Infectious Disease Special Edition by McMahon Group

The Annual Clinical Reference

IDSE net IDSE.net

Revisiting Environmental Hygiene and HospitalAcquired Infections

Volume 16 • 2013

Antibiotics and the Intestinal Microbiota: Short-Term Benefits, Long-Term Consequences

Brian Currie, MD, MPH

Julio E. Figueroa, MD

Treatment Options in HIV

Hepatitis C Virus: Year in Review

Paul E. Sax, MD P

Influenza Viruses: Epidemiology, Treatment, And Prevention Julia Garcia-Diaz, MD, MSc, FACP, FIDSA Monica Almeida Lalama, MD Obinna Nnedu, MD

REPORT Teflaro® (ceftaroline fosamil) for the Treatment of Community-Acquired Bacterial Pneumonia Caused by Designated Susceptible Bacteria

STRIBILD is indicated as a complete single-tablet regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve.

Powerful performance in HIV

STRIBILD is the first integrase inhibitor–based single-tablet regimen2 • STRIBILD achieves strong efficacy with • Safety and tolerability profile through 48 weeks an overall rapid reduction in viral load3,4 – The most common adverse drug reactions – Noninferior efficacy at week 48 (all severity grades) reported in 5% of subjects were nausea (16%), diarrhea (12%), abnormal • 90% of subjects taking STRIBILD reached dreams (9%), headache (7%), and fatigue (5%) undetectable viral loads compared to 87% of subjects taking ATV + RTV + FTC/TDF – 3.7% of subjects taking STRIBILD discontinued therapy due to adverse events compared to • 88% of subjects taking STRIBILD reached 5.1% of subjects taking either ATV + RTV + undetectable viral loads compared to FTC/TDF or EFV/FTC/TDF 84% of subjects taking EFV/FTC/TDF • Convenient single-tablet regimen dosing – 1 tablet taken once daily with food – Do not initiate in patients with eGFR <70 mL/min; discontinue in patients with eGFR <50 mL/min; not recommended in patients with severe hepatic impairment

BOXED WARNING 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, 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 effi ficacy 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 immunodefi ficiency virus-1 (HIV-1) and have discontinued EMTRIVA or VIREAD, 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. Please see additional Important Safety Information on the next page. 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 single-tablet 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. 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; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.

Important Safety Information (continued) d 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 a loss of virologic response 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. Monitor estimated creatinine clearance (CrCl), urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally monitor serum phosphorus in patients with or at risk for renal impairment. 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. Do not initiate STRIBILD in patients with CrCl below 70 mL/min. Discontinue STRIBILD if CrCl declines below 50 mL/min. Avoid concurrent or recent use with a nephrotoxic agent. • Use with 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. • Decreases in bone mineral density (BMD) and cases of 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. • 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.

• 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 virologic response and possible resistance to STRIBILD. • 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.

Pregnancy and breastfeeding • Pregnancy Category B: There are no adequate and well-controlled 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. Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages. References: 1. STRIBILD [package insert]. Foster City, CA: Gilead Sciences, Inc; 2012. 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 May 7, 2013. 3. DeJesus E, Rockstroh JK, Henry K, et al; for the GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated 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. 4. Sax P, DeJesus E, Mills A, et al; for the GS-US-236-0102 Study Team. Co-formulated 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.

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

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.

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 EMTRIVA or VIREAD, 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: The recommended dose is one tablet taken orally once daily with food. Renal Impairment: Do not initiate in patients with estimated creatinine clearance (CrCl) below 70 mL/min. Discontinue if CrCl declines below 50 mL/min during treatment [See Warnings and Precautions, Adverse Reactions, Use in Specific Populations].] Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding use in patients with severe hepatic impairment (Child-Pugh Class C). STRIBILD is not recommended for use in patients with severe hepatic impairment [See Use in Specific Populations].] 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 virologic response and possible resistance [See Drug Interactions]:] • Alpha 1-adrenoreceptor antagonists: alfuzosin. Potential for hypotension. • Antimycobacterial: rifampin. May lead to a loss of virologic response and possible resistance to STRIBILD. • 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 (Hypericum perforatum). m May lead to a loss of virologic response and possible resistance to STRIBILD. • 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. A safe and effective dose has not been established; the potential for sildenafil-associated adverse events (visual disturbances, hypotension, priapism, and syncope) is increased. • 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: It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV 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 EMTRIVA, 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 cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF and with STRIBILD [See Adverse Reactions].] In clinical trials of STRIBILD over 48 weeks (N=701), 8 (1.1%) subjects in the STRIBILD group and 1 (0.1%) subject in the combined comparator groups discontinued study drug due to a renal adverse event. Four (0.6%) of the subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups. Two of these 4 subjects had renal impairment (CrCl less than 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. Monitoring: CrCl, urine glucose and urine protein

should be documented in all patients prior to initiating therapy. STRIBILD should not be initiated in patients with CrCl below 70 mL/min. Routine monitoring of CrCl, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured 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 who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety. STRIBILD should be discontinued if CrCl declines below 50 mL/min. Use with Other Antiretroviral Products: STRIBILD is a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products. STRIBILD should not be coadministered with products containing any of the same active components (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD); or with products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR). STRIBILD should not be administered with adefovir dipivoxil (HEPSERA). Decreases in Bone Mineral Density (BMD): In previous clinical trials, tenofovir DF has been associated with decreases in BMD and increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving VIREAD. The effects of tenofovir DFassociated changes in BMD on future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with tenofovir DF [See Adverse Reactions].] In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects. Mean percentage decreases in BMD from baseline to Week 48 in the STRIBILD group (N=54) were comparable to the atazanavir + ritonavir + emtricitabine/tenofovir DF group (N=66) at the lumbar spine (-2.6% versus -3.3%, respectively) and at the hip (-3.1% versus -3.9%, respectively). In Studies 102 and 103, bone fractures occurred in 9 subjects (1.3%) in the STRIBILD group, 6 subjects (1.7%) in the efavirenz/emtricitabine/tenofovir DF group, and 6 subjects (1.7%) in the atazanavir + ritonavir + emtricitabine/tenofovir DF group. These findings were consistent with data from an earlier 144-week trial of treatment-naive subjects receiving tenofovir DF + lamivudine + efavirenz. Assessment of BMD should be considered for patients who have 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 in all patients. If bone abnormalities are suspected appropriate consultation should be obtained. 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 [such as Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as 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 WARNINGS S and WARNINGS AND PRECAUTIONS S sections for additional serious adverse reactions. Adverse Reactions from Clinical Trials Experience: The safety assessment of STRIBILD is based on pooled data from 1408 subjects in two Phase 3 trials, Study 102 and Study 103, in antiretroviral treatment-naive HIV-1 infected adult subjects. A total of 701 subjects received STRIBILD once daily for at least 48 weeks. The proportion of subjects who discontinued treatment with STRIBILD due to adverse events, regardless of severity, was 3.7%. Treatment Emergent Adverse Drug Reactions: Treatment emergent adverse drug reactions (all grades) reported in ≥5% of subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: nausea (16%); diarrhea (12%); abnormal dreams (9%); headache (7%); and fatigue (5%). Frequencies of adverse reactions are based on all treatment emergent adverse events, attributed to study drugs. See WARNINGS AND PRECAUTIONS S for a discussion of renal adverse events from clinical trials experience with STRIBILD. Laboratory Abnormalities: Treatment emergent laboratory abnormalities (Grades 3-4) occurring in ≥2% of subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: creatine kinase (≥10.0 x ULN), 5%; urine RBC (hematuria) (>75 RBC/HPF), 3%; AST (>5.0 x ULN), 2%; and amylase (>2.0 x ULN), 2%. For subjects with serum amylase >1.5 x ULN, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in STRIBILD (N=58) was 12%. Proteinuria (all grades) occurred in 39% of subjects receiving STRIBILD. Cobicistat has been shown to decrease CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, decreases in CrCl occurred early in treatment with STRIBILD, after which they stabilized. Mean ± SD changes after 48 weeks of treatment were 0.14 ± 0.13 mg/dL for serum creatinine and -13.9 ± 14.9 mL/min for estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method. Elevation in serum creatinine (all grades) occurred in 7% of subjects. Serum Lipids: In the clinical trials of STRIBILD, 11% of subjects were on lipid lowering agents at baseline. While receiving study drug through Week 48, an additional 4% of subjects were started on lipid lowering agents. Through 48 weeks, 1% or fewer subjects in any treatment arm experienced Grades 3-4 elevations in fasting cholesterol (greater than 300 mg/dL) or fasting triglycerides (greater than 750 mg/dL). Mean changes from baseline in total cholesterol, HDLcholesterol, LDL-cholesterol, and triglycerides reported in subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: total cholesterol (fasted): baseline 166 mg/dL (N=675), week 48 change +11 (N=606); HDL-cholesterol (fasted): baseline 43 mg/dL (N=675), week 48 change +6 (N=605); LDL-cholesterol (fasted): baseline 100 mg/dL (N=675), week 48 change +10 (N=606); triglycerides (fasted): baseline 122 mg/dL (N=675), week 48 change +13 (N=606). The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values.

Emtricitabine and Tenofovir DF: Adverse drug reactions:: In addition to the adverse drug reactions observed with STRIBILD, the following adverse drug reactions occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities:: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grades 3-4 laboratory abnormalities of ALT (M: greater than 215 U/L; F: greater than 170 U/L), alkaline phosphatase (greater than 550 U/L), bilirubin (greater than 2.5 x ULN), serum glucose (less than 40 or greater than 250 mg/dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750/mm3), fasting cholesterol (greater than 240 mg/dL), and fasting triglycerides (greater than 750 mg/dL). Postmarketing Events:: The following adverse reactions have been identified during post approval use of tenofovir DF: allergic reaction (including angioedema), lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT), rash, rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria, and asthenia. The following adverse reactions listed above may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia. DRUG INTERACTIONS: See CONTRAINDICATIONS S for additional serious adverse reactions. 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. STRIBILD should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. STRIBILD should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Potential for STRIBILD to Affect Other Drugs: Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include 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 plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. Potential for Other Drugs to Affect One or More Components of 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 plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance. Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma 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. 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 virologic response 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 virologic response 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 virologic response 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. • 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 events. 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 wellcontrolled 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. Renal Impairment: STRIBILD should not be initiated in patients with CrCl below 70 mL/min. STRIBILD should be discontinued if CrCl declines below 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.

COMPLERA, EMTRIVA, GILEAD, the GILEAD Logo, HEPSERA, STRIBILD, the STRIBILD Logo, 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 trademarks referenced herein are the property of their respective owners. 203100-GS-000

August 2012

table of contents

letter from the editor

Letter From the Editor

Revisiting Environmental Hygiene and Hospital-Acquired Infections Brian Currie, MD, MPH

Treatment Options in HIV Paul E. Sax, MD

REPORT

Influenza Viruses: Epidemiology, Treatment, And Prevention Julia Garcia-Diaz, MD, MSc, FACP, FIDSA Monica Almeida Lalama, MD Obinna Nnedu, MD

Antibiotics and the Intestinal Microbiota: Short-Term Benefits, Long-Term Consequences Julio E. Figueroa, MD

Hepatitis C Virus: Year in Review

Following page 50 Teflaro® (ceftaroline fosamil) for the Treatment of Community-Acquired Bacterial Pneumonia Caused by Designated Susceptible Bacteria

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

STRIBILD ÂŽ (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 EMTRIVA or VIREAD, 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-naĂŻve. DOSAGE AND ADMINISTRATION: The recommended dose is one tablet taken orally once daily with food. Renal Impairment: Do not initiate in patients with estimated creatinine clearance (CrCl) below 70 mL/min. Discontinue if CrCl declines below 50 mL/min during treatment [See Warnings and Precautions, Adverse Reactions, Use in Specific Populations]] Hepatic Impairment: No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding use in patients with severe hepatic impairment (Child-Pugh Class C). STRIBILD is not recommended for use in patients with severe hepatic impairment [See Use in Specific Populations]. 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 virologic response and possible resistance [See Drug Interactions]:] t "MQIB BESFOPSFDFQUPS BOUBHPOJTUT BMGV[PTJO 1PUFOUJBM GPSS IZQPUFOTJPO t "OUJNZDPCBDUFSJBM SJGBNQJO .BZ MFBE UP B MPTT PG WJSPMPHJD SFTQPOTF BOE possible resistance to STRIBILD. t &SHPU EFSJWBUJWFT EJIZESPFSHPUBNJOF FSHPUBNJOF NFUIZMFSHPOPWJOF 1PUFOUJBM GPS BDVUF FSHPU UPYJDJUZ DIBSBDUFSJ[FE CZ QFSJQIFSBM WBTPTQBTN and ischemia of the extremities and other tissues. t (* NPUJMJUZ BHFOUT DJTBQSJEF 1PUFOUJBM GPS DBSEJBD BSSIZUINJBT t )FSCBM QSPEVDUT 4U +PIO T XPSU Hypericum perforatum .BZ MFBE UP B m loss of virologic response and possible resistance to STRIBILD. t ).( $P" SFEVDUBTF JOIJCJUPST MPWBTUBUJO TJNWBTUBUJO 1PUFOUJBM GPS myopathy, including rhabdomyolysis. t /FVSPMFQUJDT QJNP[JEF 1PUFOUJBM GPS DBSEJBD BSSIZUINJBT t 1%& JOIJCJUPST TJMEFOBĂĽM XIFO EPTFE BT 3&7"5*0 GPS UIF USFBUNFOU PG pulmonary arterial hypertension. A safe and effective dose has not been FTUBCMJTIFE UIF QPUFOUJBM GPS TJMEFOBĂĽM BTTPDJBUFE BEWFSTF FWFOUT WJTVBM disturbances, hypotension, priapism, and syncope) is increased. t 4FEBUJWF IZQOPUJDT PSBMMZ BENJOJTUFSFE NJEB[PMBN USJB[PMBN 1PUFOUJBM 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 DBTFT IBWF CFFO JO XPNFO 0CFTJUZ BOE QSPMPOHFE OVDMFPTJEF FYQPTVSF NBZ 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 EFWFMPQT DMJOJDBM PS MBCPSBUPSZ ĂĽOEJOHT TVHHFTUJWF PG MBDUJD BDJEPTJT PS pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Patients Coinfected with HIV-1 and HBV: It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. STRIBILD is not approved for the treatment PG DISPOJD )#7 JOGFDUJPO BOE UIF TBGFUZ BOE FGĂĽDBDZ PG 453*#*-% IBWF 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

XJUI )#7 BOE USFBUFE XJUI &.53*7" UIF FYBDFSCBUJPOT PG IFQBUJUJT # 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 cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with tenofovir DF and with STRIBILD [See Adverse Reactions]] In clinical trials of STRIBILD over 48 weeks (N=701), 8 (1.1%) subjects in the STRIBILD group and 1 (0.1%) subject in the combined comparator groups discontinued study drug due to a renal adverse event. Four (0.6%) of the subjects who received STRIBILD EFWFMPQFE MBCPSBUPSZ ĂĽOEJOHT DPOTJTUFOU XJUI QSPYJNBM SFOBM UVCVMBS dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups. Two of these 4 subjects had renal impairment $S$M MFTT UIBO N- NJO BU CBTFMJOF 5IF MBCPSBUPSZ ĂĽOEJOHT JO UIFTF 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. Monitoring:: CrCl, urine glucose and urine protein should be documented in all patients prior to initiating therapy. STRIBILD should not be initiated in patients with CrCl below 70 mL/min. Routine monitoring of CrCl, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured 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 who FYQFSJFODF B DPOĂĽSNFE JODSFBTF JO TFSVN DSFBUJOJOF PG HSFBUFS UIBO 0.4 mg/dL from baseline should be closely monitored for renal safety. STRIBILD should be discontinued if CrCl declines below 50 mL/min. Use with Other Antiretroviral Products: STRIBILD is a complete regimen for the treatment of HIV-1 infection and should not be coadministered with other antiretroviral products. STRIBILD should not be coadministered with products containing any of the same active components (ATRIPLA, $0.1-&3" &.53*7" 5367"%" 7*3&"% PS XJUI QSPEVDUT DPOUBJOJOH MBNJWVEJOF $0.#*7*3 &1*7*3 &1*7*3 )#7 &1;*$0. 53*;*7*3 453*#*-% TIPVME OPU CF BENJOJTUFSFE XJUI BEFGPWJS EJQJWPYJM )&14&3" Decreases in Bone Mineral Density (BMD): In previous clinical trials, UFOPGPWJS %' IBT CFFO BTTPDJBUFE XJUI EFDSFBTFT JO #.% BOE JODSFBTFT JO CJPDIFNJDBM NBSLFST PG CPOF NFUBCPMJTN TFSVN CPOF TQFDJĂĽD BMLBMJOF phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects SFDFJWJOH 7*3&"% 5IF FGGFDUT PG UFOPGPWJS %' BTTPDJBUFE DIBOHFT JO #.% on future fracture risk are unknown. For additional information, please DPOTVMU UIF 7*3&"% QSFTDSJCJOH JOGPSNBUJPO $BTFT PG PTUFPNBMBDJB (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with tenofovir DF [See Adverse Reactions] *O 4UVEZ #.% XBT BTTFTTFE CZ %&9" JO B ] OPO SBOEPN TVCTFU PG TVCKFDUT .FBO QFSDFOUBHF EFDSFBTFT JO #.% from baseline to Week 48 in the STRIBILD group (N=54) were comparable UP UIF BUB[BOBWJS SJUPOBWJS FNUSJDJUBCJOF UFOPGPWJS %' HSPVQ /

at the lumbar spine (-2.6% versus -3.3%, respectively) and at the hip (-3.1% versus -3.9%, respectively). In Studies 102 and 103, bone fractures occurred in 9 subjects (1.3%) in the STRIBILD group, 6 subjects (1.7%) JO UIF FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' HSPVQ BOE TVCKFDUT JO UIF BUB[BOBWJS SJUPOBWJS FNUSJDJUBCJOF UFOPGPWJS %' HSPVQ 5IFTF ĂĽOEJOHT XFSF DPOTJTUFOU XJUI EBUB GSPN BO FBSMJFS XFFL USJBM PG USFBUNFOU OBĂ&#x2022;WF TVCKFDUT SFDFJWJOH UFOPGPWJS %' MBNJWVEJOF FGBWJSFO[ "TTFTTNFOU PG #.% TIPVME CF DPOTJEFSFE GPS QBUJFOUT XIP IBWF B IJTUPSZ PG pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was OPU TUVEJFE TVDI TVQQMFNFOUBUJPO NBZ CF CFOFĂĽDJBM JO BMM QBUJFOUT *G CPOF abnormalities are suspected appropriate consultation should be obtained. Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and â&#x20AC;&#x153;cushingoid appearanceâ&#x20AC;? 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 [such as Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further FWBMVBUJPO BOE USFBUNFOU "VUPJNNVOF EJTPSEFST TVDI BT (SBWFT EJTFBTF QPMZNZPTJUJT BOE (VJMMBJO #BSSF TZOESPNF IBWF CFFO SFQPSUFE UP PDDVS JO 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 WARNINGSS and WARNINGS AND PRECAUTIONSS sections for additional serious adverse reactions. Adverse Reactions from Clinical Trials Experience: The safety assessment of STRIBILD is based on pooled data from 1408 subjects in two Phase 3 trials, Study 102 and Study 103, in antiretroviral treatmentnaĂŻve HIV-1 infected adult subjects. A total of 701 subjects received STRIBILD once daily for at least 48 weeks. The proportion of subjects who discontinued treatment with STRIBILD due to adverse events, regardless of severity, was 3.7%.

Treatment Emergent Adverse Drug Reactions: Treatment emergent adverse drug reactions (all grades) reported in â&#x2030;Ľ5% of subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: nausea (16%); diarrhea (12%); abnormal dreams (9%); headache (7%); and fatigue (5%). Frequencies of adverse reactions are based on all treatment emergent adverse events, attributed to study drugs. See WARNINGS AND PRECAUTIONSS for a discussion of renal adverse events from clinical trials experience with STRIBILD. Laboratory Abnormalities: Treatment emergent laboratory abnormalities (SBEFT PDDVSSJOH JO Ăś PG TVCKFDUT SFDFJWJOH 453*#*-% / in Studies 102 and 103 (Week 48 analysis) were: creatine kinase (â&#x2030;Ľ10.0 x 6-/ VSJOF 3#$ IFNBUVSJB 3#$ )1' "45 Y 6-/ BOE BNZMBTF Y 6-/ 'PS TVCKFDUT XJUI TFSVN BNZMBTF Y 6-/ MJQBTF UFTU XBT BMTP QFSGPSNFE 5IF GSFRVFODZ PG JODSFBTFE MJQBTF (SBEFT PDDVSSJOH JO 453*#*-% / XBT 1SPUFJOVSJB (all grades) occurred in 39% of subjects receiving STRIBILD. Cobicistat has been shown to decrease CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, decreases in CrCl occurred early in treatment with STRIBILD, after XIJDI UIFZ TUBCJMJ[FE .FBO Â&#x153; 4% DIBOHFT BGUFS XFFLT PG USFBUNFOU XFSF Â&#x153; NH E- GPS TFSVN DSFBUJOJOF BOE Â&#x153; N- NJO GPS FTUJNBUFE HMPNFSVMBS ĂĽMUSBUJPO SBUF F('3 CZ $PDLDSPGU (BVMU NFUIPE &MFWBUJPO JO TFSVN DSFBUJOJOF BMM HSBEFT PDDVSSFE JO PG TVCKFDUT Serum Lipids: In the clinical trials of STRIBILD, 11% of subjects were on lipid lowering agents at baseline. While receiving study drug through Week 48, an additional 4% of subjects were started on lipid lowering agents. Through 48 weeks, 1% or fewer subjects in any treatment arm FYQFSJFODFE (SBEFT FMFWBUJPOT JO GBTUJOH DIPMFTUFSPM HSFBUFS UIBO NH E- PS GBTUJOH USJHMZDFSJEFT HSFBUFS UIBO NH E- .FBO DIBOHFT from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides reported in subjects receiving STRIBILD (N=701) in Studies 102 and 103 (Week 48 analysis) were: total cholesterol (fasted): baseline NH E- / XFFL DIBOHF / )%- DIPMFTUFSPM GBTUFE CBTFMJOF NH E- / XFFL DIBOHF / LDL-cholesterol (fasted): baseline 100 mg/dL (N=675), week 48 change

/ USJHMZDFSJEFT GBTUFE CBTFMJOF NH E- / XFFL DIBOHF / 5IF DIBOHF GSPN CBTFMJOF JT UIF NFBO PG XJUIJO patient changes from baseline for patients with both baseline and Week 48 values. Emtricitabine and Tenofovir DF: Adverse drug reactions: In addition to the adverse drug reactions observed with STRIBILD, the following adverse drug reactions occurred in at least 5% of treatment-experienced or treatment-naĂŻve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was HFOFSBMMZ NJME BOE BTZNQUPNBUJD 5IF NFDIBOJTN BOE DMJOJDBM TJHOJĂĽDBODF are unknown. Laboratory Abnormalities:: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or UFOPGPWJS %' XJUI PUIFS BOUJSFUSPWJSBM BHFOUT JO PUIFS DMJOJDBM USJBMT (SBEFT MBCPSBUPSZ BCOPSNBMJUJFT PG "-5 . HSFBUFS UIBO 6 - ' HSFBUFS UIBO 6 - BMLBMJOF QIPTQIBUBTF HSFBUFS UIBO 6 - CJMJSVCJO HSFBUFS UIBO Y 6-/ TFSVN HMVDPTF MFTT UIBO PS HSFBUFS UIBO NH E- HMZDPTVSJB HSFBUFS UIBO PS FRVBM UP

OFVUSPQIJMT MFTT UIBO NN3), fasting cholesterol (greater than 240 mg/dL), and fasting triglycerides (greater than 750 mg/dL). Postmarketing Events:: The following adverse reactions have CFFO JEFOUJĂĽFE EVSJOH QPTU BQQSPWBM VTF PG UFOPGPWJS %' BMMFSHJD SFBDUJPO (including angioedema), lactic acidosis, hypokalemia, hypophosphatemia, dyspnea, pancreatitis, increased amylase, abdominal pain, hepatic TUFBUPTJT IFQBUJUJT JODSFBTFE MJWFS FO[ZNFT NPTU DPNNPOMZ "45 "-5 HBNNB (5 SBTI SIBCEPNZPMZTJT PTUFPNBMBDJB NBOJGFTUFE BT CPOF QBJO and which may contribute to fractures), muscular weakness, myopathy, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), OFQISPHFOJD EJBCFUFT JOTJQJEVT SFOBM JOTVGĂĽDJFODZ JODSFBTFE DSFBUJOJOF proteinuria, polyuria, and asthenia. The following adverse reactions listed above may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, and hypophosphatemia. DRUG INTERACTIONS: See CONTRAINDICATIONSS for additional serious adverse reactions. 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. STRIBILD should not be used in conjunction with protease inhibitors or non-nucleoside reverse transcriptase inhibitors due to potential drug interactions including altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the coadministered antiretroviral products. STRIBILD should not be administered concurrently with products containing ritonavir or regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Potential for STRIBILD to Affect Other Drugs: Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include Q HMZDPQSPUFJO 1 HQ #$31 0"51 # BOE 0"51 # $PBENJOJTUSBUJPO PG 453*#*-% XJUI ESVHT UIBU BSF QSJNBSJMZ NFUBCPMJ[FE CZ $:1 " PS $:1 % PS BSF TVCTUSBUFT PG 1 HQ #$31 0"51 # PS 0"51 # NBZ SFTVMU JO

STRIBILD ÂŽ (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) tablets, for oral use Brief Summary (cont) JODSFBTFE QMBTNB DPODFOUSBUJPOT PG TVDI ESVHT &MWJUFHSBWJS JT B NPEFTU inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. Potential for Other Drugs to Affect One or More Components of STRIBILD: &MWJUFHSBWJS BOE DPCJDJTUBU BSF NFUBCPMJ[FE CZ $:1 " $PCJDJTUBU JT BMTP NFUBCPMJ[FE UP B NJOPS FYUFOU CZ $:1 % %SVHT UIBU induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance. Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat. Drugs Affecting Renal Function: Because emtricitabine and tenofovir are QSJNBSJMZ FYDSFUFE CZ UIF LJEOFZT CZ B DPNCJOBUJPO PG HMPNFSVMBS ĂĽMUSBUJPO 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. 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 453*#*-% 5IF MJTU JODMVEFT QPUFOUJBMMZ TJHOJĂĽDBOU JOUFSBDUJPOT CVU JT OPU BMM inclusive. An alteration in dose or regimen may be recommended for the following drugs when coadministered with STRIBILD: t "DJE 3FEVDJOH "HFOUT BOUBDJET 4FQBSBUF 453*#*-% BOE BOUBDJE administration by at least 2 hours. t "OUJBSSIZUINJDT BNJPEBSPOF CFQSJEJM EJHPYJO EJTPQZSBNJEF Ă˝FDBJOJEF systemic lidocaine mexiletine, propafenone, quinidine. Caution warranted and therapeutic concentration monitoring recommended. t "OUJCBDUFSJBMT DMBSJUISPNZDJO UFMJUISPNZDJO $MBSJUISPNZDJO OP EPTF adjustment required for patients with CrCl â&#x2030;Ľ60 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. t "OUJDPBHVMBOUT XBSGBSJO *OUFSOBUJPOBM OPSNBMJ[FE SBUJP */3 NPOJUPSJOH recommended. t "OUJDPOWVMTBOUT DBSCBNB[FQJOF PYDBSCB[FQJOF QIFOPCBSCJUBM QIFOZUPJO DMPOB[FQBN FUIPTVYJNJEF 1IFOPCBSCJUBM QIFOZUPJO DBSCBNB[FQJOF BOE PYDBSCB[FQJOF NBZ MFBE UP MPTT PG WJSPMPHJD SFTQPOTF and possible resistance to STRIBILD. Alternative anticonvulsants should CF DPOTJEFSFE $MPOB[FQBN BOE FUIPTVYJNJEF DMJOJDBM NPOJUPSJOH recommended. t "OUJEFQSFTTBOUT 4FMFDUJWF 4FSPUPOJO 3FVQUBLF *OIJCJUPST 443*T 5SJDZDMJD "OUJEFQSFTTBOUT 5$"T USB[PEPOF %PTF UJUSBUJPO PG the antidepressant and monitoring for antidepressant response recommended. t "OUJGVOHBMT JUSBDPOB[PMF LFUPDPOB[PMF WPSJDPOB[PMF ,FUPDPOB[PMF BOE JUSBDPOB[PMF UIF NBYJNVN EBJMZ EPTF TIPVME OPU FYDFFE NH EBZ 7PSJDPOB[PMF BO BTTFTTNFOU PG CFOFĂĽU SJTL SBUJP JT SFDPNNFOEFE UP justify use. t "OUJ HPVU DPMDIJDJOF %P OPU DPBENJOJTUFS JO QBUJFOUT XJUI SFOBM PS hepatic impairment. For other patients, modify the dose and/or regimen as described in the full PI for STRIBILD. t "OUJNZDPCBDUFSJBMT SJGBCVUJO SJGBQFOUJOF .BZ MFBE UP MPTT PG WJSPMPHJD response and possible resistance to STRIBILD. Coadministration not recommended. t #FUB #MPDLFST NFUPQSPMPM UJNPMPM $MJOJDBM NPOJUPSJOH SFDPNNFOEFE BOE a dose decrease of the beta blocker may be necessary. t $BMDJVN $IBOOFM #MPDLFST BNMPEJQJOF EJMUJB[FN GFMPEJQJOF OJDBSEJQJOF nifedipine, verapamil. Caution warranted and clinical monitoring recommended. t $PSUJDPTUFSPJET 4ZTUFNJD EFYBNFUIBTPOF .BZ MFBE UP MPTT PG WJSPMPHJD response and possible resistance to STRIBILD. t $PSUJDPTUFSPJET *OIBMFE /BTBM Ă˝VUJDBTPOF "MUFSOBUJWF DPSUJDPTUFSPJET should be considered, particularly for long term use. t &OEPUIFMJO 3FDFQUPS "OUBHPOJTUT CPTFOUBO %JTDPOUJOVF CPTFOUBO BU 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. t ).( $P" 3FEVDUBTF *OIJCJUPST BUPSWBTUBUJO *OJUJBUF XJUI UIF MPXFTU starting dose and titrate carefully while monitoring for safety. t )PSNPOBM $POUSBDFQUJWFT OPSHFTUJNBUF FUIJOZM FTUSBEJPM 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 QPUFOUJBM SJTLT BOE CFOFĂĽUT PG DPBENJOJTUSBUJPO TIPVME CF DPOTJEFSFE particularly in women who have risk factors for progesterone exposure. Alternative (non hormonal) methods of contraception can be considered. t *NNVOPTVQQSFTTBOUT DZDMPTQPSJOF SBQBNZDJO TJSPMJNVT UBDSPMJNVT Therapeutic monitoring recommended. t *OIBMFE #FUB "HPOJTU TBMNFUFSPM $PBENJOJTUSBUJPO OPU SFDPNNFOEFE due to the increased risk of salmeterol cardiovascular adverse events, including QT prolongation, palpitations, and sinus tachycardia. t /FVSPMFQUJDT QFSQIFOB[JOF SJTQFSJEPOF UIJPSJEB[JOF %FDSFBTF JO EPTF PG the neuroleptic may be needed.

t 1IPTQIPEJFTUFSBTF 1%& *OIJCJUPST TJMEFOBĂĽM UBEBMBĂĽM WBSEFOBĂĽM Dosage for erectile dysfunction:: TJMEFOBĂĽM B TJOHMF EPTF OPU FYDFFEJOH NH JO IPVST WBSEFOBĂĽM B TJOHMF EPTF OPU FYDFFEJOH NH JO IPVST UBEBMBĂĽM B TJOHMF EPTF OPU FYDFFEJOH NH JO IPVST JODSFBTF NPOJUPSJOH GPS 1%& BTTPDJBUFE BEWFSTF FWFOUT Dosage for pulmonary arterial hypertension (PAH):: UBEBMBĂĽM TUPQ UBEBMBĂĽM BU MFBTU 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. t 4FEBUJWF IZQOPUJDT #FO[PEJB[FQJOFT 1BSFOUFSBM NJEB[PMBN 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 DPOTJEFSFE FTQFDJBMMZ JG NPSF UIBO B TJOHMF EPTF JT BENJOJTUFSFE 0UIFS 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 TIPVME CF VTFE EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFĂĽU KVTUJĂĽFT UIF 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 NJML &NUSJDJUBCJOF BOE UFOPGPWJS IBWF CFFO EFUFDUFE JO IVNBO NJML JU JT 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: $MJOJDBM TUVEJFT PG 453*#*-% EJE OPU JODMVEF TVGĂĽDJFOU numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Renal Impairment: STRIBILD should not be initiated in patients with CrCl below 70 mL/min. STRIBILD should be discontinued if CrCl declines below 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. August 2012

COMPLERA ÂŽ (emtricitabine 200 mg/rilpivirine 25 mg/ tenofovir disoproxil fumarate 300 mg) tablets 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, 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 HIV-1 and have discontinued EMTRIVA or VIREAD, 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 $0.1-&3"ÂŽ (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naĂŻve adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. 5IJT JOEJDBUJPO JT CBTFE PO TBGFUZ BOE FGĂĽDBDZ BOBMZTFT UISPVHI XFFLT GSPN SBOEPNJ[FE EPVCMF CMJOE BDUJWF DPOUSPMMFE 1IBTF USJBMT JO treatment-naĂŻve subjects.

The following points should be considered when initiating therapy with $0.1-&3" t .PSF SJMQJWJSJOF USFBUFE TVCKFDUT XJUI )*7 3/" HSFBUFS UIBO 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA â&#x2030;Ľ50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. t 3FHBSEMFTT PG )*7 3/" MFWFM BU UIF TUBSU PG UIFSBQZ NPSF SJMQJWJSJOF USFBUFE TVCKFDUT XJUI $% DFMM DPVOU MFTT UIBO DFMMT NN3 experienced virologic failure compared to rilpivirine-treated subjects with $% DFMM DPVOU HSFBUFS UIBO PS FRVBM UP DFMMT NN3. t 5IF PCTFSWFE WJSPMPHJD GBJMVSF SBUF JO SJMQJWJSJOF USFBUFE TVCKFDUT DPOGFSSFE a higher rate of overall treatment resistance and cross-resistance to the //35* DMBTT DPNQBSFE UP FGBWJSFO[ t .PSF TVCKFDUT USFBUFE XJUI SJMQJWJSJOF EFWFMPQFE UFOPGPWJS BOE MBNJWVEJOF FNUSJDJUBCJOF BTTPDJBUFE SFTJTUBODF DPNQBSFE UP FGBWJSFO[ $0.1-&3" JT OPU SFDPNNFOEFE GPS QBUJFOUT MFTT UIBO ZFBST PG BHF [See Use in Specific Populations] DOSAGE AND ADMINISTRATION Adults:: 5IF SFDPNNFOEFE EPTF PG $0.1-&3" JT POF UBCMFU UBLFO PSBMMZ once daily with food. Renal Impairment:: #FDBVTF $0.1-&3" JT B ĂĽYFE EPTF DPNCJOBUJPO JU should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute). CONTRAINDICATIONS $0.1-&3" TIPVME OPU CF DPBENJOJTUFSFE XJUI UIF GPMMPXJOH ESVHT BT TJHOJĂĽDBOU EFDSFBTFT JO SJMQJWJSJOF QMBTNB DPODFOUSBUJPOT NBZ PDDVS EVF UP $:1 " FO[ZNF JOEVDUJPO PS HBTUSJD Q) JODSFBTF XIJDI NBZ SFTVMU JO MPTT PG WJSPMPHJD SFTQPOTF BOE QPTTJCMF SFTJTUBODF UP $0.1-&3" PS UP UIF DMBTT PG NNRTIs [See Drug Interactions]: t UIF BOUJDPOWVMTBOUT DBSCBNB[FQJOF PYDBSCB[FQJOF QIFOPCBSCJUBM phenytoin t UIF BOUJNZDPCBDUFSJBMT SJGBCVUJO SJGBNQJO SJGBQFOUJOF t QSPUPO QVNQ JOIJCJUPST TVDI BT FTPNFQSB[PMF MBOTPQSB[PMF EFYMBOTPQSB[PMF PNFQSB[PMF QBOUPQSB[PMF SBCFQSB[PMF t UIF HMVDPDPSUJDPJE TZTUFNJD EFYBNFUIBTPOF NPSF UIBO B TJOHMF EPTF

t 4U +PIO T XPSU Hypericum perforatum) m 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 disoproxil GVNBSBUF UFOPGPWJS %' B DPNQPOFOU PG $0.1-&3" JO DPNCJOBUJPO with other antiretrovirals. A majority of these cases have been in women. 0CFTJUZ BOE QSPMPOHFE OVDMFPTJEF FYQPTVSF NBZ CF SJTL GBDUPST 1BSUJDVMBS 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 XJUI $0.1-&3" TIPVME CF TVTQFOEFE JO BOZ QBUJFOU XIP EFWFMPQT DMJOJDBM PS MBCPSBUPSZ ĂĽOEJOHT TVHHFTUJWF PG MBDUJD BDJEPTJT PS QSPOPVODFE S hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Patients Coinfected with HIV-1 and HBV: It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B WJSVT CFGPSF JOJUJBUJOH BOUJSFUSPWJSBM UIFSBQZ $0.1-&3" JT OPU BQQSPWFE GPS UIF USFBUNFOU PG DISPOJD )#7 JOGFDUJPO BOE UIF TBGFUZ BOE FGĂĽDBDZ PG $0.1-&3" IBWF OPU CFFO FTUBCMJTIFE JO QBUJFOUT DPJOGFDUFE XJUI )#7 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 FNUSJDJUBCJOF PS UFOPGPWJS %' UXP PG UIF DPNQPOFOUT PG $0.1-&3" *O TPNF QBUJFOUT JOGFDUFE XJUI )#7 BOE USFBUFE XJUI &.53*7" UIF 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 TFWFSBM NPOUIT BGUFS TUPQQJOH USFBUNFOU XJUI $0.1-&3" *G BQQSPQSJBUF initiation of anti-hepatitis B therapy may be warranted. New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF [See Adverse Reactions]] It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy XJUI $0.1-&3" 3PVUJOF NPOJUPSJOH PG DBMDVMBUFE DSFBUJOJOF DMFBSBODF and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal FWFOUT XIJMF SFDFJWJOH )&14&3" $0.1-&3" TIPVME CF BWPJEFE XJUI DPODVSSFOU PS SFDFOU VTF PG B OFQISPUPYJD BHFOU &NUSJDJUBCJOF BOE UFOPGPWJS BSF QSJODJQBMMZ FMJNJOBUFE CZ UIF LJEOFZ IPXFWFS SJMQJWJSJOF JT OPU 4JODF $0.1-&3" JT B DPNCJOBUJPO product and the dose of the individual components cannot be altered, patients with creatinine clearance below 50 mL per minute should not SFDFJWF $0.1-&3" Drug Interactions: $BVUJPO TIPVME CF HJWFO UP QSFTDSJCJOH $0.1-&3" XJUI drugs that may reduce the exposure of rilpivirine [See Contraindications, Drug Interactions, and Clinical Pharmacology].] 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 [See Drug Interactions]] $0.1-&3" TIPVME CF VTFE XJUI DBVUJPO XIFO coadministered with a drug with a known risk of Torsade de Pointes.

Depressive Disorders: The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) SFQPSUFE BNPOH SJMQJWJSJOF / PS FGBWJSFO[ / XBT BOE SFTQFDUJWFMZ .PTU FWFOUT XFSF NJME PS NPEFSBUF JO TFWFSJUZ 5IF JODJEFODF PG (SBEFT BOE EFQSFTTJWF EJTPSEFST SFHBSEMFTT PG DBVTBMJUZ XBT GPS CPUI SJMQJWJSJOF BOE FGBWJSFO[ 5IF JODJEFODF PG EJTDPOUJOVBUJPO EVF UP EFQSFTTJWF EJTPSEFST BNPOH SJMQJWJSJOF PS FGBWJSFO[ XBT JO FBDI BSN 4VJDJEBM ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the rilpivirine arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess UIF QPTTJCJMJUZ UIBU UIF TZNQUPNT BSF SFMBUFE UP $0.1-&3" BOE JG TP UP EFUFSNJOF XIFUIFS UIF SJTLT PG DPOUJOVFE UIFSBQZ PVUXFJHI UIF CFOFĂĽUT Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or C, or marked elevations in serum liver biochemistries prior to treatment may be at increased risk for worsening or development of TFSVN MJWFS CJPDIFNJTUSJFT FMFWBUJPOT XJUI VTF PG $0.1-&3" " GFX DBTFT of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or other JEFOUJĂĽBCMF SJTL GBDUPST "QQSPQSJBUF MBCPSBUPSZ UFTUJOH QSJPS UP JOJUJBUJOH UIFSBQZ BOE NPOJUPSJOH GPS IFQBUPUPYJDJUZ EVSJOH UIFSBQZ XJUI $0.1-&3" JT recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in serum liver biochemistries prior to treatment initiation. Serum liver biochemistries monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. Decreases in Bone Mineral Density: #POF NJOFSBM EFOTJUZ #.% monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or are at risk for osteopenia or bone loss. Although the effect of supplementation with calcium and Vitamin D XBT OPU TUVEJFE TVDI TVQQMFNFOUBUJPO NBZ CF CFOFĂĽDJBM GPS BMM QBUJFOUT If bone abnormalities are suspected then appropriate consultation should be obtained. Tenofovir Disoproxil Fumarate:: In a 144 week study of HIV-1 infected treatment-naive adult subjects treated with tenofovir DF (Study 903), EFDSFBTFT JO #.% XFSF TFFO BU UIF MVNCBS TQJOF BOE IJQ JO CPUI BSNT PG UIF TUVEZ "U 8FFL UIFSF XBT B TJHOJĂĽDBOUMZ HSFBUFS NFBO QFSDFOUBHF EFDSFBTF GSPN CBTFMJOF JO #.% BU UIF MVNCBS TQJOF JO TVCKFDUT SFDFJWJOH UFOPGPWJS %' MBNJWVEJOF FGBWJSFO[ Â&#x153; DPNQBSFE XJUI TVCKFDUT SFDFJWJOH TUBWVEJOF MBNJWVEJOF FGBWJSFO[ Â&#x153; $IBOHFT JO #.% BU UIF IJQ XFSF TJNJMBS CFUXFFO UIF UXP USFBUNFOU HSPVQT Â&#x153; JO UIF UFOPGPWJS %' HSPVQ WT Â&#x153; JO UIF TUBWVEJOF HSPVQ *O CPUI HSPVQT UIF NBKPSJUZ PG UIF SFEVDUJPO JO #.% PDDVSSFE JO UIF ĂĽSTU o XFFLT PG UIF TUVEZ BOE UIJT SFEVDUJPO XBT TVTUBJOFE UISPVHI 144 weeks. Twenty-eight percent of tenofovir DF treated subjects vs. 21% PG UIF DPNQBSBUPS TVCKFDUT MPTU BU MFBTU PG #.% BU UIF TQJOF PS PG #.% BU UIF IJQ $MJOJDBMMZ SFMFWBOU GSBDUVSFT FYDMVEJOH ĂĽOHFST BOE UPFT were reported in 4 subjects in the tenofovir DF group and 6 subjects in the DPNQBSBUPS HSPVQ 5FOPGPWJS %' XBT BTTPDJBUFE XJUI TJHOJĂĽDBOU JODSFBTFT JO CJPDIFNJDBM NBSLFST PG CPOF NFUBCPMJTN TFSVN CPOF TQFDJĂĽD BMLBMJOF phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. The effects of tenofovir DF-associated changes JO #.% BOE CJPDIFNJDBM NBSLFST PO MPOH UFSN CPOF IFBMUI BOE GVUVSF fracture risk are unknown. For additional information, please consult the 7*3&"% QSFTDSJCJOH JOGPSNBUJPO Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with UIF VTF PG 7*3&"% [See Adverse Reactions]] Coadministration with Other Products: $0.1-&3" TIPVME OPU CF administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir %' &EVSBOU &.53*7" 453*#*-% 5367"%" 7*3&"% XJUI NFEJDJOBM QSPEVDUT DPOUBJOJOH MBNJWVEJOF &1*7*3 &1*7*3 )#7 &1;*$0. $0.#*7*3 53*;*7*3 PS XJUI BEFGPWJS EJQJWPYJM )&14&3" Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and â&#x20AC;&#x153;cushingoid appearanceâ&#x20AC;? have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established. Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral UIFSBQZ JODMVEJOH UIF DPNQPOFOUT PG $0.1-&3" %VSJOH UIF JOJUJBM phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium m infection, cytomegalovirus, Pneumocystis jiroveciii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune EJTPSEFST TVDI BT (SBWFT EJTFBTF QPMZNZPTJUJT BOE (VJMMJBO #BSSĂ? 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 WARNINGSS and WARNINGS AND PRECAUTIONSS sections for additional serious adverse reactions. Adverse Reactions from Clinical Trials Experience: 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. Studies C209 and C215 â&#x20AC;&#x201C; Treatment-Emergent Adverse Drug Reactions:: The safety assessment of rilpivirine, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 QBUJFOUT JO UIF 1IBTF USJBMT 5.$ $ &$)0 BOE 5.$ $ 5)3*7& JO BOUJSFUSPWJSBM USFBUNFOU OBJWF )*7 JOGFDUFE BEVMU QBUJFOUT A total of 686 patients received rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550) received emtricitabine/tenofovir DF as background regimen. The number of subjects SBOEPNJ[FE UP UIF DPOUSPM BSN FGBWJSFO[ XBT PG XIJDI SFDFJWFE emtricitabine/tenofovir DF as background regimen. The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse drug reactions (ADR) observed at Week 96 in patients who SFDFJWFE SJMQJWJSJOF PS FGBWJSFO[ QMVT FNUSJDJUBCJOF UFOPGPWJS %' BT background regimen are shown in Table 1. No new types of adverse SFBDUJPOT XFSF JEFOUJĂĽFE CFUXFFO 8FFL BOE 8FFL 5IF BEWFSTF ESVH reactions observed in this subset of patients were generally consistent with those seen for the overall patient population participating in these studies SFGFS UP UIF QSFTDSJCJOH JOGPSNBUJPO GPS &%63"/5 The proportion of subjects who discontinued treatment with rilpivirine or FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' EVF UP "%3 SFHBSEMFTT PG TFWFSJUZ was 2% and 5%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' BSN BOE TVCKFDUT JO UIF FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' BSN 3BTI MFE UP EJTDPOUJOVBUJPO JO TVCKFDU JO UIF SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' BSN BOE TVCKFDUT JO UIF FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' BSN Common Adverse Drug Reactions $MJOJDBM "%3T UP SJMQJWJSJOF PS FGBWJSFO[ PG BU MFBTU NPEFSBUF JOUFOTJUZ Ăś (SBEF SFQPSUFE JO BU MFBTU PG BEVMU TVCKFDUT BSF TIPXO JO 5BCMF Table 1 Selected Treatment-Emergent Adverse Reactionsa (Grades 2â&#x20AC;&#x201C;4) Reported in â&#x2030;Ľ2% of Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 analysis) Rilpivirine + FTC/TDF

Efavirenz + FTC/TDF

N=550

N=546

Gastrointestinal Disorder Nausea

Nervous System Disorders Headache %J[[JOFTT

2% 1%

2% 7%

Psychiatric Disorders Depressive disordersb Insomnia Abnormal dreams Skin and Subcutaneous Tissue Disorders Rash

2% 2% 1%

2% 2% 3%

Table 2 Selected Laboratory Abnormalities (Grades 1-4) Reported in Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) Laboratory Parameter Abnormality, (%)

DAIDS Toxicity Range

Rilpivirine + FTC/TDF N=550

Efavirenz + FTC/TDF N=546

(SBEF

Y 6-/a

(SBEF

Y 6-/

(SBEF

Y 6-/

<1%

(SBEF

Y 6-/

<1%

(SBEF

Y 6-/

16%

19%

(SBEF

Y 6-/

(SBEF

Y 6-/

(SBEF

Y 6-/

(SBEF

Y 6-/

19%

22%

(SBEF

Y 6-/

(SBEF

Y 6-/

(SBEF

Y 6-/

(SBEF

Y 6-/

<1%

(SBEF

Y 6-/

(SBEF

Y 6-/

<1%

BIOCHEMISTRY Increased Creatinine

Increased AST

Increased ALT

Increased Total Bilirubin

Increased Total Cholesterol (fasted) (SBEF

200-239 mg/dL

14%

31%

(SBEF

240-300 mg/dL

18%

(SBEF

NH E-

<1%

Increased LDL Cholesterol (fasted) (SBEF

130-159 mg/dL

13%

28%

(SBEF

160-190 mg/dL

13%

(SBEF

NH E-

Increased Triglycerides (fasted) (SBEF

500-750 mg/dL

(SBEF

751-1,200 mg/dL

(SBEF

NH E-

B 'SFRVFODJFT PG BEWFSTF SFBDUJPOT BSF CBTFE PO BMM (SBEFT USFBUNFOU emergent adverse events, assessed to be related to study drug. b. Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.

N = number of subjects per treatment group B 6-/ 6QQFS MJNJU PG OPSNBM WBMVF Note: Percentages were calculated versus the number of subjects in ITT QPQVMBUJPO XJUI FNUSJDJUBCJOF UFOPGPWJS %' BT CBDLHSPVOE SFHJNFO

Rilpivirine:: Treatment-emergent adverse drug reactions of at least NPEFSBUF JOUFOTJUZ Ăś (SBEF UIBU PDDVSSFE JO MFTT UIBO PG TVCKFDUT treated with rilpivirine plus any of the allowed background regimen (N=686) in clinical studies C209 and C215 include (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. Emtricitabine and Tenofovir Disoproxil Fumarate:: The following adverse reactions were observed in clinical trials of emtricitabine or tenofovir DF in combination with other antiretroviral agents: The most common adverse drug reactions occurred in at least 10% of treatment-naive subjects in a phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another BOUJSFUSPWJSBM BHFOU BSF EJBSSIFB OBVTFB GBUJHVF IFBEBDIF EJ[[JOFTT depression, insomnia, abnormal dreams, and rash. In addition, adverse drug reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and BTZNQUPNBUJD 5IF NFDIBOJTN BOE DMJOJDBM TJHOJĂĽDBODF BSF VOLOPXO Laboratory Abnormalities:: The percentage of subjects treated with rilpivirine

FNUSJDJUBCJOF UFOPGPWJS %' PS FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' in studies C209 and C215 with selected treatment-emergent laboratory BCOPSNBMJUJFT (SBEFT UP SFQSFTFOUJOH XPSTU HSBEF UPYJDJUZ BSF presented in Table 2.

Emtricitabine or Tenofovir Disoproxil Fumarate: The following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other DMJOJDBM USJBMT (SBEF PS MBCPSBUPSZ BCOPSNBMJUJFT PG JODSFBTFE QBODSFBUJD BNZMBTF Y 6-/ JODSFBTFE TFSVN BNZMBTF 6 - JODSFBTFE MJQBTF Y 6-/ JODSFBTFE BMLBMJOF QIPTQIBUBTF 6 - JODSFBTFE PS EFDSFBTFE TFSVN HMVDPTF PS NH E- JODSFBTFE HMZDPTVSJB Ăś

JODSFBTFE DSFBUJOF LJOBTF . 6 - ' 6 - EFDSFBTFE neutrophils (<750/mm3 BOE JODSFBTFE IFNBUVSJB 3#$ )1' PDDVSSFE Adrenal Function:: In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (95% CI: -30.9; -7.4) nmol/L in the rilpivirine HSPVQ BOE PG $* ONPM - JO UIF FGBWJSFO[ HSPVQ At Week 96, the mean change from baseline in ACTH-stimulated cortisol MFWFMT XBT MPXFS JO UIF SJMQJWJSJOF HSPVQ Â&#x153; ONPM - UIBO JO UIF FGBWJSFO[ HSPVQ Â&#x153; ONPM - .FBO WBMVFT GPS CPUI CBTBM and ACTH-stimulated cortisol values at Week 96 were within the normal SBOHF 0WFSBMM UIFSF XFSF OP TFSJPVT BEWFSTF FWFOUT EFBUIT PS USFBUNFOU EJTDPOUJOVBUJPOT UIBU DPVME DMFBSMZ CF BUUSJCVUFE UP BESFOBM JOTVGĂĽDJFODZ &GGFDUT PO BESFOBM GVODUJPO XFSF DPNQBSBCMF CZ CBDLHSPVOE / U 35*T Serum Creatinine:: In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), there was a small increase in serum creatinine over XFFLT PG USFBUNFOU XJUI SJMQJWJSJOF .PTU PG UIJT JODSFBTF PDDVSSFE XJUIJO UIF ĂĽSTU GPVS XFFLT PG USFBUNFOU XJUI B NFBO DIBOHF PG NH E- (range: -0.3 mg/dL to 0.6 mg/dL) observed through Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.

COMPLERAÂŽ (emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg) tablets Brief Summary (cont) Serum Lipids:: In clinical studies, analysis of serum lipids excluded subjects receiving lipid lowering agents during the treatment period. Through Week PS GFXFS TVCKFDUT SFDFJWJOH SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' XFSF SFQPSUFE BT IBWJOH (SBEFT FMFWBUJPOT JO GBTUJOH DIPMFTUFSPM NH E- GBTUJOH -%- DIPMFTUFSPM NH EM PS (SBEF USJHMZDFSJEFT NH EM *O TVCKFDUT JO UIF SJMQJWJSJOF USFBUNFOU BSN through Week 96 (N=550), the mean change from baseline in total cholesterol, LDL-cholesterol and triglycerides (pooled data) are as follows: UPUBM DIPMFTUFSPM <5$> GBTUFE NH E- / <NFBO CBTFMJOF 5$ NH E-> )%- DIPMFTUFSPM <)%-> GBTUFE NH E- / <NFBO CBTFMJOF HDL=42 mg/dL]; LDL-cholesterol [LDL] (fasted) -1 mg/dL (N=427) [mean CBTFMJOF -%- NH E-> BOE 5SJHMZDFSJEFT <5(> GBTUFE NH E-

/ <NFBO CBTFMJOF 5( NH E-> 5IF DIBOHF GSPN CBTFMJOF JT the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus:: In patients coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 BOE $ UIF JODJEFODF PG IFQBUJD FO[ZNF FMFWBUJPO XBT IJHIFS UIBO JO subjects receiving rilpivirine who were not coinfected. The same increase XBT BMTP PCTFSWFE JO UIF FGBWJSFO[ BSN 5IF QIBSNBDPLJOFUJD FYQPTVSF of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection. Postmarketing Experience 5IF GPMMPXJOH BEWFSTF SFBDUJPOT IBWF CFFO JEFOUJĂĽFE EVSJOH QPTUBQQSPWBM use of emtricitabine or tenofovir DF. Because postmarketing reactions BSF SFQPSUFE WPMVOUBSJMZ GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Rilpivirine 3FOBM BOE 6SJOBSZ %JTPSEFST Z nephrotic syndrome Emtricitabine: /P QPTUNBSLFUJOH BEWFSTF SFBDUJPOT IBWF CFFO JEFOUJĂĽFE GPS : inclusion in this section. Tenofovir Disoproxil Fumarate: Immune System y Disorders: allergic reaction, including angioedema .FUBCPMJTN BOE /VUSJUJPO %JTPSEFST lactic acidosis, hypokalemia, hypophosphatemia 3FTQJSBUPSZ 5IPSBDJD BOE .FEJBTUJOBM %JTPSEFST Q Z dyspnea (BTUSPJOUFTUJOBM %JTPSEFST pancreatitis, increased amylase, abdominal pain Hepatobiliary p y Disorders: hepatic steatosis, hepatitis, increased liver FO[ZNFT NPTU DPNNPOMZ "45 "-5 HBNNB (5

Skin and Subcutaneous Tissue Disorders: rash .VTDVMPTLFMFUBM BOE $POOFDUJWF 5JTTVF %JTPSEFST rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy 3FOBM BOE 6SJOBSZ %JTPSEFST Z acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal JOTVGĂĽDJFODZ JODSFBTFE DSFBUJOJOF QSPUFJOVSJB QPMZVSJB (FOFSBM %JTPSEFST BOE "ENJOJTUSBUJPO 4JUF $POEJUJPOT asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. DRUG INTERACTIONS $0.1-&3" JT B DPNQMFUF SFHJNFO GPS UIF USFBUNFOU PG )*7 JOGFDUJPO UIFSFGPSF $0.1-&3" TIPVME OPU CF BENJOJTUFSFE XJUI PUIFS BOUJSFUSPWJSBM medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. Please refer to the &%63"/5 7*3&"% BOE &.53*7" QSFTDSJCJOH JOGPSNBUJPO BT OFFEFE 5IFSF XFSF OP ESVH ESVH JOUFSBDUJPO USJBMT DPOEVDUFE XJUI UIF ĂĽYFE EPTF combination tablet. Drug interaction studies were conducted with FNUSJDJUBCJOF SJMQJWJSJOF PS UFOPGPWJS %' UIF DPNQPOFOUT PG $0.1-&3" 5IJT TFDUJPO EFTDSJCFT DMJOJDBMMZ SFMFWBOU ESVH JOUFSBDUJPOT XJUI $0.1-&3" [See Contraindications]] Drugs Inducing or Inhibiting CYP3A Enzymes: Rilpivirine is primarily NFUBCPMJ[FE CZ DZUPDISPNF 1 $:1 " BOE ESVHT UIBU JOEVDF PS JOIJCJU CYP3A may thus affect the clearance of rilpivirine [See Clinical Pharmacology, Contraindications].] Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and 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 FYQPTVSF PG ESVHT NFUBCPMJ[FE CZ $:1 FO[ZNFT Drugs Increasing Gastric pH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Drug Interactions,Table 4]] Drugs Affecting Renal Function: Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular ĂĽMUSBUJPO BOE BDUJWF UVCVMBS TFDSFUJPO DPBENJOJTUSBUJPO PG $0.1-&3" XJUI ESVHT UIBU SFEVDF SFOBM GVODUJPO PS DPNQFUF GPS BDUJWF tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited

to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. 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 electrocardiogram. 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 PG UIF FMFDUSPDBSEJPHSBN $0.1-&3" TIPVME CF VTFE XJUI DBVUJPO XIFO coadministered with a drug with a known risk of Torsade de Pointes. Established and Other Potentially Significant Drug Interactions *NQPSUBOU ESVH JOUFSBDUJPO JOGPSNBUJPO GPS $0.1-&3" JT TVNNBSJ[FE JO Table 4. The drug interactions described are based on studies conducted with emtricitabine, rilpivirine, or tenofovir DF as individual medications UIBU NBZ PDDVS XJUI $0.1-&3" PS BSF QPUFOUJBM ESVH JOUFSBDUJPOT OP ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE VTJOH $0.1-&3" 5IF UBCMFT JODMVEF QPUFOUJBMMZ TJHOJĂĽDBOU JOUFSBDUJPOT CVU BSF OPU BMM JODMVTJWF Table 4 Established and Other Potentially Significant a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name

Effect on Concentrationb

Clinical Comment

Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)

â&#x2020;&#x201D; rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) â&#x2020;&#x201C; rilpivirine (concomitant intake)

5IF DPNCJOBUJPO PG $0.1-&3" and antacids should be used with caution as coadministration NBZ DBVTF TJHOJĂĽDBOU decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours BGUFS $0.1-&3"

Azole Antifungal Agents: Ă˝VDPOB[PMF JUSBDPOB[PMF LFUPDPOB[PMF QPTBDPOB[PMF WPSJDPOB[PMF

â&#x2020;&#x2018; rilpivirinec,d â&#x2020;&#x201C; LFUPDPOB[PMFc,d

$PODPNJUBOU VTF PG $0.1-&3" XJUI B[PMF BOUJGVOHBM BHFOUT may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A FO[ZNFT /P EPTF BEKVTUNFOU JT SFRVJSFE XIFO $0.1-&3" JT DPBENJOJTUFSFE XJUI B[PMF antifungal agents. Clinically monitor for breakthrough GVOHBM JOGFDUJPOT XIFO B[PMF antifungals are coadministered XJUI $0.1-&3"

H2-Receptor Antagonists: cimetidine famotidine OJ[BUJEJOF ranitidine

â&#x2020;&#x201D; rilpivirinec,d (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) â&#x2020;&#x201C; rilpivirinec,d (famotidine taken 2 hours before rilpivirine)

5IF DPNCJOBUJPO PG $0.1-&3" and H2-receptor antagonists should be used with caution as coadministration may DBVTF TJHOJĂĽDBOU EFDSFBTFT JO rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least IPVST BGUFS $0.1-&3"

Macrolide antibiotics: clarithromycin erythromycin telithromycin

â&#x2020;&#x2018; rilpivirine â&#x2020;&#x201D; clarithromycin â&#x2020;&#x201D; erythromycin â&#x2020;&#x201D; telithromycin

$PODPNJUBOU VTF PG $0.1-&3" with clarithromycin, erythromycin and telithromycin may cause an increase in the plasma concentrations of rilpivirine JOIJCJUJPO PG $:1 " FO[ZNFT Where possible, alternatives TVDI BT B[JUISPNZDJO TIPVME CF considered.

Narcotic Analgesics: methadone

â&#x2020;&#x201C; R(â&#x2C6;&#x2019;) methadonec â&#x2020;&#x201C; 4

NFUIBEPOFc â&#x2020;&#x201D; rilpivirinec â&#x2020;&#x201D; methadonec (when used with tenofovir)

No dose adjustments are required when initiating coadministration PG NFUIBEPOF XJUI $0.1-&3" However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

a. This table is not all inclusive. b. Increase = â&#x2020;&#x2018; â&#x2020;&#x2018;; Decrease = â&#x2020;&#x201C; /P &GGFDU â&#x2020;&#x201D; c. The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. d. This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. Drugs with No Observed or Predicted Interactions with COMPLERA /P DMJOJDBMMZ TJHOJĂĽDBOU ESVH JOUFSBDUJPOT IBWF CFFO PCTFSWFE CFUXFFO emtricitabine and famciclovir or tenofovir DF. Similarly, no clinically TJHOJĂĽDBOU ESVH JOUFSBDUJPOT IBWF CFFO PCTFSWFE CFUXFFO UFOPGPWJS %' and entecavir, methadone, oral contraceptives, ribavirin, or tacrolimus JO TUVEJFT DPOEVDUFE JO IFBMUIZ TVCKFDUT /P DMJOJDBMMZ TJHOJĂĽDBOU ESVH interactions have been observed between rilpivirine and acetaminophen, BUPSWBTUBUJO DIMPS[PYB[POF EJHPYJO FUIJOZMFTUSBEJPM OPSFUIJOESPOF TJMEFOBĂĽM UFMFQSFWJS PS UFOPGPWJS %' /P DMJOJDBMMZ SFMFWBOU ESVH ESVH interaction is expected when rilpivirine is coadministered with ribavirin. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Emtricitabine:: The incidence of fetal variations and malformations was not

increased in embryofetal toxicity studies performed with emtricitabine JO NJDF BU FYQPTVSFT "6$ BQQSPYJNBUFMZ UJNFT IJHIFS BOE JO rabbits at approximately 120 times higher than human exposures at the recommended daily dose. Rilpivirine:: Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there XFSF OP UPYJDPMPHJDBMMZ TJHOJĂĽDBOU FGGFDUT PO EFWFMPQNFOUBM FOEQPJOUT 5IF FYQPTVSFT BU UIF FNCSZP GFUBM /P 0CTFSWFE "EWFSTF &GGFDUT -FWFMT JO SBUT and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Tenofovir Disoproxil Fumarate:: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of IVNBO SFTQPOTF $0.1-&3" TIPVME CF VTFE EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFĂĽU KVTUJĂĽFT UIF QPUFOUJBM SJTL UP UIF GFUVT Antiretroviral Pregnancy Registry:: To monitor fetal outcomes of pregnant XPNFO FYQPTFE UP $0.1-&3" BO "OUJSFUSPWJSBM 1SFHOBODZ 3FHJTUSZZ IBT 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. Emtricitabine: 4BNQMFT PG CSFBTU NJML PCUBJOFE GSPN ĂĽWF )*7 JOGFDUFE : mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at SJTL GPS EFWFMPQJOH WJSBM SFTJTUBODF UP FNUSJDJUBCJOF 0UIFS FNUSJDJUBCJOF associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Rilpivirine:: Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Tenofovir Disoproxil Fumarate: 4BNQMFT PG CSFBTU NJML PCUBJOFE GSPN ĂĽWF : )*7 JOGFDUFE NPUIFST JO UIF ĂĽSTU QPTU QBSUVN XFFL TIPX UIBU UFOPGPWJS is excreted in human milk. The impact of this exposure in breastfed infants is unknown. 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 if they are receiving COMPLERA. Pediatric Use $0.1-&3" JT OPU SFDPNNFOEFE GPS QBUJFOUT MFTT UIBO ZFBST PG BHF CFDBVTF OPU BMM UIF JOEJWJEVBM DPNQPOFOUT PG UIF $0.1-&3" IBWF TBGFUZ FGĂĽDBDZ BOE EPTJOH SFDPNNFOEBUJPOT BWBJMBCMF GPS BMM QFEJBUSJD BHF HSPVQT Geriatric Use Clinical studies of emtricitabine, rilpivirine, or tenofovir DF did not include TVGĂĽDJFOU OVNCFST PG TVCKFDUT BHFE BOE PWFS UP EFUFSNJOF XIFUIFS UIFZ 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 [See Clinical Pharmacology]] Renal Impairment #FDBVTF $0.1-&3" JT B ĂĽYFE EPTF DPNCJOBUJPO JU TIPVME OPU CF prescribed for patients requiring dosage adjustment such as those with moderate, severe or end stage renal impairment (creatinine clearance below 50 mL per minute) or that require dialysis [See Warnings and Precautions]] Hepatic Impairment /P EPTF BEKVTUNFOU PG $0.1-&3" JT SFRVJSFE JO QBUJFOUT XJUI NJME (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic JNQBJSNFOU $0.1-&3" IBT OPU CFFO TUVEJFE JO QBUJFOUT XJUI TFWFSF hepatic impairment (Child-Pugh Class C). OVERDOSAGE If overdose occurs the patient must be monitored for evidence of toxicity. 5SFBUNFOU PG PWFSEPTF XJUI $0.1-&3" DPOTJTUT PG HFOFSBM TVQQPSUJWF NFBTVSFT JODMVEJOH NPOJUPSJOH PG WJUBM TJHOT BOE &$( 25 JOUFSWBM BT XFMM as observation of the clinical status of the patient. *TTVFE +VOF

$0.1-&3" UIF $0.1-&3" -PHP &.53*7" (*-&"% UIF (*-&"% -PHP (4* )&14&3" 453*#*-% UIF 453*#*-% -PHP 5367"%" BOE 7*3&"% BSF USBEFNBSLT PG (JMFBE 4DJFODFT *OD PS JUT SFMBUFE DPNQBOJFT "53*1-" JT B USBEFNBSL PG #SJTUPM .ZFST 4RVJCC (JMFBE 4DJFODFT --$ "MM PUIFS trademarks are the property of their respective owners. ÂŠ2013 Gilead Sciences, Inc. All rights reserved. PTFP0026 07/13

Dear Readers: Welcome to the 2013 issue of Infectious Disease Special Edition. This annual print publication consists of clinical reviews written by leading experts and researchers. Topical stories about global health issues are covered on our website, www.IDSE.net. A few exciting developments occurred over the past 12 months. Research into a cure for HIV pressed forward, with several adults and infants now considered to be “functionally cured” of their infection. New options for HIV antiretroviral therapy also were approved, including dolutegravir, elvitegravir, and the combination regimen Stribild. Additionally, clinical trials shed further light on the potential for interferon-free regimens for hepatitis C virus, as well as the optimal treatment regimen and duration for various genotypes. However, novel pathogens such as the Middle East respiratory system coronavirus continue to threaten global health. Outbreaks from these hypervirulent strains pose a significant risk for pandemics, but unified public health efforts have proven effective in the control of such scenarios. This point was driven home recently when my otherwise healthy uncle suddenly came down with severe flu-like symptoms and required hospitalization. After a short battery of tests, he was quickly diagnosed with West Nile meningitis, which I directly attribute to effective disease surveillance and awareness efforts across Long Island, New York, the area he calls home. As always, this publication would not be possible without the efforts of its authors, who not only spend their time on the front lines of care, but also believe in continuing the dialogue therein to increase awareness about global health issues. I’d also like to thank the esteemed members of our advisory board for providing suggestions on pertinent subject matter for our readers each year. On behalf of the IDSE E team, we hope you enjoy the 2013 issue. Thanks a s for o reading, ea

Seth Kandel Managing Editor skandel@mcmahonmed.com (212) 957-5300, ext. 342

I N D E P E N D E N T LY D E V E LO P E D BY M C M A H O N P U B L I S H I N G

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Revisiting Environmental Hygiene and Hospital-Acquired Infections

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

he role of environmental hygiene in preventing hospital-acquired infections (HAIs) has been a controversial topic.1,2 It was widely accepted that the bulk of HAIs were the result of transmission

from one patient to another via the contaminated hands of caregivers or contaminated equipment that was sequentially used on patients.

However, the role of noncritical environmental surfaces as a reservoir for nosocomial pathogens to contaminate the hands of health care providers and subsequently infect patients remained undefined. Of note, a literature survey published less than 10 years ago concluded that there was no evidence to support environmental hygiene practices as a method for reducing HAIs.3 The past 10 years have seen a progressive accumulation of evidence that clearly established environmental reservoirs of nosocomial pathogens as a cause of HAIs, and this information was used to shape what has become the foundation of currently recommended hospital-based environmental hygiene practices.

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It had long been appreciated that shortly after being placed into a patient room, individuals shed bacterial organisms that contaminated environmental surfaces, including those thought to be involved in horizontal transmission and HAIs such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Acinetobacter and other gram-negative bacteria, and Clostridium difficile spores.2,3 Additional research also documented that these organisms can persist on environmental surfaces for weeks or even months.4 Culture sampling demonstrated that certain surfaces carried a much higher bacterial bioburden than others, a consequence of more frequent contact with

INFECTIOUS DISEASE SPECIAL EDITION 2013

Table 1. Objective Methods to Evaluate Environmental Hygiene Practice Method

Confirms Assesses Difficulty Pathogens Cleaning

Direct observation

High

Yes

Swab culture

Low

Yes

Possibly

Agar slide culture

Medium

Limited

Possibly

Fluorescent markers

Low

Yes

Adenosine triphosphate bioluminescence

Low

Possibly

Based on reference 14.

patients. A conceptual model of â&#x20AC;&#x153;high-touchâ&#x20AC;? surfaces evolved from these findings, which included the identification of key environmental surfaces in frequent contact with patients and health care workers such as bed rails, door knobs, etc.5-7 Subsequent studies have documented that routine cleaning and disinfection substantially reduces contamination and could be useful in controlling outbreaks.3,8-11 A landmark study published in 2013 reported that the risk for nosocomial infections could be substantially reduced by the use of environmental hygiene strategies that reduce the bacterial bioburden on high-touch room surfaces.12 A number of recent studies have documented that patients who were placed in rooms previously occupied by individuals infected or colonized with VRE, MRSA, C. difficile, or Acinetobacter were 73% more likely to acquire the same pathogens than patients who did not occupy such rooms.3,13 Bacterial strain typing often confirmed this chain of transmission. These findings strongly supported terminal cleaning, the practice of cleaning and disinfecting all room surfaces following patient transfer or discharge before use by a new patient. Current guidelines now encourage hospitals to develop programs for cleaning and disinfecting hightouch surfaces as part of terminal room cleaning using a properly applied, Environmental Protection Agency (EPA)-approved germicide.14,15

Monitoring Compliance Establishing a monitoring program for periodic or ongoing assessments of environmental hygiene practices has been shown to significantly improve compliance with hospital policies and protocols. An environmental cleaning toolkit released in 2010 by the Centers for Disease Control and Prevention encouraged hospitals to create such programs as an adjunct to terminal room cleaning to ensure high-touch surfaces are

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thoroughly cleaned.14 The toolkit further advocates for an objective assessment of hygiene practices and outlines a variety of approaches and technologies to accomplish this task (Table 1).14 Covert direct observation can provide an objective assessment of compliance with cleaning protocols and is the most frequently used monitoring tool in US hospitals. The process is labor intensive, should employ a checklist, and in actuality is quite difficult to accomplish in a covert fashion. As a result, data generated from this method is not likely to reflect or measure true hygiene practices. Serial swab cultures of environmental surfaces also can be used as a monitoring tool. Although samples are easy to acquire, processing costs and turnaround delays limit the practicality of this method as a monitoring tool. Furthermore, given the lack of established, concrete cutoffs to serve as a baseline for acceptable results, precleaning contamination levels must be determined for each surface to assess compliance with environmental cleaning policy. Agar slide cultures have been adapted for environmental surface monitoring in hospitals and are capable of quantifying aerobic colony counts (ACCs) per cm2. This technique is largely limited to culturing large flat surfaces and also requires measurements of precleaning contamination levels in order to assess the efficacy of environmental cleaning practices. Fluorescent markers also have been developed to assess hygiene practices.14,16 This commercially available method involves the application of a fluorescent gel to target surfaces, which becomes transparent after drying. Following room cleaning, ultraviolet (UV) light will expose any areas that were not adequately cleaned. There is widespread hospital experience with the use of these markers, and a number of studies have demonstrated their accuracy for objectively evaluating environmental hygiene practices.16 A second commercially available solution is the adenosine triphosphate (ATP) bioluminescence assay, which measures ATP on surfaces using a luciferase assay and luminometer.14 A specialized swab is used to sample a targeted surface area, which is then analyzed using a portable handheld luminometer. The total amount of ATP, both microbial and nonmicrobial, is expressed as relative light units. Low readings have shown a reasonable correlation with low ACCs, but very high readings may indicate bacterial contamination, organic debris containing dead bacteria, or both. Moreover, high concentrations of liquid bleach disinfectant can interfere with the assay and may result in reduced signal strength. Again, the lack of a threshold cutoff value requires an assessment of precleaning ATP levels to properly interpret results. ATP systems have proven effective for documenting improvements in daily cleaning practices for high-touch surfaces.14

Assessing Current Practice Despite existing recommendations for hospitals to establish environmental hygiene programs and monitor

their effectiveness, suboptimal practices are common.13,17 Studies have established that terminal cleaning is about 49% effective; however, success rates for high-touch surfaces show significant variation, ranging from 30% to more than 75%.13 A recent survey of infection preventionists documented that many continue to rely on direct observation to monitor environmental cleaning practices (employed by 70% of respondents on a daily, weekly, or monthly basis) as well as poor uptake of fluorescent gel or ATP systems (used by 26% to 28% of respondents on a daily, weekly, or monthly basis).13 Other recent studies have documented that even when aggressive interventions are employed, including intensive staff education and the use of newer, objective-based evaluation techniques with performance feedback, efficacy rates for high-touch surface cleaning remain in the range of 77% to 82%.13 Although these studies have documented that cleaning and disinfection need to be improved in US health care settings as part of efforts to prevent nosocomial infections, they also have resulted in the development and introduction of a variety of new technologies.

Emerging Technologies The past 5 years have seen the rapid development of emerging technologies designed to enhance environmental hygiene practice. The proliferation of products is almost bewildering, and the pace at which new technologies are being introduced is accelerating rapidly. This section is not intended to provide an all-inclusive overview of every technology in development; instead, it will provide a broad overview of currently available technologies and the level of evidence supporting their use. Infection control practitioners should appreciate the need to revisit emerging technologies on an ongoing basis and should stay abreast of the burgeoning amount of literature that continues to surface regarding their performance and effectiveness. It also should be stressed that current recommendations and guidelines consider these products as adjuncts, rather than replacements, to existing environmental hygiene programs and practices. Products and strategies have been divided into 4 categories for discussion: disinfectants and cleaning tools; soft-surface disinfection; hard-surface disinfection; and whole-room disinfection.

DISINFECTANTS

AND

CLEANING TOOLS

Products in this category are summarized in Table 2. The development of new disinfectants is largely driven by a desire to decrease the long wet-contact time required with the use of iodine-based or quaternary disinfectants (ie, up to 10 minutes) and their apparent inability to optimally disinfect C. difficile spores. Current recommendations for C. difficile disinfection rely on the use of a 5% to 6% sodium hypochlorite solution (ie, household bleach), which is corrosive to environmental fixtures, bleaches fabrics, and carries occupational exposure risks. The advantage of slow-release chlorine products is that, although they are fast acting, they exert

Table 2. Disinfectants and Cleaning Tools • Demand-release chlorine disinfectants – Chlorine dioxide – Sodium dichloroisocyanurate – Chloramine-T7 • Superoxidized water • Microfiber mops • Microfiber wipes

a prolonged bactericidal effect.15 Unfortunately, they still retain the potential to damage equipment and facilities. Another option is superoxidized water, which is created when saline is electrolyzed to produce a solution of hypochlorous acid and chlorine, with free chlorine the active microbicide.15 Point-of-use production systems are commercially available, but they are expensive and complicated to operate.15 The solutions appear to have a 48-hour shelf life.15 The product is FDA-approved for high-level disinfection, but further study of its application as an environmental disinfectant is required. Microfiber mops and microfiber wipe cloths have a long history of use in hospitals. Both products are made of a blend of microscopic polyester and polyamide fibers, which are split to create microscopic hooks that collect and retain dust, dirt, and bacteria. Microfiber mops have been demonstrated to have superior efficacy in reducing microbial levels on floors compared with conventional, cotton string mops, and achieved 95% efficacy.18 Furthermore, performance did not improve when they were used with a disinfectant. Microfiber mops are less work intensive than conventional mops, eliminate issues of cross contamination during environmental cleaning, and drastically reduce the use of water and chemicals due to more efficient cleaning and disinfection. Similarly, microfiber cleaning cloths have consistently outperformed conventional cloths in their ability to decontaminate across all surfaces, even when bacteria were coated on to the surfaces with phosphate-buffered saline (PBS) or PBS–containing horse serum.19 Designed to be used without detergents or biocides, they have been shown to effectively decontaminate hard surfaces seeded with S. aureus, Escherichia coli, and C. difficile spores under simulated conditions. An additional study compared the efficacy of 10 different microfiber cloths (9 reusable) under simulated conditions and found comparable performance among the products, even after 150 washes.20 Although the Joint Commission and the EPA have advocated for these products, continued research to evaluate their performance in real-world clinical settings is required, as well as to determine if their use can reduce HAI rates.

SOFT-SURFACE DISINFECTION Soft-surface disinfection strategies include fabric impregnation with copper or silver to take advantage

INFECTIOUS DISEASE SPECIAL EDITION 2013

Table 3. Soft-Surface Technologies

Table 4. Hard-Surface Technologies

• Copper oxide impregnation

• Copper and copper alloy cladding

• Citric acid impregnation

• Silver iodide and modified polyhexamethlyene biguanide coating

• Organosilane-based quaternary ammonium impregnation • Silver-impregnated yarn

• Silver nanoparticle incorporation • Triclosan incorporation • Quaternary ammonium salt surfactant coating • Microtopography surface • Light-activated antimicrobial coatings

of their intrinsic antimicrobial properties, citric acid impregnation of cotton cloth, and organosilane-based quaternary ammonium impregnation of fabric materials (Table 3).21 These materials have been used to produce scrubs, uniforms, linens, and privacy curtains. A doubleblind, randomized controlled trial (RCT) evaluating the use of antimicrobial-impregnated privacy curtains in the ICU setting showed a significant delay in time to colonization and an 8-fold reduction in the risk for VRE contamination compared with standard fabric curtains.21 Similarly, an ICU-based, blind, randomized crossover trial evaluating the efficacy of organosilane-based quaternary ammonium-impregnated scrub suits reported a significant reduction in MRSA contamination, with little effect on the burden of VRE or gram-negative rods.22 Further investigation is warranted to demonstrate the ability of these products to consistently perform under clinical conditions, followed by clinical trials to measure their effect on HAI rates.

HARD-SURFACE DISINFECTION Hard-surface disinfection technologies are summarized in Table 4. Copper and copper alloy cladding of high-touch hard surfaces takes advantage of the natural antimicrobial properties of copper to significantly reduce high bacterial bioburden within 2 hours.23 Copper and copper alloy surfaces have demonstrated activity against a broad spectrum of bacteria, including nosocomial pathogens known to be transmissible from environmental reservoirs. Furthermore, copper technologies provide continuous bacterial disinfection on all surfaces where it is employed. More than 200 publications have documented its potent antimicrobial activity in both simulated and actual clinical conditions. A recent RCT conducted in 3 hospitals reported a significant reduction in HAIs when copper technologies were used in conjunction with an aggressive environmental hygiene program.12 A variety of copper-based products are commercially available, including countertops, IV poles, handles, support railings, bed rails, and sinks. The principal factor that limits the widespread adoption of this technology is its high cost. Similarly, silver iodide and silver nanoparticles also are being used to develop hard surfaces with intrinsic antimicrobial activity. Silver iodide–based coatings will need to demonstrate the ability to persist after repeated washings, and they also need to verify their disinfection efficacy in both simulated and actual

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– Cellulose acetate–containing toluidine blue O and rose Bengal – Silicon polymer–containing methylene blue and gold nanoparticles – Titanium dioxide coating

clinical conditions. Silver nanotechnology products are still in early development stages. Disinfectant-based hard-surface technologies include the incorporation of triclosan into surfaces and the use of quaternary ammonium salt surfactants as a coating on hard surfaces. Triclosan-based products already have been proven to have limited application in the health care environment.23 Triclosan has a limited spectrum of antimicrobial activity and there is mounting evidence that bacteria can become triclosan-resistant in the setting of continued exposure. Triclosan-impregnated products are now primarily marketed for household use. Quaternary ammonium salt surfactants are in early development and, like all surface-coating technologies, they will need to demonstrate durability as well as efficacy. The final category of hard-surface disinfectants includes a group of light-activated antimicrobial compounds. Titanium dioxide is the most developed product, with considerable prior use in food, toothpaste, and tooth-whitening preparations, and as a disinfectant in Japanese health care environments. Titanium dioxide is produced by crystallizing titanic iron ore into a nanoliquid form. When exposed to UV light in the sub400 nm range, it becomes a photocatalyst oxidizer that produces hydroxyl radicals and superoxide ions with potent antimicrobial activity. Patented technologies now allow for the nanoliquid to penetrate and form permanent bonds with the surface that last for years. Titanium dioxide has required exposure to sunlight or UV light for maximum antimicrobial activity, and it has shown a broad spectrum of antibacterial activity, although this effect is slower in decontaminating spores. The addition of zinc to the preparation has now provided effective antimicrobial action after exposure to indoor lighting of any type, which provides continuous disinfection as long as room lighting is in use. A single application remains active on heavily used surfaces even after 1 year. Now marketed in the United States for disinfection in the health care setting, it will be interesting to see what efficacy information becomes available.

Table 5. Whole-Room Technologies • UV light • Combination of ozone/UV light/hepafiltration • Hydrogen peroxide vapor or aerosolization • Titanium dioxide spray UV, ultraviolet

WHOLE-ROOM DISINFECTION Table 5 summarizes approaches to environmental disinfection using whole-room technology. As a group, they (with the exception of titanium dioxide) employ devices placed in patient rooms and all use toxic technologies that prohibit patient or staff occupancy during the disinfection process. As a result, they all are limited to use as adjunct disinfection technologies during terminal room cleaning between patients. Disinfection cycle duration times will effect room turnover times, and this should be a consideration in addition to disinfection efficacy rates. UV light room disinfection is probably the most studied of the whole-room technologies, and the products build on a long history of the use of UV light to disinfect well water, circulating dialysis fluid, and room air for tuberculosis control. Numerous products are commercially available and all employ the use of lowpressure mercury or xenon vapor lamps to generate UV light in the germicidally active wavelength range of 200 to 320 nm.24,25 Shortwave UV-C radiation, primarily at 254 nm, kills by damaging DNA. Photon absorption leads to formation of pyrimidine dimers between adjacent thymine bases in DNA, rendering the microbe incapable of replication. These technologies offer broad-spectrum microbicidal activity, including C. difficile spores.24 A typically sized hospital patient room can be disinfected within 10 minutes, minimally affecting room turnaround times during terminal cleaning. The principal issue with UV light disinfection is that it provides for “line-of-sight” killing—meaning it does not work in shadowed areas and does not penetrate fabrics well—and there is no evidence that lack of a proper room cleaning before UV light disinfection can markedly reduce its efficacy.24 Line-of-sight killing has been addressed through the use of careful device placement in the room, rotating the light source, and UV-reflective shields and wall paint.24,27 One manufacturer provides indicators that can be placed in potential problem areas in the room and are capable of monitoring for appropriate UV light exposure. UV light has proven effective as a hospital room disinfectant, reliably reducing the bacterial bioburden of a wide spectrum of pathogens under simulated and real-time clinical situations (provided the room is cleaned first). However, its ability to reduce HAI rates has yet to be studied.

Several systems have been developed that produce hydrogen peroxide vapor, aerosolized dry-mist hydrogen peroxide, or vaporized hydrogen peroxide for whole-room disinfection. Hydrogen peroxide is converted by catalysis after bacterial contact to generate free oxygen radicals with rapid bactericidal activity. Under simulated and real-time clinical conditions, hydrogen peroxide has demonstrated broad-spectrum activity as a disinfectant, including the rapid decontamination of spores. Whole-room treatment leaves no residue.28 When used as a follow-up to bleach disinfection, whole-room disinfection is extremely effective. In a retrospective study conducted in 334 patient rooms previously occupied with individuals infected with C. difficile, use of hydrogen peroxide vapor within the terminal cleaning program reduced nosocomial infection rates from 0.88 to 0.55 cases per 1,000 patient-days.29 Of note, the hydrogen peroxide intervention was only used in 54% of rooms. Additional evidence suggests that hydrogen peroxide room disinfection can reduce VRE infection rates, but 2 studies have now identified that the process may not be as effective in reducing MRSA infection rates.30,31 It has been suggested that this may be related to the fact that MRSA are catalase-producing organisms. Similar to UV room disinfection technologies, hydrogen peroxide room disinfection carries a significant capital expenditure cost and requires the removal of surface debris before use. Finally, titanium dioxide/zinc technologies have been developed and marketed as methods of wholeroom disinfection. The technologies and means of action already have been discussed above. Beyond hard surfaces, the products also can be sprayed onto soft surfaces and brushed into fabrics to provide a long-lasting, broad-spectrum biocidal coating. A single room application would cost less than $650 and last for 1 year. The room only needs to be vacant during the application process, and these products offer continuous room disinfection whenever room lights are on, providing a biocidal disinfectant action far beyond a terminal cleaning technology. This product is in clinical testing and efficacy data should be available in the near future. A combined ozone/UV light/ hepafiltration technology product also is commercially available and requires further evaluation.

Conclusion Accumulating evidence has established that bacterial contamination of the physical hospital environment can serve as a reservoir for transmission to patients and can contribute to the acquisition of HAIs. Study findings have been used to shape current recommendations for environmental hygiene interventions, but achieving a high degree of compliance with guidelines has proven difficult. Emerging environmental hygiene technologies may provide important adjunct interventions in helping to achieve these goals.

INFECTIOUS DISEASE SPECIAL EDITION 2013

References 1.

Rutala WA, Weber DJ. Surface disinfection: should we do it? J Hosp Infect. 2001;48(suppl A):S64-S68.

2. Donskey C. Does improving surface cleaning and disinfection reduce health care-associated infections? Am J Infect Control. 2013;41(5 suppl):S12-S19. 3. Hota B. Contamination, disinfection and cross colonization: are hospital surfaces reservoirs for nosocomial infection? Clin Infect Dis. 2004;39:1182-1189. 4. Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infect Dis. 2006;6:130. 5. Carling PC, Briggs JL, Perkins J, et al. Improved cleaning of patient rooms using a new targeting method. Clin Infect Dis. 2006;42(3): 385-388. 6. Huslage K, Rutala W, Sickbert-Bennett E, et al. A quantitative approach to disinfecting â&#x20AC;&#x153;high-touchâ&#x20AC;? surfaces in hospitals. Infect Control Hosp Epidemiol. 2010;31(1):850-853. 7. Moore G, Muzlay M, Wilson A. The type, level, and distribution of microorganisms within the ward environment: a zonal analysis of an intensive care unit and a gastrointestinal surgical ward. Infect Control Hosp Epidemiol. 2013;34(5):500-506. 8. Sitzlar B, Deshpande A, Fertelli D, et al. An environmental disinfection odyssey: evaluation of sequential interventions to improve disinfection of Clostridium difficile isolation rooms. Infect Control Hosp Epidemiol. 2013;34(5):459-465. 9. Weber DJ, Rutala WA. Understanding and preventing transmission of healthcare-associated pathogens due to the contaminated hospital environment. Infect Control Hosp Epidemiol. 2013;34(5): 449-452. 10. Weber DJ, Rutala WA, Miller MB, et al. Role of hospital surfaces in the transmission of emerging health care-associated pathogens: norovirus, Clostridium difficile, and Acinetobacterr species. Am J Infect Control. 2010;38(5 suppl):S25-S33. 11. Goodman E, Platt R, Bass R, et al. Impact of an environmental cleaning intervention on the presence of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci on the surfaces in intensive care unit rooms. Infect Control Hosp Epidemiol. 2008;29(7):593-599. 12. Salgado CD, Sepkowitz KA, John JF, et al. Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit. Infect Control Hosp Epidemiol. 2013;34(5):479-486. 13. Pyrek K. Environmental cleaning and monitoring for infection prevention. http://www.infectioncontroltoday.com/reports/2013/05/ importance-of-environmental-cleaning.aspx?endpointurl=/lib/ download.ashx?id=1190. Accessed August 14, 2013. 14. Centers for Disease Control and Prevention. Options for evaluating environmental cleaning. http://www.cdc.gov/HAI/pdfs/ toolkits/Environ-Cleaning-Eval-Toolkit12-2-2010.pdf. Accessed August 14, 2013. 15. Centers for Disease Control and Prevention. Guideline for disinfection and sterilization in healthcare facilities, 2008. http://www.cdc. gov/hicpac/pdf/guidelines/Disinfection_Nov_2008.pdf. Accessed August 14, 2013. 16. Boyce JM, Havill NL, Havill HL, et al. Comparison of fluorescent marker systems with 2 quantitative methods of assessing terminal cleaning practices. Infect Control Hosp Epidemiol. 2011;32(12): 1187-1193.

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17. Carling PC, Parry MF, Von Beheren SM; Healthcare Environmental Hygiene Study Group. Identifying opportunities to enhance environmental cleaning in 23 acute care hospitals. Infect Control Hosp Epidemiol. 2008;29(1):1-7. 18. Rutala WA, Gergen MF, Weber DJ. Microbiologic evaluation of microfiber mops for surface disinfection. Am J Infect Control. 2007;35(9):569-573. 19. Wren MV, Rollins MS, Jeanes A, et al. Removing bacteria from hospital surfaces: a laboratory comparison of ultramicrofibre and standard cloths. J Hosp Infect. 2008;70(3):265-271. 20. Smith D, Gillanders S, Holah J, et al. Assessing the efficacy of different microbibre cloths at removing surface micro-organisms associated with healthcare-associated infections. J Hosp Infect. 2011;78(3):182-186. 21. Schweizer M, Graham M, Ohl M, et al. Novel hospital curtains with antimicrobial properties: a randomized, controlled trial. Infect Control Hosp Epidemiol. 2012;33(11):1081-1085. 22. Bearman G, Rosato A, Elam K, et al. A crossover trial of antimicrobial scrubs to reduce methicillin-resistant Staphylococcus aureus burden on healthcare worker apparel. Infect Control Hosp Epidemiol. 2012;33(3):268-275. 23. Weber DJ, Rutala WA. Self-disinfecting surfaces. Infect Control Hosp Epidemiol. 2012;33(1):10-13. 24. Rutala WA, Gregen MF, Weber DJ. Room decontamination with UV radiation. Infect Control Hosp Epidemiol. 2010;31(10):1025-1029. 25. Levin J, Riley L, Parrish C, et al. The effect of portable pulsed xenon ultraviolet light after terminal cleaning on hospital-associated Clostridium difficile infection in a community hospital. Am J Infect Control. 2013;41(8):746-748. 26. Andersen DJ, Gergen MF, Smathers E, et al. Decontamination of targeted pathogens from patient rooms using an automated ultraviolet-C-emitting device. Infect Control Hosp Epidemiol. 2013;34(5):466-471. 27. Rutala WA, Gregen MF, Tande BM, et al. Rapid hospital room decontamination using ultraviolet (UV) light with a nanostructered UV reflective wall coating. Infect Control Hosp Epidemiol. 2013;34(5): 527-529. 28. Rutala W, Weber D. Disinfectants used for environmental disinfection and new room decontamination technology. Am J Infect Control. 2013;41(5 suppl):S36-S41. 29. Manian F, Griesnauer S, Bryant A. Implementation of hospitalwide enhanced terminal cleaning of targeted patient rooms and its impact on endemic Clostridium difficile infection rates. Am J Infect Control. 2013;41(6):537-541. 30. Pottage T, Macken S, Walker J, et al. Methicillin-resistant Staphylococcus aureus is more resistant to vaporized hydrogen peroxide than commercial Geobacillus stearothermophilus biological indicators. J Hosp Infect. 2012;80(1):41-45. 31. Passaretti CL, Otter JA, Reich NG, et al. An evaluation of environmental decontamination with hydrogen peroxide vapor for reducing the risk of patient acquisition of multi-resistant organisms. Clin Infect Dis. 2013;56(1):27-35.

Dr. Currie reported that he serves on the advisory board for Clorox and has received grant support from the Agency for Healthcare Research and Quality.

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Now with data through

96 WEEKS Efficacy

Safety and tolerability profile

Drug interaction profile

INDICATION AND USAGE COMPLERA (emtricitabine 200mg/rilpivirine 25mg/tenofovir disoproxil fumarate 300mg) is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naïve adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. This indication is based on safety and efﬁcacy analyses through 96 Weeks from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects. The following points should be considered when initiating therapy with COMPLERA: • More rilpivirine-treated subjects with HIV-1 RNA greater than 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 less than or equal to 100,000 copies/mL • Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to subjects with CD4+ cell count greater than or equal to 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 • COMPLERA is not recommended for patients less than 18 years of age

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, 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 EMTRIVA® (emtricitabine) or VIREAD® (tenofovir disoproxil fumarate), 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 Please see additional Important Safety Information and Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages. NNRTI=non-nucleoside reverse transcriptase inhibitor.

Pregnancy category

Lipid profile

Single tablet regimen dosing*

*Taken with a meal.

For treatment-naïve adult patients with HIV-1 RNA ≤100,000 copies/mL at the start of therapy

One Complete Treatment Option Visit complera.com/hcp for the updates

IMPORTANT SAFETY INFORMATION (CONT) Contraindications • Coadministration: COMPLERA should not be coadministered with drugs that induce CYP3A enzyme or increase gastric pH as loss of virologic response and possible resistance may occur. Use of the following drugs with COMPLERA is contraindicated: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, proton pump inhibitors (such as esomeprazole, lansoprazole, dexlansoprazole, omeprazole, pantoprazole, rabeprazole), dexamethasone (more than a single dose) and Hypericum perforatum (St. John’s wort) Warnings and Precautions • New onset or worsening renal impairment: Renal impairment, including cases of acute renal failure and Fanconi syndrome may occur. Assess creatinine clearance (CrCl) before initiating treatment with COMPLERA. Monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. Patients with CrCl below 50 mL per minute should not receive COMPLERA • 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 in healthy subjects Please see the full Prescribing Information and below for more information about potential drug interactions with COMPLERA. • Depressive disorders: Depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with rilpivirine. The incidence of depressive disorders reported through 96 Weeks among rilpivirine (N=686) or efavirenz (N=682) was 9% and 8%, respectively in Phase 3 trials. Most events were mild or moderate in severity. Grade 3 and 4 depressive disorders (regardless of causality) were reported at 1% in both study arms. Suicide attempt was reported in 2 subjects and suicide ideation was reported in 4 subjects treated with rilpivirine. 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 in patients on a rilpivirine regimen. Patients with underlying liver disease and those with marked elevations in serum liver biochemistries may be at increased risk. Appropriate laboratory testing and monitoring should be undertaken for all patients before and during therapy with COMPLERA, as hepatic toxicity has been reported in patients without underlying liver disease or risk factors • Decreases in bone mineral density (BMD) and cases of osteomalacia have been seen in patients treated with tenofovir disoproxil fumarate (DF). Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for osteoporosis or bone loss • Coadministration with other antiretroviral products: Do not administer concurrently with other products containing any of the same active components (emtricitabine, rilpivirine, or tenofovir DF) or with products containing lamivudine or adefovir dipivoxil • Fat redistribution/accumulation has been observed in patients receiving antiretroviral therapy

• Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable times to onset, has been reported Adverse Reactions • The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) were depressive disorders, insomnia and headache • The most common adverse drug reactions to emtricitabine and tenofovir DF (incidence ≥10%) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash Drug Interactions • COMPLERA is a complete treatment regimen for treating HIV-1 infection and should not be coadministered with other antiretroviral agents • Drugs inducing or inhibiting CYP3A: Drugs which induce CYP3A enzymes should not be coadministered with COMPLERA due to potential for loss of virologic response and/or resistance. (See CONTRAINDICATIONS). Coadministration of COMPLERA with drugs that inhibit CYP3A may increase rilpivirine plasma concentrations - Potentially significant drug interactions may occur with azole antifungal agents and macrolide/ketolide antibiotics coadministered with rilpivirine by increasing plasma concentrations of rilpivirine (due to inhibition of CYP3A enzymes). Clinical monitoring is recommended when coadministering COMPLERA with methadone • Drugs increasing gastric pH may cause significant decreases in rilpivirine plasma concentrations (See CONTRAINDICATIONS) - Antacids should be administered at least 2 hrs before or 4 hrs after COMPLERA - H2 Receptor antagonists should be administered 12 hrs before or 4 hrs after COMPLERA • Drugs affecting renal function: Caution should be used when coadministering COMPLERA with drugs that reduce renal function or compete for active tubular secretion. Examples include acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir • QT prolonging drugs: Supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the EKG in healthy subjects Please see full Prescribing Information for more information about potential drug interactions with COMPLERA. Pregnancy and Breastfeeding • Pregnancy Category B: There are no adequate and wellcontrolled studies in pregnant women. Use during pregnancy only if potential benefits justifies the potential risk. An Antiretroviral Pregnancy Registry has been established • Breastfeeding: Mothers with HIV should be instructed not to breastfeed due to the potential for HIV transmission. Because emtricitabine and tenofovir have been detected in human milk, the risk to the infant is unknown Dosing and Administration Adults: The recommended dose of COMPLERA is one tablet taken orally once daily with a meal. Renal Impairment: Do not use with patients requiring dose adjustment or with patients with creatinine clearance below 50 mL per minute. Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages. ®

COMPLERAÂŽ (emtricitabine 200 mg/rilpivirine g p 25 mg/tenofovir g disoproxil p fumarate 300 mg) tablets Brief Coadministration with Other Products: COMPLERA should not be administered concurrently with other medicinal products containing any of UIF TBNF BDUJWF DPNQPOFOUT FNUSJDJUBCJOF SJMQJWJSJOF PS UFOPGPWJS %' "53*1-" &EVSBOU &.53*7" 453*#*-% 5367"%" 7*3&"% XJUI NFEJDJOBM Summary of full prescribing information. See full prescribing information. Rx Only. QSPEVDUT DPOUBJOJOH MBNJWVEJOF &1*7*3 &1*7*3 )#7 &1;*$0. $0.#*7*3 53*;*7*3 PS XJUI BEFGPWJS EJQJWPYJM )&14&3" WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS Fat Redistribution: Redistribution/accumulation / of bodyy fat includingg central obesity,y dorsocervical fat enlargement (buffalo hump), peripheral and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The Lactic acidosis and severe hepatomegaly p g y with steatosis, includingg fatal cases, have been reported p with the mechanism and long-term consequences of these events are unknown. A causal relationship has not been established. use of nucleoside analogs, g includingg tenofovir disoproxil p fumarate, a component of COMPLERA, in Immune Reconstitution Syndrome: y Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral combination with other antiretrovirals [See Warnings g and Precautions]]. UIFSBQZ JODMVEJOH UIF DPNQPOFOUT PG $0.1-&3" %VSJOH UIF JOJUJBM QIBTF PG DPNCJOBUJPO BOUJSFUSPWJSBM USFBUNFOU QBUJFOUT XIPTF JNNVOF TZTUFN COMPLERA is not approved pp for the treatment of chronic hepatitis p B virus (HBV) infection and the safetyy and responds may develop an inďŹ&#x201A;ammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium m infection, efďŹ cacyy of COMPLERA have not been established in ppatients coinfected with HBV and HIV-1. Severe acute cytomegalovirus, Pneumocystis jiroveciii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune exacerbations of hepatitis p B have been reported p in ppatients who are coinfected with HBV and HIV-1 and have EJTPSEFST TVDI BT (SBWFT EJTFBTF QPMZNZPTJUJT BOE (VJMMJBO #BSSĂ? TZOESPNF IBWF BMTP CFFO SFQPSUFE UP PDDVS JO UIF TFUUJOH PG JNNVOF SFDPOTUJUVUJPO discontinued EMTRIVA or VIREAD, which are components p of COMPLERA. Hepatic p function should be however, the time to onset is more variable, and can occur many months after initiation of treatment. monitored closelyy with both clinical and laboratoryy follow-upp for at least several months in ppatients who are ADVERSE REACTIONS coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B See BOXED WARNINGSS and WARNINGS AND PRECAUTIONSS sections for additional serious adverse reactions. therapy may be warranted [See Warnings and Precautions]. ] Adverse Reactions from Clinical Trials Experience: p 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 reďŹ&#x201A;ect the rates INDICATIONS AND USAGE COMPLERAÂŽ (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) is indicated for use as a complete regimen for the treatment of HIV-1 infection observed in practice. Studies C209 and C2155 o Treatment-Emergent Adverse Drug Reactions:: The safety assessment of rilpivirine, used in combination with other in antiretroviral treatment-naive adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.y BOUJSFUSPWJSBM ESVHT JT CBTFE PO UIF 8FFL QPPMFE EBUB GSPN QBUJFOUT JO UIF 1IBTF USJBMT 5.$ $ &$)0 BOE 5.$ $ 5)3*7& This indication is based on safety and efďŹ cacy analyses through 96 weeks from 2 randomized, double blind, active controlled, Phase 3 trials in in antiretroviral treatment-naive HIV-1 infected adult patients. A total of 686 patients received rilpivirine in combination with other antiretroviral drugs as treatment-naive subjects. CBDLHSPVOE SFHJNFO NPTU / SFDFJWFE FNUSJDJUBCJOF UFOPGPWJS %' BT CBDLHSPVOE SFHJNFO 5IF OVNCFS PG TVCKFDUT SBOEPNJ[FE H UP UIF DPOUSPM The following points should be considered when initiating therapy with COMPLERA: BSN FGBWJSFO[ XBT PG XIJDI SFDFJWFE FNUSJDJUBCJOF UFOPGPWJS %' BT CBDLHSPVOE SFHJNFO 5IF NFEJBO EVSBUJPO PG FYQPTVSF GPS TVCKFDUT JO t .PSF SJMQJWJSJOF USFBUFE TVCKFDUT XJUI )*7 3/" HSFBUFS UIBO DPQJFT N- BU UIF TUBSU PG UIFSBQZ FYQFSJFODFE WJSPMPHJD GBJMVSF )*7 3/" FJUIFS USFBUNFOU BSN XBT XFFLT â&#x2030;Ľ50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. "EWFSTF ESVH SFBDUJPOT "%3 PCTFSWFE BU 8FFL JO QBUJFOUT XIP SFDFJWFE SJMQJWJSJOF PS FGBWJSFO[ QMVT FNUSJDJUBCJOF UFOPGPWJS %' BT CBDLHSPVOE Q Q t 3FHBSEMFTT PG )*7 3/" MFWFM BU UIF TUBSU PG UIFSBQZ NPSF SJMQJWJSJOF USFBUFE TVCKFDUT XJUI $% DFMM DPVOU MFTT UIBO DFMMT NN3 experienced SFHJNFO BSF TIPXO JO 5BCMF /P OFX UZQFT PG BEWFSTF SFBDUJPOT XFSF JEFOUJmFE CFUXFFO 8FFL BOE 8FFL 5IF BEWFSTF ESVH SFBDUJPOT PCTFSWFE in this subset of patients were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing WJSPMPHJD GBJMVSF DPNQBSFE UP SJMQJWJSJOF USFBUFE TVCKFDUT XJUI $% DFMM DPVOU HSFBUFS UIBO PS FRVBM UP DFMMT NN3. t 5IF PCTFSWFE WJSPMPHJD GBJMVSF SBUF JO SJMQJWJSJOF USFBUFE TVCKFDUT DPOGFSSFE B IJHIFS SBUF PG PWFSBMM USFBUNFOU SFTJTUBODF BOE DSPTT SFTJTUBODF UP UIF JOGPSNBUJPO GPS &%63"/5 5IF QSPQPSUJPO PG TVCKFDUT XIP EJTDPOUJOVFE USFBUNFOU XJUI SJMQJWJSJOF PS FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' EVF UP "%3 SFHBSEMFTT PG TFWFSJUZ XBT NNRTI class compared to efavirenz. 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COMPLERA is not recommended for patients less than 18 years of age [See Use in SpeciďŹ c Populations] TVCKFDU JO UIF SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' BSN BOE TVCKFDUT JO UIF FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' BSN DOSAGE AND ADMINISTRATION Common Adverse Drug Reactions Adults: The recommended dose of COMPLERA is one tablet taken orally once daily with a meal. $MJOJDBM "%3T UP SJMQJWJSJOF PS FGBWJSFO[ PG BU MFBTU NPEFSBUF JOUFOTJUZ Ăś (SBEF SFQPSUFE JO BU MFBTU PG BEVMU TVCKFDUT BSF TIPXO JO 5BCMF Renal Impairment:: Because COMPLERA is a ďŹ xed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with Table 1 Selected Treatment-Emergent p in â&#x2030;Ľ2% of Subjects j Receivingg g Adverse Reactionsa (Grades 2â&#x20AC;&#x201C;4) Reported moderate or severe renal impairment (creatinine clearance below 50 mL per minute). Rilpivirine p or Efavirenz in Combination with Emtricitabine/Tenofovir / DF in Studies C209 and C215 ((Week 96 analysis) y ) Rilpivirine p Efavirenz CONTRAINDICATIONS + FTC/TDF + FTC/TDF COMPLERA should not be coadministered with the following drugs, as signiďŹ cant decreases in rilpivirine plasma concentrations may occur due to N=550 N=546 CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [See Drug Interactions]: Gastrointestinal Disorder /BVTFB t UIF BOUJDPOWVMTBOUT DBSCBNB[FQJOF PYDBSCB[FQJOF QIFOPCBSCJUBM QIFOZUPJO Nervous System y Disorders t UIF BOUJNZDPCBDUFSJBMT SJGBCVUJO SJGBNQJO SJGBQFOUJOF )FBEBDIF t QSPUPO QVNQ JOIJCJUPST TVDI BT FTPNFQSB[PMF MBOTPQSB[PMF EFYMBOTPQSB[PMF PNFQSB[PMF QBOUPQSB[PMF SBCFQSB[PMF %J[[JOFTT t UIF HMVDPDPSUJDPJE TZTUFNJD EFYBNFUIBTPOF NPSF UIBO B TJOHMF EPTF

Psychiatric y Disorders %FQSFTTJWF EJTPSEFSTb t 4U +PIO T XPSU Hypericum perforatum) *OTPNOJB WARNINGS AND PRECAUTIONS "COPSNBM ESFBNT Lactic Acidosis/Severe Hepatomegaly p g y with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have CFFO SFQPSUFE XJUI UIF VTF PG OVDMFPTJEF BOBMPHT JODMVEJOH UFOPGPWJS EJTPQSPYJM GVNBSBUF UFOPGPWJS %' B DPNQPOFOU PG $0.1-&3" JO DPNCJOBUJPO Skin and Subcutaneous Tissue Disorders 3BTI with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be riskk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also B 'SFRVFODJFT PG BEWFSTF SFBDUJPOT BSF CBTFE PO BMM (SBEFT USFBUNFOU FNFSHFOU BEWFSTF FWFOUT BTTFTTFE UP CF SFMBUFE UP TUVEZ ESVH been reported in patients with no known risk factors. Treatment with COMPLERA should be suspended in any patient who develops clinical or laboratory b. Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. ďŹ ndings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked Rilpivirine:: 5SFBUNFOU FNFSHFOU BEWFSTF ESVH SFBDUJPOT PG BU MFBTU NPEFSBUF JOUFOTJUZ Ăś (SBEF UIBU PDDVSSFE JO MFTT UIBO PG TVCKFDUT USFBUFE XJUI SJMQJWJSJOF QMVT BOZ PG UIF BMMPXFE CBDLHSPVOE SFHJNFO / JO DMJOJDBM TUVEJFT $ BOE $ JODMVEF HSPVQFE CZ #PEZ 4ZTUFN WPNJUJOH Z transaminase elevations). diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, Patients Coinfected with HIV-1 and HBV: It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis. before initiating antiretroviral therapy. COMPLERA is not approved for the treatment of chronic HBV infection and the safety and efďŹ cacy of COMPLERA : MT PG FNUSJDJUBCJOF PS UFOPGPWJS %' JO IBWF OPU CFFO FTUBCMJTIFE JO QBUJFOUT DPJOGFDUFE XJUI )#7 BOE )*7 4FWFSF BDVUF FYBDFSCBUJPOT PG IFQBUJUJT # IBWF CFFO SFQPSUFE JO QBUJFOUT XIP BSF Emtricitabine and Tenofovir Disoproxil Fumarate: 5IF GPMMPXJOH BEWFSTF SFBDUJPOT XFSF PCTFSWFE JO DMJOJDBM USJB DPJOGFDUFE XJUI )#7 BOE )*7 BOE IBWF EJTDPOUJOVFE FNUSJDJUBCJOF PS UFOPGPWJS %' UXP PG UIF DPNQPOFOUT PG $0.1-&3" *O TPNF QBUJFOUT JOGFDUFE DPNCJOBUJPO XJUI PUIFS BOUJSFUSPWJSBM BHFOUT 5IF NPTU DPNNPO BEWFSTF ESVH SFBDUJPOT PDDVSSFE JO BU MFBTU PG USFBUNFOU OBJWF TVCKFDUT JO B QIBTF DMJOJDBM USJBM PG FNUSJDJUBCJOF BOE UFOPGPWJS %' JO DPNCJOBUJPO XJUI BOPUIFS BOUJSFUSPWJSBM BHFOU BSF EJBSSIFB OBVTFB GBUJHVF IFBEBDIF EJ[[JOFTT with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are U coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping EFQSFTTJPO JOTPNOJB BCOPSNBM ESFBNT BOE SBTI *O BEEJUJPO BEWFSTF ESVH SFBDUJPOT UIBU PDDVSSFE JO BU MFBTU PG USFBUNFOU FYQFSJFODFE PS USFBUNFOU OBJWF TVCKFDUT SFDFJWJOH FNUSJDJUBCJOF PS UFOPGPWJS %' XJUI PUIFS BOUJSFUSPWJSBM BHFOUT JO DMJOJDBM USJBMT JODMVEF BCEPNJOBM QBJO EZTQFQTJB treatment with COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral New Onset or Worseningg Renal Impairment: 3FOBM JNQBJSNFOU JODMVEJOH DBTFT PG BDVUF SFOBM GBJMVSF BOE 'BODPOJ TZOESPNF SFOBM UVCVMBS p OFVSPQBUIZ JODMVEJOH QFSJQIFSBM OFVSJUJT BOE OFVSPQBUIZ BOYJFUZ JODSFBTFE DPVHI BOE SIJOJUJT 4LJO EJTDPMPSBUJPO IBT CFFO SFQPSUFE XJUI IJHIFS JOKVSZ XJUI TFWFSF IZQPQIPTQIBUFNJB IBT CFFO SFQPSUFE XJUI UIF VTF PG UFOPGPWJS %' [See Adverse Reactions]. frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with asymptomatic. The mechanism and clinical signiďŹ cance are unknown. COMPLERA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, Laboratory Abnormalities:: 5IF QFSDFOUBHF PG TVCKFDUT USFBUFE XJUI SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' PS FGBWJSFO[ FNUSJDJUBCJOF UFOPGPWJS %' JODMVEJOH QBUJFOUT XIP IBWF QSFWJPVTMZ FYQFSJFODFE SFOBM FWFOUT XIJMF SFDFJWJOH )&14&3" JO TUVEJFT $ BOE $ XJUI TFMFDUFE USFBUNFOU FNFSHFOU MBCPSBUPSZ BCOPSNBMJUJFT (SBEF UP SFQSFTFOUJOH XPSTU HSBEF UPYJDJUZ BSF QSFTFOUFE COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent. Emtricitabine and tenofovir are principally eliminated by the kidney; in Table 2. IPXFWFS SJMQJWJSJOF JT OPU 4JODF $0.1-&3" JT B DPNCJOBUJPO QSPEVDU BOE UIF EPTF PG UIF JOEJWJEVBM DPNQPOFOUT DBOOPU CF BMUFSFE QBUJFOUT XJUI Table 2 Selected Laboratoryy Abnormalities (Grades 1-4) Reported p in Subjects j Who Received Rilpivirine or Efavirenz in creatinine clearance below 50 mL per minute should not receive COMPLERA. Combination with Emtricitabine/Tenofovir / DF in Studies C209 and C215 ((Week 96 Analysis) y ) Drugg Interactions: Caution should be given to prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine [See Contraindications, Rilpivirine p Efavirenz Drug Interactions, and Clinical Pharmacology]. In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have Laboratoryy Parameter DAIDS Toxicityy + FTC/TDF + FTC/TDF been shown to prolong the QTc interval of the electrocardiogram [See Drug Interactions]. COMPLERA should be used with caution when coadministered Abnormality, y, ((%)) Range g N=550 N=546 with a drug with a known risk of Torsade de Pointes. BIOCHEMISTRY Depressive p Disorders: The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, Increased Creatinine OFHBUJWF UIPVHIUT TVJDJEF BUUFNQU TVJDJEBM JEFBUJPO IBT CFFO SFQPSUFE XJUI SJMQJWJSJOF %VSJOH UIF 1IBTF USJBMT / UISPVHI XFFLT UIF (SBEF Y 6-/a JODJEFODF PG EFQSFTTJWF EJTPSEFST SFHBSEMFTT PG DBVTBMJUZ TFWFSJUZ SFQPSUFE BNPOH SJMQJWJSJOF / PS FGBWJSFO[ / XBT BOE (SBEF Y 6-/ SFTQFDUJWFMZ .PTU FWFOUT XFSF NJME PS NPEFSBUF JO TFWFSJUZ 5IF JODJEFODF PG (SBEF BOE EFQSFTTJWF EJTPSEFST SFHBSEMFTT PG DBVTBMJUZ XBT GPS (SBEF Y 6-/ CPUI SJMQJWJSJOF BOE FGBWJSFO[ 5IF JODJEFODF PG EJTDPOUJOVBUJPO EVF UP EFQSFTTJWF EJTPSEFST BNPOH SJMQJWJSJOF PS FGBWJSFO[ XBT JO FBDI BSN 4VJDJEBM (SBEF Y 6-/ JEFBUJPO XBT SFQPSUFE JO TVCKFDUT JO FBDI BSN XIJMF TVJDJEF BUUFNQU XBT SFQPSUFE JO TVCKFDUT JO UIF SJMQJWJSJOF BSN 1BUJFOUT XJUI TFWFSF EFQSFTTJWF Increased AST symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine (SBEF Y 6-/ whether the risks of continued therapy outweigh the beneďŹ ts. (SBEF Y 6-/ Y 6-/ Hepatotoxicity: p y Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis (SBEF B or C, or marked elevations in serum liver biochemistries prior to treatment may be at increased risk for worsening or development of serum liver (SBEF Y 6-/ biochemistries elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine containing regimen Increased ALT who had no pre-existing hepatic disease or other identiďŹ able risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for (SBEF Y 6-/ hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with (SBEF Y 6-/ NBSLFE FMFWBUJPOT JO TFSVN MJWFS CJPDIFNJTUSJFT QSJPS UP USFBUNFOU JOJUJBUJPO 4FSVN MJWFS CJPDIFNJTUSJFT NPOJUPSJOH TIPVME BMTP CF DPOTJEFSFE GPS QBUJFOUT (SBEF Y 6-/ without pre-existing hepatic dysfunction or other risk factors. (SBEF Y 6-/ Decreases in Bone Mineral Density: y #POF NJOFSBM EFOTJUZ #.% NPOJUPSJOH TIPVME CF DPOTJEFSFE GPSS )*7 JOGFDUFE QBUJFOUT XIP IBWF B Increased Total Bilirubin Y 6-/ IJTUPSZ PG QBUIPMPHJD CPOF GSBDUVSF PS BSF BU SJTL GPS PTUFPQFOJB PS CPOF MPTT "MUIPVHI UIF FGGFDU PG TVQQMFNFOUBUJPO XJUI DBMDJVN BOE 7JUBNJO % XBT OPU (SBEF Y 6-/ studied, such supplementation may be beneďŹ cial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. (SBEF Y 6-/ Tenofovir Disoproxil Fumarate:: *O B XFFL TUVEZ PG )*7 JOGFDUFE USFBUNFOU OBJWF BEVMU TVCKFDUT USFBUFE XJUI UFOPGPWJS %' 4UVEZ EFDSFBTFT (SBEF JO #.% XFSF TFFO BU UIF MVNCBS TQJOF BOE IJQ JO CPUI BSNT PG UIF TUVEZ "U 8FFL UIFSF XBT B TJHOJmDBOUMZ HSFBUFS NFBO QFSDFOUBHF EFDSFBTF Increased Total Cholesterol (fasted) NH E- GSPN CBTFMJOF JO #.% BU UIF MVNCBS TQJOF JO TVCKFDUT SFDFJWJOH UFOPGPWJS %' MBNJWVEJOF FGBWJSFO[ Â&#x153; DPNQBSFE XJUI TVCKFDUT SFDFJWJOH (SBEF NH E- TUBWVEJOF MBNJWVEJOF FGBWJSFO[ Â&#x153; $IBOHFT JO #.% BU UIF IJQ XFSF TJNJMBS CFUXFFO UIF UXP USFBUNFOU HSPVQT Â&#x153; JO UIF (SBEF (SBEF NH E- UFOPGPWJS %' HSPVQ WT Â&#x153; JO UIF TUBWVEJOF HSPVQ *O CPUI HSPVQT UIF NBKPSJUZ PG UIF SFEVDUJPO JO #.% PDDVSSFE JO UIF mSTU o XFFLT PG UIF TUVEZ BOE UIJT SFEVDUJPO XBT TVTUBJOFE UISPVHI XFFLT 5XFOUZ FJHIU QFSDFOU PG UFOPGPWJS %' USFBUFE TVCKFDUT WT PG 5 G UIF DPNQBSBUPS TVCKFDUT Increased LDL Cholesterol (fasted) (SBEF NH E- MPTU BU MFBTU PG #.% BU UIF TQJOF PS PG #.% BU UIF IJQ $MJOJDBMMZ SFMFWBOU GSBDUVSFT FYDMVEJOH mOHFST BOE UPFT XFSF SFQPSUFE JO TVCKFDUT JO NH E- UIF UFOPGPWJS %' HSPVQ BOE TVCKFDUT JO UIF DPNQBSBUPS HSPVQ 5FOPGPWJS %' XBT BTTPDJBUFE XJUI TJHOJmDBOU JODSFBTFT JO CJPDIFNJDBM NBSLFST PG CPOF (SBEF NH E- metabolism (serum bone-speciďŹ c alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone (SBEF Increased Triglycerides gy (fasted) UVSOPWFS 4FSVN QBSBUIZSPJE IPSNPOF MFWFMT BOE 7JUBNJO % MFWFMT XFSF BMTP IJHIFS JO TVCKFDUT SFDFJWJOH UFOPGPWJS %' NH E- 5IF FGGFDUT PG UFOPGPWJS %' BTTPDJBUFE DIBOHFT JO #.% BOE CJPDIFNJDBM NBSLFST PO MPOH UFSN CPOF IFBMUI BOE GVUVSF GSBDUVSF SJTL BSF VOLOPXO (SBEF (SBEF NH E- 'PS BEEJUJPOBM JOGPSNBUJPO QMFBTF DPOTVMU UIF 7*3&"% QSFTDSJCJOH JOGPSNBUJPO (SBEF NH E- Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the / OVNCFS PG TVCKFDUT QFS USFBUNFOU HSPVQ VTF PG 7*3&"% [See Adverse Reactions]. B 6-/ 6QQFS MJNJU PG OPSNBM WBMVF /PUF 1FSDFOUBHFT XFSF DBMDVMBUFE WFSTVT UIF OVNCFS PG TVCKFDUT JO *55 QPQVMBUJPO XJUI FNUSJDJUBCJOF UFOPGPWJS %' BT CBDLHSPVOE SFHJNFO

Emtricitabine or Tenofovir Disoproxil Fumarate:: The following laboratory abnormalities have been previously reported in subjects treated with FNUSJDJUBCJOF PS UFOPGPWJS %' XJUI PUIFS BOUJSFUSPWJSBM BHFOUT JO PUIFS DMJOJDBM USJBMT (SBEF PS MBCPSBUPSZ BCOPSNBMJUJFT PG JODSFBTFE QBODSFBUJD BNZMBTF Y 6-/ JODSFBTFE TFSVN BNZMBTF 6 - JODSFBTFE MJQBTF Y 6-/ JODSFBTFE BMLBMJOF QIPTQIBUBTF 6 - JODSFBTFE PS EFDSFBTFE TFSVN HMVDPTF PS NH E- JODSFBTFE HMZDPTVSJB Ăś

JODSFBTFE DSFBUJOF LJOBTF . 6 - ' 6 - EFDSFBTFE OFVUSPQIJMT NN3 BOE JODSFBTFE IFNBUVSJB 3#$ )1' PDDVSSFE Adrenal Function:: In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimen / BU 8FFL UIFSF XBT BO PWFSBMM NFBO DIBOHF GSPN CBTFMJOF JO CBTBM DPSUJTPM PG $* ONPM - JO UIF SJMQJWJSJOF HSPVQ BOE PG $* ONPM - JO UIF FGBWJSFO[ HSPVQ "U 8FFL UIF NFBO DIBOHF GSPN CBTFMJOF JO "$5) TUJNVMBUFE DPSUJTPM MFWFMT XBT MPXFS JO UIF SJMQJWJSJOF HSPVQ Â&#x153; ONPM - UIBO JO UIF FGBWJSFO[ HSPVQ Â&#x153; ONPM - .FBO WBMVFT GPS CPUI CBTBM BOE "$5) TUJNVMBUFE DPSUJTPM WBMVFT BU 8FFL XFSF XJUIJO UIF OPSNBM SBOHF 0WFSBMM UIFSF XFSF OP TFSJPVT BEWFSTF FWFOUT EFBUIT PS USFBUNFOU discontinuations that could clearly be attributed to adrenal insufďŹ ciency. Effects on adrenal function were comparable by background N(t)RTIs. Serum Creatinine:: In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of the allowed background regimen / UIFSF XBT B TNBMM JODSFBTF JO TFSVN DSFBUJOJOF PWFS XFFLT PG USFBUNFOU XJUI SJMQJWJSJOF .PTU PG UIJT JODSFBTF PDDVSSFE XJUIJO UIF mSTU GPVS XFFLT PG USFBUNFOU XJUI B NFBO DIBOHF PG NH E- SBOHF NH E- UP NH E- PCTFSWFE UISPVHI 8FFL *O TVCKFDUT XIP FOUFSFE the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs. Serum Lipids: *O DMJOJDBM TUVEJFT BOBMZTJT PG TFSVN MJQJET FYDMVEFE TVCKFDU : T SFDFJWJOH MJQJE MPXFSJOH BHFOUT EVSJOH UIF USFBUNFOU QFSJPE 5ISPVHI 8FFL PS GFXFS TVCKFDUT SFDFJWJOH SJMQJWJSJOF FNUSJDJUBCJOF UFOPGPWJS %' XFSF SFQPSUFE BT IBWJOH (SBEFT FMFWBUJPOT JO GBT UJOH DIPMFTUFSPM NH E- GBTUJOH -%- DIPMFTUFSPM NH E- PS (SBEF USJHMZDFSJEFT NH E- *O TVCKFDUT JO UIF SJMQJWJSJOF USFBUNFOU BSN UISPVHI 8FFL / UIF NFBO DIBOHF GSPN CBTFMJOF JO UPUBM DIPMFTUFSPM -%- DIPMFTUFSPM BOE USJHMZDFSJEFT QPPMFE EBUB BSF BT GPMMPXT UPUBM DIPMFTUFSPM <5$> GBTUFE NH E- / <NFBO CBTFMJOF 5$ NH E-> )%- DIPMFTUFSPM <)%-> GBTUFE NH E- / <NFBO CBTFMJOF )%- NH E-> -%- DIPMFTUFSPM <-%-> GBTUFE NH E- / <NFBO CBTFMJOF -%- NH E-> BOE 5SJHMZDFSJEFT <5(> GBTUFE NH E- / <NFBO CBTFMJOF 5( NH E-> 5IF DIBOHF GSPN CBTFMJOF JT UIF NFBO PG XJUIJO QBUJFOU DIBOHFT GSPN CBTFMJOF GPS QBUJFOUT XJUI CPUI CBTFMJOF BOE 8FFL WBMVFT Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus:: In patients coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection. Postmarketingg Experience p 5IF GPMMPXJOH BEWFSTF SFBDUJPOT IBWF CFFO JEFOUJmFE EVSJOH QPTUUBQQSPWBM VTF PG FNUSJDJUBCJOF PS UFOPGPWJS %' #FDBVTF QPTUNBSLFUJOH SFBDUJPOT BSF SFQPSUFE voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Rilpivirine 3FOBM BOE 6SJOBSZ %JTPSEFST Z nephrotic syndrome Emtricitabine:: No postmarketing adverse reactions have been identiďŹ ed for inclusion in this section. Tenofovir Disoproxil Fumarate: *NNVOF 4ZTUFN %JTPSEFST Z allergic reaction, including angioedema .FUBCPMJTN BOE /VUSJUJPO %JTPSEFST lactic acidosis, hypokalemia, hypophosphatemia 3FTQJSBUPSZ 5IPSBDJD BOE .FEJBTUJOBM %JTPSEFST Q Z dyspnea (BTUSPJOUFTUJOBM %JTPSEFST pancreatitis, increased amylase, abdominal pain )FQBUPCJMJBSZ %JTPSEFST IFQBUJD TUFBUPTJT IFQBUJUJT JODSFBTF Q Z E MJWFS FO[ZNFT NPTU DPNNPOMZ "45 "-5 HBNNB (5

4LJO BOE 4VCDVUBOFPVT 5JTTVF %JTPSEFST rash .VTDVMPTLFMFUBM BOE $POOFDUJWF 5JTTVF %JTPSEFST rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy 3FOBM BOE 6SJOBSZ %JTPSEFST BDVUF SFOBM GBJMVSF SFOBM GBJMVSF Z BDVUF UVCVMBS OFDSPTJT 'BODPOJ TZOESPNF QSPYJNBM SFOBM UVCVMPQBUIZ JOUFSTUJUJBM OFQISJUJT (including acute cases), nephrogenic diabetes insipidus, renal insufďŹ ciency, increased creatinine, proteinuria, polyuria (FOFSBM %JTPSEFST BOE "ENJOJTUSBUJPO 4JUF $POEJUJPOT asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. DRUG INTERACTIONS COMPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, COMPLERA should not be administered with other antiretroviral NFEJDBUJPOT *OGPSNBUJPO SFHBSEJOH QPUFOUJBM ESVH ESVH JOUFSBDUJPOT XJUI PUIFS BOUJSFUSPWJSBM NFEJDBUJPOT JT OPU QSPWJEFE 1MFBTF SFGFS UP UIF &%63"/5 7*3&"% BOE &.53*7" QSFTDSJCJOH JOGPSNBUJPO BT OFFEFE 5IFSF XFSF OP ESVH ESVH JOUFSBDUJPO USJBMT DPOEVDUFE XJUI UIF mYFE EPTF DPNCJOBUJPO UBCMFU %SVH JOUFSBDUJPO TUVEJFT XFSF DPOEVDUFE XJUI FNUSJDJUBCJOF SJMQJWJSJOF PS UFOPGPWJS %' UIF DPNQPOFOUT PG $0.1-&3" 5IJT TFDUJPO EFTDSJCFT DMJOJDBMMZ relevant drug interactions with COMPLERA [See Contraindications]. Drugs g Inducingg or Inhibitingg CYP3A Enzymes: y 3JMQJWJSJOF JT QSJNBSJMZ NFUBCPMJ[FE CZ DZUPDISPNF 1 $:1 " BOE ESVHT UIBU JOEVDF or inhibit CYP3A may thus affect the clearance of rilpivirine [See Clinical Pharmacology, Contraindications]. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and 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 g Increasingg Gastric ppH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [see Drug Interactions,Table 4]. Drugs g Affectingg Renal Function: Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular ďŹ ltration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular TFDSFUJPO NBZ JODSFBTF TFSVN DPODFOUSBUJPOT PG FNUSJDJUBCJOF UFOPGPWJS BOE PS PUIFS SFOBMMZ FMJNJOBUFE ESVHT 4PNF FYBNQMFT PG ESVHT UIBU BSF eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. QT Prolonging g g Drugs: g There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. 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 electrocardiogram. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes. Established and Other Potentiallyy SigniďŹ cant g Drugg Interactions *NQPSUBOU ESVH JOUFSBDUJPO JOGPSNBUJPO GPS $0.1-&3" JT TVNNBSJ[FE JO 5BCMF 5IF ESVH JOUFSBDUJPOT EFTDSJCFE BSF CBTFE PO TUVEJFT DPOEVDUFE XJUI FNUSJDJUBCJOF SJMQJWJSJOF PS UFOPGPWJS %' BT JOEJWJEVBM NFEJDBUJPOT UIBU NBZ PDDVS XJUI $0.1-&3" PS BSF QPUFOUJBM ESVH JOUFSBDUJPOT OP ESVH JOUFSBDUJPO studies have been conducted using COMPLERA. The tables include potentially signiďŹ cant interactions, but are not all inclusive.

a Drugg Interactions: Alteration in Dose or Regimen May Be Table 4 Established and Other Potentiallyy SigniďŹ cant g Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drugg Class: l Drugg Name Antacids: antacids (e.g., g aluminium, magnesium g hydroxide, or calcium carbonate) Azole Antifungal Agents: ďŹ&#x201A;uconazole itraconazole ketoconazole posaconazole voriconazole H2-Receptor p Antagonists: cimetidine famotidine nizatidine ranitidine Macrolide antibiotics: clarithromycin erythromycin telithromycin Narcotic Analgesics: methadone

Effect ff on Concentrationb â&#x2020;&#x201D; rilpivirine (antacids taken at least 2 hours before or at least IPVST BGUFS SJMQJWJSJOF

â&#x2020;&#x201C; rilpivirine (concomitant intake) â&#x2020;&#x2018; rilpivirinec,d â&#x2020;&#x201C; ketoconazolec,d

c,d â&#x2020;&#x201D; rilpivirine p (famotidine taken 12 hours before rilpivirine p or IPVST BGUFS SJMQJWJSJOF

c,d â&#x2020;&#x201C; rilpivirine p (famotidine taken 2 hours before rilpivirine) â&#x2020;&#x2018; rilpivirine â&#x2020;&#x201D; clarithromycin â&#x2020;&#x201D; erythromycin â&#x2020;&#x201D; telithromycin

â&#x2020;&#x201C; R(â&#x2C6;&#x2019;) methadonec â&#x2020;&#x201C; 4

NFUIBEPOFc â&#x2020;&#x201D; rilpivirinec â&#x2020;&#x201D; methadonec (when used with tenofovir)

Clinical l l Comment The combination of COMPLERA and antacids should be used with caution as coadministration may cause signiďŹ cant g decreases in rilpivirine p pplasma concentrations (increase in gastric g pH). p Antacids should onlyy be administered either at least 2 hours before or at MFBTU IPVST BGUFS $0.1-&3" Concomitant use of COMPLERA with azole antifungal g agents g may cause an increase in the pplasma concentrations of rilpivirine p (inhibition of CYP3A enzymes). y No dose adjustment is required q when COMPLERA is coadministered with azole antifungal g agents. g Clinicallyy monitor for breakthrough g fungal g infections when azole antifungals are coadministered with COMPLERA. The combination of COMPLERA and H2-receptor antagonists g should be used with caution as coadministration mayy cause signiďŹ cant decreases in rilpivirine plasma concentrations (increase in ggastric ppH). H2-receptor p antagonists g should onlyy be BENJOJTUFSFE BU MFBTU IPVST CFGPSF PS BU MFBTU IPVST BGUFS COMPLERA. Concomitant use of COMPLERA with clarithromycin, erythromycin and telithromycin y mayy cause an increase in the pplasma concentrations of rilpivirine (inhibition of CYP3A enzymes). 8IFSF QPTTJCMF BMUFSOBUJWFT TVDI BT B[JUISPNZDJO TIPVME CF considered. No dose adjustments j are required q when initiatingg coadministration of methadone with COMPLERA. However, clinical monitoringg is recommended as methadone maintenance therapy may need to be adjusted in some patients.

a. This table is not all inclusive. C *ODSFBTF â&#x2020;&#x2018; %FDSFBTF â&#x2020;&#x201C; /P &GGFDU â&#x2020;&#x201D; c. The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. d. This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.

Drugs g with No Observed or Predicted Interactions with COMPLERA /P DMJOJDBMMZ TJHOJmDBOU ESVH JOUFSBDUJPOT IBWF CFFO PCTFSWFE CFUXFFO FNUSJDJUBCJOF BOE GBNDJDMPWJS PS UFOPGPWJS %' 4JNJMBSMZ OP DMJOJDBMMZ TJHOJmDBOU Z ESVH JOUFSBDUJPOT IBWF CFFO PCTFSWFE CFUXFFO UFOPGPWJS %' BOE FOUFDBWJS NFUIBEPOF PSBM DPOUSBDFQUJWFT SJCBWJSJO PS UBDSPMJNVT JO TUVEJFT conducted in healthy subjects. No clinically signiďŹ cant drug interactions have been observed between rilpivirine and acetaminophen, atorvastatin, DIMPS[PYB[POF FUIJOZMFTUSBEJPM OPSFUIJOESPOF TJMEFOBmM BOE UFOPGPWJS %' /P DMJOJDBMMZ SFMFWBOU ESVH ESVH JOUFSBDUJPO JT FYQFDUFE XIFO SJMQJWJSJOF JT coadministered with ribavirin. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Emtricitabine:: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in NJDF BU FYQPTVSFT "6$ BQQSPYJNBUFMZ UJNFT IJHIFS BOE JO SBCCJUT BU BQQSPYJNBUFMZ UJNFT IJHIFS UIBO IVNBO FYQPTVSFT BUU UIF recommended daily dose. Rilpivirine:: 4UVEJFT JO BOJNBMT IBWF TIPXO OP FWJEFODF PG FNCSZPOJD PS GFUBM UPYJDJUZ PS BO FGGFDU PO SFQSPEVDUJWF GVODUJPO *O PGGTQSJOH GSPN SBU BOE rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically signiďŹ cant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Tenofovir Disoproxil Fumarate: 3FQSPEVDUJPO TUVEJFT IBWF CFFO QFSGPSNFE JO SBUT BOE SBCCJUT B : U EPTFT VQ UP BOE UJNFT UIF IVNBO EPTF CBTFE on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COMPLERA should be used during pregnancy only if the potential beneďŹ t justiďŹ es 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 FTUBCMJTIFE )FBMUIDBSF QSPWJEFST BSF FODPVSBHFE UP SFHJTUFS QBUJFOUT CZ DBMMJOH Nursingg Mothers The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid riskingg ppostnatal transmission of HIV. Emtricitabine: 4BNQMFT PG CSFBTU NJML PCUBJOFE GSPN mWF )*7 JOGFDUFE NPUIFS : T TIPX UIBU FNUSJDJUBCJOF JT TFDSFUFE JO IVNBO NJML #SFBTUGFFEJOH infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabineassociated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Rilpivirine: 4UVEJFT JO MBDUBUJOH SBUT BOE UIFJS PGGTQSJOH JOEJDBUF UIBU SJMQJWJSJOF XBT QSFTFOU JO SBU NJML *U JT OPU LOPXO XIFUIFS SJMQJWJSJOF JT TFDSFUFE JO human milk. Tenofovir Disoproxil Fumarate: 4BNQMFT PG CSFBTU NJML PCUBJOFE GSPN mWF )*7 JOGFDUFE NPUIFS : T JO UIF mSTU QPTU QBSUVN XFFL TIPX UIBU UFOPGPWJS JT excreted in human milk. The impact of this exposure in breastfed infants is unknown. 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 if they are receiving COMPLERA. Pediatric Use COMPLERA is not recommended for patients less than 18 years of age because not all the individual components of the COMPLERA have safety, efďŹ cacy and dosing recommendations available for all pediatric age groups. Geriatric Use $MJOJDBM TUVEJFT PG FNUSJDJUBCJOF SJMQJWJSJOF PS UFOPGPWJS %' EJE OPU JODMVEF TVGmDJFOU OVNCFST PG TVCKFDUT BHFE BOE PWFSS UP EFUFSNJOF XIFUIFS UIFZ 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 [See Clinical Pharmacology]. Renal Impairment p Because COMPLERA is a ďŹ xed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate, severe or end stage renal impairment (creatinine clearance below 50 mL per minute) or that require dialysis [See Warnings and Precautions]. Hepatic p Impairment p 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. *TTVFE +BOVBSZ

COMPLERA, the COMPLERA Logo, g EMTRIVA, GILEAD, the GILEAD Logo, g GSI, HEPSERA, STRIBILD, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. p ATRIPLA is a trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other marks referenced herein are the property of their respective owners. ÂŠ2013 Gilead Sciences, Inc. All rights reserved. CPAP0019 3/13

PRINTER-FRIENDLY VERSION AVAILABLE AT IDSE.NET

Treatment Options in HIV

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

n its 2013 guidelines update, date the

When To Initiate ART

US Department of Health and

The latest update to the 2013 DHHS guidelines changes how the recommendation to initiate HIV therapy is phrased, reducing any residual ambiguity. 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 HIVinfected individuals for the prevention of transmission of HIV.” The following CD4 thresholds, with ratings of the recommendation and strength of the evidence related to preventing disease progression, are still listed as follows: • 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 2012 IAS–USA guidelines state, “all adults with HIV infection should be offered ART regardless of CD4 cell count.”2

Human Services (DHHS) reiterated

its broad recommendations to treat all patients with HIV, a perspective echoed in 2012 guidelines from the International Antiviral Society–USA (IAS–USA). Tables 1 to 4 present major recommendations from the most recent guidelines.1,2 This review discusses some important considerations from both sets of guidelines, along with summaries of recent key studies that are relevant to clinical practice.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

INFECTIOUS DISEASE SPECIAL EDITION 2013

The reasons for the shift 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 >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 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 HIVinfected 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 study-related 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, the ART group had a lower rate of clinical events; predominantly, a reduction in the risk for tuberculosis. The results of HPTN 052 have had a profound effect on the uptake in ART within certain communities. In 2010, the San Francisco Department of Public Health recommended treatment for all individuals upon diagnosis of HIV to reduce disease incidence. Local investigators subsequently reported that a significantly higher proportion of patients with a CD4 count >500 cells/mm3 are initiating ART.6 In clinical practice, I also 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 should nonetheless continue to recommend safer sexual practices to their patients because intermittent viral shedding in genital secretions is well documented, even during effective ART.7,8 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 (TDF/FTC). Although the logistics of selecting the appropriate candidates for PrEP and establishing a practical monitoring plan may be challenging, the FDA’s July 2012 approval of TDF/FTC for this purpose raises it as an important preventative option in clinical practice. The importance

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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.9 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, they state: “Patients may choose to postpone therapy, and providers, on a case-by-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 predominantly should be deferred in asymptomatic individuals with CD4 counts >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 >500 cells/mm3, citing the absence of controlled clinical trials documenting any benefit.10 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.11 Four thousand treatment-naive individuals with CD4 counts >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.12,13 The management of individuals recently infected with HIV has long been controversial. In this year’s DHHS guidelines update, 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 past 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.14 Moreover, the study confirmed previous data that CD4 cell counts decline relatively quickly in these patients if they are not treated, hence reaching commonly used CD4 thresholds for treatment shortly thereafter (ie, within 12-18 months). A second study demonstrated that the earlier ART is initiated postinfection, the lower the level of HIV in the viral reservoir.15 Patients with low viral burdens could be ideal candidates for HIV cure strategies. In aggregate, the bulk of evidence now favors the treatment of acute HIV infection with indefinite ART, which already is implied in current treatment guidelines. Clinicians should remember to order a 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.

What Treatment To Start The recommendation to begin ART earlier would not have been possible without the current generation of safer therapies that are less prone to option-limiting resistance. 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, didanosine, indinavir, and nelfinavir—no longer are 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.16 Longitudinal studies of the recent treatment era also have reported unprecedented levels of virologic suppression for patients undergoing therapy. Treatment results observed in clinical practice now are comparable with those reported in clinical trials,17 even in difficultto-treat patient populations.18,19 Additionally, treatment changes due to toxicity have dramatically decreased over time.20 Not surprisingly, these 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.21 The DHHS guidelines continue to recommend 1 of 4 initial regimens for treatment-naive patients.1,2 The preferred first-line regimens all include TDF and FTC; the third active drug is either efavirenz (EFV), atazanavir (ATV)/ritonavir (r), darunavir (DRV)/r, or raltegravir (RAL).1 The IAS–USA guidelines also list abacavir-lamivudine (ABC/3TC) as a preferred nucleoside reverse transcriptase inhibitor (NRTI) combination, provided HIV RNA levels are <100,000 copies/mL. There are several regimens listed as alternatives that, for certain patients, may be the optimal choice. For example, individuals with preexisting renal disease may warrant initial therapy with ABC/3TC instead of TDF/FTC.2 Two alternative regimens that deserve mention are the single-pill regimens of TDF/TFC plus rilpivirine (RPV) and TDF/FTC plus elvitegravir (EVG) and the pharmacokinetic booster cobicistat (COBI). Two large clinical trials evaluated the efficacy of RPV (formerly TMC 278) with that of EFV.22,23 The overall results showed that RPV was noninferior to EFV. However, patients in this study were more likely to experience virologic failure with RPV than with EFV (with possible selection of cross-resistance to etravirine), especially if their baseline viral load was >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 central nervous system [CNS] side effects) compared with EFV; lipid changes also favored RPV. Based on the results of these trials, the DHHS included RPV in its list of “alternative” options for initial ART—in combination with either TDF/FTC or ABC/3TC—along with a cautionary note about avoiding use of RPV in patients with HIV RNA levels >100,000 copies/mL or CD4 counts <200 cells/mm3.1 When prescribing RPV, clinicians need to remind their patients about the importance of taking the medication with a full meal and, furthermore, to avoid the concomitant use of proton pump inhibitors. These are essential measures to ensure the drug is fully absorbed. Two pivotal Phase III studies have compared TDF/ FTC/EVG/COBI with currently approved regimens that are recommended for initial ART, leading to its FDA approval for treatment-naive patients in 2012. 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.24 At week 48, rates of virologic suppression were 88% for TDF/FTC/EVG/COBI versus 84% for TDF/FTC/EFV, which met the study protocol criteria for noninferiority. There was significantly more nausea observed in those who received TDF/FTC/EVG/COBI, whereas significantly more incidents of rash and 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.25 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.26 An important practical consideration for TDF/FTC/EVG/COBI is that it should not be used in those with an estimated glomerular filtration rate (GFR) <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.27 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 rise in serum creatinine (≥0.4 mg/dL), proteinuria, or glycosuria, any of which should prompt discontinuation of TDF. COBI as a stand-alone pharmacokinetic booster is currently undergoing FDA review.

INFECTIOUS DISEASE SPECIAL EDITION 2013

New and Investigational Strategies for Treatment Another promising investigational integrase inhibitor is dolutegravir (DTG), which is taken once daily and has been studied in both treatment-naive and -experienced patients. In an open-label, Phase II study, DTG was comparable to EFV at weeks 48 and 96 when combined with 2 NRTIs.28,29 Two 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.30 The second trial compared ABC/3TC plus DTG with TDF/FTC/EFV in randomized doubleblind study. The results showed that the ABC/3TC plus DTG arm was superior to TDF/FTC/EFV, largely due to a higher rate of drug discontinuation in the TDF/ FTC/EFV arm. One distinct characteristic of DTG is that it retains activity against some viruses resistant to both RAL and EVG. The results from small studies that administered twice-daily DTG to this very difficult-totreat patient population with highly resistant virus have been encouraging.31 In August 2013, the FDA approved DTG for use in combination regimens in treatmentnaive and -experienced patients. A second promising investigational antiretroviral agent is tenofovir alafenamide (TAF), a prodrug form of tenofovir. This agent achieves very high intracellular concentrations of tenofovir with corresponding low plasma levels. As a result, much lower doses of TAF are required to achieve antiviral activity comparable with TDF, as shown in a recent Phase II study that compared TDF/FTC/EVG/COBI with TAF/FTC/EVG/ COBI.32 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 adolescentsâ&#x20AC;&#x201D; February 12, 2013. http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf. Accessed August 1, 2013.

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2. Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Societyâ&#x20AC;&#x201C;USA panel. JAMA. 2012;308(4):387-402. 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, Dchechter M, et al; INSIGHT SMART, ESPRIT Study Groups. Mortality in well controlled HIV in 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; HPTN 052 Study Team. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(5):493-505. 6. Truong TT, Hsu L, McFarland W, Scheer S. Dramatic improvements in early ART initiation reveal a new disparity in treatment. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle, WA. Abstract 139. 7. 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. 8. 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. 9. 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; March 3-6, 2013; Atlanta, GA. Abstract 26LB. 10. European AIDS Clinical Society. http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition. pdf. Accessed August 1, 2013. 11. 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 August 3, 2013. 12. Hunt PW, W 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. 13. 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. 14. Tuan Le, 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.

15. Ananworanich J, Vandergeeten C, N Chomchey, et al. Early antiretroviral therapy may reduce HIV viral reservoir. Presented at: 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013; Atlanta, GA. Abstract 47. 16. 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. 17. 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. 18. Moore RD, Bartlett JG. Dramatic decline in the HIV-1 RNA level over calender time in a large urban HIV practice. Clin Infect Dis. 2012;53(6):600-604. 19. Sax PE. Antiretroviral therapy: now â&#x20AC;&#x153;it just works.â&#x20AC;? Clin Infect Dis. 2011;53(6):605-608. 20. Helleberg M, Kronberg 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 Oct 16. [Epub ahead of print] 21. Yazdanpanah Y, Fagard C, Descamps D, et al; ANRS 139 TRIO Trial Group. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO Trial. Clin Infect Dis. 2009;49(9):1441-1449. 22. Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 versus efavirenz in treatment-naive, HIV-1-infected patients. Presented at: 17th International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract THLBB206. 23. Cohen C, Andrade-Villanueva J, Clotet B, et al; THRIVE study group. 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, noninferiority trial. Lancet. 2011;378(9787):229-237. 24. Sax P, DeJesus E, Mills A, et al. Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus coformulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomized, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379(9835):2439-2448.

26. Zolopa A, Sax PE, DeJesus E, et al; 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. 2013;63(1):96-100. 27. German P, Liu C, Warren D, et al. Effect of cobicistat on glomerular filtration rate (GFR) in subjects with normal and impaired renal function. Presented at: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2011; Chicago, IL. Abstract H2-804. 28. 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. 2012;12(2):111-118. 29. Stellbrink JH, Reynes J, Voronin E, et al. Dolutegravir in combination therapy exhibits rapid and sustained antiviral response in ARV-naive adults: 96-week results from SPRING-1 (ING112276). Presented at: 19th Conference on Retroviruses and Opportunistic Infections; March 5-8, 2012; Seattle, WA. Abstract 102LB. 30. Raffi F, Rachlis A, Stellbrink HJ, et al; SPRING-2 Study Group. 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. 31. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. Presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, MA. Abstract 151LB. 32. Zolopa A, Ortiz R, Sax PE, et al. Comparative study of tenofovir alafenamide vs tenofovir disoproxil fumarate, each with elvitegravir, cobicistat, and emtricitabine, for HIV treatment. Presented at: 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, GA. Abstract 99LB. Dr. Sax disclosed that he serves as a consultant for Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Inc., GlaxoSmithKline, Merck & Co., Inc., and Tibotec Pharmaceuticals. He also has received grant support from Gilead Sciences, Inc., GlaxoSmithKline, Merck & Co., Inc., and Tibotec Pharmaceuticals.

25. DeJesus E, Rochstroh JK, Henry K, et al. Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus coformulated emtricitabine, and tenofovir disoproxil fumarate for treatment treatment of HIV-1 infection: a randmized, double-blind, Phase 3, non-inferiority trial. Lancet. 2012;379(9835):2429-2438.

INFECTIOUS DISEASE SPECIAL EDITION 2013

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

Formulation

Recommended Adult Dosing

Food Effect

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Abacavir sulfate [ABC]

300-mg tablets

(Ziagen, GlaxoSmithKline)a

20-mg/mL oral solution

300 mg bid or 600 mg qd

None

Abacavir sulfate/ lamivudine

600/300-mg tablets

1 tablet qd

None

300/150/300-mg tablets

1 tablet bid

None

125-, 200-, 250-, 400-mg entericcoated capsules

Delayed-release capsule:

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

(Epzicom, GlaxoSmithKline) Abacavir sulfate/ lamivudine/zidovudine (Trizivir, GlaxoSmithKline) Didanosine [ddl] (Videx/Videx EC, Bristol-Myers Squibb Oncology/Immunology)a

10-mg/mL oral solution

<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

Emtricitabine [FTC] (Emtriva, Gilead Sciences)

Lamivudine [3TC] (Epivir, GlaxoSmithKline)a

Lamivudine/zidovudine (Combivir, GlaxoSmithKline)a Stavudine [d4T] (Zerit, Bristol-Myers Squibb Oncology/ Immunology) Tenofovir disoproxil fumarate

200-mg capsules

1 capsule qd

None

10-mg/mL oral solution

240 mg (24 mL) PO qd

150-, 300-mg tablets

150 mg bid

10-mg/mL oral solution

300 mg qd

150/300-mg tablets

1 tablet bid

None

15-, 20-, 30-, 40-mg capsules

<60 kg: 30 mg bid

None

1-mg/mL oral solution

Note: WHO recommends 30 mg bid dosing regardless of body weight

300-mg tablets

1 tablet qd

None

300/200-mg tablets

1 tablet qd

None

≥60 kg: 40 mg bid

(Viread, Gilead Sciences) Tenofovir disoproxil fumarate/emtricitabine (Truvada, Gilead Sciences)

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

Formulation

Recommended Adult Dosing

Food Effect

Zidovudine [ZDV]

100-mg capsules

None

(Retrovir, GlaxoSmithKline)

300-mg tablets

200 mg tid or 300 mg bid

NRTIs (continued)

10-mg/mL oral solution 10-mg/mL IV solution

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)b Delavirdine mesylate [DLV]

100-, 200-mg tablets

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

(Rescriptor, Pfizer)

Efavirenz [EFV]

50-, 200-mg capsules

(Sustiva, BristolMyers Squibb)

600-mg tablets

Etravirine [ETV]

Separate dosing from antacids by 1 h with or without food

600 mg qd (at bedtime)

Take on empty stomach at bedtime to reduce side effects

100-mg tablets

200 mg bid

Take after full meal

Nevirapine [NVP]

Immediate-release:

None

(Viramune and Viramune XR, Boehringer Ingelheim)a

200-mg tablets

200 mg qd x 2 wk then 200 mg bid

(Intelence, Tibotec)

50 mg/5-mL oral suspension

Extended-release:

NVP-naive:

400-mg tablets

200-mg immediate-release tablets qd x 2 wk, then 400 mg extended-release qd NVP-experienced: 400-mg tablet qd

Rilpivirine [RPV]

25-mg tablets

25 mg qd

Take with a meal

Treatment-naive patients only:

Take with food

(Edurant, Tibotec)

Protease Inhibitors (PIs)c Atazanavir sulfate [ATV]

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

(Reyataz, BristolMyers Squibb)

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

Darunavir ethanolate [DRV] (Prezista, Tibotec)

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

Treatment-experienced patients: 600 mg bid + 100 mg RTV bid

Take with food

Treatment-naive patients: 800 mg qd + RTV 100 mg qd (Unboosted DRV is nott recommended)

INFECTIOUS DISEASE SPECIAL EDITION 2013

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

Formulation

Recommended Adult Dosing

Food Effect

700-mg tablet

Treatment-naive patients:

None

PIs (continued) Fosamprenavir [FPV] (Lexiva, GlaxoSmithKline/ Vertex)

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 (unboosted FPV is nott recommended): 700 mg + 100 mg RTV bid 1,400 mg + 300 mg RTV qd

Indinavir sulfate [IDV] (Crixivan, Merck)

100-, 200-, 333-, 400-mg 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/lowfat meal Boosted: Take with or without food Separate dosing from ddl by 1 h

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

200/50-mg tablet

2 tablets bid or 5 mL bid

Tablets: None

400/100-mg per 5 mL oral solution

4 tablets qd or 10 mL qd

Oral: Take with food

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

Nelfinavir mesylate

250-, 625-mg tablets

750 mg tid

(Viracept, Pfizer)

50-mg/g oral powder

or 1,250 mg bid

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

Ritonavir

100-mg capsules or tablets

600 mg bid (when used as only PI)

(Norvir, Abbott)

80-mg/mL oral solution

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

Saquinavir mesylate [SQV]

200-mg capsules

1,000 mg + 100 mg RTV bid

500-mg tablets

(Unboosted SQV is nott recommended)

Take within 2 h of full meal

250-mg capsules

500 mg + 200 mg RTV bid

Take with food

(Invirase, Roche)

Tipranavir [TPV] (Aptivus, Boehringer Ingelheim)

(Unboosted TPV is not recommended)

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

Formulation

Recommended Adult Dosing

Food Effect

Injectable (lyophilized powder): Each single-use 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

None

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

Administered subcutaneously into upper arm, anterior thigh, or abdomen

CCR5 Co-receptor Antagonists Maraviroc (Selzentry, ViiV Healthcare/ GlaxoSmithKline)

150-, 300-mg tablets

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

Integrase Strand Transfer Inhibitors Raltegravir (Isentress, Merck)

400-mg tablets

1 tablet bid

Take with or without food

Dolutegravir (Tivicay, ViiV Healthcare/ GlaxoSmithKline)

50-mg tablets

1 tablet qd

Take with or without food

1 tablet bid for patients with resistance to integrase inhibitors

Combination Regimens Efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla, Gilead Sciences/BristolMyers Squibb)

600/200/300-mg tablets

1 tablet qd

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

Emtricitabine/ rilpivirine/tenofovir disoproxil fumarate (Complera, Gilead Sciences/Janssen Therapeutics)

200/25/300-mg tablets

1 tablet qd

Take with a meal

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

300/200/150/150-mg tablets

1 tablet qd

Take with food

bid, twice daily; CYP, cytochrome P450; IV, intravenous; PO, orally; qd, once daily; sc, subcutaneous; tid, 3 times daily; WHO, World Health Organization a

Generic formulations are also available.

During clinical trials, NNRTIs were discontinued because of rash in 7% of NVP-treated patients, 4.3% of DLV-treated patients, 1.7% of EFVtreated 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.

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.

INFECTIOUS DISEASE SPECIAL EDITION 2013

Table 2. DHHS Antiretroviral Regimens Recommended for Treatment-Naive Patients Regimen NNRTI-based (1 NNRTI + 2 NRTIs)

Preferred Regimen EFV Va + TDFb + FTCc

Alternate Regimen

Acceptable, but Less Satisfactory Regimens

• EFV Va + ABCd/3TCc

• EFV Va + ZDVf/3TCc

• NVPg + (TDFb/FTCc or ZDVf/3TCc)

• RPV V /TDF /FTC e

• NVPg,h + ABCd,h/3TCc

• RPV V + ABC /3TC

• RPV Ve + ZDVf/3TCc PI-based (1 PI + 2 NRTIs)

• ATV/ri + TDFb + FTCc

• ATV/ri + ABCd/3TCc • DRV/r + ABC /3TC

• ATV/ri + ZDVf/3TCc

• DRV/r (qd) + TDFb + FTCc

• FPV/r (qd or bid) + ABCd/3TCc or TDFb/FTCc

• DRV/r + ZDVf/3TCc

• ATV Vj + (ABCd or ZDVf)/3TCb

• LPV/r (qd or bid) + ABCd/3TCc or TDFb/FTCc

INSTI-based (1 INSTI + 2 NRTIs)

RAL + TDFb/FTCc

• RAL + ABCd/3TCc

CCR5 antagonistbased

• FPV/r + ZDVf/3TCc • LPV/rj + ZDVf/3TCc • SQV/rk + ABCd/3TC or TDFb/FTCc

RAL + ZDVf/3TCc c,m

• EVG/COBI /TDF /FTC

• MVCn + ZDVf/3TCc • MVCn + TDFb/FTCc • MVCn + 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; EFV, efavirenz; EVG, elvitegravir; FPV, fosamprenavir; FTC, emtricitabine; HLA, human leukocyte antigen; INSTI, integrase strand transfer inhibitor; LPV, lopinavir; MVC, maraviroc; NA, not applicable; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside or nucleotide reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; qd, once daily; /r, ritonavir-boosted; RAL, raltegravir; RPV, rilpivirine; SQV, saquinavir; TDF, tenofovir; ZDV, zidovudine a

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

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

3TC may substitute for FTC or vice versa.

ABC should not be used in patients who test positive for HLA-B*5701 and should be used with caution in patients at high risk for cardiovascular disease or with pretreatment HIV RNA >100,000 copies/mL.

RPV is not recommended in patients with pretreatment HIV RNA levels >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.

ZDV can cause bone marrow suppression, lipotrophy, and rarely, lactic acidosis with hepatic steatosis.

NVP should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B or C). It should not be used in women with pre-ART CD4 >250 cells/mm3 or men with pre-ART CD4 >400 cells/mm3.

Use NVP and ABC together with caution because both can cause hypersensitivity reactions within first few weeks of treatment initiation.

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 ritanovir boosting is not possible.

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

SQV/r was associated with PR and QT prolongation in a study of healthy volunteers. Baseline electrocardiogram is recommended before initiation. SQV/r is not recommended in patients with the following: pretreatment QT interval >450 msec; refractory hypokalemia or hypomagnesemia; concomitant therapy with other drugs that prolong the QT interval; complete atrioventricular block without an implanted pacemaker; and risk for complete atrioventricular block.

COBI is a potent CYP 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.

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 patient’s CrCl falls below 50 mL/min. EVG/COBI/TDF/FTC should not be used with other antiretroviral drugs or with nephrotoxic drugs.

Tropism testing should be performed before initiation of therapy; only patients with CCR5-tropic virus are candidates for MVC.

Adapted from reference 1.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 3. Initial Antiretroviral Regimens From the IAS–USA 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

b,c

PI/r plus NRTIsd

EFV plus ABC/3TC

RPV/TDF/FTC or RPV plus ABC/3TC

DRV/r plus TDF/FTC

DRV plus ABC/3TC

ATV/r plus TDF/FTC

LPV/r plus TDF/FTC (or ABC/3TC)

Other alternative PIs include FPV/r and SQV/r, but these options are rarely used for initial treatment

RAL plus ABC/3TC

RAL is administered twice daily

ATV/r plus ABC/3TCe InSTI plus NRTIsd

RAL plus TDF/FTC

EVG/COBI/TDF/FTC

3TC, lamivudine; ABC, abacavir; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; EFV, efavirenz; EVG, elvitegravir; FPV, fosamprenavir; 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 or nucleotide reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; /r, ritonavir-boosted; RAL, raltegravir; RPV, rilpivirine; SQV, saquinavir; TDF, tenofovir; ZDV, zidovudine a

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

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

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

HLA-B*5701 screening is recommended to reduce the risk for hypersensitivity reactions.

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

Adapted from reference 2.

Table 4. Initial Regimens for Use in Special Circumstances From the IAS–USA CCR5 antagonist plus NRTIs (NNRTI-, PI-, and InSTI-sparing)

PI/r plus InSTI (NRTI-sparing)

Regimens

Comments

MVC plus TDF/FTC or ABC/3TC

Perform tropism assay to confirm R5 virus before prescribing MVC. This agent is not effective in patients with X4 or dual/mixed X4/R5 virus. Few data are available for MVC with TDF/FTC or ABC/3TC

DRV/r plus RAL

Data emerging for these regimens; evidence from clinical trials is needed before a formal recommendation can be made

LPV/r plus RAL

3TC, lamivudine; CCR5, CC chemokine receptor 5; DRV, darunavir; FTC, emtricitabine; IAS–USA, International Antiviral Society–USA; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; MVC, maraviroc; NRTI, nucleoside or nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; /r, ritonavir-boosted; RAL, raltegravir Adapted from reference 2.

INFECTIOUS DISEASE SPECIAL EDITION 2013

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Influenza Viruses: Epidemiology, Treatment, and Prevention JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA Program Director Infectious Diseases Fellowship Program Ochsner Health System Clinical Assistant Professor Department of Medicine Tulane University New Orleans, Louisiana

MONICA ALMEIDA LALAMA, MD LSU Medical Center New Orleans, Louisiana

OBINNA NNEDU, MD Ochsner Health System New Orleans, Louisiana

nfluenza viruses have plagued the world for

centuries, and due to constant genetic mutations, outbreaks of novel strains with varying virulence

continue to occur.1 There are an estimated 25 million to 50 million cases of influenza in the United States each year1; moreover, the 2012-2013

flu season resulted in 44.3 hospitalizations per 100,000 population.2

Hospitalizations and complications related to influenza result in an estimated $10.4 billion in direct medical costs and $16.3 billion in lost earnings annually in the United States.3 Data from the 30-year period from 1976 to 2006 found that the average number of influenza-related deaths varied between 5,802 and 28,332 annually.4 Years of research have provided insight into the pathogenesis and transmission of the influenza virus, which allows clinicians to constantly develop new strategies for its treatment and prevention. This review will outline current knowledge as well as new developments in influenza and vaccination efforts that have taken place over the past year.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Pathogenesis The influenza virus is a negative-strand RNA virus that belongs to the Orthomyxoviridae family. There are 3 separate genera: influenzavirus A, influenzavirus B, and influenzavirus C.5 All 3 genera are composed of viral RNA segments surrounded by a lipid membrane derived from host cells in which the virus replicates.5 During replication, the virus inserts 2 distinct glycoproteins, hemagglutinin and neuraminidase, into the lipid membrane in order to infect additional cells.6 Hemagglutinin binds to receptors on the surfaces of host respiratory epithelial cells that contain sialic acid, thereby allowing membrane fusion and the release of viral genetic material into the

INFECTIOUS DISEASE SPECIAL EDITION 2013

host cell.6 Neuraminidase, on the other hand, cleaves receptors on the host cells, thus facilitating hemagglutinin binding to epithelial cells and subsequent viral infection.7 Neuraminidase also plays a role in the release and dispersion of progeny virus from infected cells by cleaving sialic acid from the viral envelope, thereby preventing viral aggregation.8 Because hemagglutinin and neuraminidase are both virally derived proteins, host immune system antibodies are specifically produced against these proteins, but studies have shown that the majority of antibodies are produced in response to hemagglutinin.5 In addition to infecting humans, influenza A has a wide range of hosts including domesticated birds and pigs, but wild birds are its primary natural reservoir.5 Unlike influenza A, influenza B and C viruses primarily infect humans, with limited evidence of infections in animals.9 Influenza A and B are responsible for the various influenza epidemics; influenza C results in mild upper respiratory symptoms similar to a cold, and infections are thought to be highly localized.9

Viral Evolution: Drift and Shift Antibodies generated against hemagglutinin and neuraminidase from previous exposure to an influenza virus provide some protection against future infections.6 However, the virus has developed a number of mechanisms, including antigenic drift and antigenic shift, that allow it to evade our immune system and cause repeated waves of infection. Outbreaks from newly evolved strains of influenza typically occur during winter months, leading to this period being referred to as flu season. Antigenic drift, which is classified as minor changes in the hemagglutinin and neuraminidase surface antigens, occurs in both influenza A and B strains and is the result of viral dependence on RNA polymerase for genetic duplication.10 RNA polymerase lacks a proofreading mechanism, so mutations may gradually be introduced during viral replication, eventually producing a new strain.10 Although some antigenic drift is too minor to evade the human immune system, other instances of antigenic drift were sufficient to cause epidemics, such as the 1968 Hong Kong H3N2 pandemic or the H3N2 outbreak in Sydney, Australia between 1997 and 1998.9 Antigenic shift is a more abrupt genetic change that exclusively occurs in the influenza A virus when there is an exchange of genetic material between human and animal strains.10 When a common host is coinfected with human and animal strains, genetic rearrangement takes place between the 2 strains to create an entirely new virus.10 Because the new strain is significantly different from its parental strains, prior exposure offers no protection and infected individuals are highly susceptible to morbidity and mortality.9 Consequently, antigenic shift is the cause of major influenza pandemics such as the “Spanish flu” H1N1 pandemic of 1918 and 1919 that resulted in an estimated 50 million to 100

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

million deaths worldwide.11 It should be noted that antigenic shift is the reason that influenza A viruses are identified by a hemagglutinin and neuraminidase antigen description (eg, H1N1, H7N9). The most recent case of antigenic shift was H7N9, also referred to as Chinese avian flu, which, before 2013, was only documented in birds.12 In early 2013, however, Chinese officials reported the first human cases of H7N9 to the World Health Organization. As of June 2013, there have been 132 confirmed cases of H7N9 in humans and 37 fatalities.13 Sustained transmission between humans has not been proven, and in 55.9% of cases, the infected individual had some exposure to animals—in particular, chickens—with a median incubation period of 5 days.14 An initial report of 111 confirmed cases revealed that advanced age (median age 61), male gender (68.3%), and the presence of underlying medical conditions (61.3%) were additional risk factors for H7N9 infection.14 Cases of H7N9 influenza have generally been associated with severe illness, including acute respiratory distress syndrome (71.2%) and pneumonia (97.3%)—98.2% of patients have required hospitalization.14 Additional complications included shock, acute kidney failure, and rhabdomyolysis.14

Epidemiology and Clinical Spectrum Respiratory droplets are the primary mode of influenza transmission between humans.9 Large, virus-laden droplets are produced when an infected individual coughs or sneezes, which can settle into the upper respiratory tract of nearby susceptible individuals.9 The virus also can be transmitted indirectly through contaminated surfaces when a susceptible individual touches the surface and then his or her eyes, nose, or mouth.9 Once infected, there is a 1- to 4-day incubation period, with an estimated median of 1.4 days for influenza A and 0.6 days for influenza B.15 Individuals become contagious about 1 day before the onset of symptoms and remain so for approximately 5 to 10 days, thus indicating that there are periods where an individual may be asymptomatic yet contagious.16 Data from the Centers for Disease Control and Prevention (CDC) showed that during the 2012-2013 flu season, peak transmission occurred between late December and early January (Figure 1).17 Typical symptoms of mild to moderate influenza are sudden onset of fever, upper respiratory symptoms (eg, nonproductive cough, sore throat, runny nose), and myalgia; vomiting and diarrhea are common in children.9 Most healthy individuals will recover on their own, but severe cases of influenza may require additional care due to serious flu-related complications such as pneumonia.9 Populations at risk for complications include the elderly, children, pregnant women, and individuals with chronic medical conditions such as diabetes and heart disease.18,19 During the 2012-2013 flu season, there were 12,337 hospitalizations admissions caused by confirmed cases of influenza, more than 50% of which were individuals aged 65 and older.17

7,000 H3N2v pH1N1 A (H3) A (subtyping not performed) B % positive

6,500 6,000 5,500

4,500

4,000 20

3,500 3,000

2,500

Positive, %

Positive Specimens, N

5,000

2,000 10 1,500 1,000

500 0

0 40 41 42 43 44 45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2012 1 2013

Surveillance week and year

Figure 1. Laboratory-confirmed cases and types of influenza during the 2012-2013 season. From reference 17.

The clinical spectrum and severity of influenza infection also may vary due to the presence of chronic disease. The most frequent comorbid conditions among adults infected with influenza who required hospitalization during the 2012-2013 flu season were chronic lung disease (26.9%), cardiovascular disease (45.6%), and metabolic disorders (39.6%).2 During the same period, 44.7% of children hospitalized with laboratory-confirmed influenza did not have an underlying medical condition; 22.5% had respiratory illnesses such as asthma or reactive airway disease.2 Pregnancy also has been identified as a risk factor for adverse outcomes; during the 2012-2013 flu season it accounted for 29.3% of hospitalizations.2

THE 2012-2013 FLU SEASON Each year a subset of confirmed influenza cases is sent to the CDC for antigenic characterization to identify the circulating viruses and to predict the strains for the upcoming flu season. A total of 2,542 viral isolates have been characterized since Oct. 1, 2012, and the 3 most common strains were H3N2 (1,324 isolates), influenza B (876 isolates), and H1N1 (252 isolates).2 These isolates were highly similar to the strains chosen for the 20122013 Northern Hemisphere vaccine. Overall, 98.8% of H1N1, 99.6% of H3N2, and 66.3% of influenza B isolates were antigenically similar.2 Of note, during the 2012-2013 flu season there were 12 cases of human infection caused by a variant influenza

A virus, H3N2v.20 This strain is a nonhuman influenza virus that normally circulates among pigs, but during the past few flu seasons, there have been confirmed cases in humans who have prolonged contact with swine.21 During the 2011-2012 flu season, 16 patients with H3N2v required hospitalization, but as of July 2013, no cases from the latest flu season required hospitalization.20

Influenza Vaccination Large-scale vaccination programs are one of the most important tools to prevent influenza epidemics, and they are of particular importance for at-risk populations. However, according to early estimates from the 2012-2013 flu season, US vaccination rates remain low.22 Data collected through a CDC survey found that only 35.2% of all adults were vaccinated by the middle of the 2012-2013 flu season, which is consistent with surveys from the previous year.22 Immunization is especially important for individuals in high-risk populations, but the CDC consistently has reported low uptake rates in these populations. The vaccination rate in pregnant women (47.3%), although low, was slightly higher than overall rates in adults and was consistent with 2011-2012 data.22 The survey also found that by the middle of the 2012-2013 flu season, only 39.9% of all children and 36.5% of those aged 6 months or older received vaccinations.22 Vaccine uptake seemed to increase with ageâ&#x20AC;&#x201D;59.2% of adults aged 65 and older

INFECTIOUS DISEASE SPECIAL EDITION 2013

Vaccination Rate, %

the 2012-2013 flu season were trivalent vaccines and they included 80 2011-2012 (through Nov.) A/California/7/2009 (H1N1)-like, A/ Victoria/361/2011 (H3N2)-like, and 2011-2012 (through Apr.) 70 B/Wisconsin/1/2010-like viruses.24 2012-2013 (through Nov.) 60 For the 2013-2014 flu season, both newer and older formulations 50 of the vaccine will be available. The trivalent vaccines will contain A/ 40 California/7/2009 (H1N1)-like virus, 30 an H3N2 virus that is antigenically similar to the cell-propagated pro20 totype virus A/Victoria/361/2011, and B/Massachusetts/2/2012-like 10 virus.17 The quadrivalent vaccines 0 will contain those 3 strains and an All persons Children Pregnant Health care additional strain, B/Brisbane/60/ women workers 2008-like virus.17 In addition to the introduction of Figure 2. US vaccine coverage during the 2011-2012 the quadrivalent vaccine, 6 new forand 2012-2013 flu seasons. mulations have been approved for From reference 22. the 2013-2014 flu season: 4 quadrivalent vaccines25-27 and 2 vaccines produced in cell culture systems.28,29 The 4 newly approved quadrivareceived the vaccine—but health care workers had the lent vaccines are FluMist® Quadrivalent (LAIV4, Med22 highest overall vaccination rate at 63.4%. Of concern, Immune), the only LAIV approved for use during the low vaccination rates continue to occur among assis2013-2014 flu season25; Fluarix® Quadrivalent (Glaxotants/aides (46.8%), nonclinical support staff (54.3%), SmithKline)26; FluLaval® Quadrivalent (GlaxoSmithKline), and health care providers in long-term care faciliand Fluzone® Quadrivalent (Sanofi Pasteur), which is the ties (47.9%), which is problematic due to the high-risk only quadrivalent vaccine currently approved for use in patient populations they care for.22 Mid-season vaccichildren aged 6 months and older.27,30 nation rates for all groups were consistent between the All LAIVs are contraindicated in individuals aged 2011-2012 and 2012-2013 flu seasons (Figure 2).22 less than 2 years or over 50 years; pregnant women; Preliminary reports from the US Influenza Vaccine children and adolescents receiving aspirin; and individuals with immunodeficiency or chronic lung, heart, or Effectiveness (Flu VE) Network for the 2012-2013 flu season suggest a total vaccine efficacy (VE) of 56% after kidney diseases.19,31 Additionally, because LAIVs contain a live virus, they are not recommended for health adjustment for age, race, self-rated health, and days of illness.23 Individual VEs for influenza A (A/H3N2) and care personnel who care for immunocompromised influenza B viruses were 47% and 67%, respectively.23 individuals.19 Table 1 provides an overview of vaccine The VEs for influenza A and B were consistent across formulations that will be available during the 20132014 flu season.24-32 all age groups, with the exception of a slightly lowered VE for influenza A in the elderly population (age ≥65 NOVEL METHODS FOR VACCINE PRODUCTION years).23 Therefore, based on available evidence, the CDC continues to recommend annual influenza vacciConventional methods for producing influenza vacnations for all individuals older than 6 months of age.19 cines are limited by a reliance on fertilized chicken eggs. Pharmaceutical companies are successful at producing VACCINE FORMULATIONS safe, effective vaccines for seasonal influenza epidemHistorically, there are 2 vaccine formulations available ics, but current methods may be insufficient to quickly during the annual flu season: an inactivated influenza produce mass amounts of vaccine in the event of a pandemic. Thus, new vaccine production methods using vaccine (IIV) and a live attenuated influenza vaccine (LAIV). The FDA’s Vaccines and Related Biological cell culture systems have recently been developed. The Products Advisory Committee makes annual recommain benefit of using a cell culture system is the readily mendations about vaccine composition based on global available supply of tested and characterized cells, which surveillance data.17 Current recommendations state that can be used to quickly and efficiently produce a large trivalent vaccines should be composed of 2 influenza amount of vaccine during pandemics. The 2 new vaccines approved by the FDA for use A viruses and 1 influenza B virus; the new quadrivalent vaccines should consist of 2 influenza A and 2 influenza during the 2013-2014 flu season are Flucelvax® (Novartis)28 and Flublok® (Protein Sciences).29 Flucelvax is B viruses.17 Both the IIV and the LAIV formulations for

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Table 1. Influenza Vaccines Available for the 2013-2014 Flu Season Vaccine

Trade Name

Manufacturer

Presentation

Mercury Content, mcg Hg/ 0.5 mL

Age Indications

Route

IIV3, standard dose

Afluria

CSL Limited

0.5 mL single-dose prefilled syringe

0.0

≥9 y

5.0 mL multidose vial

24.5

Fluarix

GlaxoSmithKline

0.5 mL single-dose prefilled syringe

0.0

≥3 y

Flucelvax (ccIIV3)

Novartis Vaccines

0.5 mL single-dose prefilled syringe

0.0

≥18 y

FluLaval

ID Biomedical Corporation of Quebec (distributed by GlaxoSmithKline)

5.0 mL multidose vial

<25.0

≥3 y

Fluvirin

Novartis Vaccines

0.5 mL single-dose prefilled syringe

≤1

≥4 y

5.0 mL multidose vial

25.0

0.25 mL single-dose prefilled syringe

0.0

6-35 mo

0.5 mL single-dose prefilled syringe

0.0

≥3 y

0.5 mL single-dose vial

0.0

≥3 y

5.0 mL multidose vial

25.0

≥6 mo

Fluzone

Sanofi Pasteur

Fluzone Intradermal

Sanofi Pasteur

0.1 mL prefilled microinjection system

0.0

18-64 y

IIV3, high dose

Fluzone High-Dose

Sanofi Pasteur

0.5 mL single-dose prefilled syringe

0.0

≥65 y

RIV3

FluBlok

Protein Sciences

0.5 mL single-dose vial

0.0

18-49 y

IIV4, standard dose

Fluarix Quadrivalent

GlaxoSmithKline

0.5 mL single-dose prefilled syringe

0.0

≥3 y

INFECTIOUS DISEASE SPECIAL EDITION 2013

Table 1. Influenza Vaccines Available for the 2013-2014 Flu Season (continued) Vaccine

Trade Name

Manufacturer

Presentation

Mercury Content, mcg Hg/ 0.5 mL

Age Indications

Route

IIV4, standard dose

Fluzone Quadrivalent

Sanofi Pasteur

0.25 mL single-dose prefilled syringe

0.0

6-35 mo

0.5 mL single-dose prefilled syringe

0.0

≥3 y

0.5 mL single-dose vial

0.0

≥3 y

LAIV4

FluLaval Quadrivalent

GlaxoSmithKline

5.0 mL multidose vial

<25.0

≥3 y

FluMist Quadrivalent

MedImmune

0.2 mL prefilled intranasal sprayer

0.0 (per 0.2 mL)

2-49 y

ccIIV3, cell culture–based inactivated influenza vaccine, trivalent; ID, intradermal; IIV3, inactivated influenza vaccine, trivalent; IIV4, inactivated influenza vaccine, quadrivalent; IM, intramuscular; IN, intranasal; LAIV4, live attenuated influenza vaccine, quadrivalent; RIV3, recombinant influenza vaccine, trivalent Adapted from references 24-32.

produced in a mammalian cell culture system that uses Madin-Darby canine kidney cells,32 whereas Flublok is produced in a lepidopteran insect cell culture system.33 Both vaccines are trivalent but, due to different production methods, Flucelvax is classified as an IIV and Flublok is considered a recombinant influenza vaccine. Safety evaluations of Flucelvax and Flublok showed that both vaccines produce localized and systemic reactions similar to traditional egg-based vaccines, which indicated they are safe for use in humans.34,35 However, because neither vaccine was evaluated in pregnant women or nursing mothers, the FDA does not recommend their use in pregnant women unless absolutely necessary; additionally, the FDA urges caution when considering their administration to nursing mothers.32,36 A clinical trial conducted in the United States and Europe found that Flucelvax is 83.8% effective in the prevention of influenza infections in adults between the ages of 18 and 49.37 A second clinical trial indicated that Flucelvax had a lower efficacy in individuals aged 50 and older, but it still produced an antibody response comparable to the traditional egg-based vaccines.35

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Based on these results, the FDA has approved the use of Flucelvax in adults aged 18 and older, but does not recommend its use in children and adolescents under the age of 18.32 The efficacy of Flublok was evaluated in a clinical trial conducted in the United States during the 2007-2008 flu season. The results showed that Flublok was 44.6% effective against all circulating influenza strains in individuals aged 18 to 49.38 Of note, at least 95% of the influenza isolates obtained in the study were not antigenically matched to the strains represented in Flublok indicating its potential to protect against antigenic drift variants.38 The combined results of these clinical trials allowed the FDA to approve Flublok for adults aged 18 to 49.36

Diagnostic Testing Multiple diagnostic tests are available to establish influenza infection; however, their sensitivity, specificity, and turnaround times are highly variable.39-42 Viral culture is the conventional diagnostic method and is considered the gold standard because it offers the highest sensitivity and specificity.40,41 Despite its long

Table 2. Neuraminidase Inhibitor Resistance Trends Since October 2012 Oseltamivir

Zanamivir

Isolates Tested, n

Resistant Isolates, n (%)

Isolates Tested, n

Resistant Isolates, n (%)

Influenza A (H3N2)

2,123

2 (0.09)a

2,123

1 (0.05)

Influenza B

961

pH1N1

542

2 (0.4)

258

One isolate was resistant to both oseltamivir and zanamivir. High levels of resistance to the adamantanes (amantadine and rimantadine persist among H1N1 and influenza A viruses currently circulating worldwide.

From reference 17.

turnaround time, viral culture remains a critical component to confirm outbreaks, as well as to identify circulating strains and subtypes and compare them with vaccine strains—all necessary information to formulate vaccines for the subsequent flu season.39 Viral culture also is essential to monitor the emergence of antiviral resistance and novel influenza A subtypes that may cause pandemics.39 Rapid influenza diagnostic tests (RIDTs) that can identify the presence of influenza viral nucleoprotein antigens are commercially available. These immunoassays offer qualitative results displayed in a simple manner (ie, positive or negative).39 However, RIDTs have a high potential for false-negative results due to their low sensitivity, so the CDC recommends the use of either viral culture or reverse transcription-polymerase chain reaction as a reference standard to confirm influenza infection.42 It should also be noted that some RIDTs are capable of identifying and distinguishing between influenza A and B; however, others can only identify a single strain or cannot distinguish one from the other.39 Despite these drawbacks, RIDTs are an important initial diagnostic step due to their ability to yield clinically relevant turnaround times (ie, ≤15 minutes).42

Antiviral Treatment Options RIDTs can be used to make rapid, informed decisions regarding the administration of antiviral agents. However, the decision to provide antiviral treatment also should be based on symptom severity and epidemiologic factors, and treatment should not be delayed in the absence of test results.43 Early initiation of antiviral therapy can shorten the duration of fever and other symptoms, and it may reduce the risk for complications and death, particularly when initiated within 48 hours of the onset of symptoms.43 For high-risk patients, treatment should be initiated even 72 hours after symptom onset.43 In the United States, 4 antiviral drugs are approved for the treatment of influenza: amantadine, rimantadine, zanamivir (Relenza®, GlaxoSmithKline), and oseltamivir (Tamiflu®, Genentech). However, due to the high levels of amantadine resistance in strains of influenza A circulating worldwide, amantadine and rimantadine were

not recommended by the CDC for the 2012-2013 and upcoming 2013-2014 flu seasons.43 More than 99% of circulating influenza strains remain sensitive to neuraminidase inhibition, so zanamivir and oseltamivir currently are the only antiviral agents recommended by the CDC for influenza.43 With the hope that amantadine-susceptible strains of influenza A may reemerge, amantadine and rimantadine remain approved by the FDA for influenza A viruses, but the CDC recommends against their use.43 Amantadine resistance among circulating influenza A viruses rapidly increased in recent years. During the 1994-1995 flu season, 0.4% of strains were resistant to amantadine, increasing to 12.3% in 2003-2004, and by 2005-2006, 92% carried this resistance trait.43 Amantadine resistance was reported in all of the recently tested H3N2 and 2009 H1N1 isolates, leading the CDC to recommend against its use in 2010.43 Because influenza viruses remain sensitive to neuraminidase inhibition, zanamivir and oseltamivir remain FDA-approved for the treatment of both influenza A and influenza B. The CDC reported that 98.6% of 2009 H1N1 viruses were susceptible to oseltamivir and 100% were susceptible to zanamivir; 100% of influenza A (H3N2) viruses and influenza B viruses were susceptible to both oseltamivir and zanamivir.43 Since Oct. 1, 2012, more than 99% of influenza A and B isolates have shown susceptibility to both of zanamivir and oseltamivir (Table 2).17

INVESTIGATIONAL ANTIVIRALS Currently, zanamivir is only available in powder form for oral inhalation (Relenza),44 whereas oseltamivir is only available in liquid or capsule forms (Tamiflu).45 Consequently, there is an unmet need for injectable antiviral drugs, especially for patients who cannot take oral medication. As a result, IV formulations of zanamivir46 and oseltamivir47 and an IV formulation of a new, long-acting neuraminidase inhibitor, peramivir, all are under development for the US market.48 A longacting, single-dose neuraminidase inhibitor, laninamivir octanoate,49 also is currently under development for the US market.

INFECTIOUS DISEASE SPECIAL EDITION 2013

Although the FDA has not approved IV zanamivir, it has been available since 2009 for compassionate use through an emergency investigational new drug (EIND) application or within clinical trials.43 Following these authorizations, Chan-Tack and colleagues conducted a review of the FDA’s EIND database and identified 200 patients who received IV zanamivir between 2009 and 2011.50 The study found that the majority of IV zanamivir use occurred for the late treatment of critically ill adults with underlying comorbidities and, therefore, conclusions regarding its safety and/or efficacy could not be reached.50 A clinical trial currently is recruiting patients to investigate the efficacy and safety of zanamivir in healthy adult patients to answer those questions.46 Clinical trials also have been performed to study the efficacy of IV oseltamivir. In these studies, 100 mg of IV oseltamivir produced the same amount of exposure to the active metabolite oseltamivir carboxylate as 75 mg of the current oral formulation.47 The data also showed that single doses of IV oseltamivir up to 400 mg were well tolerated, with no safety concerns.47 Multiple doses (100 mg twice daily for 5 days) resulted in effective exposure to the oseltamivir carboxylate and were well tolerated, thus indicating it may be possible to use IV oseltamivir over an extended period.47 Peramivir already is a first-line treatment option in Japan,49 and it is available in the United States through an EIND application or clinical trial protocol.43 Peramivir also was available for a short time during the 2009-2010 H1N1 pandemic when the FDA issued an Emergency Use Authorization.51 Clinical trials have shown that 5-day treatment with either IV peramivir (200 or 400 mg daily) or oral oseltamivir (75 mg twice daily) generally resulted in similar clinical outcomes for hospitalized adults being treated for acute seasonal influenza.48 Another clinical trial studied adult patients with seasonal influenza who received either a single IV infusion of peramivir (300 or 600 mg) or multiple doses of oral oseltamivir (75 mg twice daily for 5 days).52 The median duration of influenza symptoms was between 78 and 81.8 hours for all 3 treatment groups, indicating that either dose of peramivir achieved similar results to extended treatment with oseltamivir.52 Subsequent clinical trials have shown that peramivir may be more effective for high-risk patients by significantly reducing the duration of influenza infection; high-risk patients treated with 300-mg peramivir had a median illness duration of 114.4 hours compared with 42.3 hours for patients who received 600 mg.53 All clinical trials found that peramivir was well tolerated, with an incidence of adverse events similar to oseltamivir.48,52,53 Laninamivir octanoate is a new long-acting neuraminidase inhibitor supplied in a powder formulation. When inhaled into the lungs, laninamivir octanoate is converted into its active form, laninamivir, where a high concentration persists and inhibits influenza virus replication for at least 5 days.49 In October 2010, laninamivir octanoate was approved for the treatment of influenza in Japan. During the 2010-2011 flu season, a post-marketing

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

surveillance study was conducted there to assess the efficacy of laninamivir octanoate in clinical settings and reported efficacy rates of 97.6% for influenza A, 93.3% for influenza B, and 100% for unknown types.54 Of note, the efficacy of laninamivir was strongly dependent on patients correctly inhaling the powder, which made it more difficult to properly administer to children.54 A clinical trial that investigated the efficacy of either a single dose of laninamivir octanoate (20 or 40 mg) or multiple doses of oseltamivir (75 mg twice daily for 5 days) in adult patients found no significant differences in median illness duration between the treatment groups.55 However, the rate of viral shedding at day 3 was significantly lower in the 40-mg laninamivir octanoate group than in the oseltamivir group, indicating that laninamivir octanoate may be more effective at inhibiting viral replication.55 This study also found that laninamivir octanoate was well tolerated and resulted in adverse events similar to those induced by oseltamivir.55 A Phase II clinical trial currently is under way in the United States to determine the efficacy and safety of laninamivir octanoate.56

Conclusion Influenza affects millions worldwide each year and is highly unpredictable; it has the ability to constantly mutate and become more transmissible among humans. The virulence of influenza can clearly be seen in the H1N1 pandemic of 2009 and the recent emergence of H7N9. For this reason, continued monitoring and characterization of human infections are of the utmost importance to assess the potential for future pandemics. There has been great progress in the area of prevention over the past year, with novel cell culture–based methods of vaccine production and continued approval of new quadrivalent vaccines to provide protection against a greater number of strains. Treatment options also may increase in the near future due to the ongoing development of new antiviral agents. However, prevention is the key to controlling outbreaks, so annual vaccinations must be emphasized, particularly in high-risk populations.

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2. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/weekly/summary.htm. Accessed August 15, 2013. 3. Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086-5096. 4. Thompson MG, Shay DK, Zhou H, et al. Estimates of deaths associated with seasonal influenza—United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-1062. 5. Fodor E, Brownlee, GG. Influenza virus replication. In: Potter CW, ed. Perspectives in Medical Virology, Influenza. Vol 7. Amsterdam: Elsevier; 2002:1-29. 6. Hampson AW. Influenza virus antigens and “antigenic drift.” In: Potter CW, ed. Perspectives in Medical Virology, Influenza. Vol 7. Amsterdam: Elsevier; 2002:49-85. 7. Matrosovich MN, Matrosovich TY, Gray T, et al. Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol. 2004;78(22):12665-12667.

8. Palese P, Tobita K, Ueda M, Compans RW. Characterization of temperature sensitive influenza virus mutants defective in neuraminidase. Virology. 1974;61(2):397-410.

35. US National Institutes of Health. NCT00492063. http://clinicaltrials. gov/ct2/show/NCT00492063?term=NCT00492063&rank=1. Accessed August 15, 2013.

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10. Zambon MC. Epidemiology and pathogenesis of influenza. J Antimicrob Chemother. 1999;44(suppl B):S3-S9. 11. Johnson NP, Mueller J. Updating the accounts: global mortality of the 1918-1920 “Spanish” influenza pandemic. Bull Hist Med. 2002; 76(1):105-115. 12. Centers for Disease Control and Prevention. Emergence of avian influenza A (H7N9) virus causing severe human illness— China, February-April 2013. MMWR Morb Mortal Wkly Rep. 2013;62(18):366-371. 13. World Health Organization. http://www.who.int/influenza/human_ animal_interface/influenza_h7n9/Data_Reports/en/. Accessed August 15, 2013.

37. US National Institutes of Health. NCT00630331. http://clinicaltrials.gov/ct2/show/NCT00630331?term=NCT00630331&rank=1. Accessed August 15, 2013. 38. Treanor JJ, El Sahly H, King J, et al. Protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (FluBlok) against influenza in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011;29(44):7733-7739. 39. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/professionals/diagnosis/labrolesprocedures.htm. Accessed August 15, 2013. 40. Landry ML. Diagnostic tests for influenza infection. Curr Opin Pediatr. 2011;23(1):91-97.

14. Gao HN, Lu HZ, Cao B, et al. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med. 2013;368(24): 2277-2285.

41. Takahashi H, Otsuka Y, Patterson BK. Diagnostic tests for influenza and other respiratory viruses: determining performance specifications based on clinical setting. J Infect Chemother. 2010;16(3):155-161.

15. Lessler J, Reich NG, Brookmeyer R, et al. Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis. 2009;9(5):291-300.

42. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/professionals/diagnosis/clinician_guidance_ridt.htm. Accessed August 15, 2013.

16. Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol. 2008;167(7):775-785.

43. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60(1):1-24.

17. Brammer L, Kniss K, Epperson S, et al. Influenza activity—United States, 2012-13 season and composition of the 2013-14 influenza vaccine. MMWR Morb Mortal Wkly Rep. 2013;62(23):473-479. 18. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/about/disease/high_risk.htm. Accessed August 15, 2013. 19. Fiore AE, Uyeki TM, Broder K, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59(RR-8):1-62. 20. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/swineflu/h3n2v-case-count.htm. Accessed August 15, 2013. 21. Centers for Disease Control and Prevention. http://www.cdc.gov/ flu/swineflu/h3n2v-situation.htm. Accessed August 15, 2013. 22. FluVaxView. http://www.cdc.gov/flu/fluvaxview/1213season.htm. Accessed August 15, 2013. 23. Jackson L, Jackson ML, Phillips CH, at al. Interim adjusted estimates of seasonal influenza vaccine effectiveness - United States, February 2013. MMWR Morb Mortal Wkly Rep. 2013;62(7):119-123.

44. Relenza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 45. Tamiflu [package insert]. South San Francisco, CA: Genentech; 1999. 46. US National Institutes of Health. NCT01231620-A. http://clinicaltrials.gov/ct2/show/NCT01231620?term=NCT01231620&rank=1. Accessed July 30, 2013. 47. Brennan BJ, Davies B, Cirrincione-Dall G, et al. Safety, tolerability, and pharmacokinetics of intravenous oseltamivir: single- and multiple-dose phase I studies with healthy volunteers. Antimicrob Agents Chemother. 2012;56(9):4729-4737. 48. Ison MG, Hui DS, Clezy K, et al. A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2012 Oct 30. [Epub ahead of print] 49. Ikematsu H, Kawai N. Laninamivir octanoate: a new long-acting neuraminidase inhibitor for the treatment of influenza. Expert Rev Anti Infect Ther. 2011;9(10):851-857.

24. Grohskopf L, Uyeki T, Bresee J, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2012-13 influenza season. MMWR Morb Mortal Wkly Rep. 2012;61(32):613-618.

50. Chan-Tack KM, Gao A, Himaya AC, et al. Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis. 2013;207(1):196-198.

25. Approval Letter—FluMist Quadrivalent. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm294293.htm. Accessed August 15, 2013.

51. Birnkrant D, Cox E. The Emergency Use Authorization of peramivir for treatment of 2009 H1N1 influenza. N Engl J Med. 2009;361(23): 2204-2207.

26. Approval Letter—Fluarix. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm313171.htm Accessed August 15, 2013.

52. Kohno S, Yen MY, Cheong HJ, et al. Phase III randomized, doubleblind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother. 2011;55(11):5267-5276.

27. Approval Letter—Fluzone Quadrivalent. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm356095. htm. Accessed August 15, 2013. 28. Approval Letter—Flucelvax. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm328684.htm. Accessed August 15, 2013. 29. Approval Letter—Flublok. http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM336017.pdf. Accessed August 15, 2013. 30. Fluzone Quadirivalent [package insert]. Swiftwater, PA: Sanofi Pasteur; 2013. 31. FluMist Quadrivalent [package insert]. Gaithersburg, MD: MedImmune; 2012. 32. Flucelvax [package insert]. Cambridge, MA: Novartis; 2012.

53. Kohno S, Kida H, Mizuguchi M, et al. Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011;55(6):2803-2812. 54. Kashiwagi S, Yoshida S, Yamaguchi H, et al. Clinical efficacy of longacting neuraminidase inhibitor laninamivir octanoate hydrate in postmarketing surveillance. J Infect Chemother. 2013;19(2):223-232. 55. Watanabe A, Chang SC, Kim MJ, et al. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clin Infect Dis. 2010;51(10):1167-1175. 56. US National Institutes of Health. NCT01793883. http://clinicaltrials. gov/ct2/show/NCT01793883?term=NCT01793883&rank=1. Accessed August 15, 2013.

33. Cox MM, Hollister JR. FluBlok, a next generation influenza vaccine manufactured in insect cells. Biologicals. 2009;37(3):182-189. 34. Treanor JJ, Schiff GM, Hayden FG, et al. Safety and immunogenicity of a baculovirus-expressed hemagglutinin influenza vaccine: a randomized controlled trial. JAMA. 2007;297(14):1577-1582.

Dr. Garcia-Diaz reported that she has received grant/research support from Astellas, Cubist Pharmaceuticals, Pfizer, and Sanofi Pasteur. Drs. Lalama and Nnedu have no relevant financial disclosures.

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Antibiotics and the Intestinal Microbiota: Short-Term Benefits, Long-Term Consequences

JULIO E. FIGUEROA, MD Associate Professor of Clinical Medicine Director, Infectious Diseases Fellowship Program Louisiana State University New Orleans, Louisiana

nton van Leeuwenhoek was the first individual to notice the presence of microorganisms in the human gastrointestinal (GI) tract.1 Shortly

afterward, Louis Pasteur, Robert Koch, and others linked the presence

of certain microbes with disease.2,3 The discovery of antibiotics allowed

for inexpensive and lifesaving treatments for bacterial infections.4

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INFECTIOUS DISEASE SPECIAL EDITION 2013

However, clinicians noted the development of antimicrobial resistance shortly thereafter, particularly in Staphylococcus aureus and Neisseria gonorrheae.5 Even with the recognition of Clostridium difficile colitis, emphasis remained on antibiotic resistance issues rather than changes to the microbiota.6 With the advent of probiotics, we have had increasing interest in the role of specific â&#x20AC;&#x153;goodâ&#x20AC;? microbes for disease prevention and treatment. Studies evaluating a variety of Lactobacillus species, Bifidobacterium species, and Saccharomyces species have shown their efficacy in the prevention or treatment of conditions such as diarrhea and pneumonia.7,8 The confluence of computational and technological advances has led to a greater understanding of the importance of resident microbiota for human health and disease.9 Discovery of non-cultivable organisms also has played a vital role through the realization that there are 10 times more microbial genomes than human ones in the average person. Although thousands of papers on the microbiota have been published over the past few years, relatively few address how antimicrobials affect gut microbiota in humans. Moreover, many currently used antibiotics have not been systemically studied. According to data from the Center for Disease Dynamics, Economics & Policy, US outpatients received 801.3 antibiotic prescriptions per 1,000 population in 2010.10 Approximately 57% of prescriptions were either penicillins or macrolides/lincosamides. Antibiotic use in the hospital setting contributes an additional risk factor: exposure to multidrug-resistant organisms. The extensive use of antibiotics in animal husbandry and other agriculture also has the potential to significantly contribute to alterations of gut microbiota. This review will touch on general concepts concerning the acquisition and stability of the microbiota. Additionally, it will outline evidence that antibiotic use can have a lasting effect on gut microbiota, as well as discuss some of the worrisome consequences of excessive antibiotic use on gut microorganisms.

Methodology The study of human microbiota largely comes from analysis of relatively short genome sequences that can be tagged to specific microbial families.11 After obtaining millions of sequence reads, data can be organized using bioinformatics. These studies offer information about the percentages of major classes of microbes (eg, kingdom, phylum, or order) and allow an assessment of organism diversity (ie, metagenomics). By looking at the proportions of microbiota within a particular site, one can get a sense of the microbial community at any single time point. Moreover, one can measure differences in community structures between individuals, and movements in those structures over a particular time frame or caused by a particular intervention. To study the effects of an intervention on gut microbiota, one must first establish the subjectâ&#x20AC;&#x2122;s baseline

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community structure and then measure changes following a particular intervention; differences are usually expressed in principal coordinate plots. The anatomic source of gut microbiota being investigated has received increased attention recently. Most research uses fecal samples for the analysis; however, recent studies have shown that mucosal-associated gut microbiota may be more important, especially as they pertain to certain disease states. The consequences of any specific microbial community can be assessed in a variety of ways.11 Investigators can assess functional differences in microbiota in the mRNA, proteins, or metabolic signatures of bacterial metabolic pathways that are active within specific community structures. These aspects of the study are commonly called transcriptomes, proteomics, and metabolomics, respectively. Similarly, one can assess the effect of certain microbial community structures on metabolic pathways of human cells. Alternatively, studies can look at the relative abundance of genes for particular metabolic pathways among different microbial communities.

Human Fecal Microbiota: Acquisition, Stability, and Function Our environment has a phenomenal degree of microbial diversity. Despite exposure to this diversity, humans acquire and maintain a remarkably finite number of microbial classes in whatever niche that is studied. This does not mean humans lack substantial diversity from one person to the next, however. For example, Palmer et al studied the acquisition of fecal microbiota in 14 infants from birth to 1 year of age and compared the infant microbiota with those of different family members over time.12 Delivery type, food source, and antibiotic use also were recorded for the infants. The investigators reported variability in both timing of microbiota acquisition and microbial diversity. Of the 14 infants, only a set of fraternal twins had similar microbial community structures. The microbiota evolved over time from a predominantly maternal pattern into a unique pattern that reflected a combination of familial and environmental microbiota. One infant experienced substantial alterations in gut microbiota during administration of oral antibiotics.12 Studying 3 different cohorts, Yatsunenko et al examined the variability of fecal microbiota based on age and geography.13 They analyzed 531 individuals from 151 families: 98 families in the United States, 34 families in Malawi, and 19 Amerindian families in rural Venezuela. Of interest, they found that children under 3 years of age were significantly different from adults in the same population. After age 3, there were increasing similarities between older children and adults. This also corresponded with an increase in microbial diversity observed in older age groups. Using principal coordinate analysis, they showed marked separation of fecal microbiota among the 3 cohorts. Fecal samples from the United States were significantly less

diverse than those from Malawi and Venezuela. When looking at the relative abunBangladeshi Children dance of bacterial genes for metabolic Cyanobacteria Unclassified YS2 pathways, the investigators found a profound difference between US and non-US Succinivibrio Proteobacteria populations. Additionally, this study found Acinetobacter that fecal microbiota of members of the Prevotella same household were much more alike Bacteroidetes Unclassified Bacteroidales than those living in different households. Within a family, the degree of genetic Catenibacterium similarities (ie, monozygotic vs dizyTenericutes p-75-a5 gotic twins) did not seem to make much Bulleidia difference in the level of diversity, particuSarcina larly during the early stages of life. These Mitsuokella data support the role of common environUnclassified Clostridialesmental exposures in the development and FamilyXIII IncertaeSedis persistence of fecal microbiota and downLactobacillus play the role of genetics in the microbial Butyrivibrio diversity observed among individualsâ&#x20AC;&#x201D;in essence, â&#x20AC;&#x153;you are what you eat.â&#x20AC;? Blautia Another important issue is the stabilFirmicutes Leuconostoc Streptococcus ity of fecal microbiota in normal individClostridiaceae-Clostridium uals over time. Caporaso and colleagues Lachnospiraceae-Clostridium analyzed daily fecal samples obtained Unclassified Clostridiales from 2 individuals (1 male, 1 female) Faecalibacterium for at least 6 months to determine the Roseburia 14 degree of intraindividual variability. The investigators found substantial fluctuations in fecal flora over the 6-month Ruminococcaceae-Clostridium period. They noted persistent but nonpermanent members of the microbial Erysipelotrichaceae-Clostridium community in each person; however, no parTenericutes Holdemania ticular taxon was detectable throughout the time points. In a study of 272 healthy individuals conUS Children ducted in the United States, Huttenhower et al examined 4,788 samples from multiple sites over time.15 The data confirm the presFigure 1. Venn diagram of exclusive ence of variability within individuals over and shared genera in the distal gut of time, but less than that observed between Bangladeshi and US children. individuals. Despite dramatic disparity in the fecal taxa among these healthy individuals, Reprinted from: Lin A, et al. Distinct distal gut microbiome diversity the metagenomic profiles for specific metaand composition in healthy children from Bangladesh and the United States. PLoS One. 2013;8(10):e53838. bolic pathways were remarkably similar. Growing evidence suggests that the human fecal microbiota evolves over time, is diverse between individuals, and experiences constant change. Variability is DIFFERENT COMPARTMENTS, DISTINCT FLORA mostly due to environmental exposures, including The previously described studies primarily focused household contacts and diet. In healthy Western populations, variation may result in relatively small changes on fecal microbiota. Other studies have analyzed the in metagenomic profiles. However, individuals from microbiota of the oral cavity, gastric mucosa, and other different parts of the world can have substantial difsites.15,17,18 Through this research, it has become apparferences in their metagenomic profiles, a point reinent that gut flora is not a single entity, instead varyforced by Lin and colleagues in their analysis of the ing based on location within the GI tract (eg, mouth vs distal gut microbiome in children from Bangladesh cecum). Moreover, even in the same location, it appears and the United States (Figure 1).16 These differences that flora found in the intestinal lumen is significantly may help predict the presence of health or disease in different from flora associated with mucosal structures. certain populations. These observations demonstrate a level of complexity

INFECTIOUS DISEASE SPECIAL EDITION 2013

Sacrifice at the end of cefoperazone period

Cefoperazone for 10 d

6-wk recovery without donor in cage

6-wk recovery with no drug control donor in cage

C57BL/6 mice

Serve as donor in cage No drug control Sacrifice

Figure 2. Experimental design used by Antonopoulos et al. From reference 21.

that can confound the interpretation of scientific reports. One major question remains: Which compartment is most relevant to define health and disease in humans? Animal studies explore both mucosa-associated and fecal microbiota,19 whereas human studies primarily focus on changes in fecal flora. It seems likely that, for many diseases, mucosa-associated flora are much more relevant than luminal flora. How changes in fecal flora relate to changes in mucosa-associated flora is a subject for further investigation.

Antibiotics and Gut Microbiota A number of factors can affect gut microbiota including Western diet, GI infections, inflammatory diseases, immune deficiencies, and antibiotics.20 Although several of these factors can work in concert to change fecal flora, this review will specifically focus on the effects of antibiotics. Before the advent of modern sequencing technology, studies of antibiotic use on fecal flora used culture-based methods. Given our current understanding, many of these studies should be looked at with great skepticism. Most metagenomic studies in this field are performed using animal models. These reports should be interpreted with caution because of the potential for interspecies variation. Moreover, several of these studies use antibiotic regimens that are not commonly used in clinical practice. However, these studies provide insight into the effects of specific antibiotics. Human studies

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focus on changes in fecal flora. Therefore, there is a question about their relevance to changes in mucosaassociated flora.

ANIMAL STUDIES In an early study, Antonopoulos et al used C57BL/6 interleukin-10窶電eficient mice to study the effects of 2 antibiotic regimens on mucosa-associated flora: amoxicillin-metronidazole-bismuth and cefoperazone.21 Firmicutes and Bacteroidetes dominated the cecalmucosal flora at baseline. Proteobacteria represented 1.1% of the total bacterial genomes (ﾂｱ1.1%). Ten-day treatment with amoxicillin-metronidazole-bismuth resulted in dramatic reductions in these taxa, with a reciprocal increase in Proteobacteria. At the end of treatment, Proteobacteria represented 75% of all taxa. During a 10-day recovery phase, fecal flora trended back to baseline; however, Proteobacteria rates remained substantially increased (mean 6%ﾂｱﾂｱ4.9%).21 This finding supports the role of episodic antibiotic courses in causing persistent changes to mucosa-associated flora. In a second experiment using oral cefoperazone, the investigators took advantage of the fact that mice are coprophagic. The experimental design could, therefore, assess the effect of reconstitution of mucosa-associated flora by the transfer of normal fecal flora to cefoperazone-treated animals (Figure 2).21 Using the Bray-Curtis similarity index, they found that cefoperazone-treated mice had dramatic changes in their flora compared with

controls. Moreover, the flora of mice that recovered without exposure to normal fecal flora remained significantly altered, even 6 weeks after treatment discontinuation. Their flora was not only substantially altered, but it also was less diverse than control mice. However, mice allowed to recover with control subjects in the same cage had mucosa-associated flora that resembled the control animal’s flora both in terms of taxon distribution and diversity.21 Hill and colleagues studied the effect of an oral, 10-day, broad-spectrum antibiotic regimen (ampicillin, gentamicin, metronidazole, neomycin, and vancomycin) on luminal and mucosa-associated flora.19 They also defined the consequences on villus size and mucosal immunity. As expected, antibiotic treatment dramatically reduced the number and affected the distribution of mucosa-associated and luminal flora. These changes correlated with increases in mucosal villus length, decreases in fecal RELM-β, and alterations in interferon-γγ and interleukin-17–producing, CD4-positive T lymphocytes. Brandl et al studied the use of an oral, 7-day, broadspectrum antibiotic regimen (metronidazole, neomycin, and vancomycin [MNV]) on ileal-mucosal immunity and vancomycin-resistant enterococci (VRE) colonization.22 Wild-type mice and those with MyD88 deficiency were treated with either water or MNV; experiments were performed on the ligated ileal loop. Antibiotic treatment was associated with reductions in RegIII-γγ production by ileal epithelium. The reduction of RegIII-γγ correlated with increased VRE colonization in the ileal segment. Increases in VRE colonization could be inhibited by the administration of Escherichia colii lipopolysaccharide. These findings support the importance of gram-negative gut bacteria in the control of drug-resistant grampositive organisms, such as VRE, by inducing toll-like receptor–MyD88 signal pathways.22 In a subsequent investigation, researchers performed similar experiments on wild-type C57BL/6 mice using 3 different oral antibiotic regimens: ampicillin monotherapy, vancomycin monotherapy, or MNV.23 Oral ampicillin had significant and consistent effects on ileal and cecal flora both during and 2 weeks after the treatment phase, persisting up to 8 weeks after treatment. The effects of oral vancomycin and MNV on the microbiota were more variable. Untreated and ampicillin-treated animals were then exposed to 108 colony-forming units (CFUs) of VRE. Once again, untreated animals had lowlevel VRE colonization in both the ileum and cecum that was undetectable 15 days postexposure. Conversely, ampicillin-treated animals had increased rates of VRE colonization that persisted at high levels in both the ileum and cecum; elevated rates were observed up to 60 days after recovery from treatment cessation.23 Similarly, Ayres and colleagues described the importance of commensal gut microbiota in the modulation of potentially pathogenic symbiotic organisms, pathobionts, in a mouse model of dextran sulfate sodium (DSS)-induced enteritis.24 Mice received either water

or an oral cocktail of ampicillin, vancomycin, neomycin, and metronidazole (AVNM) for 10 days, after which they were given DSS and then monitored. Mice that received AVNM died at a much faster rate than those that received water. Additionally, these animals died of sepsis-like syndrome, with elevated levels of proinflammatory cytokines, hypothermia, and end-organ damage rather than colitis with weight loss. Similar results were observed in animals given ampicillin alone but not the other components of AVNM. Fecal flora from these mice contained substantial expansion of an AVNMresistant E. colii O21/H+. Using quantitative polymerase chain reaction testing, this strain was found to be present at low levels in fecal samples from control mice.24 Moreover, AVNM-treated animals had significantly higher bacterial colonization in the lungs and liver. These tissues exclusively contained the same AVNMresistant E. colii strain. This strain induced the Naip5Nlrc4 inflammasome leading to the sepsis syndrome seen.24 These results support the concept of dysbiosis (disruption of commensal flora) leading to the expansion of a pathobiont to cause disease. Buffie and colleagues investigated the effect of a single dose of oral clindamycin in the acquisition and persistence of another important pathogen, C. difficile, in a mouse model.25 Mice were given either saline or a single intraperitoneal dose of clindamycin. On the following day, mice were given 103 CFUs of C. difficile spores or water and followed for 30 days. Although clindamycin did not significantly decrease the total number of gut flora, there was reduction in the number of taxa both in the ileum and especially in the cecum.25 Particularly, there was an expansion of Enterobacteriaceae. In mice that received C. difficile spores, those with clindamycin exposure had a 5- to 7-log increase in C. difficile CFU/g feces over those with saline alone. This high level of C. difficile shedding was seen on days 1 to 10 following administration of clindamycin.25 These data demonstrate the effect of even a single dose of antibiotics on the acquisition of C. difficile. Perez et al studied the effects of a variety of antibiotics on the acquisition and persistence of carbapenemase-producing Klebsiella pneumoniae (KPC) in a mouse model.26 Mice received subcutaneous injections of saline, piperacillin-tazobactam, ertapenem, tigecycline, cefepime, ciprofloxacin, and clindamycin for 8 days. On antibiotic day 3, the mice were given 103 CFUs of KPC VA-367 orally. Stool samples were collected up to 11 days after KPC administration. Although KPC could be detected in all fecal samples, those treated with clindamycin had the highest CFU/g of stool (peak >1010 during the treatment phase). Piperacillin-tazobactam and tigecycline also were higher than control animals at most time points. At the end of treatment (day 11), animals that received clindamycin and piperacillin-tazobactam had approximately 1 log more KPC than other animals.26 The authors did not use a metagenomic approach to define the fecal flora; however, as expected, treatment with clindamycin and

INFECTIOUS DISEASE SPECIAL EDITION 2013

piperacillin-tazobactam was associated with fewer culturable anaerobes compared with controls. Interestingly, in a separate experiment, intermittent treatment with clindamycin resulted in detectable KPC levels in stools for up to 21 days. These data suggest that fecal anaerobes are important for protection against the colonization and persistence of KPC. Looking at route of administration, Zhang and colleagues recently published the differential effects of tetracycline and ampicillin—oral or IV—on the levels of tetracycline-resistant enterococci and ampicillinresistant E. colii in the fecal flora.27 Mice were administered resistant bacteria by gavage and subsequently treated with saline or antibiotics for 5 days. Stools were collected daily during the antibiotic period and the 10-day recovery period. Animals that received tetracycline had a dramatic expansion of resistant enterococci in their fecal flora.27 This increase occurred quickly with oral tetracycline but took 2 days with IV tetracycline. Animals who received oral ampicillin experienced a similar expansion of resistant E. coli; however, development of ampicillin resistance was not significantly different between IV ampicillin and saline. The rates of both resistant organisms declined after antibiotic discontinuation.27 Taken together, these data reinforce the potentially dramatic effect of antibiotics—even short courses—on the acquisition or expansion of important pathogens and drug-resistant organisms in gut flora. Ampicillin and clindamycin, 2 commonly prescribed agents, seem to have the ability to cause these changes. Alterations to anaerobic flora seem to be the major determinant in these effects. Although most of these studies involve oral antibiotic administration, parenteral clindamycin, ampicillin, tetracycline, and piperacillin-tazobactam also had a significant effect in some studies. The effects of other parenterally administered antibiotics are less clear. Of interest, emerging data show that antibioticinduced changes in microbiota are associated with changes in mucosal immunity and metabolism.

HUMAN STUDIES Although there are excellent animal data on the consequences of antibiotic use on the microbiome, few parallel studies have been performed in humans. Those that have been published primarily are descriptive in nature. For example, Palmer et al described the effects of antibiotics in several infants, although this was not a primary outcome in their fecal microbiota study.12 Moreover, interpreting the results of these studies is confounded by the variability of fecal flora over time as well as the absence of control participants. Recently, Fouhy and colleagues evaluated 18 infants, 9 of whom had received IV ampicillin and gentamicin for suspected sepsis within 48 hours of birth.28 The longest antibiotic course was 9 days; 6 of 9 infants received antibiotics for 2 days. Five of the antibiotictreated infants were delivered via cesarean delivery, and all of the antibiotic-naive infants were born vaginally.

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Stool samples, collected 4 and 8 weeks after birth, were analyzed. The authors found that those exposed to antibiotics had fewer Bifidobacterium species and more Proteobacteria in their feces than infants who were not given antibiotics at weeks 4 and 8. Despite several potential confounding factors, these data suggest the possibility of long-term sequelae from very early use of a standard antibiotic regimen. Dethlefsen et al attempted to define the aftermath of a single agent under more controlled settings. They studied the effects of a commonly administered antibiotic, oral ciprofloxacin, on the fecal flora of 3 normal individuals (1 Asian woman, 2 European-American men).29 The fecal flora from each subject was characterized before the antibiotic course (days –60 and –1), during the 5-day course of 500-mg oral ciprofloxacin twice daily (days 1 and 5), and then after the antibiotic course (days 33 and 180). Ciprofloxacin administration was associated with a reduction in taxon richness, diversity, and evenness. Interestingly, the 3 individuals all had different responses: 1 person experienced substantial changes, 1 had intermediate changes, and 1 underwent minor changes (Figure 3).29 These alterations were undetectable 28 days after antibiotic discontinuation in all 3 subjects. In a follow-up study, these same investigators extended the experiment using 3 different subjects and characterized significantly more stool samples (50-56 per participant) over a 10-month period.30 Participants received a 5-day course of 500-mg oral ciprofloxacin twice daily, during months 2 and 8. Once again, ciprofloxacin administration correlated with substantial changes in fecal flora with decreases in taxon richness and phylogenetic diversity. Similar to the previous study, all 3 individuals had different responses during the initial treatment and recovery periods; 1 person required several months to restore normal gut microbiota.30 Participants also had differences in their response to ciprofloxacin challenge; therefore, it appeared that there was no particular pattern associated with ciprofloxacin administration. This was in contrast to the previous study and likely was due to more robust sampling in the latter experiment. Overall, these data not only support the effect of this commonly prescribed antibiotic on fecal flora, but also the individual variability in that effect.30 After the second round of ciprofloxacin, individuals experienced different responses from those experienced after the first course.30 In other words, an individual’s recovery pattern following an antibiotic episode does not predict recovery after repeat treatment with the same drug. Interestingly, none of these individuals experienced any clinical GI symptoms. The authors pointed to the redundancy of gut flora to explain this phenomenon. Taur and colleagues studied the effects of antibiotics on the fecal flora of allogeneic stem cell transplant patients at Memorial Sloan-Kettering Cancer Center in New York City.23,31 The investigators collected fecal

Richness

1500

Diversity

5 4

1000

Evenness

0.8

0.6

3 0.4 2

500

0 A

Pre Cp Cp Post Cp

0.2

Figure 3. Taxonomic diversity within the gut microbiota before, during, and after antimicrobial administration. Cp, ciprofloxacin; OTU, operational taxonomic unit (A) Observed taxon richness (number of V3 reference OTUs) per sample; Cp-associated samples have significantly fewer OTUs than pre- and post-Cp samples for individuals A and B (P<0.005) but not individual C (P=0.129). (B) Shannon diversity index; Cp-associated samples are significantly less diverse than other samples for all individuals (P<0.001). (C) Shannon equitability index; OTU abundance in Cp-associated samples is significantly less evenly distributed than OTU abundance in other samples for all individuals (P<0.001 for A and B; P<0.05 for C). Reprinted from: Dethlefsen L, et al. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6(11):e280.

samples during the pretransplant conditioning period and again up to 35 days posttransplant. The 94 patients studied in these investigations had at least 1 pretransplant and 2 posttransplant samples. All antibiotic regimens and other clinical data were documented. Although these patients had received antibiotics before this study, the average Shannon diversity index was not significantly different from healthy volunteers at the institution. However, the dominant taxa in individuals varied considerably. Moreover, samples from the same individual could transition from one pattern to another. In the pretransplant period, patients with a pattern described as â&#x20AC;&#x153;diverseâ&#x20AC;? maintained this pattern in 77% of pretransplant samples. In the intraoperative period, only 35% of those with diverse patterns just prior to transplant remained that way immediately following transplant.31 Those who transitioned did so primarily with dominance of enterococci, streptococci, or Proteobacteria. In the posttransplant period, the diverse population continued to become less diverse and moved to dominance of enterococci, streptococci, Bacteroidetes, or

Proteobacteria. By the end of the study period (day 35), metronidazole use was associated with enterococcal dominance, whereas fluoroquinolone use was associated with protection against Proteobacterial dominance. Î˛-lactams favored dominance over diversity but did not result in any particular pattern. At posttransplant day 35, slightly more than 50% of patients had an episode of enterococcal dominance, whereas streptococcal dominance was observed in approximately 40% of patients.31 These authors also noted important consequences to intestinal dominance with specific taxa. Patients with enterococcal dominance were 9.35 times more likely to have enterococcal bacteremia; similarly, patients with Proteobacterial dominance were 5.46 times more likely to have gram-negative bacteremia.31 Human studies emphasize the diversity of response to antibiotics in terms of fecal microbiota. Importantly, the consequences of broad-spectrum antibiotic use seem to corroborate the findings reported in mouse models. In particular, alterations in anaerobic gut flora seem to correlate with the greatest effects; dominance of specific microbes can lead to a predisposition for

INFECTIOUS DISEASE SPECIAL EDITION 2013

systemic infections from those organisms. Additional findings such as changes in mucosal immunity and metabolism are topics of intensive research.

Some Answers, More Questions As more information develops about the importance of gut microbiota, it is imperative that infectious disease clinicians promote the judicious use of antibiotics. Data from animal studies with ampicillin and clindamycin call into question the routine, habitual pattern of prescribing oral antibiotics, primarily amoxicillin with or without clavulanic acid and clindamycin, for many conditions that do not require these drugs. Another commonly prescribed antibiotic, azithromycin, has not been studied adequately. Moreover, do studies using oral antibiotics predict the effects of parenteral antibiotics? It would seem to be the case for ampicillin, clindamycin, and tetracycline; in the study by Perez et al, parenteral piperacillin-tazobactam also seemed to exert some effect.26 This relationship is unclear for other parenterally administered drugs, however. As antibiotic stewards, how should clinicians select antibiotics for legitimate clinical conditions? Should we consider the effect of the antibiotic on gut microbiota, especially in young children? For example, high-dose oral amoxicillin and amoxicillin-clavulanic acid are currently recommended for the treatment of otitis media and sinusitis, respectively.32,33 Clindamycin is commonly used in the treatment of skin and soft tissue infections and is the recommended alternative for surgical site

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infection prophylaxis in penicillin-allergic patients.34,35 Although these uses are supported by current treatment guidelines, research has thus far shown that these antibiotics also cause significant effects on the microbiota. Furthermore, physician knowledge about the indications for antibiotic use is fairly poor. In a recent survey of medical residents, many said they would treat asymptomatic bacteriuria in situations that are not indicated.36 In another survey conducted in long-term care facilities, prescriber preference rather than patient characteristics predicted the duration of antibiotic treatment.37 Antibiotic stewardship programs with strong educational components are required to help curb these practices. The industrial use of antibiotics accounts for more than half of all use in the United States.38 Transmission of drug-resistant bacteria to humans through the food supply has already occurred; antibiotics introduced into the environment through these activities also can select for resistance.39 But what happens to the human microbiota as we consume products with residual antibiotics? In response to these issues, in 2012 the FDA issued guidelines for comment to control this type of antibiotic use.39 With the emerging knowledge about the importance of gut microbiota in health and disease, we need more information about how to minimize the untoward effects of antibiotic use so that we can target the pathogen without negatively affecting patient health. Only then can antibiotics truly be called magic bullets.

References 1.

Ford BJ. The Leeuwenhoek Legacy. Bristol and London: Biopress and Farrand Press; 1991.

2. Ullmann A. Pasteur-Koch: distinctive ways of thinking about infectious diseases. Microbe. 2007;2(8):383-387. 3. Mendelsohn JA. “Like all that lives”: biology, medicine and bacteria in the age of Pasteur and Koch. Hist Philos Life Sci. 2002;24(1):3-36. 4. Moellering RC. Past, present, and future of antimicrobial agents. Am J Med. 1995;99(6A):11S–18S. 5. Sabath LD. Some historical aspects of bacterial resistance. Bull N Y Acad Med. 1987;63(3):330-336. 6. Kelly CP, LaMont JT. Clostridium difficile infection. Annu Rev Med. 1998;49:375-390. 7. Johnston BC, Ma S, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157(12):878-888. 8. Heineman J, Bubenik S, McClave S, Martindale R. Fighting fire with fire: is it time to use probiotics to manage pathogenic bacterial diseases? Curr Gastroenterol Rep. 2012;14(4):343-348. 9. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859-904. 10. The Center for Disease Dynamics, Economics & Policy. http://cddep.org/map. Accessed August 15, 2013. 11. Wooley JC, Godzik A, Friedberg I. A primer on metagenomics. PLoS Comput Biol. 2010;6(2):e1000667. 12. Palmer C, Bik EM, DiGiulio DB, et al. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5(7):e177. 13. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402): 222-227.

23. Ubeda C, Taur R, Jeng RR, et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest. 2010;120(12):4332-4341. 24. Ayres JS, Trinidad NJ, Vance RE. Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. Nat Med. 2012;18(5):799-806. 25. Buffie CG, Jarchum I, Equinda M, et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect Immun. 2012;80(1):62-73. 26. Perez F, Pultz MJ, Endimiani A, et al. Effect of antibiotic treatment on establishment and elimination of intestinal colonization by KPC-producing Klebsiella pneumoniae in mice. Antimicrob Agents Chemother. 2011;55(6):2585-2589. 27. Zhang L, Huang Y, Zhou Y, et al. Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota. Antimicrob Agents Chemother. 2013 May 20. [Epub ahead of print] 28. Fouhy F, Guinane CM, Hussey S, et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother. 2012;56(11):5811-5820. 29. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6(11):e280. 30. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci. 2011;108(suppl 1): S4554-S4561. 31. Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55(7):905-914.

14. Caporaso JG, Lauber CL, Costello EK, et al. Moving pictures of the human microbiome. Genome Biol. 2011;12(5):R50.

32. Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012;54(8):1041-1045.

15. The Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012; 486(7402):207-214.

33. Lieberthal AS, Carrol AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131:e964-e999.

16. Lin A, Bik EM, Costello EK, et al. Distinct distal gut microbiome diversity and composition in healthy children from Bangladesh and the United States. PLoS One. 2013;8(10):e53838. 17. Costello EK, Lauber CL, Hamady M, et al. Bacterial community variation in human body habitats across space and time. Science. 2009;326(5960):1694-1697. 18. Li K, Bihan M, Methe BA. Analyses of the stability and core taxonomic memberships of the human microbiome. PLoS One. 2013;8(5):e63139. 19. Hill DA, Hoffman C, Abt MC, et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 2010;3(2):148-158.

34. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195-283. 35. Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373-1406. 36. Drekonja DM, Abbo LM, Kuskowski MA, et al. A survey of resident physicians’ knowledge regarding urine testing and subsequent antimicrobial treatment. Am J Infect Control. 2013 Mar 28. [Epub ahead of print] 37. Daneman N, Gruneir A, Bronskill SE, et al. Prolonged antibiotic treatment in long-term care: role of the prescriber. JAMA Intern Med. 2013;173(8):673-682.

20. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012; 148(6):1258-1270.

38. Food and Drug Administration. http://www.fda.gov/downloads/ ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM338170. pdf. Accessed August 17, 2013.

21. Antonopoulos DA, Huse SM, Morrison HG, et al. Reproducible community dynamics of the gastrointestinal microbiota following antibiotic perturbation. Infect Immun. 2009;77(6):2367-2375.

39. Finley RL, Collignon P, Larsson DG, et al. The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis. 2013 Jun 21. [Epub ahead of print]

22. Brandl K, Plitas G, Mihu CN, et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008; 455(7214):804-807.

Dr. Figueroa has no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION 2013

PRINTER-FRIENDLY VERSION AT IDSE.NET

Hepatitis C Virus: Year in Review

he past 12 months have seen continued changes in

the approach to screening

for hepatitis C virus (HCV), as well as new FDA approvals for genotyping and viral-load tests. Moreover, research into the optimal treatment regimens and duration continues to produce important e information. Although the incidence ne, of HCV infection continues to declin cases of cirrhosis and hepatocellularr carcinoma remain steady.1

As a result, early identification of infections and continued research on cure strategies—particularly using regimens that do not include interferon (IFN)—are vital to this patient population. This review will highlight advances in HCV care from the past year, including research presented at recent gastroenterology and hepatology meetings.

Screening and Diagnostics In August 2012, the Centers for Disease Control and Prevention (CDC) recommended a one-time HCV screening for all Americans born between 1945 and 1965 (aka baby boomers).2 According to the CDC report, 75% of

INFECTIOUS DISEASE SPECIAL EDITION 2013

HCV-infected individuals in the United States were born during that period, but the overwhelming majority—as many as 75%—are unaware of their HCV status. The CDC said screening baby boomers could lead to the detection of more than 800,000 HCV infections, and avert cases of advanced liver disease and as many as 120,000 deaths. But the CDC’s recommendation received a lukewarm response from the US Preventive Services Task Force (USPSTF). In its November 2012 draft opinion, the task force said screening should be offered to adults at high risk, such as those with a history of IV drug use and those who received blood transfusions before 1992. For baby boomers, the task force said clinicians may

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Table. Adverse Events in Patients Receiving PEG-IFN Lambda Compared With PEG-Interferon Alfa PEG-IFN Lambda (180 mcg)

PEG-IFN Alfa (180 mcg)

Patients with any serious AEs, n

Patients with any AEs, %

88.2

97.1

Patients with IFN dose modifications, %

7.8

28.2

Patients with ribavirin dose modifications, %

10.8

AEs, adverse events; IFN, interferon; PEG-IFN, pegylated interferon Based on reference 6.

“consider offering” HCV screening. However, in June 2013, the USPSTF changed its stance and gave a “B” recommendation to screening for this population.3 The Affordable Care Act requires private insurers to cover any preventative screening that carries an A or B recommendation from the USPSTF. Also in June 2013, the FDA approved a test that identifies HCV genotypes (GTs) in infected patients, the Abbott RealTime HCV Genotype II test (Abbott Molecular, Inc.).4 This test can differentiate between HCV GTs 1, 1a, 1b, 2, 3, 4, and 5 using a sample of blood plasma or serum. This knowledge can aid physicians in determining the appropriate approach to treatment: Because HCV GTs respond differently to various drugs, this information can result in better patient outcomes. The FDA based its approval of the Abbott RealTime HCV Genotype II in part on an assessment of the test’s accuracy in differentiating specific HCV GTs compared with a validated gene-sequencing method. The FDA also reviewed data demonstrating the relationship between HCV GT and effectiveness of drug therapy. In February 2013, the FDA approved a next-generation viral-load test from Roche to accurately quantitate HCV RNA levels in order to assess a patient’s response to antiviral therapy.5 The COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test (version 2.0) is intended for use in the management of patients with chronic HCV infection, in conjunction with clinical and laboratory markers of infection. It is an in vitro nucleic acid amplification test for the quantitation of HCV RNA GTs 1 to 6 in human plasma or serum. The test can be used to predict the probability of sustained virologic response (SVR) early during a course of antiviral therapy, and to assess response to antiviral treatment as measured by changes in HCV RNA level. This real-time polymerase chain reaction–based HCV test is designed for use with Roche’s fully automated COBAS AmpliPrep/COBAS TaqMan system, an established platform for viral-load monitoring of multiple infectious diseases that improves workflow in testing laboratories. The system can be combined with the COBAS P630 instrument that provides an integrated, preanalytical primary tube-handling solution.

Treatment Options THE LIVER MEETING 2012 At the 2012 meeting of the American Association for the Study of Liver Diseases (AASLD), a plethora of research was unveiled on the treatment of HCV infection. According to preliminary results from the EMERGE trial, the use of a novel IFN, pegylated (PEG)IFN lambda-1a (Lambda, Bristol-Myers Squibb), may improve the treatment of patients with HCV infection.6 Treatment of HCV infection with PEG-IFN alfa-2a, a type I IFN, can be effective, but it also causes frequent adverse events (AEs), including hematologic toxicity. PEG-IFN lambda is a type III IFN that uses a different signaling pathway and has demonstrated robust antiviral activity. Because it uses a receptor present on fewer types of cells, it has a more favorable tolerability profile than PEG-IFN alfa. The EMERGE study is a Phase IIb, multicenter, single-arm, open-label trial that enrolled 526 noncirrhotic, treatment-naive adults infected with chronic HCV GT 1, 2, 3, or 4. Patients were randomized 1:1:1:1 to receive PEGIFN alfa 180 mcg, or 1 of 3 dosages of PEG-IFN lambda (120, 180, or 240 mcg) administered weekly in combination with daily oral ribavirin (RBV), which was administered in accordance with the prescribing information. Patients and providers were blinded throughout the study, and a pharmacist who was not blinded prepared the drug at each study site. The IFN dose could be held and reduced in cases of moderate or severe depression in study participants or for other significant grade 3 or 4 AEs related to the study drug. SVR was defined as an HCV RNA level less than the lower limit of quantification (25 IU/mL). Results were presented through week 72 for 407 patients with HCV GT 1 or 4. Overall, AEs were similar for both treatments (Table).6 Several AEs of any grade were markedly higher in patients who received PEG-IFN lambda, including myalgia (33% vs 5.9%), pyrexia (33% vs 7.8%), chills (21.4% vs 3.9%), and arthralgia (20.4% vs 5.9%). All cases of hyperbilirubinemia resolved following discontinuation of the study drug. Elsewhere at the 2012 AASLD Meeting, late-breaking

INFECTIOUS DISEASE SPECIAL EDITION 2013

abstracts and a slew of other studies discussed new oral regimens that can be used to achieve high SVR rates in a variety of HCV patient cohorts, including null responders. The AVIATOR trial tested 8-, 12-, and 24-week regimens of a combination of RBV plus 3 direct-acting antiviral agents (DAAs) being developed by Abbott Laboratories: ABT-450, ABT-267, and ABT-333. ABT-450, an NS3/4A protease inhibitor (PI), is coadministered with ritonavir (ABT-450/r) in a once-daily dose.7 ABT-267, an NS5A inhibitor, also is a once-daily therapy. ABT-333, a non-nucleoside polymerase inhibitor, is used twice daily. In exploratory studies, combinations containing ABT-450/r have achieved SVR rates greater than 90% in HCV GT 1–infected patients. In the current study, researchers set out to identify the optimal drug combination for HCV GT 1–infected patients who were either treatment-naive or null responders to previous treatment with PEG-IFN and RBV. To be eligible, participants could not have cirrhosis or HIV infection. Seven arms of the study, which included 571 patients, were evaluated for different drug combinations and regimen durations, up to 24 weeks. SVR rates at week 12 were 97.5% in the treatmentnaive group and 93.3% in null responders. Relapses primarily occurred in patients who received 8 weeks of therapy compared with those who received 12 weeks. Ninety-six percent of HCV GT 1a–infected treatmentnaive patients and 89% of HCV GT 1a–infected null responders achieved an SVR at week 12. No AEs were observed, and only 2 of the 448 patients discontinued treatment due to an AE attributed to the study drug. The SOUND-C2 trial tested a combination of 2 drugs developed by Boehringer Ingelheim—faldaprevir and BI 207127—with or without RBV in treatment-naive patients with HCV GT 1 infection.8 Faldaprevir is an NS3/4A PI, and BI 207127 is a non-nucleoside NS5B inhibitor. The study included 362 patients (33 with cirrhosis) and had 5 arms, which tested different dosing schemes and treatment durations, from 16 to 40 weeks. The 28-week regimen, using a twice-daily dosing scheme performed best, resulting in a 69% SVR overall at week 12 and an 85% SVR at week 12 in HCV GT 1b patients. Patients with cirrhosis achieved an SVR of 67%. The most common AEs were asthenia, pruritus, rash, photosensitivity, jaundice, nausea, vomiting, diarrhea, and transient indirect hyperbilirubinemia. Overall, 36% of patients experienced AEs: 12% were considered severe, and 8% led to discontinuation of treatment. Mark Sulkowski, MD, medical director of the Viral Hepatitis Center in the Divisions of Infectious Diseases and Gastroenterology & Hepatology at Johns Hopkins School of Medicine in Baltimore, presented results of a study that tested an all-oral combination of daclatasvir (Bristol-Myers Squibb), an NS5A inhibitor, and sofosbuvir, with or without RBV.9 The combination—tested in

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treatment-naive patients—was given for 24 weeks to patients infected with HCV GT 1a, 1b, 2, or 3, and for 12 weeks to patients with HCV GT 1a or GT 1b. All patients were noncirrhotic. Researchers randomized 44 patients with HCV GT 2/3 to 1 of 3 treatment groups: daclatasvir 60 mg daily plus sofosbuvir 400 mg daily with or without RBV for 24 weeks, or sofosbuvir daily for 7 days. Researchers also randomized 44 patients with HCV GT 1a/1b to receive sofosbuvir every day for 7 days followed by daclatasvir and sofosbuvir daily for a total of 24 weeks, or daclatasvir plus sofosbuvir daily, with or without RBV, for 24 weeks. During a second stage of the study, 82 patients with HCV GT 1a or 1b were randomized to receive 12 weeks of daclatasvir plus sofosbuvir, with or without RBV. Overall, more than 93% of patients with HCV GT 1, 2, or 3 achieved an SVR with the drug combinations. Among the 44 patients with HCV GT 2 or 3 infection, 93% achieved an SVR at week 24, with 1 patient having a confirmed relapse. Among the 126 patients with HCV GT 1 infection, 96% of those who had reached the 12 weeks post-treatment stage had an SVR at week 12; this included 3 patients who did not have an SVR at week 4. The SVR rate at week 24 in this group was 98%. The drug combination was well tolerated. Gregory Everson, MD, director of the Section of Hepatology at the University of Colorado Denver, in Aurora, presented results from a Phase IIa open-label study of AI443-014, which tested a 12-week regimen of 3 drugs developed by Bristol-Myers Squibb: daclatasvir, asunaprevir, and BMS-791325.10 The 4-arm study included treatment-naive, noncirrhotic patients with HCV GT 1 infection. Results were presented only for the 2 arms of the study that included BMS-791325 75 mg plus daclatasvir and asunaprevir. One group of patients was treated for 12 weeks (n=16) and the other was treated for 24 weeks (n=16). Patients (mean age, 48 years) had a high viral load and 75% were infected with HCV GT 1a. (The other 2 arms received 150 mg of the investigational agent.) In the group receiving treatment for 24 weeks, researchers only had complete data for SVR at week 4 (94%). Two patients assigned to this arm discontinued treatment before completing the 24-week phase: One patient, who withdrew consent at week 9 of treatment, was lost to follow-up (HCV RNA was undetectable at week 8), and the other patient, who stopped treatment at week 14 due to poor venous access, achieved SVR at week 4. In the group that received 12 weeks of treatment, SVR was 94% at weeks 4 and 12. Two patients assigned to this arm discontinued treatment before completing the full 12-week phase: One patient stopped treatment at week 11 but still achieved SVR at week 12, and the other completed the 12 weeks of treatment but did not return for post-treatment follow-up (HCV RNA

was undetectable at end of treatment). These high SVR rates were achieved despite the more difficult-to-treat characteristics of HCV GT 1a infection and non窶的L28B CC GTs of the patients. Although 4 patients in the study discontinued treatment prematurely, there were no discontinuations because of AEs.

EASL 2013 The 2013 Annual Meeting of the European Association for the Study of the Liver (EASL) also provided a forum for researchers to present significant advances in HCV care. The NEUTRINO study, a Phase III, open-label trial, investigated a combination of sofosbuvir, PEG-IFN, and RBV for 12 weeks in 292 treatment-naive patients with chronic HCV GT 1; 28 patients with HCV GT 4; and 7 patients with HCV GT 5/6.11 The combination regimen led to an SVR rate of 90% 12 weeks after completing treatment, a rate significantly higher than that reported in historical controls (60%). All patients received daily 400-mg sofosbuvir, a pangenomic NS5B HCV polymerase inhibitor, along with RBV 1,000 to 1,200 mg daily, and PEG-IFN 180 mcg weekly, for 12 weeks. Seventeen percent of patients had compensated cirrhosis and 29% had IL28B CC GTs. At baseline, patients had platelet counts greater than 90,000/mcL, none had neutropenia, and the mean HCV RNA viral load was 6.4 log IU/mL. All of the patients who did not achieve SVR at week 12 relapsed following an initial response to treatment. None of these patients were found to have NS5B S282T resistance after relapse. Subgroup-specific SVR rates at week 12 were 80% in patients with cirrhosis, 89% in cirrhotic and noncirrhotic patients with HCV GT 1, 96% in HCV GT4 patients, and 100% in HCV GT 5/6 patients. Common AEs of treatment included fatigue (59%), headache (36%), nausea (34%), and insomnia (25%); 2% of patients discontinued treatment. Serious AEs occurred in 1% of patients. Results from the FUSION trial also were unveiled at the 2013 EASL Meeting. FUSION was a randomized, placebo-controlled, double-blind Phase III study of dual therapy with sofosbuvir 400 mg daily and RBV 1,000 to 1,200 mg daily, and included 201 treatment-experienced patients with HCV GT 2/3.12 Most of the patients were white men, with a mean age of 54 years. Thirty percent of patients had the IL28B CC GT, 34% had compensated cirrhosis, 63% had HCV GT 3, 75% had relapsed following previous treatment, and 25% were prior null responders. Patients were randomized to receive either 12 weeks of treatment with sofosbuvir and RBV followed by 4 weeks of placebo, or 16 weeks of treatment with sofosbuvir and RBV. In the 16-week treatment group, 78% of HCV GT 2 patients with cirrhosis and 100% of HCV GT 2 patients without cirrhosis achieved SVR compared with 60% and 96%, respectively, of patients in the 12-week treatment group. SVR rates in HCV

GT 3 patients in the 16-week treatment group were 61% and 63% for patients with or without cirrhosis, respectively, compared with 19% and 37%, respectively, of patients in the 12-week treatment group. Serious AEs occurred in 3% and 5% of patients in the 16- and 12-week treatment groups, respectively, but no patients discontinued treatment because of drug-related AEs. Of patients in the 16- and 12-week groups, 10% and 5%, respectively, experienced a drop in hemoglobin greater than 10 g/dL, and 2% of patients in the 12-week treatment group had hemoglobin less than 8.5 g/dL. Common AEs in both treatment groups included fatigue, headache, insomnia, nausea, irritability, cough, and diarrhea. Results also were presented from the ELECTRON trial, in which investigators set out to determine whether combining sofosbuvir, a uridine nucleotide analog HCV polymerase inhibitor, and a second DAA agent with a different mechanism of action could improve SVR rates when administered with RBV in patients with HCV GT 1.13 To this end, they evaluated sofosbuvir 400 mg once daily plus RBV 1,000 to 1,200 mg in 25 treatmentnaive patients and 10 prior null responders with HCV GT 1; 2 other groups of similar numbers of patients received the same treatment regimen plus either ledipasvir (GS-5885), an HCV NS5A inhibitor, 90 mg daily, or GS-9669, a non-nucleoside NS5B inhibitor, 500 mg daily. Treatment duration in all groups was 12 weeks. Mean baseline HCV RNA levels ranged from 5.9 log10 to 6.9 log10. None of the patients had cirrhosis, and most had HCV GT 1a. In the control group, 84% and 10% of treatmentnaive and null responders, respectively, achieved an SVR at week 12. In the ledipasvir treatment group, 100% of patients achieved SVR at week 12. In the GS-9669 group, 92% of treatment-naive patients achieved an SVR at week 12, and among 3 prior null responders with data available at week 12 post-treatment, all achieved an SVR. Serious AEs occurred in 1 treatment-naive patient in the control group and in 2 treatment-naive patients who received ledipasvir. Researchers from the CUPIC (Compassionate Use of Protease Inhibitors in Cirrhotics) trial also were in attendance to report their findings at EASL 2013. As part of the French Early Access Program, 485 treatmentexperienced HCV GT 1a/b patients with cirrhosis were offered treatment with a first-generation HCV PI in combination with PEG-IFN and RBV in an open-label fashion.14 The treating physicians decided whether to prescribe bocepreviror telaprevir-based triple therapy:

INFECTIOUS DISEASE SPECIAL EDITION 2013

190 individuals received the standard boceprevirbased regimen, and 295 patients underwent standard telaprevir-based treatment. The majority of patients were prior relapsers. All patients had cirrhosis; nearly all were Child-Pugh class A; and patients had a mean Model for End-stage Liver Disease score of 8.1. Findings of the intent-to-treat analysis showed that 79% of telaprevir recipients had a virologic response at week 8, and 40% continued with SVR at week 12: This included 53% of prior relapsers, 32% of partial responders, and 29% of null responders. Among those who discontinued treatment early, approximately 19% did so because of detectable HCV RNA, 27% relapsed, 41% experienced viral breakthrough, and 14% experienced AEs. In the boceprevir treatment group, 51% had a virologic response at week 8, and 41% continued with SVR at week 12, including 51% of prior relapsers, 40% of partial responders, and 11% of null responders. Premature treatment discontinuation in this group was due to detectable HCV RNA in approximately 36% of patients, relapse in 27%, viral breakthrough in 26%, and AEs in 11%. Serious AEs occurred in 54% and 51% of telaprevir and boceprevir recipients, respectively, and included a 2.4% and 1.6% mortality rate, respectively. Grade 3/4 infections occurred in 9.1% and 4.2% of telaprevir and boceprevir recipients, respectively; grade 3/4 hepatic decompensation occurred in 5.1% and 4.7%, respectively; grade 3 rash occurred in 5.4% and 1%, respectively; and grade 3/4 anemia occurred in 12.9% and 10%, respectively. Following preliminary results presented at the Liver Meeting 2012, subanalysis data from the AVIATOR study was presented at EASL 2013. The population included 247 noncirrhotic patients with HCV GT 1 who received a 4-drug treatment regimen for 12 or 24 weeks in a randomized open-label fashion.15 Treatment included 100 or 150 mg once daily of ABT-450, a potent HCV NS3/4A PI, administered orally with 100 mg of ritonavir, as well as 25 mg once daily of ABT-267, an HCV NS5A inhibitor, 400 mg twice daily of ABT-333, a non-nucleoside HCV polymerase inhibitor, and 1,000 to 1,200 mg daily of RBV, administered in 2 doses. The 12-week treatment group included 79 treatment-naive patients and 45 prior null responders; the 24-week group had 80 treatmentnaive patients and 43 prior null responders. Results showed that 99% of treatment-naive patients and 93% of null responders in the 12-week treatment arm achieved SVR at week 12, and 96% and 93% of the 2 groups, respectively, achieved an SVR at week 24. In the 24-week treatment group, SVR at week 12 occurred

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in 93% and 98% of treatment-naive patients and null responders, respectively, whereas 90% and 95% had an SVR at week 24. One treatment-naive patient in the 12-week treatment group and 2 in the 24-week group experienced relapse. Additionally, 3 prior null responders in the 12-week group and one in the 24-week group experienced viral breakthrough. Six patients discontinued treatment due to AEs, but researchers considered only 4 of these related to treatment. Four serious AEs were reported, but only 1â&#x20AC;&#x201D;a case of arthralgiaâ&#x20AC;&#x201D;was believed to be treatment-related. Finally, researchers described a study in which they randomized 41 HCV GT 1 patients without cirrhosis who had failed prior treatment with telaprevir or boceprevir in combination with PEG-IFN and RBV to 1 of 2 treatment regimens: 21 patients received 60 mg daily of daclatasvir, an HCV NS5A replication complex inhibitor, along with sofosbuvir 400 mg daily, and 20 patients received the same regimen plus RBV, both for 24 weeks.16 Most patients had received telaprevir previously, most were white, and approximately 60% were men. The majority of patients had HCV GT 1a and IL28B CT or TT GTs. More than 80% had METAVIR scores of F2 or higher. Mean HCV RNA for both groups was 6.3 log10 IU/mL. None of the participants had discontinued prior treatment with telaprevir or boceprevir because of an AE. Findings showed that 91% and 80% of the RBV-free and RBV-containing treatment groups, respectively, experienced a virologic response 2 weeks after treatment initiation, and 100% had a virologic response by the end of treatment. All participants also experienced an SVR at weeks 4 and 12. Common mild or moderate AEs in both groups included fatigue, headache, alopecia, and arthralgia. Constipation and diarrhea each occurred in 5% of non-RBV recipients and in 20% of RBV recipients. No severe AEs occurred in the RBVfree group.

Conclusion Important advances pertaining to treatment efficacy, SVRs, and targeted therapy through the use of genotyping and viral-load monitoring continue to occur. The clinical landscape is also moving toward IFNfree therapy, an important development for reducing treatment-related AEs. Research continues to inform the ideal uses for the recently approved DAAs, telaprevir and boceprevir. Moreover, several new agents are currently being investigated in clinical trials; 2 of these agents, sofosbuvir and simeprevir, have shown exciting results and are now under FDA review for use in HCV combination regimens. All of these new therapies will require continued research to inform their role within specific HCV GTs, but all told, these advances ensure that patients will not have to suffer the long treatment durations and related morbidity of old, with the potential for curing their infection.

References 1.

Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138(2):513-521.

2. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012; 61(RR-4):1-32. 3. Ngo-Metzger Q, Ward JW, Valdiserri RO. Expanded hepatitis C virus screening recommendations promote opportunities for care and cure. Ann Intern Med. 2013 Jun 25. [Epub ahead of print] 4. Food and Drug Administration. Abbott RealTime HCV Genotype II. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ ucm359536.htm. Accessed August 22, 2013. 5. Food and Drug Administration. February 2013 PMA approvals. http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/PMAApprovals/ ucm348014.htm. Accessed August 22, 2013. 6. Muir A, Hilson J, Gray T, et al; EMERGE Study Group. Peginterferon lambda-1a (Lambda) compared with peginterferon alfa-2a (alfa) in treatment naive patients with HCV genotypes 1 or 4: SVR24 results from EMERGE phase 2b. Presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA. Abstract 214. 7. Kowdley KV, Lawitz E, Poordad F, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection. Presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA. Abstract LB-1. 8. Soriano V, Gane E, Angus P, et al. Efficacy and safety of the interferon (IFN)-free combination of BI 201335 + BI 207127 +/- ribavirin in treatment-na誰ve patients with HCV genotype (GT) 1 infection and compensated liver cirrhosis: results from the SOUND-C2 study. Presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA. Abstract 84. 9. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B

inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV genotype 1, 2, or 3. Presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA. Abstract LB-2. 10. Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 yielded SVR4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection. Presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases; November 9-13, 2012; Boston, MA. Abstract LB-3. 11. Lawitz E, Wyles D, Davis M, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in GT 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. Presented at: 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, the Netherlands. Abstract 1411. 12. Nelson DR, Field J, Kowdley KV, et al. All oral therapy with sofosbuvir + ribavirin for 12 or 16 weeks in treatment experienced genotype 2/3 HCV-infected patients: results of the phase 3 trial. 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, the Netherlands. Abstract 6. 13. Gane E, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. Presented at: 48th Annual Meeting of the European Association for the Study of the Liver. April 24-28, 2013; Amsterdam, the Netherlands. Abstract 14. 14. Fontaine H, Hezode C, Dorival C, et al; ANRS CO20 CUPIC Study Group. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non-responders treated in the French Early Access Program (ANRS CO20-CUPIC). Presented at: 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, the Netherlands. Abstract 60. 15. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV genotype 1 infection: results from the AVIATOR study. Presented at: 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, the Netherlands. Abstract 3. 16. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Sustained virological response with daclatasvir plus sofosbuvir +/- ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). Presented at: 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, the Netherlands. Abstract 1417.

INFECTIOUS DISEASE SPECIAL EDITION 2013

Table 3. Selected* Treatment-Emergent Adverse Reactions in Adult Patients with Candidemia and Other Candida Infections

MYCAMINE® (micafungin sodium) for injection INTRAVENOUS INFUSION (not for IV bolus injection) Brief Summary of Prescribing Information INDICATIONS AND USAGE MYCAMINE is an echinocandin indicated in adult and pediatric patients 4 months and older for: Treatment of Patients with Candidemia, Acute Disseminated Candidiasis, Candida a Peritonitis and Abscesses MYCAMINE has not been adequately studied in patients with endocarditis, osteomyelitis and meningitis due to Candidaa infections. Treatment of Patients with Esophageal Candidiasis Prophylaxis of Candida a Infections in Patients Undergoing Hematopoietic Stem Cell Transplantation NOTE: The efficacy of MYCAMINE against infections caused by fungi other than Candida a has not been established. CONTRAINDICATIONS MYCAMINE is contraindicated in persons with known hypersensitivity to micafungin, any component of MYCAMINE, or other echinocandins. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving MYCAMINE. If these reactions occur, MYCAMINE infusion should be discontinued and appropriate treatment administered. Hematological Effects Acute intravascular hemolysis and hemoglobinuria was seen in a healthy volunteer during infusion of MYCAMINE (200 mg) and oral prednisolone (20 mg). This reaction was transient, and the subject did not develop significant anemia. Isolated cases of significant hemolysis and hemolytic anemia have also been reported in patients treated with MYCAMINE. Patients who develop clinical or laboratory evidence of hemolysis or hemolytic anemia during MYCAMINE therapy should be monitored closely for evidence of worsening of these conditions and evaluated for the risk/benefit of continuing MYCAMINE therapy. Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with MYCAMINE. In some patients with serious underlying conditions who were receiving MYCAMINE along with multiple concomitant medications, clinical hepatic abnormalities have occurred, and isolated cases of significant hepatic impairment, hepatitis, and hepatic failure have been reported. Patients who develop abnormal liver function tests during MYCAMINE therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing MYCAMINE therapy. Renal Effects Elevations in BUN and creatinine, and isolated cases of significant renal impairment or acute renal failure have been reported in patients who received MYCAMINE. In fluconazole-controlled trials, the incidence of drug-related renal adverse events was 0.4% for MYCAMINE treated patients and 0.5% for fluconazole treated patients. Patients who develop abnormal renal function tests during MYCAMINE therapy should be monitored for evidence of worsening renal function. ADVERSE REACTIONS The overall safety of MYCAMINE was assessed in 3227 adult and pediatric patients and 520 volunteers in 46 clinical trials, including the invasive candidiasis, esophageal candidiasis and prophylaxis trials, who received single or multiple doses of MYCAMINE, ranging from 0.75 mg/kg to 10 mg/kg in pediatric patients and 12.5 mg to 150 mg/day or greater in adult patients. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of MYCAMINE cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does provide a basis for identifying adverse events that appear to be related to drug use and for approximating rates. Infusion Reactions Possible histamine-mediated symptoms have been reported with MYCAMINE, including rash, pruritus, facial swelling, and vasodilatation. Injection site reactions, including phlebitis and thrombophlebitis have been reported, at MYCAMINE doses of 50-150 mg/day. These reactions tended to occur more often in patients receiving MYCAMINE via peripheral intravenous administration. Clinical Trials Experience in Adults In all clinical trials with MYCAMINE, 2497/2748 (91%) adult patients experienced at least one treatment-emergent adverse reaction. Candidemia and Other Candida Infections Selected treatment emergent adverse reactions, those occurring in 5% or more of the patients and more frequently in a MYCAMINE treatment group are shown in Table 3.

System Organ Classs¥ (Preferred Term) †

Mycamine 100 mg n (%)

Number of Patients

Mycamine 150 mg n (%)

Caspofungin‡ n (%)

200

202

193

81 (41)

89 (44)

76 (39)

Diarrhea

15 (8)

26 (13)

14 (7)

Nausea

19 (10)

15 (7)

20 (10)

Vomiting

18 (9)

15 (7)

16 (8)

77 (39)

83 (41)

73 (38)

Gastrointestinal Disorders

Metabolism and Nutrition Disorders Hypoglycemia

12 (6)

14 (7)

9 (5)

Hypernatremia

8 (4)

13 (6)

8 (4)

Hyperkalemia

10 (5)

8 (4)

5 (3)

59 (30)

56 (28)

51 (26)

14 (7)

22 (11)

15 (8)

36 (18)

49 (24)

37 (19)

11 (6)

16 (8)

8 (4)

Cardiac Disorders

35 (18)

48 (24)

36 (19)

Atrial Fibrillation

5 (3)

10 (5)

General Disorders/ Administration Site Conditions Pyrexia Investigations Blood Alkaline Phosphatase Increased

Patient base: all randomized patients who received at least 1 dose of trial drug * During IV treatment + 3 days ¥ MedDRA v5.0 † Within a system organ class patients may experience more than 1 adverse reaction. ‡ 70 mg loading dose on day 1 followed by 50 mg/day thereafter (caspofungin)

Esophageal p g Candidiasis Selected treatment-emergent adverse reactions, those occurring in 5% or more of the patients and more frequently in a MYCAMINE group, are shown in Table 4. Table 4. Selected* Treatment-Emergent Adverse Reactions in Adult Patients with Esophageal Candidiasis System Organ Class¥ (Preferred Term)†

Mycamine 150 mg/day n (%)

Fluconazole 200 mg/day n (%)

Number of Patients

260

258

Gastrointestinal Disorders

84 (32)

93 (36)

Diarrhea

27 (10)

29 (11)

Nausea

20 (8)

23 (9)

Vomiting

17 (7)

General Disorders/Administration Site Conditions Pyrexia Nervous System Disorders Headache Vascular Disorders Phlebitis Skin and Subcutaneous Tissue Disorders Rash

52 (20)

45 (17)

34 (13)

21 (8)

42 (16)

40 (16)

22 (9)

20 (8)

54 (21)

21 (8)

49 (19)

13 (5)

36 (14)

26 (10)

14 (5)

6 (2)

Patient base: all randomized patients who received at least 1 dose of trial drug * During treatment + 3 days. ¥ MedDRA v5.0 † Within a system organ class patients may experience more than 1 adverse reaction.

Prophylaxis p y of Candida Infections in Hematopoietic p Stem Cell Transplant p Recipients p Selected adverse reactions, those reported in 15% or more of adult patients and more frequently on the MYCAMINE treatment arm, are shown in Table 5. Table 5. Selected Adverse Reactions in Adult Patients During Prophylaxis of Candida a Infection in Hematopoietic Stem Cell Transplant Recipients System Organ Class¥ (Preferred Term) †

Mycamine 50 mg/day n (%)

Fluconazole 400 mg/day n (%)

Number of Patients

382

409

Gastrointestinal Disorders Diarrhea

377 (99)

404 (99)

294 (77)

327 (80)

Table 5 Continued

Table 6 Continued Mycamine 50 mg/day n (%)

Fluconazole 400 mg/day n (%)

Nausea

270 (71)

290 (71)

Vomiting

252 (66)

274 (67)

Abdominal Pain

100 (26)

93 (23)

Blood and Lymphatic System Disorders

368 (96)

385 (94)

Neutropenia

288 (75)

297 (73)

Thrombocytopenia

286 (75)

280 (69)

Skin and Subcutaneous Tissue Disorders

257 (67)

275 (67)

95 (25)

91 (22)

250 (65)

254 (62)

System Organ Class¥ (Preferred Term) †

Rash Nervous System Disorders Headache

169 (44)

154 (38)

233 (61)

235 (58)

Insomnia

142 (37)

140 (34)

Anxiety

84 (22)

87 (21)

Cardiac Disorders

133 (35)

138 (34)

Tachycardia

99 (26)

91 (22)

Psychiatric Disorders

C/IC

All MicafunginSystem Organ Class¥ treated Patients Mycamine AmBisome Mycamine Fluconazole † n = 479 (Preferred Term) n = 56 n = 56 n = 43 n = 48 n (%) n (%) n (%) n (%) n (%)

Epistaxis

4 (9)

8 (17)

Blood and lymphatic system disorders

161 (34)

17 (30)

13 (23)

40 (93)

44 (92)

Thrombocytopenia

70 (15)

5 (9)

3 (5)

31 (72)

37 (77)

Neutropenia

61 (13)

3 (5)

4 (7)

33 (77)

34 (71)

Anemia

63 (13)

10 (18)

6 (11)

22 (51)

24 (50)

Febrile neutropenia

23 (5)

7 (16)

7 (15)

191 (40)

12 (21)

8 (14)

24 (56)

25 (52)

45 (10)

7 (16)

1 (2)

18 (4)

10 (23)

8 (17)

Cardiac disorders

97 (20)

7 (13)

3 (5)

10 (23)

17 (35)

Tachycardia

47 (10)

2 (4)

1 (2)

7 (16)

12 (25)

Renal and urinary disorders

78 (16)

4 (7)

16 (37)

15 (31)

Alanine aminotransferase increased Urine output decreased

Clinical Trials Experience in Pediatric Patients The selected treatment-emergent adverse reactions, those occurring in 15% or more of the patients and more frequently in the MYCAMINE group, for all MYCAMINE pediatric studies and for the two comparative studies (candidemia and prophylaxis) are shown in Table 6. Table 6. Selected Treatment-Emergent Adverse Reactions in All Pediatric Patients, in Patients with Candidemia and Other Candida a Infections (C/IC), and in Hematopoietic Stem-Cell Recipients During Prophylaxis of Candida Infections Prophylaxis

All MicafunginSystem Organ Class¥ treated Patients Mycamine AmBisome Mycamine Fluconazole n = 479 (Preferred Term)† n = 56 n = 56 n = 43 n = 48 n (%) n (%) n (%) n (%) n (%)

Gastrointestinal disorders

45 (9)

Investigations

Patient base: all randomized adult patients who received at least 1 dose of trial drug ¥ MedDRA v12.0 † Within a system organ class patients may experience more than 1 adverse reaction.

C/IC

285 (60)

22 (40)

18 (32)

43 (100)

45 (94)

Hematuria

18 (4)

10 (23)

7 (15)

Psychiatric disorders

80 (17)

3 (5)

1 (2)

20 (47)

9 (19)

Anxiety

35 (7)

10 (23)

3 (6)

Patient base: all randomized patients who received at least one dose of trial drug. ¥ MedDRA v12.0 † Within a system organ class, patients may experience more than 1 adverse reaction.

Postmarketing Adverse Reactions The following adverse reactions have been identified during the post-approval use of micafungin sodium for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency. • Blood and lymphatic system disorders:: disseminated intravascular coagulation • Hepatobiliary disorders:: hepatic disorder • Renal and urinary disorders:: renal impairment • Skin and subcutaneous tissue disorders:: Stevens-Johnson syndrome, toxic epidermal necrolysis • Vascular disorders:: shock DRUG INTERACTIONS Monitor for sirolimus, itraconazole or nifedipine toxicity, and dosage of sirolimus, itraconazole or nifedipine should be reduced, if necessary. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. No human data. Adverse effects in animals. Use if potential benefits of treatment outweigh potential fetal risk. Nursing Mothers Caution should be exercised if administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients younger than 4 months of age have not been established.

Vomiting

146 (31)

10 (18)

8 (14)

28 (65)

32 (67)

Diarrhea

106 (22)

4 (7)

5 (9)

22 (51)

31 (65)

Nausea

91 (19)

4 (7)

30 (70)

25 (52)

Abdominal pain

76 (16)

2 (4)

15 (35)

12 (25)

Abdominal distension

29 (6)

1 (2)

8 (19)

6 (13)

256 (53)

14 (25)

41 (95)

46 (96)

Product of Japan

103 (22)

5 (9)

9 (16)

26 (61)

31 (65)

24 (5)

3 (5)

7 (16)

4 (8)

Manufactured by: Astellas Pharma Tech Co., Takaoka city, Toyama 939-1118, Japan

Skin and subcutaneous tissue disorders

197 (41)

11 (20)

8 (14)

33 (77)

38 (79)

Pruritus

54 (11)

1 (2)

14 (33)

15 (31)

Rash

55 (12)

1 (2)

13 (30)

13 (27)

Urticaria

24 (5)

1 (2)

8 (19)

4 (8)

194 (41)

9 (16)

13 (23)

30 (70)

33 (69)

General disorders and administration site conditions Pyrexia Infusion related reaction

Respiratory, thoracic and mediastinal disorders

Prophylaxis

Marketed by: Astellas Pharma US, Inc. Northbrook, IL 60062 USA Revised: June 2013 MYCAMINE is a registered trademark of Astellas Pharma, Inc., Tokyo, Japan. 12F040-MYC-BRFS

NOW APPROVED in pediatric patients 4 months and older The #1 used echinocandin for candidemia in adults* is now indicated for use in pediatric patients 4 months and older† *With the experience of patient-days, derived from the calculation of total milligrams sold/average grams per day. Information provided by Wolters Kluwer Pharma Solutions, Source Non-Retail, January 2012–March 2013. †Safety and effectiveness in pediatric patients younger than 4 months of age have not been established.

NEW

PEDIATRIC INDICATION!

INDICATIONS MYCAMINE is indicated in adult and pediatric patients 4 months and older for: • Treatment of candidemia, acute disseminated candidiasis, Candida peritonitis, and abscesses − MYCAMINE has not been adequately studied in patients with endocarditis, osteomyelitis, and meningitis due to Candida infections • Treatment of patients with esophageal candidiasis • Prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation NOTE: The efficacy of MYCAMINE against infections caused by fungi other than Candida has not been established.

IMPORTANT SAFETY INFORMATION MYCAMINE is contraindicated in patients with known hypersensitivity to micafungin, any component of MYCAMINE, or other echinocandins. Isolated cases of serious hypersensitivity (anaphylaxis and anaphylactoid) reactions (including shock) have been reported in patients receiving MYCAMINE. In these cases, MYCAMINE should be discontinued and appropriate treatment administered.

Elevations in BUN and creatinine, and isolated cases of clinically significant hepatic dysfunction, hepatitis, hepatic failure, renal dysfunction, acute renal failure, hemolysis, or hemolytic anemia have occurred in some patients who have received MYCAMINE. Patients who develop these conditions, or abnormal liver or renal function tests, should be monitored closely for worsening function and evaluated for risk/benefit of continuing MYCAMINE therapy. In clinical trials, possible histamine-mediated symptoms have been reported with MYCAMINE (including rash, pruritus, facial swelling, and vasodilatation). In clinical trials, the most common treatmentemergent adverse reactions in adults for all indications included diarrhea, nausea, vomiting, pyrexia, thrombocytopenia, and headache. The most common treatment-emergent adverse reactions observed in pediatric patients 4 months and older included vomiting, diarrhea, pyrexia, nausea, abdominal pain, and thrombocytopenia.

Please see the adjacent pages for the brief summary of full prescribing information.

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SEPTEMBER 2013

REPORT Teflaro® (ceftaroline fosamil) for the Treatment of Community-Acquired Bacterial Pneumonia Caused by Designated Susceptible Bacteria Community-acquired pneumonia Streptococcus pneumoniae is the Faculty (CAP) is a common illness that causes most common cause of CAP; comsignificant morbidity and mortality, bined with Staphylococcus aureus, Donald Low, MD particularly among elderly individuals these 2 organisms account for more Chief, Department of Microbiology and in those with serious comorbidithan 50% of cases. Several GramMount Sinai Hospital ties.1 CAP can be caused by bacterial negative pathogens, including HaeToronto, Ontario, Canada mophilus influenzae and Klebsiella pathogens or certain respiratory pneumoniae, are common etiologies viruses, and the etiology is often of CAP.5 unknown initially. For cases with a confirmed bacterial etiology, the FDA uses a more precise Over the past several decades, trends in antimicrobial designation: community-acquired bacterial pneumonia susceptibility patterns have complicated the treatment of (CABP). Despite the availability of potent treatment options CAP.6 For example, mutations to penicillin-binding proand effective vaccines, an estimated 5.4 million cases of teins (PBPs) have resulted in an increased resistance to CAP occur in the U.S. each year, leading to 1.2 million hosβ-lactam antibiotics among strains of S. pneumoniae.7 2,3 4 pitalizations and 53,692 deaths. The cost to treat CAP in The pneumococcal conjugate vaccine (PCV), first introthe U.S. is estimated to exceed $17 billion annually.2 duced in the latter half of 2000, has also led to changes

INDICATION

IMPORTANT SAFETY INFORMATION

• TEFLARO (ceftaroline fosamil) is indicated for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilius influenzae, Klebsiella pneumoniae, and Klebsiella oxytoca, and Escherichia coli.

Contraindications • TEFLARO is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class. Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 8.