Crowther GS, et al. Effectiveness of a short (4 day) course of oritavancin in the treatment of simulated

Clostridium difficile infection using a human gut model.

J Antimicrob Chemother. 2012;67(10):2434-2437.

49. Chilton CH, Freeman J, Baines SD, et al. Evaluation of the effect of oritavancin on Clostridium difficile spore germination, outgrowth and recovery. J Antimicrob Chemother. 2013;68(9):2078-2082.

50. Howerton A, Patra M, Abel-Santos E. A new strategy for the prevention of Clostridium difficile infection. J Infect Dis. 2013;207(10):1498-1504.

51. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362(3):197-205.

52. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.

53. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107(7):1079-1087.

54. Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-508.

55. Kelly CR, Ihunnah C, Fischer M, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jun 3. [Epub ahead of print].

56. Konijeti GG, Sauk J, Shrime MG, Gupta M, et al. Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis. Clin Infect Dis. 2014;58(11):1507-1514.

57. ACG, AGA, ASGE, IDSA, NASPGHAN. Current consensus guidance on donor screening and stool testing for FMT. http://www.gastro. org/research/Joint_Society_FMT_Guidance.pdf.

58. Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013;4(2):125-135.

59. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58(11):1515-1522.

60. North York General Hospital. Spotlight on research: Sumit Raybardhan, infectious diseases pharmacy practitioner. http://www.nygh. on.ca/Default.aspx?cid=2492&lang=1. Accessed July 1, 2014.

61. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146(6):1573-1582.

62. Louie T, Cannon K, O’Grady H, et al. Fecal microbiome transplantation (FMT) via oral fecal microbial capsules for recurrent Clostridium difficile infection (rCDI). Presented at IDWeek; San Francisco, CA: October 2-6, 2013. Abstract 89.

63. Merrigan MM, Sambol SP, Johnson S, et al. New approach to the management of Clostridium difficile infection: colonisation with non-toxigenic C. difficile during daily ampicillin or ceftriaxone administration. Int J Antimicrob Agents. 2009; 33(suppl 1):S46-S50.

64. Villano SA, Seiberling M, Tatarowicz W, et al. Evaluation of an oral suspension of VP20621, spores of nontoxigenic Clostridium difficile strain M3, in healthy subjects. Antimicrob Agents Chemother.

2012;56(10):5224-5229.

65. Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev. 2013;5:CD006095.

66. Torres JF, Lyerly DM, Hill JE, Monath TP. Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters. Infect Immun. 1995;63(12):4619-4627.

67. Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile. Hum Vaccin Immunother. 2014;10(6).

68. Valneva website. http://www.valneva.com/?page=85. Accessed June 28, 2014.

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INDICATION SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen.

• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing Considerations: • Monotherapy of SOVALDI is not recommended.

• Treatment regimen and duration are dependent on both viral genotype and patient population.

• Treatment response varies based on baseline host and viral factors.

SOVALDI REGIMENS WERE STUDIED ACROSS MANY TYPES OF HCV-INFECTED SUBJECTS Treatment-naïve and -experienced subjects1 • Treatment-naïve GT 1, 4, 5 and 6 subjects achieved an overall SVR12 of 90% (N=327), with GT 1 subjects achieving an SVR12 of 89% (n=292) and GT 4 subjects achieving an SVR12 of 96% (n=28), with SOVALDI + peginterferon (Peg-IFN) alfa + ribavirin (RBV) for 12 weeks in NEUTRINO1,a • Treatment-experienced GT 1 patients can be treated with SOVALDI + Peg-IFN + RBV for 12 weeks, with an estimated SVR of 71%1,b • An all-oral regimen of SOVALDI + RBV for 12 weeks (GT 2) and 24 weeks (GT 3) demonstrated efficacy in treatment-naïve and treatment-experienced subjects1 Subjects with traditionally lower rates of response to treatment2 • SOVALDI delivered high SVR rates in GT 1, 4, 5 and 6 subjects with compensated cirrhosis (80%; n=54) and without cirrhosis (92%; n=273)1 • SVR12 was comparable in subjects with HCV GT 1a and 1b, IL28B C/C and non-C/C alleles, high and low baseline viral load and in Black and non-Black subjects1,3,4 HCV/HIV-1 co-infected subjects1 • SOVALDI is indicated for the treatment of HCV in HCV/HIV-1 co-infected patients. Treatment regimens recommended for co-infected patients are the same as those for HCV mono-infected patients1 NEUTRINO—GT 1 and 4 treatment-naïve adult subjects1 An open-label, single-arm trial evaluating 12 weeks of treatment with SOVALDI in combination with peginterferon (Peg-IFN) alfa 2a and ribavirin (RBV) in treatment-naïve subjects (N=327) with genotype 1, 4, 5 or 6 HCV infection, compared to a pre-specified historical control.

In each of the phase 3 studies, sustained virologic response (SVR) was the primary endpoint, which was defined as HCV RNA <25 IU/mL at 12 weeks after the end of treatment.1 Achieving SVR is considered a virologic cure.2 b The response rate in treatment-naïve subjects with difficult-to-treat factors in NEUTRINO (n=52) may approximate the response rate in patients who previously failed pegylated interferon and ribavirin therapy. (Difficult-to-treat factors include GT 1 subjects with IL28B non-C/C alleles, HCV RNA >800,000 IU/mL and Metavir F3/F4 fibrosis.)1 a

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS • SOVALDI combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to SOVALDI combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

WARNINGS AND PRECAUTIONS • Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use 2 forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

Please see Brief Summary of full Prescribing Information on the following pages.

sovaldi.com/hcp

ADDITIONAL SUBJECTS STUDIED WITH SOVALDI REGIMENS IFN-unable subjects1 • SOVALDI + RBV was evaluated in GT 2 and GT 3 subjects who were IFN-intolerant, -unwilling, or –ineligible1 • An IFN-free regimen of SOVALDI + RBV is the recommended regimen for GT 2 and 3 patients and can be considered as a therapeutic option for GT 1 patients who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by an assessment of the potential benefits and risks for the individual patient1 Patients with HCC awaiting liver transplant1 • SOVALDI + RBV is the first approved, all-oral regimen for HCV-infected subjects with HCC meeting the Milan criteria who are awaiting liver transplantation. Recommended treatment duration is up to 48 weeks or until the time of transplantation, whichever comes first, to prevent post-transplant HCV reinfection1 • The safety and efficacy of SOVALDI have not been established in post-liver transplant patients1

IMPORTANT SAFETY INFORMATION (CONTINUED) WARNINGS AND PRECAUTIONS (CONTINUED) • Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with SOVALDI as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

ADVERSE REACTIONS Most common (*20%, all grades) adverse reactions for: • SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia • SOVALDI + ribavirin combination therapy were fatigue and headache

DRUG INTERACTIONS • In addition to rifampin and St. John’s wort, coadministration of SOVALDI is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

Please see Brief Summary of full Prescribing Information on the following pages.

SOVALDI (sofosbuvir) ®

Brief summary of full Prescribing Information. Please see full Prescribing Information.

Rx Only.

INDICATIONS AND USAGE: SOVALDI is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) as a component of a combination antiviral treatment regimen.

• SOVALDI efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection Prescribing considerations: • Monotherapy of SOVALDI is not recommended • Treatment regimen and duration are dependent on both viral genotype and patient population • Treatment response varies based on baseline host and viral factors DOSAGE AND ADMINISTRATION: Adult Dosage: one 400 mg tablet, taken orally, once daily with or without food. SOVALDI should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for treatment of CHC in adults.

Recommended dose and treatment duration for SOVALDI combination therapy for patients with: genotype 1 or 4 CHC is SOVALDI + peginterferon alfa + ribavirin for 12 weeks; genotype 2 CHC is SOVALDI + ribavirin for 12 weeks; and genotype 3 CHC is SOVALDI + ribavirin for 24 weeks. See peginterferon alfa prescribing information for dosing recommendation for patients with genotype 1 or 4 CHC. Dose of ribavirin is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg). Daily dose of ribavirin is administered orally in two divided doses with food. Patients with renal impairment (CrCl ≤50 mL/min) require ribavirin dose reduction; refer to ribavirin prescribing information.

SOVALDI in combination with ribavirin for 24 weeks can be considered as a therapeutic option for CHC patients with genotype 1 infection who are ineligible to receive an interferon-based regimen. Treatment decision should be guided by assessment of potential benefits and risks for individual patient.

Patients with Hepatocellular p Carcinoma Awaitingg Liver Transplantation: p SOVALDI in combination with ribavirin is recommended for up to 48 weeks or until time of liver transplantation to prevent post-transplant HCV reinfection.

ADVERSE REACTIONS: Adverse Reactions from Clinical Trials Experience: SOVALDI should be administered with ribavirin or peginterferon alfa/ribavirin. Refer to the prescribing information of peginterferon alfa and ribavirin for a description of adverse reactions associated with their use. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety assessment of SOVALDI is based on pooled Phase 3 clinical trial data (both controlled and uncontrolled) including 650 subjects who received SOVALDI + ribavirin combination therapy for 12 weeks, 98 subjects who received SOVALDI + ribavirin combination therapy for 16 weeks, 250 subjects who received SOVALDI + ribavirin combination therapy for 24 weeks, 327 subjects who received SOVALDI + peginterferon alfa + ribavirin combination therapy for 12 weeks, 243 subjects who received peginterferon alfa + ribavirin for 24 weeks and 71 subjects who received placebo (PBO) for 12 weeks. The proportion of subjects who permanently discontinued treatment due to adverse events was 4% for subjects receiving placebo, 1% for subjects receiving SOVALDI + ribavirin for 12 weeks, <1% for subjects receiving SOVALDI + ribavirin for 24 weeks, 11% for subjects receiving peginterferon alfa + ribavirin for 24 weeks and 2% for subjects receiving SOVALDI + peginterferon alfa + ribavirin for 12 weeks.

Treatment-emergent adverse events observed in ≥15% of subjects in clinical trials are provided in Table 1. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs. The most common adverse events (≥ 20%) for SOVALDI + ribavirin combination therapy were fatigue and headache. The most common adverse events (≥ 20%) for SOVALDI + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia.

Table 1 Treatment-Emergent Adverse Events (All Grades) Reported in ≥15% of Subjects in Any Treatment Arm Interferon-free Regimens

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN alfa + RBVb 24 weeks

SOVALDI + Peg-IFN alfa + RBV Va 12 weeks

N=71

N=650

N=250

N=243

N=327

Fatigue

24%

38%

30%

55%

59%

Headache

20%

24%

30%

44%

36%

Nausea

18%

22%

13%

29%

34%

Insomnia

4%

15%

16%

29%

25%

Pruritus

8%

11%

27%

17%

17%

Ribavirin dose modification guideline for coadministration with SOVALDI: Reduce the ribavirin dose to 600 mg/daya in patients with no cardiac disease if hemoglobin is <10 g/ dL and discontinue ribavirinb if it is <8.5 g/dL. Reduce the ribavirin dose to 600 mg/daya in patients with history of stable cardiac disease who have ≥2 g/dL decrease in hemoglobin during any 4 week treatment period and discontinue ribavirinb if it is <12 g/dL despite 4 weeks at reduced dose.a Daily dose of ribavirin is administered orally in two divided doses with food.b Once ribavirin has been withheld due to either laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase dose to 800 mg daily. It is not recommended that ribavirin be increased to original assigned dose (1000 mg to 1200 mg daily). Discontinuation of Dosing: If other agents used in combination with SOVALDI are permanently discontinued, SOVALDI should also be discontinued.

Anemia

0%

10%

6%

12%

21%

Asthenia

3%

6%

21%

3%

5%

Rash

8%

8%

9%

18%

18%

Decreased Appetite

10%

6%

6%

18%

18%

Severe Renal Impairment and End Stage Renal Disease: No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.

Pyrexia

0%

4%

4%

14%

18%

Diarrhea

6%

9%

12%

17%

12%

Neutropenia

0%

<1%

<1%

12%

17%

CONTRAINDICATIONS: When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, contraindications applicable to those agents are applicable to combination therapies. Refer to prescribing information of peginterferon alfa and ribavirin for a list of their contraindications. SOVALDI combination treatment with ribavirin or peginterferon alfa/ ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin.

Myalgia

0%

6%

9%

16%

14%

Irritability

1%

10%

10%

16%

13%

Dose Modification: Dose reduction of SOVALDI is not recommended.

Genotype yp 1 and 4: If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced or discontinued. Refer to peginterferon alfa and ribavirin prescribing information for additional information about how to reduce and/or discontinue peginterferon alfa and/or ribavirin dose.

Genotype yp 2 and 3: If a patient has a serious adverse reaction potentially related to ribavirin, ribavirin dose should be modified or discontinued, if appropriate, until adverse reaction abates or decreases in severity.

WARNINGS AND PRECAUTIONS: Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin may cause birth defects and/or death of the exposed fetus and animal studies have shown that interferons have abortifacient effects. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy.

When SOVALDI is used in combination with ribavirin or peginterferon alfa/ribavirin, women of childbearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI, therefore, two non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin. Refer also to the prescribing information for ribavirin.

Use with Potent P-gp Inducers: Drugs that are potent P-gp inducers in the intestine (e.g., rifampin, St. John’s wort) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI. Rifampin and St. John’s wort should not be used with SOVALDI.

Chills

1%

2%

2%

18%

17%

Influenza Like Illness

3%

3%

6%

18%

16%

a

b

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg).

Subjects received 800 mg ribavirin per day regardless of weight.

With the exception of anemia and neutropenia, the majority of events presented in Table 1 occurred at severity of grade 1 in SOVALDI-containing regimens.

Less Common Adverse Reactions Reported in Clinical Trials (<1%): The following ADRs occurred in <1% of subjects receiving SOVALDI in a combination regimen in any one trial.

These events have been included because of their seriousness or assessment of potential causal relationship. Hematologic Effects:: pancytopenia (particularly in subjects receiving concomitant pegylated interferon).

Psychiatric Disorders:: severe depression (particularly in subjects with pre-existing history of psychiatric illness), including suicidal ideation and suicide.

Laboratory Abnormalities: Changes in selected hematological parameters are described in Table 2. A side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Brief Summary (cont.)

Table 2 Percentage of Subjects Reporting Selected Hematological Parameters

Interferon-free Regimens

Hematological Parameters

Interferon-containing Regimens

PBO 12 weeks

SOVALDI + RBV Va 12 weeks

SOVALDI + RBV Va 24 weeks

Peg-IFN + RBVb 24 weeks

SOVALDI + Peg-IFN + RBV Va 12 weeks

N=71

N=647

N=250

N=242

N=327

Hemoglobin (g/dL) <10

0

8%

6%

14%

23%

<8.5

0

1%

<1%

2%

2%

1%

<1%

0

12%

15%

0

<1%

0

2%

5%

3%

<1%

1%

7%

<1%

0

0

0

0

0

9

Neutrophils (x10 /L) ≥0.5 - <0.75 <0.5 Platelets (x109/L) ≥25 - <50 <25 a

Subjects received weight-based ribavirin (1000 mg per day if weighing <75 kg or 1200 mg per day if weighing ≥75 kg). b Subjects received 800 mg ribavirin per day regardless of weight.

Bilirubin Elevations: Total bilirubin elevation of more than 2.5xULN was observed in none of the subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks group and in 1%, 3% and 3% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + ribavirin 12 weeks and SOVALDI + ribavirin 24 weeks groups, respectively. Bilirubin levels peaked during levels by post-treatment Week 4. These bilirubin elevations were not associated with transaminase elevations.

Creatine Kinase Elevations: Creatine kinase was assessed in the FISSION and NEUTRINO trials. Isolated, asymptomatic creatine kinase elevation of greater than or equal to 10xULN was observed in <1%, 1% and 2% of subjects in the peginterferon alfa + ribavirin 24 weeks, SOVALDI + peginterferon alfa + ribavirin 12 weeks and SOVALDI + ribavirin 12 weeks groups, respectively.

Lipase p Elevations: Isolated, asymptomatic lipase elevation of greater than 3xULN was observed in <1%, 2%, 2%, and 2% of subjects in the SOVALDI + peginterferon alfa + ribavirin 12 weeks, SOVALDI + ribavirin 12 weeks, SOVALDI + ribavirin 24 weeks and peginterferon alfa + ribavirin 24 weeks groups, respectively.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy g y Category g y X: Use with Ribavirin and/or Peginterferon g Alfa/Ribavirin: Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients while taking this combination. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two forms of effective contraception during treatment with ribavirin and for 6 months after treatment has concluded. There are no data on the effectiveness of systemic hormonal contraceptives in women taking SOVALDI. Therefore, two effective non-hormonal methods of contraception should be used during treatment with SOVALDI and concomitant ribavirin.

In case of exposure during pregnancy, a Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling Ribavirin Pregnancy Registry at 1-800-593-2214. For patients who are HCV/HIV-1 co-infected and taking concomitant antiretrovirals, an Antiretroviral Pregnancy Registry is also available at 1-800-258-4263.

Animal Data: animal species exposed to ribavirin; and therefore ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Interferons have abortifacient effects in animals and should be assumed to have abortifacient potential in humans.

Pregnancy g y Category g y B: SOVALDI: There are no adequate and well-controlled studies with SOVALDI in pregnant women.

Animal Data:: No effects on fetal development have been observed in rats and rabbits at the highest doses tested. In the rat and rabbit, AUC exposure to the predominant circulating metabolite GS-331007 increased over the course of gestation from approximately 5 to 10-fold and 12 to 28-fold the exposure in humans at the recommended clinical dose, respectively.

Nursing Mothers: It is not known whether SOVALDI and its metabolites are present in human breast milk. The predominant circulating metabolite GS-331007 was the primary component observed in the milk of lactating rats, without effect on nursing pups. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin containing regimens, taking into account the importance of the therapy to the mother. See also the prescribing information for ribavirin.

Pediatric Use: Safety and effectiveness of SOVALDI in children less than 18 years of age have not been established.

Geriatric Use: Clinical studies of SOVALDI included 90 subjects aged 65 and over. The response rates observed for subjects over 65 years of age were similar to that of younger subjects across treatment groups. No dose adjustment of SOVALDI is warranted in geriatric patients.

Renal Impairment: No dose adjustment of SOVALDI is required for patients with mild or moderate renal impairment. The safety of SOVALDI has not been assessed in patients with severe renal impairment (eGFR <30 mL/min/1.73m2) or end stage renal disease (ESRD) requiring hemodialysis. Refer also to ribavirin prescribing information for patients with CrCl<50 mL/min.

Hepatic Impairment: No dose adjustment of SOVALDI is required for patients with mild,

DRUG INTERACTIONS: Potential for Drug Interactions: After oral administration of SOVALDI, sofosbuvir is rapidly converted to the predominant circulating metabolite GS-331007 that accounts for greater than 90% of drug related material systemic exposure, while the parent sofosbuvir accounts for approximately 4% of drug related material. In clinical pharmacology studies, both sofosbuvir and GS-331007 were monitored for purposes of pharmacokinetic analyses. Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP) while GS-331007 is not. Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John’s wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors. Sofosbuvir and GS-331007 are not inhibitors of P-gp and BCRP and thus are not expected to increase exposures of drugs that are substrates of these transporters. The intracellular metabolic activation pathway of

of SOVALDI have not been established in patients with decompensated cirrhosis. See peginterferon alfa prescribing information for contraindication in hepatic decompensation.

phosphorylation pathways that are unlikely to be affected by concomitant drugs.

pre-transplant to prevent post-transplant HCV reinfection. See Dosage and Administration for

Recommended Based on Drug Interaction Studies or Predicted Interaction:: Drug interaction information for SOVALDI with potential concomitant drugs is summarized as follows and the list is not inclusive. The drug interactions described are based on potential drug interactions that may occur with SOVALDI. Anticonvulsants: Coadministration of SOVALDI with carbamazepine, phenytoin, phenobarbital, oxcarbazepine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. Antimycobacterials: Coadministration of SOVALDI with rifabutin or rifapentine is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Such coadministration is not recommended. SOVALDI should not be used with rifampin, a potent intestinal P-gp. Herbal Supplements: SOVALDI should not be used with St. John’s wort (Hypericum perforatum), m a potent intestinal P-gp inducer. HIV Protease Inhibitors: Coadministration of SOVALDI with tipranavir/ritonavir is expected to decrease the concentration of sofosbuvir, leading to reduced therapeutic effect of SOVALDI. Coadministration is not recommended.

In addition to the drugs listed above, the interaction between SOVALDI and the following drugs was evaluated in clinical trials and no dose adjustment is needed for either drug: cyclosporine, darunavir/ritonavir, efavirenz, emtricitabine, methadone, raltegravir, rilpivirine, tacrolimus, or tenofovir disoproxil fumarate.

Patients with HCV/HIV-1 Co-infection: in 223 HCV/HIV-1 co-infected subjects. See Dosage and Administration for dosing co-infected subjects was similar to that observed in HCV mono-infected subjects. Elevated total bilirubin (grade 3 or 4) was observed in 30/32 (94%) subjects receiving atazanavir as part of the antiretroviral regimen. None of the subjects had concomitant transaminase increases.

Among subjects not taking atazanavir, grade 3 or 4 elevated total bilirubin was observed in 2 (1.5%) subjects, similar to the rate observed with HCV mono-infected subjects receiving SOVALDI + ribavirin in Phase 3 trials.

Patients with Hepatocellular Carcinoma (HCC) Awaiting Liver Transplantation: SOVALDI was studied in HCV-infected subjects b with HCC prior to undergoing liver transplantation in an

of SOVALDI and ribavirin in HCV-infected subjects prior to liver transplantation was comparable to that observed in subjects treated with SOVALDI and ribavirin in Phase 3 clinical trials.

Post-Liver Transplant Patients: in post-liver transplant patients.

CHC Patients with Genotype 5 or 6 HCV Infection: Available data on subjects with genotype References: 1. SOVALDI® (sofosbuvir). US Prescribing Information. Gilead Sciences, Inc. Foster City, CA. December 2013. 2. US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry. Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf. Published October 2013. Accessed May 6, 2014. 3. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. d 2013;368(20):1878-1887. 4. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. d 2013;368(20)[suppl].

SOVALDI, the SOVALDI Logo, GILEAD and the GILEAD Logo are trademarks of Gilead Sciences, Inc., or its related companies. ©2014 Gilead Sciences, Inc. All rights reserved. SVDP0021 07/14

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

The Changing HCV Landscape: Update on Diagnosis and Treatment

SONAL KUMAR, MD, MPH Assistant Professor of Medicine Weill Medical College of Cornell University New York, New York

IRA M. JACOBSON, MD Chief of the Division of Gastroenterology and Hepatology Vincent Astor Distinguished Professor of Medicine Weill Medical College of Cornell University New York, New York Dr. Kumar reports that he serves as an advisor to Gilead Sciences.

Dr. Jacobson reports that he has received grant and/or research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech Sciences, Gilead Sciences, Janssen, Merck, Novartis, and Vertex, and that he serves on the speakersâ&#x20AC;&#x2122; bureaus of BristolMyers Squibb, Genentech, Gilead Sciences, Janssen, and Vertex.

He also reports that he serves as a consultant or advisor to AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, Idenix, Janssen, Merck, and Vertex

W

ith more than 170 million people worldwide infected with the hepatitis C virus (HCV), the burden of the disease is indisputably significant.1-4 In 2010, there were an estimated 2.7 to 3.9 million

cases of chronic HCV in the United States alone, with up to 75% of individuals unaware of their diagnosis.5 Due to the high prevalence and underdiagnosis of disease, the Centers for Disease Control and Prevention in 2012 and the U.S. Preventive Services Task Force in 2013 modified their guidelines to recommend a one-time screening of adults born between 1945 and 1965.5

W W W. I D S E . N E T

INFECTIOUS DISEASE SPECIAL EDITION 2014

61

The goal of identifying undiagnosed adults is to eradicate the virus and avoid the development of cirrhosis and its life-threatening complications. Pegylated interferon (PegIFN) and ribavirin (RBV) have served as the foundations of HCV therapy for years but are accompanied by suboptimal rates of sustained virologic response (SVR) and significant adverse events (AEs).

The lack of ideal treatment options was the impetus for further study of HCV and the development of novel therapies.

Hitting the Target (Molecule) Stages of the HCV life cycle have become targets of newer direct-acting antivirals (DAAs) that target several molecules required for HCV infection, such as the NS3/4a protease, NS5B RNA-dependent RNA polymerase, or the NS5A protein.6,7 The NS3/4A serine protease is a noncovalent heterodimer with a catalytic subunit (the NS3 N terminal) and an activating cofactor (NS4A protein), which plays an important role in viral replication through cleavage of 4 sites of the HCV polyprotein.8 The HCV NS5A phosphoprotein is also essential for viral RNA synthesis and virion assembly and secretion. The exact mechanism of action of NS5A inhibitors is unknown, but one route is through inhibition of hyperphosphorylation, which has an essential role in replication.9 The NS5B polymerase is another enzyme involved in viral replication. Inhibitors of this enzyme are classified as either nucleoside/nucleotide or non-nucleoside

Table 1. HCV Infection (Antibody Positive Only or RNA Positive) 2011 Site

N

Site Population

Rate per 100,000

Colorado

2,901

5,116,796

56.7

New Mexico

3,188

2,082,224

153.1

San Francisco

1,944

812,826

239.2

Minnesota

1,925

5,344,861

36.0

New York state

7,047

11,220,287

62.8

Oregon

5,464

3,871,859

141.1

Connecticut

2,898

3,580,709

80.9

New York City

8,749

8,244,910

106.1

Total

33,919

40,274,472

84.7

Source: Sou ce Centers Ce te s for o Disease sease Co Control o to a and d Prevention eve t o

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inhibitors. Non-nucleoside/nucleotide inhibitors bind to sites away from the active site of the polymerase and cause conformational changes in the protein. Nucleoside/nucleotide analogs mimic the natural substrate of the NS5B protein, leading to RNA chain termination.10 In 2011, the protease inhibitors (PIs) telaprevir (Incivek, Vertex) and boceprevir (Victrelis, Merck) became the first approved DAAs to be combined with PegIFN/RBV for the treatment of genotype 1 (G1) HCV. The regimens significantly increased SVR rates, serving as a major advance in the treatment of HCV and opening the door for DAA therapy. However, the incremental adverse reactions were significant, and the regimen was not well tolerated by many patients.11-13 More recently, the FDA approved sofosbuvir (SOF; Sovaldi, Gilead), an NS5B nucleotide polymerase inhibitor, and simeprevir (Olysio, Janssen), a second-wave PI, used with PegIFN/RBV. Simeprevir was studied extensively with PegIFN/RBV before its approval. The QUEST-1 and QUEST-2 studies randomized G1, treatment-naive patients to receive simeprevir combined with PegIFN/RBV for 24 or 48 weeks based on response-guided therapy. In QUEST-1, the overall SVR at 12 weeks (SVR12) after therapy with simeprevir was 80% versus 50% in controls; 85% were able to shorten therapy to 24 weeks and 91% of these patients achieved SVR.14 In QUEST-2, therapy was shortened in 91% of patients, of whom 86% achieved SVR12 after treatment.15 The PROMISE trial had a similar study design except study patients had relapsed after prior IFN-based therapy.16 Results also were similar, reporting SVR rates of 80%. All of these studies showed lower SVR rates in patients with advanced fibrosis and in patients with IL28B non-CC genotype.

Adverse events associated with simeprevir included hyperbilirubinemia related to interactions with transporters but no actual hepatotoxicity; a slight increase in photosensitivity; and in one study, mild pruritus. No additional hemoglobin decline was noted. Based on these studies, the FDA approved simeprevir for use in G1 patients, as a regimen consisting of 12 weeks of triple therapy and 12 to 36 weeks of PegIFN/RBV for treatment-naive or relapsed patients and prior nonresponders, respectively, with or without cirrhosis.

Response-guided therapy is not a component of the approved regimen but parameters of viral response must be met at 4 weeks (HCV RNA <25 IU/mL) for treatment to continue.

Sofosbuvir also has been studied comprehensively, leading to its approval nearly contemporaneously with simeprevir. The Phase II trials initially demonstrated promising results in G1 patients treated with PegIFN/ RBV and SOF with SVR rates of 87% to 92%,17,18 which led to the Phase III NEUTRINO study of 12 weeks with the same regimen in patients with HCV genotypes 1, 4, 5, or 6.19 Most of the study population consisted of G1 patients, who overall achieved 89% SVR. The study also included a significant number of patients with compensated cirrhosis, with an SVR of 80% in patients

with cirrhosis compared with 92% without cirrhosis. No incremental AEs were ascribed to SOF compared with those historically attributed to PegIFN/RBV alone, and only 2% of patients discontinued treatment due to AEs. The shortened treatment duration, higher success rate, and superior tolerability compared with the previous standard of care with PIs took IFN-based therapy to a new plateau, the utility of which has only been limited by the even greater paradigm shift to IFN-free regimens.

New Backbones of Therapy The high barrier to resistance imposed on viral replication by nucleotide polymerase inhibitors, related to the highly conserved structure of the polymeraseâ&#x20AC;&#x2122;s active binding site, makes potent nucleotide analogs like SOF highly attractive as a backbone of regimens consisting of DAA agents. One of the first trials demonstrating success with SOF and RBV was the ELECTRON trial, revealing SVR in 84% of 25 treatment-naive patients. Subsequent studies with the same drugs given for 12 to 24 weeks yielded SVR12 rates of 52% to 68% after therapy.20,21 Although promising, this regimen was unsuccessful in the few study patients with cirrhosis, as well in null responders in a separate arm, with only a 10% SVR (1 out of 10),22 signaling an inability of the regimen to overcome undefined factors linking IFN nonresponsiveness to impaired clearance of virus with SOF as the sole active agent in 12 weeks.

The PHOTON study was the only Phase III study of this regimen in treatment-naive, mainly non-cirrhotic G1 patients, which resulted in 76% SVR in patients with HIV-HCV coinfection.23 This accounts for the stipulation in the US labeling that SOF and RBV for 24 weeks could be an option for IFN-ineligible patients with G1 infection.

Other regimens of DAAs combined with a nucleoside polymerase inhibitor have shown additional advances in oral treatment relative to the regimen of SOF and RBV alone. For example, the potent pangenotypic activity of the NS5A inhibitor daclatasvir complements the broad genotypic activity and high barrier to resistance of SOF.24 This was demonstrated in a Phase II trial in which non-cirrhotic treatment-naive patients and patients who had previously failed treatment with a PI received daclatasvir and SOF, with or without RBV.25 Treatmentnaive patients were treated for 12 or 24 weeks, and the previously treated patients were treated for 24 weeks.

Collectively, there was a 98% SVR12 after therapy, with all 3 treatment failures being due to loss to followup. Two had documented SVR24 after treatment. No patient had virologic breakthrough during treatment, and rates of virologic response were similar across subgroups, including genotype subtypes, IL28B genotype, race, RBV treatment, and PI resistance.

Ledipasvir (LDV) is another NS5A inhibitor that has yielded similar results in combination with SOF and RBV. In additional arms of the ELECTRON trial, treatment-naive patients and previous null responders,

which included those who failed prior treatment with PIs, had an SVR of 100%.26 The Phase II LONESTAR study substantiated these results with SVR rates of 95% to 100% in both treatment-naive patients and those who had previously failed treatment with a PI, including cirrhotics and prior nonresponders.27 Notably, similarly high rates of SVR were seen in treatment arms with only 8 weeks of therapy, raising the possibility of even shorter regimens. More recent Phase III studies involving 1,952 patients treated with LDV/SOF have focused on optimizing duration, need for RBV, and treatment in subpopulations. ION-1 randomized patients to receive the fixed-dose LVD/SOF for 12 or 24 weeks. All treatment arms had 97% to 99% SVR12 after treatment.28 Even in patients with cirrhosis, SVR was 94% to 100%.

ION-2 used the same regimen in patients who had previously failed IFN-based treatment with or without a PI. Again SVR rates were high; 96% and 94% with and without RBV, respectively, in the 12-week treatment arm and 99% in both 24-week arms.29 Baseline PI resistance did not affect treatment outcome, but prior treatment failures with cirrhosis had a higher rate of relapse, resulting in SVR of 82% to 86%.

Still with such high overall SVR12 and the results of the LONESTAR trail, the ION-3 trial evaluated 8 weeks of treatment in treatment-naive, non-cirrhotic patients.

There was no difference based on the use of RBV (SVR 93%-94%) in the 8-week arm and SVR was 95% in the 12-week arm.30 Although the frequency of relapse in patients treated for 8 weeks was somewhat higher, these findings introduced the possibility of highly successful treatment with an 8-week regimen. Patients with characteristics historically associated with poorer response, including cirrhosis, G1a subtype, non-CC IL28B allele, and race, all still had SVR rates higher than 90%. Mild AEs were common, including fatigue and insomnia, and were incrementally observed in treatment arms containing RBV. Anemia generally was only seen in RBV recipients. Given that RBV did not improve efficacy, collectively, the data from these trials support the absence of RBV from this regimen. Of note, deepsequencing analyses revealed that most of the patients who failed to have SVR in these studies had NS5A-resistant variants, some at baseline. Conversely, however, the SVR rates in patients with baseline NS5A-resistant variants were very high.

Interferon-Free Regimens The FDA has not approved simeprevir and SOF for use in combination, but this regimen has been studied as part of Phase II trials. Its success has motivated clinicians to treat selected G1 patients with an IFN-free regimen. Moreover, the new online guidance from the American Association for the Study of Liver Diseases/ Infectious Diseases Society of America has recommended the regimen in IFN-ineligible treatment-naive patients, as well as treatment-experienced patients, whether IFN eligible or not, as long as they have not previously received a PI. The COSMOS trial evaluated

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the 2 drugs, with or without RBV for 12 or 24 weeks in G1 patients. There were 2 cohorts, the first of which enrolled previous null responders with METAVIR F0-F2 fibrosis.31 In this group, SVR12 post-therapy ranged between 79% and 93% by intent-to-treat analysis with 4 patients with nonvirologic failure clustered in the group receiving 24 weeks of therapy, including RBV. The second cohort included treatment-naive and prior null responders (without prior PI exposure) with METAVIR F3-F4 fibrosis.32 Overall SVR12 ranged from 93% to 100%; 3 patients who relapsed were in the 12-week arm. Of the 6 patients who relapsed in the entire study, 4 had G1a with the Q80K polymorphism, leaving open the possibility of a small effect of this polymorphism but with insufficient numbers to definitively address the issue until the completion of ongoing Phase III trials.

Although regimens without a nucleotide polymerase inhibitor lack a single class that has the high barrier to resistance of a nucleotide polymerase inhibitor, potent combinations of other classes cumulatively impose the high barrier to resistance needed to attain SVR rates similar to those seen with the nucleotides. One emerging regimen is the combination of the PIs ABT-450/r boosted with low-dose ritonavir and ombitasvir (ABT257, NS5A inhibitor), coformulated in a single-daily pill, with twice-daily ABT-333 (non-nucleoside NS5B inhibitor) and RBV. This regimen was studied initially in the AVIATOR trial for 12 weeks, yielding SVR rates in non-cirrhotic, treatment-naive patients and prior null responders of 96% and 93%, respectively.33 With these SVR rates comparing favorably with those obtained with 24 weeks of therapy or with regimens containing 3 of the 4 components previously outlined, the “3D plus RBV” regimen was chosen as the foundation of a robust Phase III program. SAPPHIRE-1 studied the 3D plus RBV regimen for 12 weeks in non-cirrhotic, treatment-naive patients.34 Of the 473 patients, 96% achieved SVR12 after therapy, 95% in G1a, and 98% in G1b, with no difference in outcome due to baseline characteristics including HCV RNA, gender, race, age, fibrosis, and IL28B genotype.

In SAPPHIRE-2, the same regimen was evaluated in treatment-experienced patients, with the same overall SVR12 rate of 96% (96% and 97% in genotypes 1a and 1b, respectively).35 TURQUOISE-II included both treatment-naive and treatment-experienced patients with compensated cirrhosis.36 SVR12 after therapy was 92% in patients treated for 12 weeks and 96% in those treated for 24 weeks. With subgroup analysis, it became evident that G1a null responders were the treatment population that drove the difference in SVR based on treatment duration. SVR12 post-therapy was achieved in 93% of the group that was treated for 24 weeks but only 80% in those who were treated for 12 weeks, suggesting a continued effect of prior IFN response, as well as a difference between G1a and G1b patients. SAPPHIRE-1 and SAPPHIRE-2 were both placebo-controlled trials allowing for a true assessment of safety and tolerability of the regimen. Patients receiving active treatment experienced more AEs, although

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the overall rate of such events was high even among patients who received placebo (88%-91% in treatment arms compared with 73%-83% with placebo). Adverse events were generally mild but included fatigue, headache, nausea, and pruritus. Elevations in alanine transaminase, through which most patients were able to continue treatment, occurred in about 1% of patients.

No patient discontinued treatment as a result of laboratory abnormalities. Some patients required a lower dose of RBV, however, the outcome of treatment was not affected. Baseline resistance data were unavailable, however, most patients who failed treatment had 2 or 3 class drug-resistant variants after treatment.

Additional studies include PEARL-4 in G1a treatment-naive patients without cirrhosis who received the 3D regimen for 12 weeks, with or without RBV. In this group, RBV did appear to have an added benefit, with SVR12 after treatment of 97% compared with 90% without RBV.37 RBV appears to have no effect with G1b infection as demonstrated in the PEARL-2 and PEARL-3 studies in treatment-experienced and treatment-naive patients, respectively (all without cirrhosis).37,38 In PEARL-2, 97% of patients achieved SVR with RBV and 100% achieved SVR without RBV. In PEARL-3, SVR was 99% in both groups.

Other non-nucleotide–containing regimens being studied include daclatasivir combined with the PI asunaprevir and BMS-791325, a non-nucleoside inhibitor.

This treatment was evaluated in 166 treatment-naive G1 patients for 12 weeks.39 There was 3% viral breakthrough, all in G1a, and 3.6% viral relapse, also restricted to G1a, resulting in an overall SVR of 92%. This regimen also was well-tolerated, with treatment discontinuation as a result of AEs of only 1.2%. The HALLMARK study looked at asunaprevir and daclatasvir in G1b patients.

Patients received 24 weeks of treatment and the study included cirrhotics. SVR ranged from 80% to 90% based on prior treatment history, with the highest SVR rates in treatment-naive patients.49

Efficacy Across Genotypes?

The effectiveness of HCV treatment varies with nature of the infection. Genotype 2 and 3 HCV had been more successfully treated with IFN and RBV, with SVR rates of 70% to 85%, compared with the lower rates in G1 infection.41 Some of the newer DAAs have demonstrated efficacy across genotypes, allowing for IFN-free regimens to be formulated in this population as well. With 100% SVR in G2 and G3 patients treated for 12 weeks with SOF and RBV as part of the original arms of the ELECTRON trial,22 Phase III studies sought to corroborate the results. The FISSION trial compared 12 weeks of SOF and RBV with the standard of care.19 The trial demonstrated that G2 and G3 patients could no longer be grouped together appropriately, as 97% of G2 patients achieved SVR compared with only 56% of G3 patients (78% and 63%, respectively, in the standard-of-care arm).

Cirrhosis was a strong predictor of poor outcome in G3 patients, with SVRs of 61% without and 34% with

Table 2. Interpretation of Results of Tests for HCV Infection and Further Actions Test Outcome

Interpretation

Further Action

HCV antibody nonreactive

No HCV antibody detected

Sample can be reported as nonreactive for HCV antibody. No further action required.

If recent HCV exposure in person tested is suspected, test for HCV RNAa

HCV antibody reactive

Presumptive HCV infection

A repeatedly reactive result is consistent with current HCV infection, or past HCV infection that has resolved, or biologic false positivity for HCV antibody. Test for HCV RNA to identify current infection.

HCV antibody reactive, HCV RNA detected

Current HCV infection

Provide person tested with appropriate counseling and link person tested to medical care and treatmentb

HCV antibody reactive, HCV RNA not detected

No current HCV infection

No further action required in most cases.

If distinction between true positivity and biologic false positivity for HCV antibody is desired, and if sample is repeatedly reactive in the initial test, test with another HCV antibody assay.

In certain situationsc follow up with HCV RNA testing and appropriate counseling.

HCV, hepatitis C virus a

If HCV RNA testing is not feasible and person tested is not immunocompromised, do follow-up testing for HCV antibody to demonstrate seroconversion. If the person tested is immunocompromised, consider testing for HCV RNA.

b

It is recommended before initiating antiviral therapy to retest for HCV RNA in a subsequent blood sample to confirm HCV RNA positivity.

c

If the person tested is suspected of having HCV exposure within the past 6 months, or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Source: Centers for Disease Control and Preventio Prevention on

cirrhosis. Similar outcomes were seen with the POSITRON trial, which studied the SOF and RBV regimen for 12 weeks in G2 and G3 patients who were IFN intolerant to the drugs, or ineligible or unwilling to take them.42 SVR in G2 was 93% in G2 and 61% in G3. Cirrhosis again predicted poorer outcome, with SVR of 94% in G2 and 21% in G3.

The FUSION trial evaluated the effect of extending treatment to 16 weeks instead of 12 for patients who had failed prior therapy.42 SVR increased from 86% to 94% with longer treatment in G2 patients, and from 30% to 62% in G3 patients. The additional benefit was seen in cirrhotic patients as well, with SVR increased to 78% from 60% with the additional 4 weeks of treatment in G2 and 61% from 19% in G3. However, the number of G2 patients with cirrhosis was too small to draw meaningful comparisons.

In the VALENCE trial, G2 treatment-naive patients treated for 12 weeks had 97% to 100% SVR, as did 78%

of G2 treatment-experienced patients with cirrhosis, and 94% of G2 treatment-experienced patients without cirrhosis.43 Treatment was extended to 24 weeks in G3 treatment-naive patients, with 95% of patients without cirrhosis achieving SVR compared with 92% in the cirrhotic population. Those who had failed prior therapy had SVR rates of 87% in the non-cirrhotic population and 62% in patients with cirrhosis. These results led to the approval of SOF and RBV for 24 weeks in G3 and 12 weeks in G2 patients.

With still suboptimal results, especially in G3 patients, LONESTAR-2 evaluated the addition of PegIFN to the regimen for treatment-experienced G2 and G3 patients with or without compensated cirrhosis.44 G2 patients had an overall SVR of 96%. G3 patients, including both cirrhotics and non-cirrhotics, had an SVR of 83%, supporting the concept of an ongoing role of PegIFN at least in treatment-experienced cirrhotic patients.

Recent data also show that among patients with G3

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who had failed a 12- to 16-week regimen of SOF and RBV, a 12-week retreatment regimen of PegIFN/RBV and SOF can act as a salvage regimen, even in patients with cirrhosis, with higher SVR rates than patients retreated with 24 weeks of SOF and RBV alone.45 Collectively, analysis from the NEUTRINO, FUSION, FISSION, POSITRON, and VALENCE trials has shown that no single AE led to discontinuation in more than 1 patient receiving SOF and RBV, and anemia was the only AE leading to discontinuation of treatment in more than 1 patient receiving IFN, RBV, and SOF.46 However, the use of IFN likely will be unnecessary in the future, as regimens combining SOF with other DAAs, including pan-genotypic NS5A inhibitors, currently in development appear to have high rates of SVR.47 Although limited data exist on treatment in other genotypes, the NEUTRINO trial did include G4, G5, and G6 patients, all of whom had more than 95% SVR, most notably 27 of 28 (96%) G4 patients.19 A small study of G4 Egyptian patients in the United States provided data for the use of SOF and RBV only. In treatment-naive patients, the highest rate of SVR24 was 100%, compared with SVR12 of 79%. In treatment-experienced patients, SVR was 59% with 12 weeks and 87% with 24 weeks of treatment.48 The combination of ABT-450/ritonavir and ombitasvir also was studied in G4 patients in the PEARL-1 trial.49 Treatment-naive patients received the combination, with or without RBV, for 12 weeks. The RBV-free arm had SVR of 91%, and 100% in the RBV-containing arm.

In this study, the 2-drug regimen with RBV added was given to 49 treatment-experienced patients, all of whom achieved SVR.

The Most Difficult Patient The treatment of HCV historically has been the most difficult in patients who need it most urgently, especially those with decompensated cirrhosis. In addition to success rates being dismal, treatment regimens, particularly those containing IFN and RBV, have been intolerable for most of these patients. A safe, well-tolerated oral DAA regimen would be ground-breaking for this population. The initial report of SOF and RBV in patients on the transplant list showed that longer duration of undetectable HCV RNA before transplant (>30 days) predicted prevention, although this study included only patients listed because of hepatocellular carcinoma who were otherwise well compensated.50 An arm of the ELECTRON-2 trial administered LVD/SOF for 12 weeks in patients with decompensated cirrhosis. Of the 20 patients, 13 achieved SVR (65%). Seven of the 13 relapsed.51 Ongoing studies are evaluating additional regimens in the decompensated population. Sofosbuvir also has been studied as a regimen for recurrent HCV in patients who have undergone liver transplantation. As part of a compassionate-use program, 104 patients with severe recurrent hepatitis or fibrosing cholestatic hepatitis were treated with SOF and RBV for 24 to 48 weeks.52

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Physicians could add PegIFN at their discretion, which was done in about 25% of patients. Of the patients for whom there are data, 62% achieved SVR. Most patients also had improved liver function tests and clinical outcomes with treatment, including resolution of ascites, even in the absence of SVR. The 3D/RBV regimen also has been studied in the post-transplant population.53 Thirty-four patients received the regimen for 24 weeks. Data so far have shown a 96% (25 of 26) SVR, although patients with more aggressive liver disease were excluded. Importantly, there were no major interactions or apparent effects of immunosuppression, no organ rejections, and no serious AEs associated with the regimen.

Conclusion With the global burden of HCV, the need for effective, well-tolerated treatment regimens is essential. Elucidation of the HCV life cycle has allowed for newer drugs to be developed, overcoming some of the major disadvantages of prior standard of care with IFN-based therapy.

The DAAs are anticipated to completely replace IFN as the foundation of HCV treatment.

Among the major advantages of these oral regimens beyond their increased efficacy has been their relatively clean safety profile. Although AEs are common, they generally are mild, including headache, fatigue, and insomnia, and trivial relative to that of telaprevir and boceprevir.46 The low rate of discontinuation in all the trials further attests to the tolerance of the regimens, even in those containing RBV. In addition, the once-daily dosing and limited drug窶電rug interactions has minimized the AEs of treatment for most patients.

As newer medications and regimens get approved, the next dilemma will be to determine the ideal combination of medications and treatment duration for each patient. Ideally, predictors of response to treatment would aid in the decision making, but none has consistently been identified. Although one study has suggested that early viral kinetics may identify those with a higher risk for relapse,21 such predictive value has not been gleaned from the Phase III databases.

Importantly, these new regimens also have been able to overcome baseline factors previously associated with poorer outcomes including G1a subtype, race, non-CC IL28B allele, and prior treatment history. Although treatment-failure rates now appear to be minimal and routes to treatment failure have all but eliminated nonresponse and viral breakthrough, some patients will relapse. SOF has been associated in vitro T signature mutation, but it is replicatively with a S282T unfit54 and rarely found in samples from SOF-treated relapsers, providing a foundation for retreatment with a SOF-containing regimen in these failures. Now that the fundamental paradigm shift toward IFN-free regimens is imminent, further research will be needed to identify effective salvage therapies for patients who have failed both nucleotide-containing and nucleotide-free combination regimens.

References 1.

Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(suppl 1):74-81.

2. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol.

2013;10(9):553-562.

3. Global surveillance and control of hepatitis C. J Viral Hepatol.

1999;6(1):35-47.

4. Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(suppl 2):3-8.

5. CDC. New CDC Vital Signs: Hepatitis C testing. http://www.cdc. gov/media/dpk/2013/dpk-vs-hepatitisC_testing.html. Accessed July 29, 2014.

6. Poenisch M, Bartenschlager R. New insights into structure and replication of the hepatitis C virus and clinical implications.

Semin Liver Dis. 2010;30(4):333-347.

7. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med. 2013;19(7):837-849.

8. Tan S-L. Hepatitis C Viruses: Genomes and Molecular Biology.

Indianapolis, IN: Lilly Research Laboratories; 2006.

9. Pawlotsky JM. NS5A inhibitors in the treatment of hepatitis C. J Hepatol. 2013;59(2):375-382.

10. Koch U, Narjes F. Recent progress in the development of inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. Curr Top Med Chem. 2007;7(13):1302-1329.

11. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.

N Engl J Med. 2009;360(18):1827-1838.

12. Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716.

13. Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatmentexperienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) NCT01514890. J Hepatol. 2013;59(3):434-441.

14. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet.

2014;384:1-311.

15. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014;384:1-13.

16. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.

Gastroenterology. 2014;146(7):1669-1679.

17. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet.

2013;381(9883):2100-2107.

20. Lalezari JP, Nelson DR, Hyland RH, et al. Once daily sofosbuvir plus ribavirin for 12 and 24 weeks in treatment-naive patients with HCV infection: the QUANTUM study. J Hepatol. 2013;58(1):S346.

21. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811.

22. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368(1):34-44.

23. Sulkowski MS, Rodriguez-Torres M, Lalezari J, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1).

Hepatology. 2013;58:313–314A. 24. Guedj J, Dahari H, Rong L, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proc Natl Acad Sci USA. 2013;110(10):3991-3996.

25. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221.

26. Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J Hepatol. 2013;58:S6–S7.

27. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatmentnaive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383(9916):515-523.

28. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014:140411220115009.

29. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1483-1493.

30. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.

31. Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Hepatology. 2013;58:LB3.

32. Lawitz EJ, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior nullresponder/treatment-naive patients (COSMOS study): primary endpoint (SVR12) results in patients with Metavir F3-4 (cohort 2).

Paper presented at: International Liver Congress 2014; April 2014; London.

33. Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370(3):222-232.

34. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1594-1603.

35. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(20):1604-1614.

36. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370(20):1973-1982.

18. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408.

37. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370(20):1983-1992.

19. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.

38. Andreone P, Colombo MG, Enejosa J V, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced

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patients with HCV genotype 1b infection. Gastroenterology.

2014;147(2):359-365.

of sofosbuvir + GS-5816 for 12 weeks in treatment naive patients with genotype 1-6 HCV infection. J Hepatol. 2014;60:S46.

39. Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology. 2014;146(2):420-429.

48. Ruane PJ, Ain D, Meshrekey R, et al. Sofosbuvir plus ribavirin, an interferon-free regimen, in the treatment of treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection. J Hepatol. 2014;60:S503-S504.

40. Manns M, Pol S, Jacobson IM, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 HALLMARK-DUAL study results. J Hepatol.

2014;60:O166.

49. Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PearlI study: Interferon-free regimens of Abt-450/R + Abt-267 with or without ribavirin in patients with HCV genotype 4 Infection.

J Hepatol. 2014;60:S24.

41. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology.

2009;49(4):1335-1374.

50. Curry MP, Forns X, Chung R, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58:314-315A.

42. Jacobson IM, Gordon SC, Kowdley K V, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.

51. Gane EJ, Hyland RH, An D, et al. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience. J Hepatol. 2014;60:S3-S4.

43. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993-2001.

44. Lawitz E, Poordad F, Brainard D, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Paper presented at: AASLD: The Liver Meeting; November 2013; Washington DC. Abstract LB-4.

45. Esteban R, Nyberg L, Lalezari J, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. J Hepatol. 2014;60:S4-S5.

46. Gordon SC, Towner W, Aggarwal A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Gastroenterology. 2014;146:S921.

47. Everson GT, Tran TT, Towner WJ, et al. Safety and efficacy of treatment with the interferon-free, ribavirin-free combination

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52. Forns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation.

J Hepatol. 2014;60:S26.

53. Kwo P, Mantry P, Coakley E, et al. Results of the phase 2 study M12999: Interferon-free regimen of Abt-450/R/Abt-267 + Abt-333 + ribavirin in liver transplant recipients with recurrent HCV genotype 1 infection. Paper presented at: International Liver Congress 2014; April 2014; London.

54. Mariño Z, van Bömmel F, Forns X, et al. New concepts of sofosbuvir-based treatment regimens in patients with hepatitis C. Gut. 2014;63(2):207-215.

55. Osinusi A, Marti M, Townsend K, et al. Retreatment of relapsers to sofosbuvir/ribavirin with sofosbuvir/ledipasvir: complete and rapid virologic suppression by week 4. J Hepatol. 2014;60:S5–S6.

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The Accentuated Challenges Of Aging With HIV KELLY A. GEBO, MD, MPH Co-Principal Investigator, HIV Research Network Associate Professor of Medicine Division of Infectious Diseases The Johns Hopkins University School of Medicine Baltimore, Maryland

JENNIFER A. SCHRACK, PHD Core Faculty, Center on Aging and Health Assistant Professor Department of Epidemiology The Johns Hopkins Bloomberg School of Public Health Baltimore, Maryland Dr. Schrack reports that she has received grant and/or research support from the National Institute on Aging as well as a developmental scholar award from the Center for AIDS Research. Dr. Gebo reports that she serves as a consultant with Bristol-Myers Squibb and Tibotec and has received grant and/or research support from Tibotec, as well as from the Agency for Healthcare Research and Quality and the Health Resources and Services Administration.

T

here is an ongoing debate within the field about whether persons living with HIV (PLWH) are aging at an “accelerated” or “premature” rate.1 Before the introduction of combination antiretroviral therapy (cART)

in 1996, HIV was a terminal illness.2 Currently, the life expectancy for PLWH

receiving cART and adequate clinical care may be approaching that of the uninfected population.3 Compared with uninfected individuals, however, older PLWH have demonstrated an increased prevalence of cardiovascular disease,4-6 lipodystrophy,7,8 osteoporosis,9 liver disease,10,11 renal dysfunction,12,13 and neurologic disease14,15; it remains unclear whether this means they are aging at a rate that is faster than their uninfected counterparts.

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This review discusses some of the important studies from the past year that investigated differences in aging patterns and trends among the HIV-infected and uninfected populations, and the implications for care of the aging HIV-infected patient.

Frailty and Functional Decline In a November 2013 report, the Centers for Disease Control and Prevention estimated that almost 19% of the 1.1 million PLWH in the United States were aged 55 or older, and that people aged 50 and older accounted for 24% (7,771) of new AIDS diagnoses.16 As the US population continues to age, these statistics are likely to increase as the long-term management of HIV infection becomes a way of life for all persons living and aging with the virus. Accordingly, management of common age-related comorbidities, as well as common geriatric conditions such as mobility limitations, disability, and cognitive decline, are coming to the forefront of HIV care.

In the general population, aging is characterized by a loss of physiologic reserve, impaired response to stressors, and unstable homeostasis, which contribute to disease susceptibility and impaired recovery from ailments and injury.17,18 Similar pathologies have been observed in PLWH, particularly with regard to the development of frailty.19,20 The frailty phenotype is considered to be a reflection of the dysregulation of multiple geriatric syndromes and is commonly comprised of a combination of 3 or more of the factors listed in Table 1.21 In MACS (Multicenter AIDS Cohort Study), a prospective observational cohort study of the natural and treated histories of HIV infection among men who have sex with men (MSM), Althoff and colleagues evaluated the expression and predictors of frailty, comparing trends between infected and uninfected participants.19 The prevalence of frailty among men aged 50 to 64 years was significantly higher in HIV-infected men (12%) than in HIV-seronegative men (9%). Conversion to frail status was associated with the presence of comorbidities and conditions known to be associated with frailty in the general aging population, including depression, diabetes, kidney disease, and smoking. Among the HIV-infected participants, the odds of conversion to frail status were significantly associated with a history of AIDS (adjusted odds ratio, 2.26), but not with a history of HIV. These results suggest a propensity for multisystem dysregulation in HIV-infected MSM, which appears to be greater among those who are not virologically well controlled or who developed AIDS before the availability of cART. Clinically, this may reflect a loss of reserve and an inhibited ability to resist and recover from stressors in this patient population.21,22 Piggott and colleagues recently evaluated correlates of frailty and their effects on mortality in a subset of participants of the ALIVE (AIDS Linked to the IntraVenous Experience) study.23 ALIVE is a prospective

Table 1. Factors Contributing to Development of Frailty in Older Adults Frailty Factor

Assessment Method(s)

Unexplained Self-report weight loss Objective weight monitoring

Symptom/ Association Wasting

Weakness

Self-report Muscle loss Grip strength Sarcopenia (hand dynamometer)

Slowness

Self-report Walking speed (usual speed >4-6 m, expressed in m/sec)

Decreased activity Low endurance

Low activity

Self-report

Low energy High sedentary behavior

Exhaustion

Self-report

Low energy Tiredness Great effort to perform daily activities

study of HIV-infected and HIV-seronegative individuals (median age 48 years) who are current or former injection drug users. Of the 1,230 participants, 29% were HIV-infected and demonstrated a 66% greater likelihood of frailty compared with uninfected participants.

The risk for frailty was highest in those with advanced HIV disease (CD4 <350 cells/mm3 and detectable HIV-1 RNA), as well as those suffering from depression and 2 or more comorbidities. Although generalizability of this study may be limited to those with a history of injection drug use, these findings further highlight the importance of treatment and control of HIV infection and comorbid conditions with age.

The syndrome of frailty is often a precursor to the development of age-related mobility limitations and disability.24 Although not synonymous with disability, frailty has been shown to increase the risk for disability in the general aging population (Figure).24,25 Given the increased propensity for the development of frailty in PLWH, monitoring functional ability and disability status in clinical populations is of utmost importance. Richert and colleagues compared lower extremity function in HIV-infected patients with published data from healthy persons of similar age in the

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ANRS (Agence Nationale de Recherche sur le Sida) CO3 Aquitane Cohort, an open prospective cohort of hospital patients with confirmed HIV infection in southwestern France.26 Baseline 5 times sit-to-stand test time and 6-minute walk distance were poorer at baseline and over time in those infected with HIV, and also associated with a greater subsequent risk for falls.

Furthermore, age, diabetes, cerebral complications, and history of injection drug use contributed to functional performance, but not viral load, CD4 cell count, type of antiretroviral therapy (cART), or cumulative exposure to ART therapy. Although the sample size of those with follow-up was fairly small (n=178) and lacked an appropriate control group, this study demonstrates important differences in ambulatory abilities among HIV-infected patients compared with the general aging population, and highlights increased susceptibility to age-related functional decline.

Cognitive Impairment Cognitive impairment is a common geriatric condition resulting from changes in brain volume and structure.27 HIV-associated neurocognitive disorder (HAND) typically presents as a disturbance in psychomotor and processing speeds, executive function, or memory. 28 Mild forms of HAND are common in virologically well-controlled patients, but more severe forms of dementia, myelopathy, and neuropathy may exist among patients who are not virologically controlled.29 Cognitive impairment in these individuals may reflect irreversible damage to the central nervous system before the initiation of cART, progressive low-level damage in the presence of cART, or damage

Pathophysiology and management of HIV infection

Development of functional impairments

from the accumulation of age-related comorbidities.28 In a recent study investigating the combined effects of age and HIV infection on changes in cognitive function, Seider and colleagues screened 54 HIV-infected and 30 negative controls aged 40 to 74 years at baseline and 1-year follow-up.30 HIV status significantly predicted overall baseline performance and longitudinal change. Furthermore, an interaction between HIV and age significantly predicted change in verbal memory performance, indicating that the HIV-infected individuals declined more quickly than their uninfected counterparts and that age and HIV may interact to produce larger declines in verbal memory over time.30 Pfefferbaum et al examined the brains of 51 HIVinfected participants and 65 uninfected controls, using magnetic resonance imaging and a neuropsychological test battery collected 2 or more times over a follow-up period ranging from 6 months to 8 years.31 Those infected with HIV showed an accelerated loss of cortical tissue over time. Additionally, a longer duration of illness was associated with an accelerated rate of progression. HIV-infected participants with higher CD4 counts showed slower declines, suggesting virologic control may abate these declines and delay the onset of cognitive impairment. Although there were significant losses to follow-up, this study shows the importance of proper treatment for maintenance of cognitive health in PLWH.

Chronic Inflammation It has been postulated that much of the morbidity and development of age-related chronic diseases

Mobility limitations in daily living

Disability

Frailty

Figure. Hypothesized pathway to functional disability in HIV-infected older adults.

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and conditions in those infected with HIV is driven by a state of chronic inflammation. In the general aging population, serum measures of inflammatory activity are reliable markers of adverse health outcomes as they correlate with highly prevalent chronic diseases that often contribute to the development of disability.32 Despite the apparent control of overt HIV replication through cART, inflammation remains incompletely suppressed in PLWH,33-35 and may be an important contributor to signs of accelerated aging and the subclinical stage of disease development.36,37 Although the specific mechanisms linking inflammation to disability and mortality have not been discerned, serum inflammatory markers may be useful clinical tools to assess risk and gauge effectiveness of therapies for the management of chronic conditions.

Investigators on the VACS (Veterans Aging Cohort Study), a large sample of HIV-infected veterans, recently published a report about inflammatory markers and coagulation as primary mechanisms leading to HIV-associated, non-AIDS conditions.38 Among those receiving cART, D-dimer, interleukin (IL)-6, and a monocyte activation marker (sCD14) were measured to assess correlation with mortality and the VACS index, a prognostic scoring system that predicts patientsâ&#x20AC;&#x2122; risk for hospitalization and mortality. Both D-dimer and sCD14 elevation correlated with an increased risk for mortality. When these markers were incorporated into the VACS index, they improved the precision of its predictive model for mortality; however, the addition of IL-6 did not improve the predictive accuracy. Additionally, anemia, renal dysfunction, and markers of liver injury also predicted risk for increased inflammation (as measured by D-dimer, IL-6, and sCD14), even after controlling for age, CD4 cell count, and HIV viral load.

Accelerated Aging?

A study by Althoff et al in the VACS found that HIV-infected adults are at greater risk for myocardial infarction or end-stage renal disease than seronegative veterans, but that events occurred at similar ages compared with HIV-uninfected adults39 and did not support the concept of premature aging in PLWH. This paper also evaluated the risk for malignancies and found no difference in the risk for nonâ&#x20AC;&#x201C;AIDS-related cancers among those with and without HIV; however, the age of onset of cancer was several months younger in those with HIV. This suggests that the concept of premature aging may exist in PLWH, but is dependent on the outcome under investigation and the control

Table 2. Common Geriatric Clinical Assessment Tools Assessment Tool

Purpose

Description

Mini-Mental State Examination

Screen for cognitive impairment

30-point questionnaire test

Short Physical Performance Battery

Evaluate lower extremity function and screen for physical disability

Combination of gait speed, chair stands, and standing balance tests

population used for assessment. It is possible that there is both accelerated and accentuated aging, but this will need to be assessed with future studies looking at other comorbid conditions in HIV populations that are more generalizable.

The increased risk for comorbid diseases among those with HIV indicates a loss of reserve and resiliency similar to that of older uninfected patients. Over time, this loss may contribute to a greater susceptibility to the common geriatric conditions outlined in this report. This underscores the importance of careful screening mechanisms in the care of HIV-infected patients, including common geriatric clinical tools such as the Mini-Mental State Examination40 and the Short Physical Performance Battery41 (Table 2), that may be untraditional in infectious disease clinical settings.

Modifying risk factors such as smoking, obesity, and lack of exercise are also important in the treatment of HIV-infected older patients. Additionally, older patients should have appropriate screening for malignancies and treatment of other common comorbid conditions like hyperlipidemia and hypertension to reduce the risk for serious comorbid illnesses, such as stroke, myocardial infarction, and end-stage renal disease. Older HIV-infected persons also should receive appropriate age-related prophylaxis, including pneumococcal and influenza vaccines as well as HIV-related screening for sexually transmitted infections and counseling on safe sexual practices.

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Conclusion Progress in the treatment of HIV infection has led to a large increase in the aging HIV-infected population. Aging with HIV has been associated with the early onset of multiple chronic conditions typically seen in older adults. Age is a nonmodifiable risk factor; therefore, a focus on minimizing changeable risk factors and comorbidities is critical for PLWH. Efforts to understand the seemingly accelerated pathogenesis of aging seen in PLWH must continue. The National Institutes of Health Office of AIDS Research

Working Group Report recently emphasized highneed research areas regarding the interface of HIV and aging.42 There also remains a critical need to develop evidence-based guidelines for the treatment of older patients with HIV, regarding both disease management and prevention of geriatric conditions. For now, consensus recommendations from expert panels must guide these decisions as new research in the area of aging with HIV continues to emerge.43,44

References 1.

Pathai S, Bajillan H, Landay AL, et al. Is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sci. 2014;69(7):833-842.

2. Bunting E, Rajkumar C, Fisher M. The human immunodeficiency virus and ageing. Age Ageing. 2014;43(3):308-310.

3. Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according to timing of diagnosis. AIDS. 2012;26(3):335-343.

16. Center for Disease Control and Prevention. HIV among older Americans. CDC Reports; 2013.

17. Ruggiero C, Metter EJ, Melenovsky V, et al. High basal metabolic rate is a risk factor for mortality: the Baltimore longitudinal study of aging. J Gerontol A Biol Med Sci. 2008;63(7):698-706.

18. Ferrucci L, Bandinelli S, Benvenuti E, et al. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J Am Geriatr Soc. 2000;48:1618-1625.

4. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation. 2008;118(2):198-210.

19. Althoff KN, Jacobson LP, Cranson R, et al. Age, comorbidities, and AIDS predict a frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci. 2014;69(2):189-198.

5. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009;23(14):1841-1849.

20. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty.

J Gerontol A Biol Sci Med Sci. 2007;62(11):1279-1286.

6. Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-2512.

21. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56(3):M146-M157.

7. Gazzaruso C, Sacchi P, Garzaniti A, et al. Prevalence of metabolic syndrome among HIV patients. Diabetes Care.

2002;25(7):1253-1254.

8. Martinez E, Mocroft A, Garcia-Viejo MA, et al. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet. 2001;357(9256):592-598.

22. Fried LP, Waltson J. Frailty and failure to thrive. In: Hazzard WR, Blass JP, et al, eds. Principles of Geriatric Medicine and Gerontology. 4th ed. New York, NY: McGraw-Hill; 1999:1387-1402.

23. Piggott DA, Muzaale AD, Mehta SH, et al. Frailty, HIV infection, and mortality in an aging cohort of injection drug users. PLoS One. 2013;8(1):e54910.

9. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS. 2006;20(17):2165-2174.

24. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59(3):M255-M263.

10. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of nonAIDS diseases following initial treatment for HIV infection. AIDS. 2008;22(7):841-848.

25. Ensrud KE, Ewing SK, Taylor BC, et al. Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures. J Gerontol A Biol Sci Med Sci. 2007;62(7):744-751.

11. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166(15):1632-1641.

26. Richert L, Brault M, Mercie P, et al. Decline in locomotor functions over time in HIV-infected patients. AIDS. 2014;28(10):1441-1449.

12. Choi AI, Shlipak MG, Hunt PW, et al. HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy. AIDS. 2009;23(16):2143-2149.

13. Longenecker CT, Scherzer R, Bacchetti P, et al.. HIV viremia and changes in kidney function. AIDS. 2009;23(9):1089-1096.

27. Glisky EL. Changes in cognitive function in human aging. In: Riddle DR, ed. Brain Aging: Models, Methods, and Mechanisms. Boca Raton, FL: CRC Press; 2007.

28. Spudich S. HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep. 2013;10(3):235-243.

14. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009;338:a3172.

29. Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology. 2010;75(23):2087-2096.

15. Robertson KR, Smurzynski M, Parsons TD, et al. The prevalence and incidence of neurocognitive impairment in the HAART era.

AIDS. 2007;21(14):1915-1921.

30. Seider TR, Luo X, Gongvatana A, et al. Verbal memory declines more rapidly with age in HIV infected versus uninfected adults.

J Clin Exp Neuropsychol. 2014;36(4):356-367.

74

W W W. I D S E . N E T

31. Pfefferbaum A, Rogosa DA, Rosenbloom MJ, et al. Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiol Aging. 2014;35(7):1755-1768.

39. Althoff KN, Wyatt C, Gilbert C, et al. HIV-infected adults are at greater risk for myocardial infarction, end-stage renal disease, and non-AIDS-defining cancers, but events occur at similar ages compared to HIV-uninfected adults. Under review.

32. Cesari M, Penninx BWJH, Pahor M, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study.

J Gerontol A Biol Sci Med Sci. 2004;59(3):M242-M248.

40.Folstein MF, Folstein SE, McHugh PR. â&#x20AC;&#x153;Mini-mental stateâ&#x20AC;?: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.

33. Kirk JB, Goetz MB. Human immunodeficiency virus in an aging population, a complication of success. J Am Geriatr Soc. 2009;57(11):2129-2138.

41. Guralnik JM, Simonsick EM, Ferrucci L, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol A Biol Sci Med Sci. 1994;49(2):M85-M94.

34. High KP, Effros RB, Fletcher CV, et al. Workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis. 2008;47(4):542-553.

35. Deeks SG. Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. Top HIV Med. 2009;17(4):118-123.

36. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-1695.

37. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87-91.

38. Justice AC, Freiberg MS, Tracy R, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis. 2012;54(7):984-994.

42. High KP, Brennan-Ing M, Clifford DB, et al. HIV and aging: State of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Defic Syndr. 2012;60(suppl 1):S1-S18.

43. Gallant JE, Adimora AA, Carmichael JK, et al. Essential components of effective HIV care: a policy paper of the HIV Medicine Association of the Infectious Diseases Society of America and the Ryan White Medical Providers Coalition. Clin Infect Dis. 2011;53(11):1043-1050.

44. Working Group for HIV and Aging Consensus Project. Summary report from the Human Immunodeficiency Virus and Aging Conensus Project: treatment strategies for clinicians managing older individuals with the human immunodeficiency virus. J Am Geriatr Soc. 2012;60(5):974-979.

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Antimicrobial Stewardship: Current State of Affairs A commentary by:

LILIAN M. ABBO, MD Medical Director, Antimicrobial Stewardship Program Department of Medicine Division of Infectious Diseases Associate Professor of Clinical Medicine University of Miami Miller School of Medicine Miami, Florida

MARISSA TYSIAK, PHARMD Infectious Disease Clinical Pharmacy Specialist Antimicrobial Stewardship Program Department of Pharmacy University of Miami Hospital Miami, Florida

A

ntimicrobials are one of the most important

advancements in modern

medicineâ&#x20AC;&#x201D;yet their use, whether appropriate or inappropriate, is linked with selection for antimicrobialresistant organisms. Infections caused by these organisms are associated with higher rates of treatment failures, prolonged hospitalizations, increased costs, and mortality.

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The global spread of antimicrobial resistance and the slowed development of novel antimicrobials have generated the need for global solutions, such as antimicrobial stewardship programs (ASPs), in an effort to delay (if not altogether avert) the onset of a postantibiotic era.1

Ongoing Progress In 2007, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America published guidelines for developing institutional ASPs.2 These guidelines defined the primary goal of stewardship and have served as the basis for the establishment of formal ASPs at many institutions, which are structured primarily with front-end (eg, preauthorization) and/or back-end (eg, prospective audit and feedback) interventions.

Indeed, successful ASPs have bloomed through multidisciplinary collaborations, dedicated personnel, and leadership support (typically, a dedicated physician leader and a clinical pharmacist, each with

background in infectious diseases). Despite the triumphs, challenges continue to limit the success of ASPs. These include prescriber buy-in, patient complexity, diagnostic uncertainty, increased rates of antimicrobial-resistant organisms, and limited options to effectively streamline antimicrobial therapy. Unfortunately, adequate financing for these programs remains an issue at many institutions, despite their importance.

Recently, concerns regarding patient safety due to unnecessary and inappropriate antimicrobial use, coupled with the financial burden of health care–associated infections, have been gaining public attention. An emphasis on “accountable” health care—with mandatory public reporting of specific infection control process measures—may increase the pressure on acute care hospitals to establish effective ASPs. There is also a surge in legislative, regulatory, and funding proposals aimed at barriers to, and revitalization of, antimicrobial development and approval pathways.

In the United States, California is the only state to date that requires hospitals to monitor judicious use of antibiotics. The Veterans Health Administration (VHA) chartered a National Antimicrobial Stewardship Task Force and published the VHA Directive 1031, which requires ASPs to be established in all of their facilities

by July 31, 2014.3 Hopefully, others will soon follow California and the VHA in leading efforts to overcome barriers and establish more effective ASPs.

Future Perspectives There has been great progress in understanding the effect of ASPs on antimicrobial usage and the development of resistance, but further research evaluating the strategies and outcomes of ASPs in adult and pediatric patients is needed. There is an urgent call for standardized metrics and quality indicators to measure appropriate antimicrobial use across health care settings, and user-friendly methods to measure and benchmark antimicrobial usage.

The future of ASPs is beyond the walls of our acute care hospitals and long-term care facilities. Time and effort needs to be invested to improve the stewardship education of future prescribers in medical, pharmacy, and nursing schools. There is evidence that gaps exist in the education of medical students in the United States and Europe.4,5 The majority of future prescribers are eager for more antimicrobial stewardship education but only one-third feel well prepared to adequately use antimicrobials.4 Outreach programs need to assist health care providers in evidence-based antimicrobial use and increase awareness among patients, families, and state legislators of the benefits of judicious antimicrobial use.

Antimicrobial prescribing should be thoughtful, prudent, and rational. To avoid a postantibiotic era, every prescriber must be an antimicrobial steward.

References 1.

World Health Organization. World Health Organization Antimicrobial Resistance Global Report on Surveillance 2014. http:// www.who.int/drugresistance/documents/surveillancereport/en.

Accessed June 30, 2014.

2. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177.

3. Department of Veterans Affairs. VHA Directive 1031: Transmittal Sheet. January 22, 2014. http://www.va.gov/vhapublications/index. cfm. Accessed June 30, 2014.

4. Abbo LM, Cosgrove SE, Pottinger PS, et al. Medical students' perceptions and knowledge about antimicrobial stewardship: how are we educating our future prescribers? Clin Infect Dis. 2013;57(5):631-638.

5. Dyar OJ, Pulcini C, Howard P, Nathwani D, ESGAP. European medical students: a first multicentre study of knowledge, attitudes and perceptions of antibiotic prescribing and antibiotic resistance.

J Antimicrob Chemother. 2014;69(3):842-846.

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