Infectious Disease Special Edition - Spring 2021 by McMahon Group

Volume 26 • Spring 2021

Routine Vaccinations on the Rebound Transitioning Youth With HIV to Adult Care The Symbiotic Relationship of HIV + Opioids Fungal Disease Deaths on the Rise The Heart of the Matter: The Effect of ART on HIV

TREATMENT FOR NOSOCOMIAL PNEUMONIA HAS ARRIVED

In HABP/VABP and cUTI caused by susceptible Gram-negative microorganisms

OUTSMART RESISTANCE Fetroja outsmarts pathogens by using iron to gain cell entry, like a Trojan horse.1,2

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1 INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with CarbapenemResistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenemresistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

Stable in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM, IMP, and NDM)1 Active against pathogens with porin channel deletions and efflux pump up-regulation1,3,4 The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Fetroja has an extensive Gram-negative spectrum that includes hard-to-treat pathogens1 Fetroja has demonstrated activity against the following Gram-negative bacteria, both in vitro and in HABP/VABP: Acinetobacter baumannii complex, Escherichia coli*, Enterobacter cloacae complex*, Klebsiella pneumoniae*, Pseudomonas aeruginosa*, Serratia marcescens *Also included in cUTI indication.

In a seriously ill patient population with HABP or VABP, Fetroja exhibited non-inferiority to extended-infusion, high-dose meropenem1

Fetroja is highly active in vitro vs Gramnegative carbapenem-NS pathogens5 In this study, susceptibility of >38,000 Gram-negative clinical isolates from multiple countries (2013-2018) was tested against Fetroja

• Study highlights:

In vitro activity does not necessarily correlate with clinical efficacy.

Enterobacteralesa Overall

Enterobacteralesa carbapenem-non-susceptible

P aeruginosaa

(n=25,995)

100%

(n=814)

97%

– 60% of patients were ventilated, while approximately 33% had failed empiric treatment1,5

98%

– The top 5 baseline Gram-negative pathogens were K pneumoniae, P aeruginosa, A baumannii, E coli, and E cloacae5

(n=6213)

Overall

P aeruginosaa

95%

(n=1416)

carbapenem-non-susceptible

A baumannii complexa A baumannii complex

85%

(n=2274)

carbapenem-non-susceptible

S maltophilia b

100%

(n=1565)

Overall

• At Day 14, all-cause mortality (primary endpoint) in the mITT population was 12.4% for Fetroja vs 12.2% for extended-infusion, high-dose meropenem (95% CI, -7.2, 7.7)1

90%

(n=4185)

Overall

(inherently carbapenem-resistant)5,7

– Meropenem was used as a comparator in the trial and was optimized (2 grams IV over 3 h q8h) for seriously ill patients with a multidrug-resistant Gram-negative infection in the ICU1

PERCENT

100

In a phylogenetic reclassification performed in 2016, the nomenclature of Enterobacterales was proposed, which includes formerly established Enterobacteriaceae family and other genera such as Proteus spp, Providencia spp, Photorhabdus spp, and Serratia spp.8

In vitro susceptibility study design Clinical isolates of Gram-negative bacteria were collected from 4 global surveillance studies (SIDERO-WT-2014, SIDERO-WT-2015, SIDERO-WT-2016, and SIDERO-WT-2018) that included Enterobacterales* and non-fermenter strains. The global surveillance study (Proteeae†) collected clinical isolates from 2013-2016, and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using irondepleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex‡ MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for S maltophilia MIC ≤4 μg/mL. Carbapenem-nonsusceptible strain was defined as meropenem MIC ≥2 μg/mL for Enterobacterales strains (including Proteeae) and MIC ≥4 μg/mL for P aeruginosa and A baumannii complex.5 a FDA breakpoints used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex MIC ≤1 μg/mL. b CLSI investigational breakpoint used for S maltophilia MIC ≤4 μg/mL. *E coli, K pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. † Morganella morganii, P mirabilis, Proteus vulgaris, and Providencia rettgeri. ‡ A baumannii complex consists of A baumannii, A calcoaceticus, A dijkshoorniae, A nosocomialis, A pittii, and A seifertii.

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs. Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

• Fetroja exhibited comparable safety vs extended-infusion, high-dose meropenem in HABP/VABP1 Study Design Multicenter, double-blind, parallel-group, randomized, active-controlled Phase 3 study in approximately 300 adults with documented nosocomial pneumonia caused by Gram-negative bacteria. Subjects were randomized (1:1) to either cefiderocol, 2 grams, administered IV over 3 hours every 8 hours (q8h) or extended-infusion, high-dose meropenem, 2 grams, administered IV over 3 hours q8h. Randomization was performed by the stratified randomization method using their infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology And Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16) as allocation factors. Linezolid was administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA), and to maintain the study blind.1,5 CI=confidence interval.

FOR MORE INFORMATION, VISIT

Fetroja.com Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). Please see a Brief Summary of Prescribing Information on following page.

References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2020. 2. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. 3. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):1-5. 4. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7) (suppl):S1-S3. 5. Data on file. 6. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41. 7. Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gramnegative bacilli. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0. 8. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the 'Enterobacteriales': proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66(12):5575-5599. © 2020 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USFET-0209 09/20

FETROJA (cefiderocol) for injection, for intravenous use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1) in the full prescribing information]. 1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospitalacquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2) in the full prescribing information]. 1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA-treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. 5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued. 5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)]. 6

ADVERSE REACTIONS

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 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. Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%). Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1. Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148)

Table 4

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

Diarrhea

Infusion site reactionsc

5.3 Clostridioides difficile-associated Diarrhea (CDAD)

Constipation

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

Rashd

< 1%

Candidiasise

Cough

< 1%

Elevations in liver testsf

< 1%

Headache

Hypokalemiag

3% (continued)

Table 4

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa (N = 300)

Imipenem/Cilastatinb (N = 148)

Nausea

Vomiting

Adverse Reaction

cUTI = complicated urinary tract infection. a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritis Psychiatric disorders: insomnia, restlessness Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem. Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem. The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests. Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial. Table 5

Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 FETROJAa N = 148

Meropenemb N = 150

Elevations in liver testsc

16%

Hypokalemiad

11%

15%

Diarrhea

Hypomagnesemia

< 1%

Atrial fibrillation

Adverse Reaction

HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). c Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. d Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2:

Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose. 8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition.

Data

Patients Receiving CRRT

Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.

A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. While on CRRT, a patient’s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established. 8.5 Geriatric Use cUTI Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients. HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older. The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups. Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.

Patients with CLcr 120 mL/min or Greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function. 10

OVERDOSAGE

There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information].

cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min. Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932 FET-PI-02A USFET-0247 09/20

IDSE EDITORIAL ADVISORY BOARD John A. Bosso, PharmD, FCCP, FIDSA

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Resurgence: Déjà Vu All Over Again?

t’s been a year since the stay-at-home orders were issued, and we are finally seeing some positive trends: COVID-19 vaccinations are increasing, and hospitalizations and deaths are decreasing. The country is averaging about 2.4 million COVID-19 vaccinations per day, and nearly 30% of adults have received at least one dose of COVID-19 vaccine as of March 15. Hospital admissions have declined to just over 4,700 per day, and the latest seven-day average for deaths is just over 1,200 per day, according to CDC Director Rochelle P. Walensky, MD, MPH. So is it time to dust ourselves off and go back to normal? The governors of several states seem to think it is the right thing to do, but history tells us that maybe it is not. Several times last year saw decreases change course by people ignoring the mitigation factors. “With the coming warmer weather, I know it’s tempting to want to relax and to let our guard down, particularly after a hard winter that sadly saw the highest level of cases and deaths during the pandemic so far,” Walensky said at a White House briefing. And that seems to be what people are doing. On March 12, 1.3 million travelers passed through U.S. airports. “This is the most travelers that we’ve had in a single day since last March, before the WHO declared the global pandemic,” she said. And news reports of people enjoying spring break shows many people, crowded together without wearing masks. It is understandable—we are tired of putting our lives on hold—but is it prudent when there are still 50,000 to 60,000 new COVID-19 cases reported daily? Will we continue to see the gains our sacrifices have won and finally see the end of this virus, or will we see yet another resurgence like the one occurring in some European countries—countries with similar trends and surges as the United States experienced last year? “Each of these countries has had nadirs like we are having now, and each took an upward trend after they disregarded known mitigation strategies. They simply took their eye off the ball,” she said. “I’m pleading with you, for the sake of our nation’s health. These should be warning signs for all of us. Cases climbed last spring. They climbed again in the summer. They will climb now if we stop taking precautions,” Walensky said. The data tell us that we are starting to turn a corner, but to maintain that trend, more people need to be vaccinated and everyone must protect themselves until they are. The CDC said some activities can resume among people who are fully vaccinated, but for most of us, the agency still recommends wearing a mask and practicing social distancing and handwashing (https://www.cdc.gov/coronavirus/2019-ncov/more/fullyvaccinated-people.html). I am so tired of this sequestration, and even though I enjoy gardening, I would really love to get off my property and start seeing family and friends, and visiting all the wonderful U.S. cities I love. We have come this far. Can’t we just stay put with masks on our faces, for a little longer to defeat this virus? —Marie Rosenthal, MS

The views expressed here belong to the author and do not necessarily reflect those of the publisher.

Continuous COVID-19 news for ID specialists at www.idse.net/Section/Covid-19/664 INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Spring 2021 7 Editor’s Blog: Resurgence: Déjà Vu All Over Again? 10 Improving the Journey for COVID Long Haulers 16 The Sophisticated, Changing World of COVID-19 Testing 19 After Plummeting From COVID-19, Routine Vaccinations Start to Rebound 22 Love in the Time of COVID: Pandemic’s Effects on HIV Patients 23 Access to ART 24 Formal Transition Plans Essential for Youths With HIV Moving to Adult Care 28 HIV and Opioid Use: A Symbiotic Relationship 30 After Decades of Decline, Fungal Disease Deaths Are Rising 34 New Antibiotics Strengthen Arsenal Against cIAIs 36 Innovative Microbiome-Based C. difficile Treatments in Pipeline 38 Update on CMV Management in Transplant Patients 47 Can Human Deaths From Canine Rabies Be Eliminated?

IDSE Reviews

49 How Long Is Long Enough? The Ongoing Saga of Antibiotic Therapy By Glenn Tillotson, PhD, FIDSA, FCCP

56 The Heart of the Matter: Understanding the Effect of ART on Cardiovascular Health By Jacob Boudreaux, MD, and Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

69 Rapid Diagnostic Tests: Modern-Day Tools in the Realm of Infectious Diseases By Karen Fong, PharmD, BCIDP

81 New Data on HIV Prevention By Sarah Michienzi, PharmD, BCPS, AAHIVP, and Eric Wenzler, PharmD, BCPS, BCIDP, AAHIVP

IDSE.NET

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BY MARIE ROSENTHAL, MS

or some patients, SARS-CoV-2 doesn’t just run its course. They continue to experience myriad sequelae after the acute phase of COVID-19. Long-term symptoms vary. Some, such as cardiopulmonary issues, are serious; some, such as alterations in anosmia and hypogeusia, are less so, but they continue to alarm patients for weeks to months after the original illness. These patients are truly in it for the long haul. “Once they were discharged from the hospital, patients were so happy that they got over the illness, that they survived,” said Soo Yeon Kim, MD, the medical director of musculoskeletal medicine and an assistant professor of physical medicine and rehabilitation, at Johns Hopkins Medicine, in Baltimore. They expected to return to their normal lives. “They go back to work and then realize that, oh, their executive functions are not as good as what they were before.” Kim also has seen patients who never were admitted to the hospital with post–COVID-19 sequelae. “The patients who were never hospitalized can present with severe ongoing cognitive, functional and mental issues, which may affect their life significantly,” she added, and they did

IDSE.NET

not expect to have these ongoing symptoms because they were not seriously ill in the first place (Clin Microbiol Infect 2020;27[2]:258-263). “What we are seeing is prolonged issues with lung function, and with the ability to walk distances or having the ability to just have day-to-day functionality,” said Susan M. Mashni, PharmD, BCPS, the vice president and chief pharmacy officer at Mount Sinai Health System, and an associate professor at the Icahn School of Medicine at Mount Sinai, in New York City. “And, of course, [there’s] the post-COVID brain fog that people talk about, with neurologic difficulties in their inability to concentrate, overwhelming feeling of fatigue, and just the inability to really sit down and keep on a task for a long period.” Fatigue is one of the most common symptoms reported, “sometimes weeks, even months, after apparently recovering from COVID,” said Rajesh T. Gandhi, MD, FIDSA, a professor of medicine at Harvard Medical School and the director of HIV clinical services at Massachusetts General Hospital, in Boston. “That’s sometimes accompanied by

brain ‘fog’ or a cognitive feeling that is ‘off ’—that is different than they were before the infection.” In addition to the abovementioned issues, continued anosmia and hypogeusia, gastrointestinal problems, rashes, arthralgia, and alopecia are also common occurrences, according to Luis Ostrosky-Zeichner, MD, FIDSA, a professor and the chief of the Division of Infectious Diseases, and the vice chair of Medicine for Healthcare Quality, at the McGovern Medical School, part of UTHealth in Houston. “It’s almost like the symptoms are a continuation of the symptoms they had when they had COVID,” said OstroskyZeichner, who is also the medical director of epidemiology and antimicrobial stewardship at Memorial Hermann Texas Medical Center, also in Houston. Although most symptoms resolve within weeks or months, some patients still have symptoms a year later, the experts told Infectious Disease Special Edition. In a study from Wuhan, China, 76% of patients still experienced some symptoms at six months follow-up after discharge (Lancet 2021;397[10270]:220-232). There is no clear consensus definition for post–COVID-19 syndrome, but now that the number of acute cases is slowing, and the hospitalizations and deaths are declining, researchers can turn their attention to finding out more about this manifestation that patients call “long-haul COVID.”

Why? Although there is a multitude of various symptoms, they fit into various containers: cardiology, neurology, physiatry, psychiatry and psychology, and pulmonary. One of the things that every health care provider will consider when looking at a patient with long-haul COVID-19 is

In a study from Wuhan, China, 76% of patients still experienced some symptoms at 6 months follow-up after discharge. Source: Lancet 2021;397[10270]:220-232

“who the person was before this started happening to them,” said Kathleen Bell, MD, the Kimberly-Clark Distinguished Chair in Mobility Research and chair of the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center, in Dallas. In the case of many long haulers, “we’re seeing a lot of people, for instance, with diabetes, with obesity, with hypertension, who have all of those kinds of preexisting diseases that predispose them to having more severe infections with COVID,” who are also seeing post–COVID-19 syndrome manifest as worsening of their comorbidities. For instance, those with hypertension might see chronic microvascular disease in the brain. Those with diabetes could see chronic neuropathy in their extremities, she explained at a press briefing sponsored by the Infectious Diseases Society of America (IDSA). The disease itself can cause “all sorts of problems with inflammatory responses in the brain, around the heart, around the muscles, etc.,” she said. Postural orthostatic tachycardia syndrome, which manifests

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

as extreme fatigue, headache, nausea and dizziness, is common, according to Kim, as are myocarditis and exercise intolerance. In addition, Bell added, issues follow the trauma of an extended ICU stay that can affect the mental health of the person, including depression and anxiety. “What is not fully understood is if these symptoms are

unique to COVID-19, are a general post-viral syndrome that is just being recognized because of the sheer numbers of recovered patients; or are the result of a long ICU stay for those who had severe COVID infection,” noted Allison Navis, MD, an assistant professor in the Division of Neuro-Infectious continued on page 14

COVID-19 Management Today Versus Last Year There is a clear difference in how COVID-19 was managed in the early months of the pandemic versus now, explained John W. Devlin, PharmD, a critical care specialist at Brigham and Women’s Hospital, in Boston. Back in March and April 2020, there were no treatments with proven value, except for supportive care and ventilation. And people were coming in by the hundreds (by the thousands in some places) with oxygen saturations that were so low, they were downright scary; therefore, ventilator support was offered aggressively and early. In addition, hospitals were well beyond capacity. The COVID-19 census in one New York hospital in April 2020 was around 2,000 patients. Now, it’s closer to 500. Morbidity also was much higher last April than today, explained Susan M. Mashni, PharmD, BCPS, of the Icahn School of Medicine at Mount Sinai, in New York City. There was also a lot of fear, Devlin explained, which led to greatly reduced interaction between ICU staff and the patients. Besides being unclear exactly how the virus was transmitted—whether environmental contamination was a factor—hospitals were overrun, and staff were brought in from other areas because there just were not enough bodies to handle the crisis. Even the best OR nurse may have challenges in delivering exemplary patient care in an ICU where they have never practiced, particularly in a pandemic, Devlin reminded (Critical Care Explorations. 2(6):e0149, June 2020). Under normal circumstances, most hospitals practice the ABCDEF bundle (awakening and breathing

IDSE.NET

coordination, delirium monitoring/ management and early exercise/ mobility), which is an evidencebased, interprofessional, multicomponent strategy to minimize the use of sedatives, reduce the duration of mechanical ventilation and lower the risk for delirium in the ICU. The bundle often went by the wayside when ICUs experienced surges, personal protective equipment shortages existed, non-ICU clinical staff were asked to provide care, and a lack of knowledge about COVID-19 transmission and aerosolization existed. Today, thanks to new knowledge about strategies that can be used to manage severe hypoxemia in severe COVID-19 patients before intubation and mechanical ventilation are considered, along with the important roles of dexamethasone and other pharmacologic interventions, health care providers have proven approaches to shorten the time spent

in the ICU, and to reduce post–intensive care syndrome and other postICU sequelae, Devlin said. “What was happening in the spring is everybody was immediately like, ‘Oh my God, their oxygen’s where? We need to ventilate them right away.’ Now, we’re waiting and doing other things to try to optimize their oxygenation before we intubate. “What we see a lot now is these patients with horrible numbers are still actually stable enough” to just receive nasal cannula oxygen, Devlin explained. Mashni said her experience was the same. “When COVID first encountered us, a lot more patients were intubated early on in the course. [We were trying to respond] to something that was happening very quickly, but was not part of normal medical treatment. When patients were intubated, they needed really high doses of anxiolytics and really high doses of sedatives. If we had to paralyze, then really high doses of paralytics, and the mortality at that time for patients when it came to hospitalization for COVID was really high,” Mashni said. “There are a lot more tools in our toolbox to keep people out of the hospital and to keep them out of the ICU, which is absolutely our goal,” she said. They are using fewer paralytics, avoiding deep sedation more often, starting to get back to pre–COVID-19 mobility efforts and introducing family members back to the bedside. Great use of the ABCDEF bundle is again an essential part of the ICU care. And all of that, Devlin said, “is a good thing for our COVID-19 patients.” —MR

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Long Haulers continued from page 12

Diseases at the Icahn School of Medicine, who also spoke at the IDSA briefing. The long haulers with an extended ICU stay often had prolonged periods of medication-induced coma and delirium, were likely to received continuous neuromuscular blocker therapy, and experienced damage to organs other than the lungs. Patients with a prolonged critical illness like this, regardless of whether COVID-19 is the underlying cause, frequently suffer post–intensive care syndrome (i.e., PICS), explained John W. Devlin, PharmD, a professor of pharmacy at Northeastern University and an associate scientist in the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital, in Boston. “Patients with PICS may experience prolonged post-ICU cognitive decline, psychologic sequelae including PTSD, depression, anxiety and poor sleep,” which can make it difficult to determine “in those COVID-19 ICU survivors whether the PICS is partially related to persistent effects of COVID-19 or simply related to their prolonged critical illness and PICSrelated sequelae of it,” Devlin said. “During prior ICU COVID-19 surge situations, delivery of the ABCDEF bundle, an interprofessional, multicomponent strategy focused on daily sedation interruption, delirium recognition and reduction, early mobilization, and family engagement—and shown to reduce post-ICU PICS—has been compromised,” Devlin explained. (See sidebar on page 12.)

Never Hospitalized Although those who had moderate to severe COVID-19 that resulted in an ICU stay are more likely to see a continuation of their COVID-19 symptoms, the really puzzling patients are the ones who were never hospitalized. Many report having brain fog and other cognitive issues, anosmia and hypogeusia, rashes, depression, breathlessness, and difficulty walking, as well as many of the other symptoms suffered by those who had more severe COVID-19. One study explored 20 athletes with mild to asymptomatic COVID-19 and found imaging evidence of myocarditis in five. The damage was enough to restrict their participation in professional sports (JAMA Cardiol 2021 Mar 4. doi:10.1001/ jamacardio.2021.0565). “In general terms, my observation is that the more severe that COVID is, the more likely people are going to end up with long-term symptoms,” Ostrosky-Zeichner said, “but occasionally, we do find somebody that had a relatively mild illness, and they have more severe long-term issues, but that is not the rule.” However, Navis has found that “the vast majority” of her post–COVID-19 patients were not hospitalized. Bell agreed that her group also has seen persistent symptoms

IDSE.NET

“Certainly, there are people who have severe disease that then take weeks, if not months, to get better. What’s less clear is whether the severity of the initial COVID predicts the likelihood of long COVID. We don’t know that yet.” —Rajesh T. Gandhi, MD, FIDSA

in patients who were never hospitalized, but that doesn’t mean most of those people were not very sick. “There are a number of people who self-treated, self-quarantined at home who still may have been ill for two, three, four or five weeks—acutely ill, but managed at home,” she said. Gandhi agreed. “Certainly, there are people who have severe disease that then take weeks, if not months, to get better. What’s less clear is whether the severity of the initial COVID predicts the likelihood of long COVID. We don’t know that yet.”

Management While researchers are still working to better understand the syndrome—the National Institutes of Health recently announced a study to identify the causes of and the treatment for post–COVID-19—providers are focusing on managing the symptoms that are so distressing to patients. COVID-19 specialty clinics are cropping up all over the country, and many of the experts interviewed by Infectious Disease Special Edition work with these clinics. Harvard, Hopkins, Mount Sinai and UTHealth are among the institutions that developed clinics early last year based on the patients they were seeing, and have become the standards for care. But not all clinics are created equal, the experts said. Any health care provider wanting to refer patients should take a close look at those providing care, the experts suggested. Because the symptoms are so diverse and very few patients have only one symptom, the workup and management of long haulers takes a multidisciplinary team, Gandhi said, including pulmonologists, continued on page 32

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The Sophisticated, Changing World of COVID-19 Testing BY DAVID C. HOLZMAN

n less than a year, testing for SARS-CoV-2 has become sophisticated and accurate, with a multitude of choices that meet various circumstances and needs. That said, the world of testing for COVID-19 is rapidly changing: “a revolution in terms of development of new diagnostics, rollout of diagnostic tests faster than ever before, new types of samples for testing [such as saliva], making testing available in convenient ways including home testing, and learning when and how to use diagnostics for a new virus,” said Robin Patel, MD, an immediate past-president of the American Society for Microbiology, and the Elizabeth P. and Robert E. Allen Professor of Individualized Medicine at Mayo Clinic in Rochester, Minn.

COVID-19 Test Decision Making in Action Steven J. Martin, PharmD, BCPS, FCCP, FCCM, the dean and a professor, Rudolph H. Raabe College of Pharmacy at Ohio Northern University, in Ada, illustrated the type of decision making that goes into choosing diagnostics for COVID-19 under difficult circumstances. Just before the 2,000 students returned to campus last fall,

IDSE.NET

“we contracted with a laboratory to do PCR [polymerase chain reaction] testing,” said Martin, who is also a pharmacist at the college’s ONU Healthwise Pharmacy. They chose PCR tests where students could collect saliva samples at home and send them in to be tested. Sample collection at home was critical to prevent SARS-CoV-2 from invading the campus—so was PCR’s high level of accuracy. “We didn’t want 2,500 students to come back to campus and find out that 40 to 50 were positive, because then we would have become responsible for isolating them, housing them and feeding them,” Martin said. Another advantage was that the saliva did not have to be frozen or refrigerated, according to Martin. “Individual students would take a sample of their saliva and send it in. We facilitated everything.” However, PCR is not perfect. Among the returning students who were tested, about 40 of the tests had inconclusive results, meaning the specimens may have been positive for SARSCoV-2, Martin explained. But now that the students’ return was continued on page 18

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COVID Tests

but other factors enter into the equation. “How much does it cost to buy reagents, as well as any instrumentation needed?” continued from page 16 That, she said, depends on who pays and how imminent, time was of the essence. Martin retested much they are willing to pay: for example, the labothe students with antigen tests and found eight ratory conducting the test or the person having the cases among the 40 students. test. However, antigen tests may be less expensive For testing students on campus who think they than viral RNA tests. may be sick, they use a rapid antigen system, The speed of obtaining results also gets comaccording to Martin. Although a specificity of 98% plicated. “It’s not just how long it takes to run the to 99% is not as accurate as PCR testing, “antigen test but whether it can be tested on-site or has to gives us results within 15 minutes, and if posibe shipped to a lab elsewhere, and whether the test tive, we can remove students from campus.” The can be run upon arrival, or whether it goes into a downside of false positives is much less onerous queue,” Patel said. Source: CDC, March 12, 2021. than false negatives, since it wouldn’t contribute to There’s also an extensive menu of tests, and to de spreading the disease. decide from among them, “you have to determine re nasal tthe question you are trying to answer,” she said. Unlike PCR tests, samples for antigen tests are swabs, which are not shelf stable, and must be “You have to pick the right test for the right processed promptly. question.” For much of the pandemic, shortages of To clarify, Patel said “the most ideal tests tests were a problem, but that’s no longer the today are some of the rapid nucleic acid amplifiped case, Martin said. “Once the government stopped cation tests [PCR is the oldest and best known] buying everything they could get their handss on that provide the same sensitivity and specificity ped up [things eased up, and] companies have really ramped as a traditional in-laboratory test.” production. As long as we order a steady supply, we get it.” Two problems: “First and most importantly, tibody the Martin said some people want COVID-19 antibody there is not a robust supply chain behind them at ase, this point,” Patel said. The second is cost. “Given tests, hoping that if they have had the disease, ctthe situation, one might consider reserving such they won’t need to be vaccinated. The CDC recommends that people who have had COVID-199 tests for certain patient populations, where use should still be vaccinated, he said. of the most accurate, fastest test will have the greatest impact. Conversely, using these tests Diagnostics for screening otherwise healthy people may be Not everyone has had Martin’s experience, and nd le less justified.” some are still seeing shortages. hree The R Revolution and the Future “As a diagnostician, I look at new tests with three The revolution in COVID-19 diagnostics that criteria, and now have a fourth from COVID,” Patel P Patel described was brewing before SARS-CoV-2 said. “The three are ‘better, faster, cheaper,’ and the leapt from bats into humans, but the pandemic’s fourth is ‘supply chain issues.’ nge arrival shifted that change into high gear, Patel “It has been, and continues to be, a challenge or said. She expects that revolution to blossom in to reliably obtain the supplies needed to test for n– other infectious diseases, and even into antimiSARS-CoV-2—and interestingly, also for non– crobial resistance. SARS-CoV-2—infections,” Patel said. “Because of “Part of the solution is better use of antibiotthis, for SARS-CoV-2 many laboratories have to ever iics, and for that we need better diagnostics,” Patel offer multiple tests, just to make sure that whenever med.” said said. The kinds of tools developed to detect SARSa SARS-CoV-2 test is needed, one can be performed.” hort CoV-2 ““can detect the changes in genes that cause the Even if just one component of the test is in short o resis resistance, and we figure out how to treat them as we supply, “that can be enough to bring everything to did ffor SARS-CoV-2.” n a halt. We don’t usually offer multiple tests for thee s, same disease, as that’s inefficient on many levels, Dr. P Patel reported relationships with 1928 Diagnostics, but that has become necessary in the pandemic.”” Curetis, ContraFect, Next Gen Diagnostics, PathoQuest, Cure Cost considerations can be more complicated PhAST, PhAS Qvella, Selux Diagnostics, Specific Technologies, than you would think. “One would think aboutt TenNor TenNo Therapeutics Ltd, Hylomorph and Shionogi. Martin reported ,” reporte no relevant financial disclosures. antigens as being cheaper than viral nucleic acids,”

8.78% positive from 346 million U.S. tests

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After Plummeting From COVID-19, Routine Vaccinations Start to Rebound BY BOB KRONEMYER

.S. Routine vaccination rates fell sharply last spring due to COVID-19, but have shown a promising rebound. “During the period of active shutdown for most of the country in early 2020, there was a substantial dip in the provision of routine immunizations for people of all ages, with demand down as much as 95% for some vaccines,” said William Schaffner, MD, the medical director of the National Foundation for Infectious Diseases (NFID). “However, since venues started reopening last summer, there has been an uptick in vaccinations, including catch-up for those vaccinations that were missed. We are moving back up to 80% of children who are current on vaccinations. But an ideal percentage to meet public health goals is well over 90%.” Schaffner noted that even during the pandemic, it is critical that everyone stay up-to-date on all recommended vaccinations to avoid further strain on the health care system. That is why NFID launched a national, multimedia campaign dubbed “Keep Up The Rates” to encourage everyone to receive recommended vaccines that may have been postponed during the pandemic. “Once a patient returns to the doctor’s office for his or her routine checkup or other patient care, it is important that practitioners review the patient’s immunization history and make sure they are up-to-date,” said Schaffner, a professor of

infectious diseases at Vanderbilt University School of Medicine, in Nashville, Tenn. It is unclear what impact the push for adults to be vaccinated against COVID-19 might have on other vaccinations. “We are monitoring very carefully the side effects of these new COVID-19 vaccines. We do not want to confuse the issue by giving another vaccine at the same time,” he said. Even after COVID-19 vaccines become more widely available, Schaffner does not anticipate much dual immunization initially. Melinda Wharton, MD, MPH, the director of the Immunization Services Division at the CDC, hopes that the focus on COVID-19 vaccines will not affect non-COVID vaccination rates, despite the CDC recommendation that a non-COVID vaccination be spaced at least 14 days after a COVID-19 shot. This lag time is due “to the absence of data about concurrent administration,” Wharton said. “The COVID vaccines are new, and there are no data about the impact on either safety or efficacy if the COVID vaccines are given at the same time as other vaccines.” The CDC has better and more timely data on childhood immunization rates than adult rates. “We do not purchase many doses of vaccines for adults, unlike providing vaccines for around 50% of the children in the United States through our federal

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Vaccines for Children program,” Wharton said Beginning last mid-March, there was a precipitous drop in pediatric ambulatory visits, including well-child visits, and a dramatic reduction in vaccine orders, according to the CDC. “Although there has been a good deal of recovery since last early May, we are still down about 14%—or more than 10 million doses—for public-sector pediatric vaccines, other than flu, since the pandemic began,” Wharton said. About 1.3 million of these doses are measles-containing vaccines. This is disconcerting because of the large measles outbreak of 2018-2019 that nearly resulted in the United States losing measles elimination status. “Thus, we are incredibly concerned about the number of children who have apparently not received measles vaccine,” Wharton said. The CDC has been working with the American Academy of Pediatrics and American Academy of Family Physicians to develop strategies to bring the population up-to-date on vaccinations. “It is crucial that providers reach out directly to families because they may not know they have missed an appointment,” Wharton said. “For those families that may know they have missed an appointment, they may not realize that appointment was for a recommended vaccine.” Angela Shen, ScD, MPH, a visiting scientist at the Vaccine Education Center at Children’s Hospital of Philadelphia (CHOP), said there was a dramatic decline of potentially up to 80% to 90% in vaccine doses administered to children, adolescents and adults following stay-at-home orders in many parts of the country in early spring of last year. “This trend slowly began to reverse last May and June,” she said. “In fact, some states and jurisdictions may have rebounded to pre-COVID levels in certain populations, like children under age 2.” Children younger than 24 months were initially given priority in bringing their vaccinations up-to-date because when children miss their primary series of vaccinations, “it is very difficult to catch up,” Shen said. Certain types of vaccines may have had a stronger rebound than others possibly because of people’s concern about other respiratory viruses that are co-circulating with SARS-CoV-2, according to Shen. “For example, this influenza season is a really good year for people to get a flu shot if they had never had one before,” she said. Similarly, Shen thought people might have been incentivized to receive a recent pneumococcal vaccine. Office practices and health systems can scan their electronic health records to determine who needs to be vaccinated. “They can also look at their state or jurisdiction’s immunization registry to see which children and adolescents have missed their shots and have their families schedule an appointment,” said Shen, a retired captain with the U.S. Public Health Service. Practices should also tell families about the precautions in place for safe delivery of in-person services. “Families should be notified by text messaging or a phone call that they are not vulnerable to just COVID, but to other diseases

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During the Pandemic Sequester: ster:

• Fewer than 50% of

ts 5 months Michigan infants and younger were up-to-date on routine vaccinations.

• Vaccines dropped 91% for NYC toddlers older than 24 months from March to May 2020. • Miami-Dade County found a 60% decline in children’s vaccinations in April 2020. Source: NFID, http://bit.ly/3rKgNsu-IDSE

that are preventable with currently available vaccines,” Shen said. However, more vulnerable families may not have access to transportation or lost health insurance due to a job loss that limits their ability to go to appointments. Extending hours to encompass a Saturday clinic or one evening per week may increase compliance, according to Shen. “There has clearly been a decline in immunization rates against polio, whooping cough and measles,” added Paul Offit, MD, the director of the Vaccination Education Center at CHOP. “As we moved into the winter months, there was a worry of increased incidence of viruses or bacteria spread by the respiratory route. But we really have not seen that, thanks to masking and physical distancing.” Because there are no COVID-19 vaccines for people under the age of 16 years in the United States, childhood vaccination rates should not be impacted by the goal to immunize most adults. “Right now, we are in the midst of the pandemic and everyone’s eyes are on this particular virus,” said Offit, also a professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, in Philadelphia. “But there are a lot of different viruses and bacteria that can hurt children. That has not changed, so we need to ensure that children receive the vaccines they need.” Reminiscent of the polio era, Offit proposes that children after vaccination be given a sticker or hat labeled “I’m Immune,” to reinforce a happy and worthwhile accomplishment rather than an unpleasant experience. Meanwhile, Offit apprehensively awaits the collateral damage of the pandemic. “Children may be more susceptible now to disease because parents were scared to subject their families to a n group setting of a practice to be immunized,” he said. The sources reported no relevant financial disclosures.

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Love in the Time of COVID: Pandemic’s Effects on HIV Patients BY DAVID C. HOLZMAN

s COVID-19 swept the United States, clinicians who treat people with HIV wondered how their patients would fare during the pandemic: Would they be at risk for more severe disease than the general population? While the evidence is still limited, it does not suggest that COVID-19 is more virulent among people with HIV, according to W. David Hardy, MD, AAHIVS, a scientific and medical consultant and an adjunct professor of medicine, Division of Infectious Diseases, the Johns Hopkins University School of Medicine, in Baltimore. If people with HIV were more vulnerable, “most people feel we would have seen evidence in New York hospitals,” because New York has among the highest concentration of people with HIV in the United States (~1.5%), Hardy said. Asked whether people with HIV who are not completely adherent with their antiretroviral therapy are more vulnerable than others to COVID-19, Antonio E. Urbina, MD, said the evidence is not yet

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there. “From my experience, the biggest drivers for hospitalization are the number of comorbidities present, in particular, cardiovascular and kidney disease, diabetes and obesity,” said Urbina, an associate professor of medicine at Icahn School of Medicine at Mount Sinai and the medical director of The Blavatnik Family – Chelsea Medical Center, in New York City. But Rachel Bender Ignacio, MD, MPH, said even for medication-adherent patients, the jury is still out. “Many patients are concerned that they are at greater risk for COVID-19. Since we lack data, there is tremendous anxiety that they might be at higher risk,” said Bender Ignacio, an assistant professor and the associate director of the UW AIDS Clinical Trials Unit, Division of Allergy and Infectious Diseases, University of Washington, in Seattle. That anxiety is especially onerous for those who lived through the early stages of the AIDS epidemic—“something I’ve learned from talking with many longterm survivors of HIV,” Bender Ignacio

said. Politicization, and the lack of a science behind some putative treatments, “mirrors the first years of the HIV epidemic. Anyone who is HIV-positive and lived through the 1980s is reexperiencing [that era] in a powerful way.” As yet, no estimates exist for the number of people with HIV who have become infected by SARS-CoV-2, Bender Ignacio said. Several studies are collecting data, including one at several Centers for AIDS Research, to determine whether HIV increases a person’s risk for becoming infected, being hospitalized, requiring ventilation or dying from COVID-19. “One of the really tricky problems is that the population of people with HIV has a higher burden of many cardiovascular risk factors or comorbidities, such as higher [rates of] smoking,” Bender Ignacio said. (See “The Heart of the Matter” on page 56.) It is also too soon to know whether social distancing is reducing new cases of HIV, according to Bender Ignacio. The number of people who will be tested for HIV will likely decrease, as people avoid unnecessary care, but that doesn’t

translate to fewer new cases. But at least one observation suggests cases might fall. “From my anecdotal experience, patients are less likely to ‘hook up’ on social apps like Grindr,” Urbina said.

Social Distancing and Mental Health Social distancing may increase feelings of isolation for people with HIV and affect them more than those without the disease. “People with HIV, and in particular certain subsets of that group—the LGBTQ community, older adults aging with HIV, etc.—face more mental health issues than the general population,” said Sarah Schmalzle, MD, an assistant professor of medicine, Institute of Human Virology of the University of Maryland School of Medicine, in Baltimore. “Many of our patients also already face significant isolation and loneliness, due to a combination of HIV stigma, losses of friends and family to HIV, and aging.” According to Hardy, social distancing deprives patients of activities and community support that help keep people with HIV motivated to take their medications. The flip side: “Anecdotally, I have noticed so much resilience in many patients,” Schmalzle said. “One possible explanation is that because our patients have dealt with stigma, loss and isolation for so long, they may actually be fairly well equipped to deal with COVID-19 restrictions and fears.” Hardy recommended that patients use technology to attend support meetings online, and to maintain their human connections. At least for the duration of social distancing, physicians meeting patients via telehealth should conduct a mental health assessment, suggested Jeffrey Kirchner, DO, AAHIVS, the chief medical officer for the American Academy of HIV Medicine, Lancaster General Hospital, in Pennsylvania.

Telemedicine Telemedicine has soared during the pandemic. “For patients with chronic diseases, such as HIV, the majority of outpatient appointments are done with telemedicine,” said Ann Woolley, MD, MPH, the associate clinical director of Transplant Infectious Diseases, Brigham and Women’s Hospital, and an instructor of medicine, Harvard Medical School, in Boston.

Access to ART By David C. Holzman For the most part, the supply of pre-exposure prophylaxis and antiretroviral medications has not been an issue during the COVID-19 pandemic. Nonetheless, various forces have affected access—some for the better. For example, Maryland loosened its restrictions on refill dates so that patients could obtain their medications on their own schedule rather than being asked to return to a pharmacy at a later date if their prescriptions were not yet due, said Sarah Schmalzle, MD, an assistant professor of medicine, at the University of Maryland School of Medicine, in Baltimore. At THRIVE, a clinic primarily for HIV patients that Schmalzle directs, “we are using our team of social workers, nurses, medical assistants and peer support coaches to reach out to all patients and ensure they have no problems getting their medications,” she said. During the quarantines, “many insurance companies are allowing three-month supplies [of medications],” said Melissa Badowski, PharmD, MPH, FCCP, BCIDP, BCPS, AAHIVP, a clinical associate professor, Department of Pharmacy Practice, Section of Infectious Diseases Pharmacotherapy, University of Illinois at Chicago, College of Pharmacy. But red tape has been an obstacle for people who need financial assistance to pay for their medications. “Many Medicaid offices are not open, and patients frequently are unable to come to the clinic to complete paperwork,” especially during the pandemic, Badowski said. “Signing up for these types of programs requires proof of income, financial documentation, getting baseline blood work done, and a lot of the people we take care of come from populations that have barriers to accessing health care,” said Rachel Bender Ignacio, MD, MPH, an HIV specialist at the University of Washington, in Seattle. Nonetheless, “the offices have been more lenient in allowing us as practitioners to provide photos and submitting those documents through Office Lens [an app],” Badowski said. “For programs such as ADAP [AIDS Drug Assistance Program], we have been completing paperwork remotely.” Physicians having trouble getting affordable medications for their patients should ask drug companies for samples, or ask to get connected to drug assistance programs for the medications, Badowski said. Case managers or social workers can help patients navigate insurance bureaucracies.

continued on page 26

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Formal Transition Plans Essential For Youths With HIV Moving to Adult Care BY KAREN BLUM

any youths living with HIV disengage from medical care at some point, and for a significant number of people this happens during the transition from pediatric/adolescent to adult clinics. A number of infectious disease programs have protocols to help pave the way for their patients and keep them engaged, but experts say more education is needed for patients and health providers. Adolescence is a time of co-occurring transitions, with developmental milestones and the formation of romantic and personal, school and work relationships, explained Bill Kapogiannis, MD, the director of the Adolescent Medicine Trials Network for HIV/AIDS Interventions at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. “Because of all of this, there’s a period where if a medical situation takes you from a familiar place to a suddenly unfamiliar place, that’s a challenge to adapt to, and what can cause the disconnect,” Kapogiannis said. “That isn’t something that’s going to change, but there are things we can do to help and improve it.” Care can become more sporadic among all young people

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during these times, even more so for those with conditions such as HIV that require them to be engaged in care, take medications and share decision making with clinicians, said Allison Agwu, MD, ScM, an associate professor of pediatric and adult infectious diseases at the Johns Hopkins University School of Medicine, in Baltimore.

No Time for Wallflowers With HIV, “there are reminders about being [HIV] positive, and a stigma you may feel about walking into a clinical setting,” Agwu said. “It may seem easier to be out of sight and out of mind and disappear.” There are approximately 47,800 people aged 13 to 24 years living with HIV in the United States, not all of whom know they are infected, according to 2018 estimates from the CDC. Young Blacks and young men who have sex with men are disproportionately represented. With no official evidence-based interventions, every pediatric and adolescent clinic has its own process, more formalized

Steps for Transitioning HIV Care

1 Develop written policies to guide transitions 2 Create transition plans with youths and families 3 Facilitate the new connection with the adult clinic 4 Facilitate communication between adolescent and adult clinics Source: Pediatrics 2013;132(1):192-197. https://doi.org/10.1542/ peds.2013-1073

in some places than others, said Amanda Tanner, PhD, MPH, an associate professor of public health at the University of North Carolina in Greensboro. A previous study of hers looking at 14 adolescent medicine clinics (J Adolesc Health 2018;63[2]:157-165) found a range of transition practices, from official “Moving Up” ceremonies to celebrate transition to informal discussions. Some programs have a social worker or case manager accompany patients to their first adult appointment, or have adult practitioners see them in the pediatric space to ease their comfort. A 2013 guideline from the American Academy of Pediatrics recommends four steps for transitioning youths: developing written policies to guide transition; creating transition plans together with youths and families; facilitating youths’ connection to adult clinics; and communicating between adolescent and adult clinics during the transition process. Having a plan in place is essential to ensure expectations are understood, Kapogiannis said (Pediatrics 2013;132[1]:192-197).

have a point of contact, or to help plug them in to additional resources like social work or housing, if necessary. “It is much more hand-holding than just transitioning to adult care,” Sanders said. “Many patients are going through mental health or other social crises. They just need some additional wraparound services to get to the other side.” Those who become infected as adolescents are closer to adulthood when they enter care and generally transition to adult care more easily, said Michael Rosenberg, MD, PhD, a pediatric infectious diseases specialist with Jacobi Medical Center in the Bronx, N.Y. By contrast, those who were infected perinatally have seen pediatric practitioners their entire lives, and are more reluctant to leave. The median age of patients attending his clinic is 26. Young women who become pregnant tend to transition to adult care more easily due to the availability of enhanced prenatal services and their recognition of pregnancy as a marker of adulthood, he said.

Championing the Transition To improve the transition, Tanner and Sophia Hussen, MD, MPH, an associate professor of medicine and public health at Emory University School of Medicine, in Atlanta, are launching a study looking to engage youths with HIV and their providers using a mobile health app, website and transition champions. continued on page 26

When to Start Kapogiannis begins conversations with patients about moving to adult care as early as age 14, depending on their emotional maturity. “Some may not be ready and push back, but it’s good to keep the discussion going because it is a healthy approach for setting the stage for their developmental maturity and getting them to that next stage in their lives.” Johns Hopkins has a full transition team in place, said Renata Sanders, MD, MPH, ScM, an associate professor of pediatrics and adolescent medicine specialist. This includes a social worker, nurse, medical and nonmedical case managers from the pediatric/adolescent clinic, an outreach specialist/ patient navigator, and a nurse from the adult clinic. During monthly meetings, staff from both the pediatric and adult programs discuss how to successfully help adolescents and young adults transition to adult care, review individual patient cases and any present challenges. As patients reach age 23, the team will determine which adult practitioner would be the best fit, and have that person see the patient initially in the adolescent clinic to help secure the transition. Patients also are introduced to a patient navigator from the adult clinic to

Are They Ready? • Can they describe their symptoms? • Do they know what to do in an emergency? • Can they manage appointments with multiple providers? • Can they manage their prescriptions, including the timing of refills? • Do they understand how to obtain and keep health insurance? • Do they know how to access relief and social programs? • Do they have a good working relationship with their caseworker?

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Transition in HIV Care

COVID and HIV

continued from page 25

continued from page 23

Called iTransition, the program will enroll patients and providers from Children’s Hospital of Philadelphia, the University of Pennsylvania in Philadelphia, and Grady Memorial Hospital in Atlanta, beginning this year. The patient-facing app will include educational modules, relationship development strategies and communication features like chats to help foster autonomous disease management. A related website will allow providers to track patients’ progress and offer reminders and checklists for transitioning patients. Champions will promote use of the program to patients and providers.

“Many clinics were unable to provide telehealth services before [COVID-19] because of [Centers for Medicare & Medicaid Services] rules and restrictions,” Schmalzle said. “These restrictions have been significantly lifted.” Besides safety in a pandemic, convenience is an obvious advantage for those who live far from a clinic, Bender Ignacio added. Telemedicine is also advantageous for those people with HIV who would feel stigmatized walking into a clinic. “We try to do video visits as much as possible, because there is actually quite a bit you can gain from having a face-to-face interaction with a person rather than a phone call,” Schmalzle said. However, “many of our patients don’t have internet access or an email to receive video links,” she said. Some don’t have a phone, are homeless, or lack a private space at home that is suitable for a doctor’s visit, according to Schmalzle. “We are utilizing our peer support coaches now to call all patients and talk them through the telemedicine technology, and schedule a visit for anyone that hasn’t had one,” Schmalzle said. She added that with time, people are adjusting to the technology. COVID-19 may have both beneficial and detrimental effects on the HIV epidemic, according to Helen C. Koenig, MD, MPH, an associate professor of clinical medicine at the University of Pennsylvania, in Philadelphia. “Some of the good things are surprising, like using telehealth to reach patients who have been out of care for quite some time!” She said. However, she thinks COVID-19 may exacerbate the opioid epidemic in a number of ways, and thus negatively affect the overall time line for ending the HIV epidemic. The overall effect of COVID-19 on HIV, she said, is uncertain, but probably negative. For more, read about how COVID-19 affected the program to end HIV in America (http://bit.ly/2OPFchOIDSE), as well as a review about COVID-19 and HIV by Amit C. Achhra, MD, PhD, MPH, and Rajesh T. Gandhi, MD, from Massachusetts General (http://bit. n ly/3rOr5I6-IDSE).

Possible Interventions • Addressing comprehensive care needs including medical, psychosocial and financial aspects of transitioning • Identifying adult care providers willing to care for adolescents and young adults • Addressing patient and family resistance to transitioning • Helping youths develop life skills • Educating HIV care teams and staff about transitioning Source: National Institutes of Health HIV clinical practice guidelines.

“We really wanted to target patients to work on readiness and independently managing their disease,” Hussen said. “On the pediatric provider side, we want to help them prepare patients earlier and in a more methodical way. Adult providers tend to be much less aware that the transition is a big deal or an issue, so having some educational material for them and guidance on how to help youth through the transition is another part of this. We’re trying to help make this a planned, well-thought-out process.” Adult practitioners receiving these patients may not recognize this period might be fraught with personal, developmental and systemic challenges for patients, Agwu added: “We need to set up systems on the adult side where the receiving team is aware they may need to focus a little more and provide a little more support and care for this group.” The good news, Kapogiannis said, is that youths are resilient and very capable of adapting to changes. “With a little bit of support, they can really take care of themselves and do well long term with HIV,” he said. “Transition is a key area where getting services tailored [to their needs] ensures n optimal health outcomes.” The sources reported no relevant financial disclosures.

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Bender Ignacio reported a financial relationship with the National Institutes of Health and Novartis. Hardy reported financial relationships with Enochian Biosciences, Gilead, Merck and ViiV Healthcare. Schmalzle reported a financial relationship with Gilead Sciences. Urbina reported a financial relationship with VIIV Healthcare. Badowski, Kirchner, Koenig and Woolley reported no relevant financial disclosures.

Microbiome-Based Therapy: Th Next The N tF Frontier ti iin th the M Managementt off Clostridioides difﬁcile Infections and Recurrence Download a PDF or request free hard copy reprints

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levels. 55,56 Patients infected by also have strains tha higher mo t produce rta strains of all 3 toxins C. dif ficile. 57 lity rates than pa tients wh In addition In 2017, o carry oth the es tim to gastrointes er cated by ate d na tio associated tinal dama the devel na l bu rde CDI was ge, CDI ca opment of stream infe 235,700 n of he ca se s) wit n no be socomial cti case s complialt h ca re– h an estim infections pathogen. 58 ons with enteric pa 77 ate d inc ide (95% CI, 221,700 .6) pe r 10 and blood thogens It -249,700 0,0 as the ma 00 rity enables has been hypothe po pu lation 62 nc e of 73.3 (95% associated in causati sized tha microbial . CI, 68.9CD Th ve I t e wa the burde n of tra circulation 59 s 226,400 cases) wit . Transloc nslocation from the altered gut integco ca mmunity h se an s (95% CI, estimated ation is the ity due to gut to the per 10 0,0 20 inc 6,9 disruption ide systemic increased 00 00 populat nce of 70 -245,9 00 of the gu tinal overg .4 ion. 62 Mo likely unde t barrier fun intestinal permea row th and st estimate (95% CI, 64.3-76 restimate bilction. Mo general ch .4) are asso s s becaus in terms reover, int ciated wit anges in e data are of CDI incidence are of cases esthe bacte h CDI. Tra lipopolys ad typ mitted to fore do no ically only rial micro nslocation accharide the hosp biota t include reported leads to s (LPS), cell wall, ital people tre ratio shifte the relea a compon into the blo ated as ou for CDI, and therese of d toward ent of the odstream. 60 response tpatients 62 a higher ting from gram-nega pro This induc . Thus, incidence the healt tive the es produ against LP teins and consum h care se in the co ste wa cti pti on ttin mm rds S antigen 60 on of neutr of host g becaus hip pro unity sets. Follow can lead alization an e of a lac Another fac grams. 62 to sepsis ing trans k of antib tibodies tor that fra loc in initial CD iotic cantly wit ho sp ita ls me s the da I (16%), an ation, this cascad h recurren be ing e ta d t pe rep ep ca 33.1% wit na lize d for n increase isodes: 27. orted abov rCDI ) in the h the seco the ir rates 3% with e involves Un ite d Sta nd, and 43 the first rec signifiof CD I (es there is so tes. 63 Giv .3% with urrence, pe cia lly for en this fin metimes Epidemio more. 61 ancial co a reluctan symptoms logy and nsideration ce to tes for CDI an Burden of t , pa Recent stu d na tie a rio nts rec , empiric ent infectio 63 with class CDI dies on the therapy is ic States sh n. In tha the patie incidence usually sta t clinical ow a de nt is of C. dif fic rted and cre ing propo ile in the recurrence 63 not accounted for likely effec scertion of co as e in overa ll nu Un . ep ite tive ide d Un but mb ers bu miologically der the mmunity mated na tion Progra -acquired t tio na l bu as having m of the Ce Hospital-Acquired infections 62 a growrde health ca a hospitals’ nters for Condition . The es re– associa n of both co mm Medicare reimburs tiun ted C. dif 428,600 -49 ement is & Medicaid Reducacquired ficile is 42 ity-as so ciated an reduced 5,600 ca CDI are ele Services, d 8,600 ca if ses). 62 Alt the natio the va 64 ir rec ted. Th rates of ho ses (95% urrence of nal burde hough the e estimate CI, sp n of healt CD ita ad by 36 % I, ljus hospitaliza d frequen of acquisit ted estim h care– as (95% CI, tions for cy of firs ate of ion, and sociated 24 natio na l CD t in-hospita CDI decre The rates bu rde n of %- 54%) , the ad jus l deaths are I regardless of sit ased ted estim co unchange e shown in very high; of CDI have decre ate of the d over tim 62mm unity-ac qu ire Table 1. 62 ased rec however, d CDI ha e. The in 2017 for en the be tly, mo s inf bu ov rem ain ed ections tha era re refractor t still rem he alth ca ain t (95% CI, y re– as socia ll national burden pa to ren tie an nts ce. In 20 timicrobial 428,600 -49 estimate ted CDI 17, Ma et therapy res get seem to was 462,1 5,600 ca mated as Unite d Sta al studie se ulting in 143.6 (95 00 case s d the inc tes us ing recur% CI, 133.2 s), and the incide idence of me rci ally a databas nce was -154.0 ) pe rCDI in the ins ure d e of alm estir 100,000 pe op le, ost 39 mi between population 62 of llio n co mwh 20 01 and 20 65 om 45,34 . de nc e of 12. Durin 1 deve lop CDI inc rea g ed CD I se d by 42 this period, the an nual inci.7% , fro m Table 1. 0.440 8 to Estimate 0.6289 s of First Associa

Microbiome-Based Therapy: The Next Frontier in the Management of Clostridioides difﬁcile Infections and Recurrence Faculty Teena Chopra, MD, MPH Professor, Infectious Disease Wayne State University School of Medicine Detroit, Michigan

Paul Feuerstadt, MD, FACG, AGAF

Kevin Garey, PharmD, MS, FASHP

Assistant Clinical Professor of Medicine/ Attending Physician Yale University School of Medicine/ Gastroenterology Center of Connecticut New Haven, Connecticut

Chair, Department of Pharmacy Practice and Translational Research Professor, Pharmacy Practice University of Houston College of Pharmacy Houston, Texas

he microbiota is a community of microorganisms, such as bacteria, fungi, and viruses, that inhabits a particular location, including the human body.1-4 The human body is home to about 100 trillion bacteria and other microbes comprising up to 36,000 distinct species of bacteria—collectively known as the microbiome.4,5 The gut microbes that inhabit the human body outnumber human cells by several times.6,7 It is recognized that the number of genes in the majority of microbes (microbiome) exceeds the total number of human genes by hundreds-fold.8 Advances in DNA sequencing and bioinformatics made the progress in human microbiome research possible. Driven by the Human Microbiome Project and European MetaHIT program, there are many groups studying the relationships between the microbiome and human health and disease.6,7,9 Gut microbiota have roles in health and disease states across several fields, including gastrointestinal diseases (ie, inflammatory bowel

disease, fatty liver), metabolic diseases (eg, diabetes, obesity), immunologic diseases (ie, allergic conditions), and brain–gut disorders (eg, autism, Parkinson’s disease).2,4,10-12 Change in microbiome, known as dysbiosis, is often caused by dietary factors, stress, and the use of broadspectrum antibiotics, such as cephalosporins or fluoroquinolones.13-15 Such disruption to the gut microbiome leads to an environment suited for the proliferation of Clostridioides difficile (C. difficile). Although antimicrobial therapy is currently the standard of care for the treatment of C. difficile, these agents are somewhat nonspecific. They target C. difficile but also alter the surrounding microbiota milieu, leading to an imbalance of gut microflora and causing recurrence of C. difficile infection (CDI).14,16 Among patients receiving antibiotic treatment for CDI, 20% to 35% experience a recurrence and 40% to 60% of patients have a second recurrence.17-22 Specifically, the risk for a second recurrence increases to 40%,

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Faculty Teena Chopra, MD, MPH Professor, Infectious Disease Wayne State University School of Medicine Detroit, Michigan

Paul Feuerstadt, MD, FACG, AGAF Assistant Clinical Professor of Medicine/ Attending Physician Yale University School of Medicine/ Gastroenterology Center of Connecticut New Haven, Connecticut

Kevin Garey, PharmD, MS, FASHP Chair, Department of Pharmacy Practice and Translational Research Professor, Pharmacy Practice University of Houston College of Pharmacy Houston, Texas

Supported by

HIV and Opioid Use: A Symbiotic Relationship BY ETHAN COVEY

he HIV and opioid epidemics are intrinsically entwined. People who are using opioids—especially those who inject drugs—are at increased risk for HIV, and one epidemic could undo strides made against the other, experts said. “Any uptake in injection drug use is likely to lead to more HIV cases,” explained Ricky N. Bluthenthal, PhD, the associate dean for social justice and a professor in the Department of Preventive Medicine at the University of Southern California’s Keck School of Medicine, in Los Angeles. For instance, an HIV transmission cluster was found in Scott County, Ind., where 181 people were diagnosed with HIV from Nov. 18, 2014 to Nov. 1, 2015, 87.8% of whom reported injecting oxymorphone. Nearly 93% of the patients were coinfected with hepatitis C virus (HCV) (N Engl J Med 2016;375[3]:229-239). Clusters like these highlight the risks for reversing the progress made in preventing the spread of HIV, according to Jen Kates, PhD, the vice president and director of Global Health and HIV Policy at the Kaiser Family Foundation in Washington, D.C. “While the share of HIV infections associated with injection drug use has declined dramatically since the beginning of the HIV epidemic—which is a major success in the fight against HIV—the 2015 outbreak drove an increase,” she said. “This highlights the intersection of the two epidemics and the fragility of success, particularly in the absence of access to syringe exchange and other prevention services that can curb transmission.” According to UNAIDS, about 12.7 million people inject drugs worldwide, and more than 10% are also living with HIV.

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“Injection drug use was a significant contributor to HIV transmission in the U.S. in the 1980s and early 1990s,” said Bluthenthal, so it stands to reason that it would continue to be a risk factor with the opioid epidemic (Drug Alcohol Depend 2018;185:253-259). “We are likely to have more cases of HIV due to drug injection, and these cases are likely to occur in areas such as rural communities with inadequate HIV prevention services and HIV care services,” he said.

An Intertwined ‘Syndemic’ “The opioid and HIV epidemics are unassailably intertwined into a ‘syndemic’,” agreed Nabila El-Bassel, PhD, a professor at the Columbia University School of Social Work, in New York City. “The availability of opioids is ubiquitous, both through misuse of prescribed opioid pharmaceuticals and illicit drugs. This has led more individuals to inject and share needles and syringes; thus, more people have become infected with HIV.” In many of the areas hardest hit, harm reduction programs such as needle exchange programs are scarce. “The geographic spread of new people who inject drugs is an independent problem in and of itself,” Bluthenthal added. “Many regions hit with these increases missed the advent of syringe exchange programs that were implemented locally in major cities and regions. These programs are generally credited with the overall reductions in HIV transmission among people who inject drugs, particularly in the Northeast. The political will to implement this program in the face of poor federal support is modest, and several programs that were

started have already been stopped in West Virginia and Indiana.” In addition, he said, the program models do not embrace best practices such as the delivery of safer injection supplies to participants, needle-exchange programs and extended hours. Also, the emergence of fentanyl as a popular substitute for heroin is increasing injection-related risks due to its shorter half-life. “People who inject fentanyl inject eight or more times a day instead of the typical two to four times a heroin user might inject,” El-Bassel added. “By injecting more frequently, users of fentanyl have a greater likelihood of sharing needles/syringes. This behavior and others associated with HIV risks such as trading sex for drugs, money or a place to sleep all lead to new HIV infections.” And a recent report from the National Institute of Drug Abuse found that methamphetamine use and deaths have also increased, especially among Native Americans and Alaska Natives. Many of the same infections seen in opioid abusers occur in methamphetamine users (JAMA Psychiatry 2021 Published online Jan. 20 DOI: 10.1001/jamapsychiatry.2020.4321). Methacillin-resistant Staphylcococcus aureus is also a problem (Frontiers in Neuroscience 2015;8:445 doi: 10.3389/fnins.2014.00445).

Unique Challenges The characteristics of IV drug users often complicate treatment approaches, and provide a challenge for health care professionals attempting to address both HIV and drug abuse. “Injection drug users tend not to be linked to substance abuse treatment or medical care and are unlikely to seek HIV testing,” El-Bassel said. “They become a community of individuals with unknown HIV status whose drug using and sexual behaviors are capable of turning them into a vector and transmitting the HIV virus to others.” This, according to Bluthenthal, increases the importance of quickly getting these individuals appropriate treatment. “Rapid implementation of medication treatment, such as buprenorphine, methadone and naltrexone, is needed to both prevent HIV spread and assist with engagement in HIV treatment,” he said. Equally important is managing factors that may make adherence to HIV therapy harder for patients abusing opioids. “It is in patients’ best interests that providers work with them to increase antiretroviral therapy (ART) adherence, as well as adjust therapeutic doses to improve HIV-related outcomes,” El-Bassel commented. “Opioid use should not be considered a contraindication to ART.” Medications for opioid use disorder (MOUD), such as buprenorphine and naltrexone, have been shown to improve adherence to ART and increase viral suppression (Curr HIV/ AIDS Rep 2019;16[1]:1-6). “Strategies that integrate MOUD into HIV care are critical to achieving HIV viral suppression among

patients living with HIV and opioid use disorder,” El-Bassel said. And the nature of addiction itself may change the way patients approach adherence. “When individuals have cooccurring HIV and an addiction to substances, such as opioids or methamphetamine, nothing else matters but the drug,” said Susanne Astrab Fogger, DNP, a professor in the School of Nursing at the University of Alabama at Birmingham. “Their brain has been hijacked, with the drug being the priority. Medication adherence, which is vital to viral suppression, is lost in the addiction.”

1 in 10 new HIV infections is among people who inject drugs. Source: CDC

A Governmental Failing and Need for Response For some experts, the greatest failing has been in the government’s response to the threat. “I lament this country’s failure to fully understand and integrate the management of HIV care and drug treatment into primary care for people with HIV and opioid use disorders,” El-Bassel said. “Injection drug users who are living with HIV have very limited access to opioid use treatment. Attempting to retain patients with opioid use disorders who are not receiving opioid treatment combined with their HIV care remains serious, and needs attention.” El-Bassel noted that “the opioid and HIV syndemic share major structural drivers such as poverty, economic inequities, health disparities, a lack of integrations of services, and a market-driven health care system with poor access to health care insurance, and a lack of rules and regulations for pharmaceutical market placement. “Each of these drivers limits access to drug treatment, HIV services and care, and continue to heighten the spread of the syndemic,” she said. Appropriately addressing these challenges will require programs designed with the intersection of opioid abuse and infectious diseases in mind. “To ultimately reduce HIV transmissions and opioid use disorders, the U.S. health care system, and the government programs that finance it, need to have a major paradigm shift to address both of these comorbidities, at the same time with a comprehensive assessment of the individual patient’s treatment needs, and provide treatment for the comorbidities through accessible integrated community-based medical and n drug treatment services,” El-Bassel added. The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

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lthough deaths associated with fungal diseases have decreased significantly over the last 20 years, they are beginning to increase again, according to a CDC study.

In addition, a new look at fungal disease mortality trends shows that deaths related to fungal infections are likely undercounted across the United States, according to epidemiologists at the CDC. “Historically, viruses and bacteria have had the spotlight in infectious diseases, and fungal diseases have taken a back seat,” said Mitsuru Toda, PhD, an Epidemic Intelligence Service officer in the CDC’s Mycotic Diseases Branch. During 1980 through 1997, fungal disease deaths increased four times, but there is scant information about deaths after a 2001 report (Clin Infect Dis 2001;33[5]:641-647. doi: 10.1086/322606). “We wanted to pick up where the previous study left off to examine the mortality trends in the past 20 years from 1999 to 2018,” Toda explained. Toda and her colleagues reviewed death certificate data gathered by the National Center for Health Statistics and analyzed fungal disease–associated mortality trends during 1999-2018. Records that had any mention of fungal disease were extracted. The investigators specifically looked for aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, pneumocystosis, unspecified mycoses and other mycoses. They also looked at 12 concurrent conditions that are frequently affected by fungal coinfections: chronic obstructive pulmonary disease, diabetes, hematologic and solid organ malignancies, HIV, immune-mediated inflammatory disease, influenza, neutropenia, opioid-related conditions, pneumonia, and solid organ and stem cell transplantation. “This is one of the largest studies looking at data on fungal disease mortality trends in the U.S.,” said Tom M. Chiller, MD, the chief of the Mycotic Diseases Branch at the CDC. In total, the researchers reviewed information on more than 50 million deaths that occurred during the study period. They found 90,772 people, or one in 500 deaths, had one or more fungal diseases listed on the death certificate as a contributing cause of death—an average of 4,539 deaths annually. Of those with fungal disease–related mortality, 28% had a fungal disease as the underlying cause of death (ID Week 2020 Virtual, oral abstract 148). Nationally, the rate of fungal disease mortality declined dramatically from 2.2 per 100,000 population in 1999 to 1.2 per 100,000 in 2013, a decrease of 44%. The steepest decline was

seen in infants younger than 12 months of age: The mortality rate in this group fell by 83% over the 20-year survey period. Overall, Chiller noted that the decline was probably the result of “improvements in infection control strategies, prophylaxis, antifungal treatment and improved HIV treatment.” However, since 2013, the trend has reversed, with fungal disease mortality rates rising by 17%. “Although mortality rates declined substantially in the 2000s, they have increased modestly in recent years,” Toda said. “More study is warranted to examine what may be driving the recent increases.” The highest mortality rates were listed as “unspecified mycoses,” and Toda admitted they are not sure what that means, but it is not uncommon for physicians to list unspecified fungal disease in their records, she said. Candidiasis and aspergillosis were the second- and third-leading causes of fungal deaths, Toda said. Rates of coccidioidomycosis, while generally low, have fluctuated greatly over the past 20 years, and have risen strikingly from a low in 2015. “The reasons for the possible changes in coccidioidomycosis deaths are not well understood,” Chiller said. “However, the recent increase in mortality parallels increases in reported cases according to national surveillance data.” Fortunately, the mortality rates for histoplasmosis and blastomycosis were much lower, Toda said. Generally, both Toda and Chiller cautioned that fungal diseases are likely underreported. Fungal disease diagnosis can be difficult; death certificates frequently mention only a vague “unspecified mycoses”; and autopsy rates in the United States are low, being conducted in an average of 7% of annual deaths, so they are less likely to be found postmortem. “Given the issues that fungal diseases are often misdiagnosed or not diagnosed at all, that training on death certificates may be limited, and that autopsies are not done routinely, we do not actually know what the true death burden may be,” Chiller said. “We believe fungal disease mortality is higher than what we report in the study.” In addition to attempts to better determine the number of fungal disease–related deaths, Toda stressed the need to prevent future fungal infections, as well as better treatment for existing infections. “Better prevention, diagnosis, treatment and awareness are important to reduce fungal disease n mortality.” The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Long Haulers continued from page 14

neurologists, rehabilitation medicine specialists, etc. The initial workup includes a thorough physical examination looking for organic explanations for the symptoms, Ostrosky-Zeichner explained. Blood work is typically done to review renal and liver function, among other things, and then other tests are ordered based on the presentation. “It’s fairly important not to assume that everything is due to COVID,” Gandhi reminded, “and to make sure you have an open mind as to what else might be causing this.” Bell agreed. “You can never take a presentation of a patient and divorce it from who the person is and what their environment and context is. So, [for] every single person who comes in, whether they have COVID or they don’t have COVID, it is very important to put that person into context of who they were before, what their premorbid conditions were and what the context of their lives are,” she said. “I like to work up the specific symptoms if it seems appropriate,” Navis added. “So, for example, I will do blood work to look for potential causes that could be contributing. If there are more severe deficits with the neuropathy, for example, I might get nerve conduction studies.” If someone has vascular risk factors, some imaging might be in order, she added. “I do like to get cognitive testing for everybody.”

Then other tests will depend on the symptoms. For instance, if the concern is headaches and brain fog, MRI might be done to look for inflammation or ischemia. Cardiopulmonary issues might require chest radiographs, CAT scans, an echocardiogram or pulmonary function test. This is one reason why it helps to have a team of specialists available for consultation, they said. Regardless of the reasons that bring the patient to the office or clinic, there is no cure for post–COVID-19 syndrome, but there are medications that can be prescribed to help alleviate some of the symptoms. These need careful consideration, according to Navis. For instance, if a person is suffering from depression and posttraumatic stress disorder and can’t sleep, a drug that might be sedating might be considered, but it might not be appropriate for someone who reports depression and fatigue. This is where a pharmacist could play an important role on the team, ensuring that the medications subscribed by various specialists work together to improve the situation, Mashni said. Some of the best medicine, Gandhi said, is to listen to patients and understand what they are going through as they try to put their lives back together. “We need to take this seriously,” he added. “Many millions of people have been infected. Many will resolve on their own, n but not all of them will, and we need to help them.” The sources reported no relevant financial disclosures.

Post–COVID-19 Syndrome: Can It Be Prevented? The challenges to treating post–COVID19 syndrome are many because there is no clear consensus definition for it, no treatment, not even a clear line from severity of illness to manifestation or duration of symptoms. One of the research questions that many would like to see answered is whether one could predict, based on the clinical course of the original disease, who would develop sequelae, and how to prevent it. For instance, if monoclonal antibodies can prevent severe disease, would they also prevent post–COVID19 syndrome? “Antibodies fundamentally work as antivirals,” explained Rajesh T. Gandhi, MD, FIDSA, an infectious diseases specialist at Harvard and Massachusetts General Hospital, in Boston. “The evidence supports their use

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in early COVID, which is when people are not sick enough to need hospitalization, to keep those at high risk of complications from getting g sicker and prevent them from ending ding up in the hospital.” As to whether preventing venting a hospitalization would prevent event lingering symptoms, “that’s a critical question. I hope so, but u we ut don’t know,” he said. Although most patients nts who present with post– st– COVID-19 have had serierious disease, not all of them have. Luis Ostrosky-Zeichner, i hner, ic MD, FIDSA, an epidemiologist e iologist em at the McGovern Medical edical School, in Houston, called the e idea a good research question, not just for monoclonal antibodies but also so convalescent

plasma and maybe even steroids. “But we are not there, yet,” he said. “We haven’t found the role of the therapeutics that p people p may y have received in the hospital as a prognostic marker of having those COVID symptoms or not,” so it’s hard to say who would benefit from one of these medications as a prophylaxis. However, since most cases involved an ICU stay, keeping people out of the ICU would be a key strategy in preventing more cases, they said. Vaccination could help in the same way.

New Antibiotics Strengthen Arsenal Against complicated IntraAbdominal Infections BY LYNNE PEEPLES

growing number of new antibiotics, including novel beta-lactam and beta-lactamase inhibitors, is adding welcome treatment options for complicated intraabdominal infections (cIAIs). The additions may prove especially valuable in light of a troubling rise in multidrug-resistant (MDR) organisms. cIAIs, defined as infections of the peritoneal space that are associated with either peritonitis or abscess formation, are a common cause of morbidity and mortality in surgical patients. Certain clinical situations can lead to a cIAI, from perforated appendicitis to a postsurgical abscess. And infections are produced by a variety of microorganisms, including both aerobes and anaerobes. “This makes the definition challenging, since it covers a range of heterogeneous causes,” said Jason Gallagher, PharmD, a clinical professor of infectious diseases at Temple University, in Philadelphia. The best management of cIAIs involves early surgery with antibiotics, he explained. Anything surgically drainable needs to be drained, with antibiotics mainly used to “mop up” whatever bugs are left, Gallagher said. David Epstein, MD, a clinical assistant professor of infectious diseases at Stanford University, in Palo Alto, Calif., emphasized the difficulty of treating IAIs without drainage. “Still, antibiotic therapy is critical even if effective drainage is pursued,” Epstein said. Data from clinical trials support short durations of antibiotics—as few as four days— after adequate drainage or source control (N Engl J Med 2015;372[21]:1996-2005). Use of a broad-spectrum single-agent or combination drug

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regimen is the standard for targeting infections caused by both gram-negative bacteria and anaerobes. But the development of antimicrobial resistance has become more serious. MDR organisms are linked with a higher rate of inadequate antimicrobial therapy, which in turn is associated with a higher mortality rate, a longer hospital stay and increased cost (Eur J Clin Microbiol Infect Dis 2019;38[5]:819-827). This trend has raised the urgency of expanding the infectious disease provider’s antibiotic arsenal. The FDA approved several new antimicrobial agents for the treatment of cIAIs, including ceftazidime-avibactam (Avycaz, AbbVie), imipenemcilastatin-relebactam (Recarbrio, Merck) and eravacycline (Xerava, Tetraphase). AbbVie is also investigating the efficacy of aztreonam-avibactam for cIAIs. Another formulation of ceftazidime-avibactam (Zavicefta, Pfizer) also combines an old cephalosporin with a relatively new beta-lactamase inhibitor. The combination of ceftazidime-avibactam has good activity against several gram-negative bacteria, including ceftazidime-resistant strains, as well as against carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta-lactamase (ESBL) producers and Klebsiella pneumoniae carbapenemase. Its activity against anaerobes, however, is marginal, Gallagher noted. So, an additional antibiotic such as metronidazole is needed to target those bacteria. In the phase 3 clinical trial data considered by the FDA for approval of Avycaz, ceftazidime-avibactam plus metronidazole was noninferior to the comparator, meropenem. The researchers looked at 1,058 patients in this multinational, double-blind study. Eravacycline is a broad-spectrum synthetic fluorocycline

antibiotic with activity against CRE and ESBL producers, but not against Pseudomonas aeruginosa. Among its top selling points: It packs a punch against anaerobes, the experts said. Eravacycline is structurally similar to tetracyclines, but has a better tolerability profile. Its approval was based in part on results of the IGNITE (Investigating Gram-Negative Infections Treated with Eravacycline) phase 3 trials. In the first pivotal phase 3 trial in patients with cIAI, twice-daily IV eravacycline met the primary end point by demonstrating statistical noninferiority of clinical response compared with ertapenem. In the second phase 3 clinical trial in patients with cIAI, twice-daily IV eravacycline met the primary end point by demonstrating statistical noninferiority of clinical response compared with meropenem. In both trials, eravacycline achieved high cure rates in patients with gram-negative pathogens, including resistant isolates. Imipenem-cilastatin-relebactam also has strong anaerobic activity on its own. The carbapenem and beta-lactamase inhibitor combination is active against gram-negative bacteria producing ESBLs and K. pneumoniae carbapenemase. Another Merck contender, ceftolozane-tazobactam (Zerbaxa) is a beta-lactam and beta-lactamase inhibitor combination. It has activity against many gram-negative bacteria, including ESBL-producing Enterobacteriaceae. It is also stable against many P. aeruginosa resistance mechanisms but is ineffective against CRE and anaerobes. nd “Ceftazidime-avibactam, eravacycline and ortant imipenem-cilastatin-relebactam are important agents to have available in patients with drug-resistant gramnegative rod infections,” Epstein said. “Aztreonam-avibactam, when it becomes available, will likely fulfill a similar role.” When using ceftazidime-avibactam, aztreonam-avibactam or ceftolozane-tazobactam for cIAIs, Gallagher underscored the importance of adding an antibiotic with activity against anaerobes such as metronidazole. “No matter what, make sure to give therapy that is active against anaerobes,” Gallagher warned. “They are always there.”

ensuring that therapies are “active against both aerobic and anaerobic bacteria causing infections of the abdominal tract, where they shouldn’t be.” Enterobacteriaceae, in combination with anaerobes, are the most common culprits in community-acquired cIAIs, while other difficult-to-treat microorganisms such as P. aeruginosa, Staphylococcus aureus, Enterococcus and Candida often drive hospital-acquired cIAIs. The 2010 Infectious Diseases Society of America’s IAI guidelines are being revised. Yet, much of the old guidelines remain accurate, according to Epstein (https://www. idsociety.org/practice-guideline/intra-abdominal-infections/). Treatment with cefazolin, cefuroxime or ceftriaxone is still reasonable for mild community-acquired cholecystitis, an inflammation of the gallbladder. Metronidazole or other agents with robust anti-anaerobic activity are not mandatory in this case. Other IAIs, however, should be treated with agents that target gram-negative anaerobes. For mild to moderate communityacquired IAIs, reasonable choices include one of the cephalosporins with metronidazole, according to Epstein. And for patients with nosocomial infections, or who have risk factors for clinical deterioration or severe illness, he recommended using agents active against drug-resistant gram-negative rods and P. aeruginosa. Piperacillin and tazobactam, a combination penicillin antibiotic, and meropenem, a broad-spectrum carbapenem antibiotic, are am among the best options. Ove Overall, choosing the appropriate antibiotics depends on patient-specific factors, including severity of illness and risk factors for MDR organisms. Patients with recent antibiotic exposure or those with extensive health care contact are more likely to be colonized with—and, therefore, develop infections from—MDR organisms, including vancomycin-resistant Enterococcus and MDR gram-negative rods. Antimicrobial stewardship programs can bolster both the appropriate treatment for patients and the preservation of antibiotic effectiveness. Furthermore, effective infection control practices can prevent the transmission of antibioticresistant bacteria. “Generally, to minimize development of drug-resistant organisms, antibiotics should be targeted to those organisms either cultured or reasonably expected to be present in the infection,” Epstein said. “Some organisms are n more virulent than others.”

cIAIs are a leading cause of emergency surgery and ICU admission.

Friend and Foe The human gastrointestinal tract contains five to 10 times as many bacteria cells as human cells. “They are happy copatriots of ours the vast majority of the time,” Gallagher said. “But if they access another site, that’s when things go wrong.” Most of the time, he explained, people become infected with their own flora. Escherichia coli and other anaerobe species in the gut flora need to be treated. Gallagher advised

Gallagher reported receiving research funding from Allergan, Merck and Tetraphase. Epstein reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

Innovative Microbiome-Based C. difficile Treatments in the Pipeline BY DAVID WILD

ecal microbiota transplantation (FMT) has unarguably changed the landscape of Clostridioides difficile infection (CDI) management. Now, in its wake is a drug pipeline replete with promising microbiome-based treatments aimed at overcoming some of the safety and logistical challenges of FMT, experts told Infectious Disease Special Edition. “Based on the initial success of FMT, the therapeutic world of the microbiome is exploding,” said Kevin Garey, PharmD, MS, a professor and the chair of the Department of Pharmacy Practice and Translational Research at the University of Houston College of Pharmacy. With a treatment success rate of up to 96% for the management of recurrent CDI (Am J Health Syst Pharm 2019;76[13[:935-942. doi: 10.1093/ajhp/zxz078), FMT has “dramatically improved the lives of patients with CDI, especially those with recurrent CDI,” Garey said.

Downsides of FMT However, Garey noted there are disadvantages to FMT. “Use of fecal samples has always made this procedure somewhat unpalatable. More importantly, although stool samples can be screened for certain known pathogenic bacteria, there is the possibility of other pathogenic bacteria being present in the samples.” Indeed, a report described two patients who received FMT in two separate clinical trials for hepatic encephalopathy (N Engl J Med 2019;381:2043-2050. doi: 10.1056/NEJMoa1910437). Both patients experienced bacteremia after exposure to extendedspectrum beta-lactamase (EBSL)-producing Escherichia coli through FMT, leading to death in one case. In both trials, donor stool was screened according to an FDA-approved protocol. The second generation of microbiome products now in the pipeline should reduce the potential for transmission of undetected pathogens by using standardized stool collection and processing protocols, according to Garey. “In some cases, these treatments use very specific bacterial consortia or individual organisms,” he explained.

Agents on the Horizon One experimental agent is RBX2660 (Rebiotix, a Ferring company), a microbiota suspension treatment packaged for rectal administration that includes a broad grouping of humanderived microbiota. In a phase 2, randomized trial including 107 patients with recurrent CDI, the treatment prevented

IDSE.NET

More attention is being paid to the microbiome. further recurrence in 67% of patients, compared with 46% of those given placebo. These results were presented at the 2016 annual meeting of the American Gastroenterological Association. The findings prompted the FDA to award the treatment orphan drug status, fast track status and breakthrough therapy designation in 2015, and a phase 3 study is now underway. The company is also developing an oral formulation of the microbiota product. An oral treatment in the pipeline is SER-109 (Seres Therapeutics), which includes a narrower range of microorganisms, in this case purified bacterial spores of multiple Firmicutes spp derived from human stool. Unpublished phase 3 results released by the manufacturer, including over 180 patients with multiply recurrent CDI, found that eight weeks of treatment led to an absolute decrease of 30% in CDI recurrences, compared with placebo. “By administering this immediately after antibiotic treatment, these nontoxigenic spores colonize the intestines before toxigenic C. difficile can take hold,” said Dale Gerding, MD, a C. difficile researcher who was previously the associate chief of staff for research and development at the Hines VA Hospital, in Illinois. Gerding himself has invented a microbiome-based treatment for CDI: an oral product using spores from a nontoxigenic strain of C. difficile (NTCD-M3, Destiny Pharma). In a multicenter, phase 2 study of NTCD-M3 involving 168 participants, 11% of patients with recurrent CDI who received the treatment experienced another recurrence, compared with 30% of placebo recipients (JAMA 2015;313[7]:1719-1727. continued on page 40

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Update on CMV Management In Transplant Patients Prophylaxis is paramount, and surgeons should be aware of atypical presentations and the emergence of CMV-associated infections BY CONNI BERGMANN KOURY

s one of the most common opportunistic infections in immunocompromised people, cytomegalovirus (CMV) is an important cause of morbidity and mortality, and it continues to represent a management challenge for solid-organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) patients.

IDSE.NET

CMV is a ubiquitous DNA virus that infects about half of the U.S. population (Clin Infect Dis 2010;50[11]:1439-1447). There is no cure, so current treatment strategies encompass identification and management. “For most people infected, CMV is dormant,” said Raymund R. Razonable, MD, the vice chair of the Division of Infectious Diseases, William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, Minn. “Immunocompromised SOT and bone marrow transplant patients lack the ability to suppress the virus, allowing it to reactivate and cause infection and illness,” he added. The American Society of Transplantation Infectious Diseases Community of Practice has described evidencebased and expert recommendations for screening, diagnosis, prevention and treatment of CMV in SOT (Clin Transplant 2019;33[9]:e13512). The European Conference on Infections in Leukaemia has issued guidance for HSCT recipients (Lancet Infect Dis 2019;19[8]:e260-e272). “For the SOT recipient, the greatest risk is in the immunologically naive person, who receives an organ from a seropositive individual with latent infection,” said Jay A. Fishman, MD, the director of the Transplant Infectious Diseases and Compromised Host Program and associate director of the Mass General Transplant Center at Massachusetts General Hospital, and a professor of medicine at Harvard Medical School, in Boston. “They receive a ‘dose’ of the virus with the transplanted organ in the setting of prescribed immunosuppression,” he said. Antiviral drugs, most commonly valganciclovir or IV ganciclovir, are used to treat transplant patients who develop CMV disease. Individuals who do not yet have an active infection are managed based on their perceived risk for infection, and transplant induction and maintenance therapy play key roles in determining this risk. Prophylaxis comprises the management approaches. “Antiviral prophylaxis is the practice of giving antiviral drug after transplantation for a defined period, usually at least three months, but it can be longer depending on the organ type,” Razonable said. “Most commonly, oral valganciclovir is used for SOT recipients and letermovir [Prevymis, Merck] for allogeneic bone marrow transplant patients.” With preemptive therapy, antiviral drugs are given only when there is evidence of virus in the blood. “These patients need weekly CMV testing, typically via a polymerase chain reaction method. Once the virus is detected, then valganciclovir is administered,” Razonable noted.

Disease Presentation Without a prophylactic strategy, CMV presents more frequently during the first three to six months after SOT (Clin Transplant 2019;33[9]:e13512). This is the window during which immunosuppressive therapy is the most intensive. When prophylaxis is given, delayed disease can manifest, the experts said.

In transplant patients on immunosuppressive therapy without prophylaxis, particularly with induction therapy that includes T-cell-depleting agents, the rate of infection is anywhere from 66% to 75%, Fishman noted. In patients receiving an organ who have had CMV, the risk for infection is lower, ranging from 25% to 30% (Clin Transplant 2007;21[2]:149-158). “A small 4% risk exists when a CMV-negative organ is transplanted in a CMV-negative person. In these cases, individuals can acquire CMV through sexual/social contact or via blood transfusions,” he said. The risk for CMV illness is much lower in the setting of costimulatory blockade. Of note, symptoms from CMV-related illness are different in SOT and HSCT patients versus immunocompetent individuals. In the normal population, CMV has a similar presentation to an infectious mono-like illness with leukopenia and lymphopenia. Muscle aches and elevated liver function tests are typical, and some pneumonia or other types of infection can occur. “In the immunocompromised host, we see a lot of colitis and some hepatitis, although fever and relative neutropenia is the standard for CMV presentation,” Fishman said. Donor-positive and recipient-seronegative patients can have minor to severe infection when prophylaxis is stopped, and therefore require monitoring. CMV infection is immunosuppressive, and in SOT patients, it predisposes individuals to other infections and secondary effects. “Specifically, CMV can activate other latent infections in all transplant types and cause an inflammatory syndrome that can contribute to graft rejection,” Fishman said. “Late CMV disease in the stem cell transplant population can lead to graft-versus-host disease.” Diagnostic and therapeutic approaches serve to mitigate these risks; however, ganciclovir-resistant CMV is a possibility. Secondary antiviral agents are not as successful at fending off toxicities. “Ultimately, prevention is always much better than treatment because patients do not have to suffer through disease and the associated costs of therapy,” Fishman said.

Difficult and Atypical Patients Patients who do not tolerate prophylaxis due to the associated neutropenia, and those with atypical presentations of disease, are more difficult to treat. “People who develop CMV colitis or pneumonitis can be a management challenge, and they can develop a variety of super infections. Diagnosis and treatment of those infections is more complicated,” Fishman said. Patients on belatacept (Nulojix, Bristol-Myers Squibb) therapy can often have atypical CMV presentations as well as EpsteinBarr virus, causing post-transplant lymphoproliferative disorders. The virus can reemerge when allodepletion, IV bolus, or other intensification of underlying immunosuppression treatment is being used to manage graft rejection. “Because it was shown to be useful in preventing long-term graft injury from calcineurin inhibitors, belatacept is increasingly common in the renal transplant population,” Fishman said.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

CMV management can be challenging for surgeons partly due to just how common it is: They should not let their guard down, and an ID consult might be warranted. “It’s an important infection,” he said. “It may be less well known that because of immune suppression for CMV, other infections can appear, for example, pneumocystis pneumonia, Aspergillus infection, as well as community-acquired infections like hepatitis viruses.”

Notes on Drugs If there is resistance to IV ganciclovir or oral valganciclovir, physicians might have to use cidofovir or foscarnet, Fishman said. “These drugs have been useful in many of our resistant patients, but they have accompanying toxicities that are significant.” Side effects associated with CMV prophylaxis “are real,” with decreased white blood cell (WBC) counts being common, according to Elizabeth A. Cohen, PharmD, a senior transplant data administrator at Yale New Haven Hospital, in Connecticut. Rather than reducing doses, which can lead to resistant CMV, physicians should treat through or stop therapy completely and start monitoring. “The biggest thing to be aware of is that you cannot dose-reduce for side effects because that can lead to resistant and breakthrough CMV,” she emphasized. Antiproliferative agents also reduce WBC counts, causing additive pharmacodynamic effects when paired with valganciclovir. “The compounded effect can be tricky to treat through,” Cohen said. “It is also important to note that valganciclovir increases the risk for fetal abnormalities, and CMV itself is associated with severe birth defects.” Letermovir also carries a risk for fetal abnormalities, albeit not quite as high as with valganciclovir, she said. “Post-transplant patients trying to conceive must be counseled on this adverse effect,” she noted. “Some of the other medications, like the antiproliferatives, also cause birth defects. We instruct patients to use birth control methods to avoid becoming pregnant while they are on these therapies.” Even when CMV infection does not cause systemic illness, it can present in other ways, for example, graft rejection in kidney transplants and accelerated atherogenesis in transplanted hearts. “In transplanted lungs, patients can develop chronic lung allograft dysfunction that diminishes the transplanted organ’s survival,” Fishman said. “Injuries to and a loss of bile ducts may be seen in liver transplants. HSCT patients can experience CMVcaused rejection, in addition to colitis, pneumonitis and other forms of disease.” Recent drug advances and reliable quantitative molecular diagnostics with rapid turnaround boost effective and more efficient n management of CMV in transplant patients, they said. Fishman reported a relationship with Astellas Pharma, Biogen IDEC, Gilead Pharmaceuticals, Hoffmann-La Roche, Merck, Primera, ViroPharma, Pfizer, and Schering-Plough Primera. Razonable reported relationships with Roche, Merck and Novartis. Cohen reported no relevant financial disclosures.

IDSE.NET

C. diff Impact continued from page 36

doi: 10.1001/jama.2015.3725). The recurrence rate in the treatment group fell to 5% at the most successful dose, and the findings led to fast track status from the FDA. “NTCD-M3 also possibly has a role in preventing CDI in the first place in high-risk patients, if given prophylactically during hospitalization,” Gerding said, noting the agent has not been studied in this way.

Long-Term Effects Unknown Vincent Young, MD, PhD, a professor in the Department of Internal Medicine, Division of Infectious Diseases at the University of Michigan, in Ann Arbor, said building a microbial treatment “from the bottom up theoretically means you know what it contains. “However, we still don’t necessarily know how these microbes will affect the microbiota—and, subsequently, the host—in the long run, so there is the potential for longer-term side effects,” Young said. In the meantime, he said until there is an efficacious defined microbial consortium, FMT remains an attractive option for recurrent CDI treatment because of its low cost, ready availability and effectiveness.

Third-Generation Treatments According to Garey, a longer range forecast for microbiome-based CDI treatments could include therapies that “go beyond the microorganism to the metabolites that the organisms are producing to provide their beneficial effects. “This third generation of therapeutics is theoretical at the moment, but will eventually allow for personalized medicine for human and microbial health,” Garey said.

The Pharmacist’s Role As the microbiome therapeutics pipeline grows, pharmacists will play “an outsized role” in the development and administration of these emerging treatments, Garey noted. “For example, the pharmacokinetics and pharmacodynamics of the microbiome as it relates to health and disease is poorly understood, and pharmacists have the expertise to shed light on these topics,” he said. “And from proper dosing to proper storage conditions, the skill of the pharmacist will play a vital role in establishn ing these emerging therapies.” Garey and Young reported no relevant financial disclosures. Gerding has licensed the NTCD-M3 technology to Destiny Pharma.

with CABENUVA, the ﬁrst and only, once-monthly, long-acting, complete injectable treatment regimen for virologically suppressed adults living with HIV-1.1* Michael, living with HIV.

Michael has been compensated by ViiV Healthcare. *Prior to initiating treatment with CABENUVA, prescribe cabotegravir 30-mg and rilpivirine 25-mg oral tablets, both taken once daily with a meal, for approximately 1 month (at least 28 days) to assess tolerability.1 HIV-1=human immunodeficiency virus type 1.

INDICATION

IMPORTANT SAFETY INFORMATION

CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

CONTRAINDICATIONS • Do not use CABENUVA in patients with previous hypersensitivity

Please see additional Important Safety Information for CABENUVA throughout. Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

reaction to cabotegravir or rilpivirine

• Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort

INTRODUCING CABENUVA ONCE-MONTHLY TREATMENT HAS ARRIVED First and only, once-monthly, complete treatment regimen for HIV-11 CABENUVA is for virologically suppressed adults living with HIV-1.*†

Proven as effective as continuing a daily oral regimen1,2† Primary endpoint: proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 via FDA Snapshot Algorithm. Proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 in pooled analysis was 2% for CABENUVA vs 2% for daily oral comparator (non-inferior treatment difference: 0.2% [95% CI: -1.4, 1.7]).

Preferred by 9 out of 10 patients in clinical trials2-4 In an exploratory endpoint in ATLAS and FLAIR Phase 3 clinical trials, patients completed a single-item question assessing their preference for CABENUVA vs their previous oral regimen.† At Week 48, 88% (523/591) of ITT-E population preferred CABENUVA vs 2% (9/591) who preferred their previous oral regimen†; 59 patients did not respond to the question. These results are descriptive in nature and should not be used to infer clinical signiﬁcance.

Adverse Reactions1 The most common adverse reactions (Grades 1–4) observed in ≥2% of subjects receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. *HIV-1 RNA <50 copies/mL.1 Based on a pooled analysis from two Phase 3, international, randomized, non-inferiority trials (ATLAS and FLAIR) in virologically suppressed (HIV-1 RNA <50 copies/mL) adults ≥18 years with HIV-1.1-4 In ATLAS, 616 treatment-experienced, virologically suppressed (for ≥6 months) patients on 2 NRTIs + an INSTI, NNRTI, or PI were randomized 1:1 to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current therapy.1,3 In FLAIR, patients without previous ARV exposure were given ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive) for 20 weeks to achieve suppression and then randomized 1:1 (N=566) to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current regimen.1,4 At baseline, in FLAIR and ATLAS, the median age was 34 and 40 years, respectively.1 In both studies, 7% had CD4+ cell count <350 cells/mm3.1 In ATLAS, baseline third-agents were 50% NNRTIs, 33% INSTIs, or 17% PIs.1 Patients were excluded if they were pregnant or breastfeeding, had moderate to severe hepatic impairment, or evidence of HBV infection at screening.3,4 Non-inferiority of CABENUVA would be shown if the upper bound of the 95% CI for the treatment difference was <6% for the individual studies or <4% for the pooled analysis.2-4

†

3TC=lamivudine; ABC=abacavir; ARV=antiretroviral; CI=confidence interval; DTG=dolutegravir; FDA=Food and Drug Administration; HBV=hepatitis B virus; HLA-B=human leukocyte antigen complex B; INSTI=integrase strand transfer inhibitor; ITT-E=intent-to-treat efficacy; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

References: 1. CABENUVA [package insert]. Research Triangle Park, NC: ViiV Healthcare; 2021. 2. Overton ET, Orkin C, Swindells S, et al. Monthly long-acting cabotegravir and rilpivirine is noninferior to oral ART as maintenance therapy for H I V -1 infection: week 48 pooled analysis from the phase 3 ATLAS and FLAIR studies. Poster presented at: 10th IAS Conference on HIV Science: July 21-24, 2019; Mexico City, Mexico. Poster MOPEB257. 3. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. 4. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: • Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries • Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA

• Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction Post-Injection Reactions: • Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection • Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated Hepatotoxicity: • Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors • Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations • Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected Depressive Disorders:

• Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual products • Promptly evaluate patients with depressive symptoms Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: • The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) • Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

Long-Acting Properties and Potential Associated Risks with CABENUVA: • Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance • To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible

ADVERSE REACTIONS The most common adverse reactions (incidence ≥2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

DRUG INTERACTIONS • Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA, or EDURANT

• Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended • Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine • CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

USE IN SPECIFIC POPULATIONS • Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established • Lactation: The CDC recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA

Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

Visit CABENUVAhcp.com

BRIEF SUMMARY

CABENUVA

(cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use

The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS CABENUVA is contraindicated in patients: ∞ with previous hypersensitivity reaction to cabotegravir or rilpivirine. ∞ receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response: • Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: Rifabutin, rifampin, rifapentine • Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) • Herbal product: St John’s wort (Hypericum perforatum) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported during postmarketing experience with rilpivirine-containing regimens. Reactions include cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected. Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, see section below. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction. Post-Injection Reactions: In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were reported in less than 1% of subjects and began to resolve within a few minutes after the injection. These events may have been associated with inadvertent (partial) intravenous administration. Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated. Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding long-acting properties of CABENUVA, see section below. Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual drug products. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance. Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral dosage) in healthy adults resulted in mean steady-state Cmax values 4.4-fold and 11.6fold higher than Cmax values associated with the recommended 600-mg dose of rilpivirine extended-release injectable suspension and prolonged the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. See the Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of CABENUVA; review concomitant medications during therapy with CABENUVA. Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance. To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

ADVERSE REACTIONS 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 with rates in the clinical trials of another drug and may not reﬂect rates observed in practice. The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS. Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety proﬁle of CABENUVA. Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure: 54 weeks) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine. The most common adverse reactions regardless of severity reported in greater than or equal to 2% of adult subjects in the pooled analyses from FLAIR and ATLAS are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group discontinued due to adverse events. Non-injectionsite-related adverse events leading to discontinuation and occurring in more than 1 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence less than 1%). Table 3. Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses) Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

All Grades

At Least Grade 2

All Grades

At Least Grade 2

Injection site reactionsb

83%

37%

Pyrexiac

Fatigued

<1%

Headache

<1%

Musculoskeletal paine

<1%

Nausea

<1%

Sleep disordersf

<1%

Dizziness

<1%

Rashg

<1%

Adverse Reactions

Adverse reactions deﬁned as “treatment-related” as assessed by the investigator. See Injection-Associated Adverse Reactions for additional information. c Pyrexia: includes pyrexia, feeling hot, chills, inﬂuenza-like illness, body temperature increased. d Fatigue: includes fatigue, malaise, asthenia. e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity. f Sleep disorders: includes insomnia, poor quality sleep, somnolence. g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular. b

Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): The most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs were reported. One percent (1%) of subjects discontinued treatment with CABENUVA because of ISRs. Most ISRs were mild (Grade 1, 75%) or moderate (Grade 2, 36%). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized pain/discomfort (79%) regardless of severity or relatedness. Other manifestations of ISRs reported in more than 1% of subjects over the duration of the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in less than 1% of subjects. The median duration of ISR events was 3 days. Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects receiving current antiretroviral regimen. No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) injection. Reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection. Vasovagal or pre-syncopal reactions were reported in less than 1% of subjects after injection with rilpivirine or cabotegravir. Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in less than 2% of subjects receiving cabotegravir plus rilpivirine. Gastrointestinal Disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and ﬂatulence. Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams. Skin and Hypersensitivity Reactions: Hypersensitivity reactions. Weight Increase: At Week 48, subjects in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in subjects receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg in the ATLAS trial in subjects receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively. Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 4. Table 4. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled Analyses) in FLAIR and ATLAS Trials

Laboratory Parameter

Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

ALT (*5.0 x ULN)

<1%

AST (*5.0 x ULN)

<1%

Total bilirubin (*2.6 x ULN)

<1%

Creatine phosphokinase (*10.0 x ULN)

Lipase (*3.0 x ULN)

ULN = Upper limit of normal.

Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) micrograms/ dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) micrograms/ dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information. Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving an oral rilpivirine-containing regimen. Because these reactions are reported 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. Renal and Genitourinary Disorders: Nephrotic syndrome. Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions, including DRESS. DRUG INTERACTIONS Concomitant Use with Other Antiretroviral Medicines: Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of CABENUVA. Potential for Other Drugs to Affect CABENUVA: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir: Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1

or 1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated. Rilpivirine: Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA 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 CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. QT-Prolonging Drugs: At mean steady-state Cmax values 4.4-fold and 11.6-fold higher than those with the recommended 600-mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. Established and Other Potentially Significant Drug Interactions: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Information regarding potential drug interactions with cabotegravir and rilpivirine is provided below. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response. The following includes potentially significant interactions but is not all inclusive. ∞ Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin— coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterials: rifampin, rifapentine—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterial: rifabutin—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Herbal product: St. John’s wort (Hypericum perforatum)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Macrolide or ketolide antibiotics: azithromycin, clarithromycin, erythromycin— macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. ∞ Narcotic analgesic: methadone—no dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. Drugs without Clinically Significant Interactions: Cabotegravir: Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine. Rilpivirine: Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CABENUVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drugassociated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to CABENUVA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Cabotegravir use in pregnant women has not been evaluated. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) gestation. In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data). No adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD (see Data). Clinical Considerations: Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on CABENUVA during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Data: Human Data: Cabotegravir: Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Rilpivirine: Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 170 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and second/third trimester exposures, respectively compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. Refer to the prescribing information for EDURANT for additional information on rilpivirine. Animal Data: Cabotegravir: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/ kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/ kg/day (greater than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) and no drug-related fetal malformations were observed at any dose. Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue. Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the RHD. Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known if the components of CABENUVA are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, cabotegravir and rilpivirine were present in milk (see Data). If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), (3) adverse reactions in a breastfed infant similar to those seen in adults, and (4) detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA, instruct mothers not to breastfeed if they are receiving CABENUVA. Data: Animal Data: Cabotegravir: Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study. Rilpivirine: Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on Lactation Day 7 in the rat pre- and postnatal development study. Pediatric Use: The safety and efficacy of CABENUVA have not been evaluated in pediatric patients. Geriatric Use: Clinical trials of CABENUVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently

from younger subjects. In general, caution should be exercised in administration of CABENUVA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than 15 mL/min), increased monitoring for adverse effects is recommended. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. Hepatic Impairment: Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown. OVERDOSAGE There is no known specific treatment for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery.

Manufactured for:

CABENUVA and VOCABRIA are trademarks owned by or licensed to the ViiV Healthcare group of companies. The other brand listed is a trademark owned by or licensed to its respective owner and is not a trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not afﬁliated with and does not endorse the ViiV Healthcare group of companies or its products. ©2021 ViiV Healthcare or licensor. CBRADVT190003 January 2021 Produced in USA.

From

Y U

Can Human Deaths From Canine Rabies Be Eliminated? BY ETHAN COVEY

n international goal of eliminating human deaths due to canine rabies by 2030 is a challenging, yet essential benchmark in global efforts to manage the disease, according to experts. A program titled “Zero by 30” has been developed by the United Against Rabies collaboration, a joint partnership of the World Health Organization (WHO), World Organization for Animal Health (OIE), Food and Agriculture Organization of the United Nations (FAO), and Global Alliance for Rabies Control (GARC), to reach that goal. Eliminating the canine rabies virus variant “is absolutely possible, but is a very ambitious goal,” said Ryan M. Wallace, DVM, the deputy director of One Health Office and director of the OIE Reference Laboratory for Rabies at the CDC. “It is a tragedy that rabies, the oldest zoonosis known to mankind, remains a scourge to the present day, still posing a constant danger to human health,” added Thomas Müller, Dr Med. Vet, the laboratory director at the WHO Collaborating Centre for Rabies Surveillance and Research, Institute of Molecular Virology and Cell Biology, FriedrichLoeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, in Germany. “Considering that rabies is entirely preventable and can be controlled at the animal source, it is no longer socially and ethically acceptable that tens of thousands of people are dying from dog-mediated rabies every year, particularly in Africa and Asia,” Müller said. “Therefore, the goal of eliminating human deaths from dog-mediated rabies proclaimed by the United

Against Rabies collaboration cannot be considered important enough.”

The Impact of Rabies Globally, the burden of rabies is devastatingly high. Rabies is estimated to cause nearly 60,000 deaths each year, 98% of which is caused by bites from infected dogs. Currently, the rabies virus exists in 155 countries, with more than 20 known reservoir species, and enzootic canine rabies is found in 122 countries, affecting about half of the world’s population. The annual estimated economic cost of the disease is $8.6 billion. According to Wallace, one of the biggest economic costs is the loss of future earnings from children who died of rabies. Although younger people are not more susceptible to rabies, children are more likely to put themselves in a situation where they may be bitten by an infected animal. “There is also a fear factor where [children] might be afraid to tell parents or other authorities that they were bitten out of fear that they’ll get in trouble or their animals will get in trouble,” Wallace added. “This sometimes results in a higher exposure rate and lower health care–seeking behavior rate.” When discussing rabies elimination, different approaches exist. “There are many different ways we can define this,” Wallace said. “If we’re going to put a global goal out there, we need to be very specific.” Many proposed solutions, such as total elimination of the 15 different lyssaviruses that can cause rabies, are likely impossible. “While we do have tools to address the disease in a lot of

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

ZToY terrestrial mammals, we’re very unlikely to at JFK International Airport from Cairo. Worldwide, Two transporters and one owner retrieved be able to eliminate rabies virus everywhere in the world and in every animal species,” four dogs with planned distribution rabies is the Wallace noted. to people in Connecticut, Maryland and Eliminating the canine virus variant is estimated to Virginia. A fifth dog that traveled separately far more achievable, due to available vacshared the cargo hold, and was housed in cause nearly New Jersey and West Virginia before endcines. In addition, many countries, such as the United States where canine rabies ing up in Washington. One of the dogs died elimination was achieved in 2007, have shortly after landing in the United States succeeded. However, even with the suceach year; and was determined to be rabid. cessful elimination of most canine rabies in Public health officials interviewed this country, rabid domestic dogs (and cats) many people in each state to find who still appear. About 60 to 70 domestic dogs was exposed to rabies virus. The investigaare caused tion also included employees of Border and more than 250 cats are reported rabid each year in the United States, according the Department of Agriculture’s by bites from Protection, to the CDC. (Approximately 5,000 animal Animal and Plant Health Inspection Service, rabies cases are reported annually to the infected dogs. the airline that transported the animals, and CDC, and 90% occur in wildlife. Before the domestic cargo offloading company at 1960, however, most U.S. cases occurred JFK. State health department staff memprimarily after dog bites, which demonstrates the importance bers interviewed caretakers, volunteers and employees associatof animal vaccination.) ed with the rescue groups and veterinary hospital staff members The number of rabies-related human deaths in the United for potential exposure. PEP was finally recommended for two States declined from more than 100 annually in the early 1900s people who had been bitten, including a veterinary technician, to just one or two per year. This decline can be attributed to and several caretakers of the dog (Morb Mortal Wkly Rep MMWR successful pet vaccination and animal control programs, public 2018:67[50];1388-1391). health surveillance and testing, and availability of post-exposure This was not the first case report from Egypt, and in May prophylaxis (PEP) for rabies. 2019, the CDC announced a temporary suspension of dogs entering the country from Egypt. A Continuing U.S. Problem Issues such as false vaccination records highlight the imporDespite the success seen in this country, rabies, including tance of transparent, coordinated action among all countries canine rabies, is still a problem here. From 1960 to 2018, 127 aiming to reach the Zero by 30 goal, the experts said. human rabies cases were reported in the United States, with “With only 10 years to go, action is needed to make a reality roughly one-fourth resulting from dog bites—many received of that ambition,” Müller said. “What we will end up achieving during international travel. by 2030 depends on all stakeholders involved. Achieving this In one case, a woman from Haiti died in a New Jersey hos- goal as best as we can would be a historic milestone in rabies pital after being bitten by a dog while visiting relatives in Haiti. control.” The bite was not severe, so she did not receive medical care. Yet, global success is extremely ambitious, the experts said. Family members and members of the woman’s church con- “This can be achieved through a combination of ensuring peogregation were identified as close contacts in the two weeks ple do appropriate post-exposure health care–seeking behavior, leading up to her death. Three family members and a house while also vaccinating dogs to an adequate level to reduce the guest received PEP. Public health officials also reviewed pos- risk of exposure to people,” Wallace said. sible exposures in the hospital, and 246 hospital staff members “This is absolutely achievable,” he added, noting numerous encountered the woman during emergency department visits pilot programs around the world that have shown this intervenand hospitalization. Ten received PEP (Morb Mortal Wkly Rep tion can be successfully accomplished. MMWR 2012;60[51]:1734-1736). Currently, much effort is built around reactive approaches, Several cases have been reported among rescued dogs, which such as human vaccination and prophylaxis. There is not led to expensive multistate investigations and ultimately ended enough focus on proactive efforts, such as dog vaccinations, with several people receiving PEP. These incidents are typically they said. “The goal by 2030 is very ambitious and poses an due to incomplete or falsified vaccination documents. enormous challenge,” Müller said. “But we all know nothing n Such was the case in 2017 and 2019, when rabies was identi- happens without a deadline. The foundations are laid.” fied in a dog rescued from Egypt and imported to the United States. The dog traveled with several other dogs and arrived The sources reported no relevant financial disclosures.

60,000 deaths 98%

IDSE.NET

How Long Is Long Enough? The Ongoing Saga of Antibiotic Therapy By Glenn Tillotson, PhD, FIDSA, FCCP

argely driven by inappropriate use of antibiotics, antimicrobial resistance continues to rise despite multiple efforts to reverse this process. Inappropriate use not only encompasses the wrong drug for the wrong bug, but also applies to giving too much antibiotic—toxic doses based on pharmacologically high concentrations or giving the antibiotic for too long. The duration of treatment (DOT) has been the subject of recent discussion in which we are reminded that a week is 7 days, as defined by Constantine the Great almost 2,000 years ago, and this is one of the most frequently prescribed periods of antibiotic use.1,2 However, evidence to support this duration is scant. The examination of the most appropriate DOT has been inconsistent. In principle, the ideal DOT would be one that maximizes clinical efficacy while reducing associated risks, such as emergence of resistance, drug toxicities, and Clostridioides difficile infection.

Not a New Idea More than a century ago, Ehrlich advocated the “frapper fort et frapper vite,” or “hit hard and hit fast” philosophy,3 which was included in the World Health Organization recommendations4 20 years ago. The report suggested that clinicians should first prescribe the most pharmacologically potent member of the relevant class for a short period to minimize the development of resistance. Geli et al applied mathematical modeling to better understand the complexities of dosing and DOT.5 They noted that these decisions should be influenced by the dynamics of infection and immunity, stating that a drug should be given for a sufficient period and at a sufficiently high dose; the dose should be above the minimum inhibitory concentration (MIC) but not too high that it’s toxic. Drlica et

al proposed that the drug concentration tion should exceed the MIC value of the firststep mutant in a heterogeneous population, known as the mutant prevention concentration.6 But these decisions do not consider immunity, which is a strong factor in most infections where patients have intact primary and secondary defense mechanisms. Geli et al also considered the effect ffect of drug exposure to the host commenmensal flora and the likelihood of selecting ting antibiotic-resistant strains, which can confer this resistance to pathogenic species.5 Using a series of coupled ordinary differential equations, they hypothesized that the best strategy to combat infections caused by commensal flora was to give a short, aggressive therapy early in the infection to keep the population low enough to allow the immune system to complete the treatment. By imputation of the dynamics of the commensal reservoir, the host immune system, the heterogeneous bacterial population, patient metabolism, and pharmacology, the authors suggest that “shorter duration is usually, but not always, optimal.”5 Gjini et al developed a similar mathematical approach to improve the understanding of short and long antibiotic therapy in relation to the timing of antibiotic treatment initiation; the model is based on 16 parameters including the growth rate of the bacteria, fitness of resistant bacteria, initial inoculum, initial immunity, antibiotic kill rate of drug-sensitive bacteria, and DOT, among others.7 They observed that optimal treatments tended to favor extremes in the 2 axes of control—either the antibiotic kill rate or treatment duration—depending on the timing of administration. High-killing rates and short treatments are favored in early

Optimal treatments tended to favor extremes in the 2 axes of control: either antibiotic kill rate or treatment duration. Source: Evol Med Pub Health 2020;2020(1):249-263.

treatments, which suggests a “short and strong” principle of treatment. Conversely, when therapy occurs later in the infection cycle, a long duration and lowkilling rates are preferred, thus providing support for mild and long therapy. Of note, Gjini et al strongly suggest that bactericidal versus bacteriostatic antibiotics could be used in different patient types.7 However, this categorization of patients would be very challenging, as this was not included in the model. Moreover, Wald-Dickler et al published a systematic literature review of “static versus cidal” drugs.8 The perception that bacteriostatic drugs kill bacteria but need higher concentrations to achieve this outcome was evaluated by reviewing 56 randomized clinical trials that compared the clinical efficacy of bacteriostatic and bactericidal agents in headto-head trials of patients with serious or life-threatening infections. Eighty-one percent of studies found no significant difference in the outcomes among the antibacterial mechanisms of action, even

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

for diseases such as pneumonia, typhoid fever, and bacteremia. Ironically, 6 trials found a significant difference in efficacy in favor of bacteriostatic agents. Only 1 study showed a bactericidal agent, imipenem, to be superior to tigecycline in ventilator-associated pneumonia (VAP). However, there was a pharmacologic explanation for this outcome relating to the dosing of tigecycline. It is essential to remember that the 2 terms bactericidal and bacteriostatic are laboratory-based criteria, which are an effort to standardize characteristics of drugs.

The ideal DOT would maximize clinical efficacy while reducing associated risks, drug toxicities, and Clostridioides difficile. Over the past 40 years, multiple studies have examined the efficacy of various DOTs with their effects on urinary tract infections (UTIs) being highly investigated, specifically in uncomplicated disease regimens ranging from single dose to 14 days of multiple doses per day. The advent of the fluoroquinolones provided evidence that 3 to 5 days of therapy in simple cystitis was adequate for drugs such as ciprofloxacin or levofloxacin, given once or twice daily. Single dosing was inadequate, with efficacy rates usually around 80% or less compared with longer courses yielding outcomes of 90% or better.9 Complicated UTIs, which include pyelonephritis, were studied by Peterson et al10 who compared levofloxacin 750 mg once daily for 5 days with ciprofloxacin given as either an IV or oral

IDSE.NET

formulation at 400/500 mg twice daily for 10 days.10 The shorter course was non-inferior. Sandberg et al compared ciprofloxacin over 2 periods in women with acute pyelonephritis.11 Again, the shorter treatment was non-inferior, and the longer course was associated with oral candidiasis. Community-acquired pneumonia (CAP) has been extensively studied over various durations and doses, with the 2019 American Thoracic Society (ATS) guidelines recommending 5 days of therapy for mild to moderate pneumonia but 7 days for multidrug-resistant infections or significant comorbidities.12 One of the earliest studies in CAP, which investigated shorter courses, was reported by Dunbar et al13 who evaluated a 5-day course of 750 mg of levofloxacin compared with the same drug at 500 mg for 10 days and demonstrated improved symptoms and defervescence with the shorter course. Similar observations have been reported with various antibiotics, including moxifloxacin, gemifloxacin, delafloxacin (Baxdela, Melinta), telithromycin, and lefamulin (Xenleta, Nabriva). The DOT for VAP has been a long subject of discussion. Almost 20 years ago, Chastre et al reported a major study in which 8 days of treatment was non-inferior to 15 days for 28-day mortality and infection recurrence, except for Pseudomonas aeruginosa and other non-fermenting gram-negative bacilli.14 Acute bacterial skin and soft tissue infection management depends on the type and site of infection. Abscesses require incision and drainage and antibiotics, but until a recent study by Lake et al,15 the effect of DOT was uncertain. Abscess size has been cited as a factor in choosing an antibiotic regimen and its duration.16 Their subanalysis of a larger study17 showed a lower likelihood of cure in patients who took fewer than 5 or 7 days of antibiotics than that expected with incision and drainage alone, suggesting that 10 days may be better. They concluded that abscess size had no effect on outcome, as is the general perception.

Bloodstream infections (BSIs) pose their own challenges. The source and etiology of the infection dictate the drug, dose, and duration. Yahav et al investigated gram-negative BSI duration, demonstrating that 7 days of therapy was non-inferior to 14 days of treatment in terms of clinical stability, 90-day mortality, clinical failure, and hospital length of stay (LOS).18 However, the same has not be seen in BSIs caused by Staphylococcus aureus. Current guidelines recommend at least 14 days of antibiotics for BSIs caused by S. aureus to minimize risks for secondary deep infections and relapse. However, a Danish team is currently comparing 7 days of antibiotic therapy with 14 days.19 This study is expected to yield results in 2022. For now, clinicians will likely prescribe 14 days for BSIs caused by S. aureus. Other infections, such as osteomyelitis, joint infections, and chronic prostatitis, require longer courses; 6 to 8 weeks of treatment is the norm. In addition, serious infections in neutropenic patients or those in critical care units need personalized therapy.

Applying the Guidance It is all well and good having guidance for DOT, but can it be applied? Patel and Murrey20 examined a pharmacy-driven antibiotic time-out program for CAP at a community hospital. Prompt assessment of appropriateness of the selected drug, clinical response, and DOT was undertaken by pharmacy at a 48-hour time point. This was a 2-stage study: a retrospective phase and post-implementation cohort. The primary outcome was the total DOT between hospitalization and hospital discharge. Secondary outcomes included hospital LOS, duration of IV therapy, rates of treatment failure, relapse, and antibiotic-associated adverse events. Intervention led to a reduction in DOT of 2.14 days. Significant reductions were also seen with IV therapy and 30-day emergency department visits. Antibioticassociated events such as acute kidney injury, C. difficile, and treatment failure

were lower in the intervention group. The authors concluded that a pharmacyimplemented antibiotic time-out program led to a reduction in antibiotic use in hospitalized CAP patients; however, the actual durations were still longer than those in the recent ATS guidelines. Another serious infection, gramnegative bacteremia, was evaluated by Bae et al.21 Again, a pharmacy-led intervention successfully shortened DOT, increased conversion or de-escalation from IV to oral therapy, and reduced LOS without adversely affecting the number of patients with recurrent gramnegative BSIs. Evidence from these 2 recent examples shows that antibiotics are used longer than necessary to achieve a satisfactory clinical outcome. It should be clear from FDA-developed study designs for CAP and surgical site infection trial programs that early clinical improvement at 3 to 5 days is indicative of a positive course, although further evaluation at test of cure is the designated decision point.22,23 Although some guidelines provide recommendations for DOT, the enforcement is arbitrary. Perhaps using DOT as part of a stewardship program or a regulatory agency evaluation could be a good incentive to more appropriate therapy. As Spellberg and Rice said, “Change is scary, and medicine is a conservative profession.”24 However, it is incumbent on our oath to “first do no harm” as we select an antibiotic and factor in the appropriate length of course.

References 1. Wald-Dickler N, Spellberg B. Short course antibiotic therapy-replacing Constantine units with “shorter is better.” Clin Infect Dis. 2019;69(9):1476-1479. 2. Spellberg B. The maturing mantra: “shorter is better.” J Hosp Med. 2018;13(5):361-362. 3. Ehrlich P. Address in pathology in chemotherapeutics: scientific principles, methods and results. Lancet. 1913;182(4694):445-451. 4. World Health Organization. Overcoming antimicrobial resistance. World Health Organization; 2000. Accessed February

24, 2021. https://apps.who.int/iris/ handle/10665/66672 5. Geli P, Laxminarayan R, Dunne M, et al. “One size fits all”? Optimizing treatment duration for bacterial infections. PLoS One. 2012;7(1):e29838. doi: 10.1371/ journal.pone.00298 6. Drlica K, Schmitz F. Therapeutic options in an era of decreasing antimicrobial susceptibility J Chemother. 2002;14(suppl 2):5-12. 7. Gjini E, Pauperion FFS, Ganusov VV. Treatment timing shifts the benefits of short or long treatment over infection. Evol Med Public Health. 2020;(1):249-263. https://doi.org/10.1093/emph/eoaa033 8. Wald-Dickler N, Holtom P, Spellberg B. Busting the myth of “static vs cidal”: a systematic literature review. Clin Infect Dis. 2018;66(9):1470-1474. 9. Nicolle LE. Use of quinolones in urinary tract infection and prostatitis. In: Andriole VT, ed. The Quinolones. 3rd ed. Academic Press; 2000:203-225. 10. Peterson J, Kaul S, Khabash M, et al. A double-blind randomized comparison of levofloxacin 750 mg once-daily for 5 days with ciprofloxacin 400/500mg for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology. 2008;71(1):17-22. 11. Sandberg T, Skoog G, Hermansson AB, et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomized, open label and double-blind placebo-controlled, non-inferiority trial. Lancet. 2012;380(9840):484-490. 12. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Disease Society of America. Am J Resp Med Crit Care. 2019;200(7):e45-e67. doi: 10.1164/rccm.201908-1581ST 13. Dunbar L, Wunderink RG, Habib MP, et al. High dose short course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis. 2003;37(6):752-760. 14. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilatorassociated pneumonia. JAMA. 2003;290(19):2588-2598. 15. Lake JG, Miller LG, Fritz SA. Antibiotic duration, but not abscess size, impacts clinical cure of limited skin and soft tissue infection after incision and drainage. Clin Infect Dis. 2020;71(3):661-663.

16. Mascitti KB, Gerber JS, Zaoutis TE, et al. Preferred treatment and prevention strategies for recurrent communityassociated methicillin Staphylococcus aureus skin and soft tissue infections: a survey of adult and pediatric providers. Am J Infect Control. 2010;38(4):324-328. 17. Talan DA, Moran GJ, Krishnadasan A, et al. Subgroup analysis of antibiotic treatment for skin abscesses. Ann Emerg Med. 2018;71(1):21-30. 18. Yahav D, Franschesini E, Koppel F, et al. Seven days versus 14 days of antibiotic therapy for uncomplicated gramnegative bacteremia: a noninferiority randomized controlled trial. Clin Infect Dis. 2019;69(7):1091-1098. 19. Thorlacius-Ussing L, Anderson L, Andersen CO, et al. Efficacy of seven and fourteen days of antibiotic treatment in uncomplicated Staphylococcus aureus bacteremia (SAB7): a study protocol for a randomized controlled clinical trial. Trials. 2019;20:250-258. https://doi. org/10.1186/s13063-019-3357-9 20. Patel AR, Murrey TF. 68. Impact of a pharmacy-driven antimicrobial time out (ATO) on duration of therapy in community-acquired pneumonia. Open Forum Infect Dis. 2020;7(suppl 1):S53. https://doi.org/10.1093/ofid/ofaa439.113 21. Bae EY, Bernice F, Dzintars K, et al. 52. Development and implementation of a short duration of antibiotic therapy algorithm for uncomplicated gramnegative bacteremia. Open Forum Infect Dis. 2020;7(suppl 1):S48. https://doi. org/10.1093/ofid/ofaa439.097 22. FDA. Guidance for industry. Acute bacterial skin and skin structure infections: developing drugs for treatment. Accessed January 27, 2021. http://bit.ly/2Pgaezy-IDSE 23. FDA. Guidance for industry. Communityacquired bacterial pneumonia: developing drugs for treatment. Accessed January 27, 2021. http://bit.ly/3kyVUxI-IDSE 24. Spellberg B, Rice LB. Duration of antibiotic therapy: shorter is better. Ann Intern Med. 2019;171(3):210-211. The author reported no relevant financial disclosures.

About the author Glenn Tillotson, PhD, FIDSA, FCCP, is a medical microbiologist and consultant with over 30 years of pharmaceutical experience in both large pharmaceutical and biotech companies.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

For challenging cases in cIAI... Reported penicillin allergy

WHEN THE RESISTANCE RISK IS HIGH,

EMPIRIC CHOICE IS CLEAR

THE

Indications and Usage XERAVA is indicated for the treatment of complicated intraabdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older. Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information

Long-term care resident at risk for resistant pathogens

Recent travel to an ESBL-endemic area

are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Important Safety Information XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth.

All trademarks and registered marks are the property of their respective owners. XERAVA™ is a trademark of Tetraphase Pharmaceuticals. ©2019 Tetraphase Pharmaceuticals All rights reserved. 01/19 PM-ERV-00049-US

HIGHLY EFFECTIVE NON–BETA-LACTAM ANTIBACTERIAL WITH APPROPRIATE EMPIRIC COVERAGE 1

Clinical cure rate, %

Clinical Cure Rate at TOC in Enterobacteriaceae2,a Pooled data from IGNITE1 and IGNITE4 100 90 80 70 60 50 40 30 20 10 0

89.6

88.9

87.0

88.9

43/48

32/36

40/46

40/45

90.6

86.2

Active against key Gram-negative, Gram-positive, and anaerobic bacteria, including isolates expressing a variety of multidrug resistance mechanisms 1,2 CEPH-R (n/N1)

Enterobacteriaceae (N=314) XERAVA

25/29

29/32

Enterobacteriaceae (N=325)

Confirmed ESBL (n/N1) MDRb (n/N1)

POOLED COMPARATORS

• The first fully synthetic fluorocycline antibacterial for cIAI1,3 • Proven as effective as carbapenems in cIAI1,a • Low rates of GI-related adverse reactions reported in 2 large clinical trials – Those that occurred in >2% of patients were nausea (6.5%), vomiting (3.7%), and diarrhea (2.3%)1

Study design: XERAVA was compared with carbapenems in 2 phase 3, randomized, double-blind, active-controlled, multinational, multicenter, prospective studies in 1,041 adult subjects with cIAI to demonstrate non-inferiority. Treatment was for 4 to 14 days. The primary efficacy endpoint was clinical response at the TOC visit in the micro-ITT population. IGNITE1 compared XERAVA 1 mg/kg IV q12h with ertapenem 1 g IV q24h. IGNITE4 compared XERAVA 1 mg/kg IV q12h with meropenem 1 g IV q8h.

MDR pathogens were defined as resistant to at least 1 member of 3 or more antibiotic classes.1,4,5

Important Safety Information (cont’d) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. The most common adverse reactions observed in clinical trials (incidence ≥3%) were infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%). XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected.

CEPH-R, cephalosporin-resistant; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta-lactamase; GI, gastrointestinal; IV, intravenous; MDR, multidrug-resistant; micro-ITT, microbiologic intent-to-treat; q8h, every 8 hours; q12h, every 12 hours; q24h, every 24 hours; TOC, Test of Cure. References: 1. XERAVA [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals, Inc.; 2018. 2. Ditch K, Newman J, Izmailyan S, Fyfe C, Tsai L. Microbiological efficacy of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including MDR isolates: a pooled analysis from IGNITE1 and IGNITE4, two phase 3 trials of complicated intra-abdominal infection. Poster presented at: ASM Microbe; June 7-11, 2018; Atlanta, GA. Poster 629. 3. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588. 4. Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232. 5. Tsai L, Horn P, Solomkin J, Evans D, Gardovskis J, Fonte A. Results of IGNITE4: a phase 3 study to evaluate the efficacy and safety of eravacycline versus meropenem in complicated intra-abdominal infections. Poster presented at: 28th European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain. Encore poster presentation at: 2018 Annual Making a Difference in Infectious Diseases (MAD-ID) Meeting; May 8-11, 2018; Orlando, FL.

To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase Pharmaceuticals Inc., at 1-833-7-XERAVA (1-833-793-7282) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of full Prescribing Information on the following pages.

LEARN MORE AT XERAVA.COM/IDSE

XERAVA may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of XERAVA with 0.9% Sodium Chloride Injection, USP.

Brief Summary XERAVATM (eravacycline) for injection Brief Summary of full Prescribing Information. See full Prescribing Information. Rx only. INDICATIONS AND USAGE Complicated Intra-abdominal Infections XERAVA is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older. Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. DOSAGE AND ADMINISTRATION Recommended Adult Dosage The recommended dose regimen of XERAVA is 1 mg/kg every 12 hours. Administer intravenous infusions of XERAVA over approximately 60 minutes every 12 hours. The recommended duration of treatment with XERAVA for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response. Dosage Modifications in Patients with Hepatic Impairment In patients with severe hepatic impairment (Child Pugh C), administer XERAVA 1 mg/kg every 12 hours on Day 1 followed by XERAVA 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 Isoenzymes (CYP) 3A Inducer With concomitant use of a strong CYP3A inducer, administer XERAVA 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer. Preparation and Administration XERAVA is for intravenous infusion only. Each vial is for a single dose only. Preparation XERAVA is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. XERAVA does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows: 1. Calculate the dose of XERAVA based on the patient weight; 1 mg/kg actual body weight. Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of XERAVA with 5 mL of Sterile Water for Injection, USP. When the XERAVA vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents). 2. Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted XERAVA solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection. 3. The reconstituted XERAVA solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag. 4. The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2°C to 8ºC (36ºF to 46ºF). Reconstituted XERAVA solutions and diluted XERAVA infusion solutions should not be frozen. 5. Visually inspect the diluted XERAVA solution for particulate matter and discoloration prior to administration (the XERAVA infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution. Administration of the Intravenous Infusion The diluted XERAVA solution is administered as an intravenous infusion over approximately 60 minutes.

Drug Compatibilities XERAVA is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XERAVA with other drugs and infusion solutions has not been established. XERAVA should not be mixed with other drugs or added to solutions containing other drugs. CONTRAINDICATIONS XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. XERAVA is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue XERAVA if an allergic reaction occurs. Tooth Discoloration and Enamel Hypoplasia The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline-class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy. Inhibition of Bone Growth The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy. Clostridium difficile-Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Tetracycline Class Adverse Reactions XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected. Potential for Microbial Overgrowth XERAVA use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue XERAVA and institute appropriate therapy. Development of Drug-Resistant Bacteria Prescribing XERAVA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria. ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section: • Hypersensitivity Reactions • Tooth Discoloration • Inhibition of Bone Growth • Clostridium difficile-Associated Diarrhea • Tetracycline Class Adverse Reactions 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.

XERAVA was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1 and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with XERAVA and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with XERAVA was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with XERAVA were predominantly male (57%) and Caucasian (98%). The XERAVA-treated population included 31% obese patients (BMI ≥30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving XERAVA and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of XERAVA were related to gastrointestinal disorders. Most Common Adverse Reactions Adverse reactions occurring at 3% or greater in patients receiving XERAVA were infusion site reactions, nausea and vomiting. Table 1 lists adverse reactions occurring in ≥1% of patients receiving XERAVA and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3). Table 1. Selected Adverse Reactions Reported in ≥1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2) Adverse Reactions

XERAVAa N=520 n (%)

Comparatorsb N=517 n (%)

Infusion site reactionsc Nausea Vomiting Diarrhea Hypotension Wound dehiscence

40 (7.7) 34 (6.5) 19 (3.7) 12 (2.3) 7 (1.3) 7 (1.3)

10 (1.9) 3 (0.6) 13 (2.5) 8 (1.5) 2 (0.4) 1 (0.2)

Abbreviations: IV=intravenous a XERAVA dose equals 1 mg/kg every 12 hours IV. b Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV. c Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling. Other Adverse Reactions of XERAVA The following selected adverse reactions were reported in XERAVA-treated patients at a rate of less than 1% in the Phase 3 trials: Cardiac disorders: palpitations Gastrointestinal System: acute pancreatitis, pancreatic necrosis General Disorders and Administrative Site Conditions: chest pain Immune system disorders: hypersensitivity Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia Metabolism and nutrition disorders: hypocalcemia Nervous System: dizziness, dysgeusia Psychiatric disorders: anxiety, insomnia, depression Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea Skin and subcutaneous tissue disorders: rash, hyperhidrosis DRUG INTERACTIONS Effect of Strong CYP3A Inducers on XERAVA Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of XERAVA. Increase XERAVA dose in patients with concomitant use of a strong CYP3A inducer. Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary XERAVA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data with XERAVA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8-times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased postimplantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit. A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post-Natal Day 111 that may have been at least partially related to lower body weights in this group. Tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. Lactation Risk Summary It is not known whether XERAVA is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats. Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of XERAVA on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with XERAVA and for 4 days (based on half-life) after the last dose. Data Animal Data Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline. Females and Males of Reproductive Potential Infertility Based on animal studies, XERAVA can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of XERAVA on male fertility have not been studied. Pediatric Use The safety and effectiveness of XERAVA in pediatric patients have not been established. Due to the adverse effects of the tetracycline-class of drugs, including XERAVA on tooth development and bone growth, use of XERAVA in pediatric patients less than 8 years of age is not recommended. Geriatric Use Of the total number of patients with cIAI who received XERAVA in Phase 3 clinical trials (n=520), 158 subjects were ≥65 years of age, while 59 subjects were ≥75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects. No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline. Hepatic Impairment No dosage adjustment is warranted for XERAVA in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust XERAVA dosage in patients with severe hepatic impairment (Child Pugh C). Renal Impairment No dosage adjustment is necessary for XERAVA in patients with renal impairment. OVERDOSAGE No reports of overdose were reported in clinical trials. In the case of suspected overdose, XERAVA should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of XERAVA.

Distributed by: Tetraphase Pharmaceuticals, Inc. 480 Arsenal Way, Ste 110 Watertown, MA 02472 XERAVATM is a trademark of Tetraphase Pharmaceuticals, Inc. ©2018, Tetraphase Pharmaceuticals, Inc. All rights reserved. 09/18 PM-ERV-00012-US

IDSE Review

The Heart of The Matter Understanding the Effect of ART on Cardiovascular Health

BY JACOB BOUDREAUX, MD,

AND

JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI

arlier detection of HIV infection, along with more effective antiretroviral therapy (ART), has markedly increased the life expectancy of people with HIV (PWH) in the United States, and ART is recommended for all people diagnosed with HIV.

Samji et al reported that PWH in their 20s on ART living in the United States and Canada are expected to survive into their early 70s, which is approaching the estimates of their contemporaries without HIV. However, this applies only to new ART patients and not those who have lived with HIV for longer periods.1 One study indicates that the median age of PWH on ART, which was 43.9 years in 2010, will increase to 56.5 years by 2030.2 According to Siddiqi et al, from 2008 to 2011, the average life expectancy after HIV transmission increased by approximately 3 years across all races and ethnicities and in all modes of transmission. Of note, a disproportionate increase in life expectancy of men with HIV compared with women was also observed in this study.3 In 2015, only 39% of PWH in the United States were age 50 years or older. By 2035, 74% will fall into this age bracket,

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and 44% of PWH will have 3 or more chronic diseases related to aging, compared with 2015 when most had none or only 1 chronic condition. Concerns are increasing about the effects of longterm treatment of HIV on comorbidities associated with aging, such as accelerated atherosclerosis and increased risk for cardiovascular disease (CVD). Moderate CVD, defined as hypertension and/or dyslipidemia, will comprise a large portion of this burden with a predicted increase from 61% of HIV-positive (HIV+) people on ART in 2015 to 84% by 2035. This increased burden of noncommunicable diseases is projected to account for 55.7% of HIV-related care expenditures by 2035.4 As of 2020, HIV-associated CVD represents the predominant cause of morbidity and mortality for PWH, who experience a nearly 2-fold increased

Epidemiology of Cardiovascular Disease Although there are several health complications related to HIV faced by this community, CVD deserves careful consideration. From 1999 to 2013, the incidence of CVD mortality has increased more than 2-fold among men and women with HIV. When examining the categories of CVD, PWH experienced a 3-fold increase in deaths associated with ischemic heart disease, while the general population saw a decrease. In addition, CVD in women with HIV is more common than in women without HIV.5 Regarding CVD-related death, PWH typically experience signs and symptoms of disease later in the disease process but tend to present at younger ages than the general population.5 People diagnosed with HIV are more likely to die of hypertensive heart, renal, and pulmonary circulatory diseases, including sudden cardiac death, whereas the general population tends to have higher mortality associated with heart failure (HF) and/or cardiomyopathy or cerebrovascular disease.3 The incidence of HIV-related HF has fallen significantly with increased access to ART, and AIDS-related cardiomyopathy is now a rare event.2 The most common presentation of CVD among PWH remains the acute coronary syndrome, which manifests in a younger cohort compared with HIV-negative people. Individuals with HIV have a higher rate of multivessel coronary disease and an increased incidence of MI recurrence.6-8 Similar to people without HIV, traditional risk factors for CVD contribute to the overall poor cardiac health profile of the HIV+ population. Levy et al reported the prevalence of various comorbidities in the HIV+ population as follows: 50% hypertension, 48% dyslipidemia, 46% multiple conditions, 35% obesity, and 13% type 2 diabetes mellitus. The longer an individual has HIV, the higher the probability of developing type 2 diabetes and dyslipidemia, since longer duration of ART is associated with a higher metabolic risk. Men with HIV are more likely to have dyslipidemia, yet women with HIV are more likely to develop metabolic syndrome.2,9-11

While PWH were once more likely to be affected by HIV-related acute malnutrition, they are now more likely to be affected by obesity, which has led to complications from numerous metabolic comorbidities. From 1998 to 2010, the median body mass index (BMI) of PWH increased from 23.8 to 24.8 kg/m2, and the percentage of individuals with obesity doubled from 9% to 18% at initiation of ART. After ART initiation, weight gain commonly occurs, leading to an increased prevalence of obesity. Smoking also is a risk factor for CVD and is associated with a 2-fold increase in mortality among PWH who smoke tobacco compared with nonsmokers, and the prevalence of smoking is nearly twice as high among PWH as those without HIV.12 This excess mortality in HIV+ smokers is mainly due to CVD and cancers unrelated to HIV. Comparing 35-year-old men with HIV who smoke with those who don’t, smokers lose an estimated 7.9 life-years. Age and smoking also are associated with carotid intima-media thickness (CIMT), a measure of subclinical atherosclerosis. Older PWH who smoke have a higher average CIMT than those of the same age without HIV who smoke. This finding suggests that HIV infection changes how age and smoking jointly affect CIMT, further increasing the risk for CVD development.13-16 PWH also engage in comparatively less physical activity, an important component of cardiovascular health and disease prevention. Men and women with HIV have on average less ventilatory efficiency, an indicator of cardiovascular fitness, than those without HIV. Webel et al demonstrated associations among higher step counts, a measure of physical fitness; reduced insulin resistance; and improved oxygen uptake in PWH who are physically active. Thus, a key aspect of HIV management, especially for those with greater CVD risk, is increased promotion of physical activity.17 PWH, even if they are on ART, have an increased risk for developing focal carotid artery plaques compared with individuals without HIV. The risk for plaque formation associated with HIV is greater than that associated with smoking.18 In a study by O’Dwyer et al, men with HIV and acute coronary syndrome were found to have a lower plaque burden than matched controls without HIV. The ability of a lower plaque burden to cause acute coronary syndrome suggests the presence of vulnerable or high-risk plaques, and emphasizes the danger of subclinical atherosclerosis in PWH.19 Other nontraditional CVD risk factors are accentuated in HIV+ people, such as increased alcohol consumption, which has been associated with decreased ART adherence. The subsequent increase in viral load might raise the risk for CVD.2 Hepatitis C and cytomegalovirus, which are common coinfections among PWH, also have been associated with increased CVD

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relative risk for myocardial infarction (MI) and a higher rate of MI recurrence than those without HIV. In view of these trends, understanding the care needs of PWH who have CVD or are at increased risk for developing CVD is of increased importance, particularly in countries where, due to easier access to ART, the epidemiology of HIV has shifted to a chronic disease process. This review serves as an update to information presented in the Winter 2019 Infectious Disease Special Edition and examines the factors that influence cardiovascular health in HIV+ people, including ART and HIV infection itself, and assesses current and potential future management practices.

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risk due to inflammatory mechanisms, although specific studies in the HIV+ population are lacking.

HIV-Related Risk Factors The increased prevalence of CVD among those with HIV is thought to be due to several complex and competing processes, such as endothelial dysfunction, microvascular disease, hypercoagulability, host factors, and genetic viral variation. Elevated biomarkers of inflammation, increased monocyte activation, and altered coagulation profiles are noted among PWH, and many of these biomarkers are known to induce atherogenesis.2,6 While contracting HIV induces a variety of cellular abnormalities, the primary target of HIV is CD4+ lymphocytes, but studies show the virus also targets macrophages, monocytes, and endothelial cells, resulting in a proinflammatory state. Macrophages infected with HIV-1 exhibit impaired cholesterol efflux, leading to elevated levels of intracellular cholesterol, triggering necrosis or apoptosis, and potentially inducing plaque formation.20 Khera et al showed that patients with greater efflux capacity tend to have lower levels of coronary disease, and greater efflux is known to protect macrophages from apoptosis.21 The proatherogenic status of monocytes continues in PWH even after starting ART and may contribute mechanistically to increased atherosclerosis in this population.22 There is also a correlation between HIV diagnosis and increased left ventricular dysfunction leading to HF. A higher left ventricular mass index and lower CD4+ level compared with controls and an increased incidence of diastolic dysfunction among PWH suggest a role of immunodeficiency in HF risk in addition to traditional risk factors.23,24 A study in Nigeria recruited 150 age- and sexmatched controls and found echocardiogram abnormalities in 55.3% of those with HIV compared with 2.7% in controls without HIV (P<0.001). In the HIV+ group, all structural dimensions of the cardiac chambers were significantly greater than those in controls except for left atrial dimension. When the patients were further stratified into 2 groups with a CD4+ lymphocyte count less than or more than 200 cells/ mm3, the structural chamber dimensions were similar in both groups. However, this did not appear to be related to HIV stage, as the chamber dimensions were similar in patients regardless of whether they had fewer than or more than 200 cells/mm3.4,25 The role of echocardiography in stratifying CVD among PWH remains unclear and needs to be better defined.

ART-Related Risk ART has contributed to the increase in life expectancy among PWH. However, it has also increased the risk for CVD, and the adverse event risk of ART must be balanced against its life-preserving effects. One of

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From 1999 to 2013, the incidence of CVD mortality has increased more than 2-fold among men and women with HIV.

the main concerns with ART involves serum lipid levels resulting in dyslipidemia. Among PWH, those on ART have on average higher total cholesterol and higher low-density lipoprotein (LDL) cholesterol levels than those without HIV; the former is especially associated with protease inhibitor (PI)-based regimens. ART regimens also result in higher rates of hypercholesterolemia and hypertriglyceridemia. For PWH treated with PIs, 27.2% have hypercholesterolemia compared with 9.3% of those with HIV not treated with PIs. Similarly, 37.1% HIV+ people on ART have hypertriglyceridemia versus 17.7% of those with HIV yet to begin ART. Both levels of hypercholesterolemia and hypertriglyceridemia have been shown to increase progressively with duration of ART.26 The main risk factors for PIinduced metabolic syndrome include endothelial dysfunction, atherogenic dyslipidemia, abdominal obesity, insulin resistance, and elevated blood pressure.27 PWH treated with PIs who have HF have been shown to be at increased risk for developing CVD, diabetes, and dyslipidemia compared with those with HIV/HF on ART that does not include PIs.27 The exception to this is atazanavir, which has yet to be linked to an excess risk for cardiovascular events and may potentially be protective against CVD, according to a 2017 large observational study.28 In addition to dyslipidemia, PWH on ART are susceptible to increases in BMI. Treatment duration of 3 years or more is associated with increases in BMI regardless of ART adherence.29-32 The resulting insulin resistance, dyslipidemia, and diabetes induced by long-term ART contribute to the increased risk for accelerated coronary atherosclerosis and early development of associated coronary events in those with HIV.6

It has been noted that newer ART regimens tend to have an improved effect on lipid profiles over older drug management protocols such as lopinavir, ABC, or ritonavir (RTV), which have side effects potentially detrimental to cardiovascular health.2 Implementing strict control of HIV, better managing factors that contribute to CVD risk, and increasing ART adherence are crucial to the overall reduction in morbidity and mortality due to CVD in HIV+ people.6

Drug–Drug Interactions The underuse of cardiovascular medications in individuals with HIV may be due in part to concerns about drug interactions with ART (Tables 1 and 2). Molas et al describe the potential drug–drug interactions in PWH on ART and show the importance of ongoing monitoring to ensure safety. In the study population, 70% of those with HIV on ART received co-medications, the most common category being cardiovascular drugs. Evaluating potential drug–drug interactions via an online system, the investigators found that 44.7% of the study population had at least 1 clinically significant potential drug–drug interaction.37 RTV-boosted PIs were a risk factor for potential drug–drug interactions, as were non-NRTIs and taking 2 or more co-medications. A management plan changing co-medications or the ART regimen therefore was recommended for 23.6% of study participants to prevent potential drug– drug interactions.38,39 In addition, McNicholl et al studied polypharmacy among older PWH to evaluate potentially inappropriate prescribing. Cardiovascular conditions, such as hypertension, dyslipidemia, and coronary artery disease, contributed to the list of common comorbidities in this population. In 20 study participants with HIV, a total of 25 contraindicated drug interactions were discovered, with 11.5% involving cardiovascular medications. Most of the contraindicated drug interactions associated with ART were from PI use.40 Overall, the understanding of potential drug–drug interactions remains limited, and there is a scarcity of data on cardiovascular risks associated with some ART regimens. More research is needed to elucidate these risks.

Prevention and Screening To better manage CVD risk for PWH, emphasis must be placed on both efficient and cost-effective prevention and screening strategies. Most screening guidelines in place for determining CVD risk were developed for use in the general population and not specifically for individuals with HIV, especially those who are also on ART. Phan et al assessed the value of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and 2004 Adult Treatment Panel III (ATP III) guidelines for statin therapy when applied to HIV+ people. In their overall study population, the ACC/AHA recommended 26.4%

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A 2015 study by D’Ascenzo et al noted that among 1,229 asymptomatic study participants with HIV who were taking ART, there was a 3-fold prevalence of noncalcified at-risk coronary artery plaques present on coronary angiography when compared with HIV control subjects. These vulnerable plaques underscore the increased risk for major coronary events due to subclinical atherosclerosis. This study also noted a decreased CD4+ cell level correlated to an increased number of vulnerable plaques.6 In a study by Drojee et al, use of abacavir (ABC), a nucleoside reverse transcriptase inhibitor (NRTI), was associated with an increased risk for CVD events. While the incidence of CVD events related to ABC exposure was 9.74 per 1,000 person-years, the rate in relation to other current ART use was 5.75 per 1,000 person-years. The risk for CVD events among individuals exposed to ABC remained elevated even after 6 months of stopping use compared with those with HIV without exposure to ABC.33,34 ABC also may have a role in increasing platelet reactivity, exacerbating the risk for MI.6 ABC alone and in combination is associated with increased rates of MI compared with ABCfree ART regimens.27 Maraviroc (MVC), a CC chemokine receptor 5 (CCR5) antagonist, was evaluated to see whether it could modulate the atherosclerotic burden in PItreated people with an undetectable viral load who underwent MVC intensification. Intensification (n=6) resulted in a significant reduction in intima-media thickness, pulse wave velocity, and triglyceride levels compared with baseline. Intensification also was associated with a significant reduction in interleukin-6 microbial translocation indexes and improvement in endothelial function. In a 2011 study, MVC was shown not to be associated with increases in total cholesterol, LDL, or triglyceride levels, and improved the lipid profiles of HIV+ people with prior dyslipidemia related to drug exposure.27 These changes support a protective role of CCR5 antagonists on atherosclerotic burden and associated reduction in CVD risk.35 In the NEAT 022 study, 415 HIV+ people on ART with high CVD risk (age >50 years and/or Framingham risk score >10% at 10 years) were randomly assigned to either continue a regimen of a boosted PI plus 2 NRTIs or switch to dolutegravir (DTG) plus two NRTIs. The 48-week data showed similar virologic suppression (93%) on both regimens. Dramatic improvements in lipid parameters (including total cholesterol, non– high-density lipoprotein [HDL] and LDL cholesterol, triglycerides, and total cholesterol-to-HDL ratio) were observed in patients switching to DTG-based ART; however, HDL remained largely unchanged in either group. These data support switching from a boosted PI-based ART to a DTG-based regimen to improve lipid parameters and possibly reduce CVD risk.36

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Table 1. Statin Guidance for Use With ART Statin (Brand Name, Manufacturer)

Use With ART

Pitavastatin

• Generally safe, but few supporting data for use • Start with approved initial dose and titrate

(Livalo, Kowa Pharmaceuticals America)

Rosuvastatin

• Generally safe; however, caution for use with PI-based regimens (should be avoided if possible) • Start at low dose (5 mg/d) and titrate slowly (maximum dose, 20 mg/d) • ATV or LPV: maximum dose, 10 mg/d

Atorvastatin

• Safe in PI-based regimen • Use low dose and titrate carefully • Do not exceed 20 mg/d when used with RTV- or COBI-boosted regimens (except TPV and LPV/RTV) • Safe with NNRTIs; no dose adjustment when used with RPV • Do not exceed 80 mg/d when used with efavirenz or etravirine

Pravastatin

• Safe in PI-based regimens • No dose adjustment for SQV/RTV and may consider higher starting dose in SQV-based regimens • No dose adjustment for LPV/RTV • ATV: Use lowest necessary dose and monitor • DRV/RTV: Use lowest necessary dose and monitor • COBI-boosted: No dose adjustment (report of rhabdomyolysis in 1 patient on pravastatin/fenofibrate) • Safe with NNRTIs • May consider high starting dose in use with EFV

Fluvastatin

Should be avoided

Simvastatin Niacin ER-simvastatin Simvastatin-ezetimibe

Contraindicated

Lovastatin Lovastatin ER Niacin ER-lovastatin

Contraindicated

ART, antiretroviral therapy; ATZ, atazanavir; COBI, cobicistat; DRV, darunavir; EFV, efavirenz; ER, extended release; LPV, lopinavir; LPV/RTV, lopinavirritonavir; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitor; RPV, rilpivirine; RTV, ritonavir; SQV/RTV, saquinavir-ritonavir; TPV, tipranavir Adapted from Chastain DB, et al. Evidence-based review of statin use in patients with HIV on antiretroviral therapy. J Clin Transl Endocrinol. 2017;8:6-14.

Table 2. Drug–Drug Interactions of Antiplatelets/Anticoagulants and ART Antiplatelet/Anticoagulant

Use With ART

Clopidogrel (Plavix)

• Acceptablea for use with PIs, some NNRTIs (nevirapine and rilpivirine), integrase inhibitors, NRTIs, maraviroc, and cobicistat

Prasugrel (Effient)

• Not recommended for use with PIs and cobicistat • Acceptable for use with NNRTIs, integrase inhibitors, NRTIs, and maraviroc

Ticagrelor (Brilinta)

• Avoid use with PIs (possible increased bleeding risk) • Not recommended for use with cobicistat • Acceptable for use with NNRTIs, integrase inhibitors, NRTIs, and maraviroc

Dabigatran (Pradaxa)

• Acceptable for use with PIs (administration times should be separated by ≥2 h) • Acceptable for use with NNRTIs, integrase inhibitors, NRTIs, maraviroc, and cobicistat

Rivaroxaban (Xarelto)

• Not recommended for use with PIs, NNRTIs, and cobicistat • Acceptable for use with integrase inhibitors, NRTIs, and maraviroc

Apixaban (Eliquis)

• Not recommended for use with PIs, NNRTIs, and cobicistat • Acceptable for use with integrase inhibitors, NRTIs, and maraviroc

No expected clinically significant interactions of suggested medication (study-based findings on potential mechanisms of drug interactions due to lack of data).

Integrase inhibitors: dolutegravir, elvitegravir, and raltegravir. NNRTIs: efavirenz, etravirine, nevirapine, and rilpivirine. PIs: atazanavir, darunavir, lopinavir, and ritonavir. ART, antiretroviral therapy; NNRTIs, non-nucleoside reverse transcriptase inhibitors; NRTIs, nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors Adapted from Egan G, et al. Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications. Ann Pharmacother. 2014;48(6):734-740.

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of PWH for statin therapy, while the ATP III guidelines recommended only 13.6%. Regardless of which guidelines were applied, all HIV+ study participants tended to have more comorbidities and traditional cardiovascular risk factors. Among those with HIV who also had evidence of carotid plaque, both guidelines did not recommend initiating statin therapy for roughly two out of three participants with HIV. Although HIV was associated with baseline CIMT and CIMT progression, they did not serve as predictors of mortality.41-44 The use of statins as a primary prevention strategy for CVD among HIV+ people was investigated by Gill et al in a 2016 meta-analysis that proposed atorvastatin and simvastatin as causing the largest reduction in LDL in those with HIV. ART regimens that excluded an NRTI also were shown to be associated with reduced statin efficacy in lowering total cholesterol levels, suggesting a role for NRTIs to help reduce overall CVD risk.6 Despite the benefit of statins in CVD event reduction, the rate of statin prescribing remains low.2 There are many evidence-based CVD risk estimators available for use, but no consensus exists on which one is best for stratifying CVD risk in PWH. Krikke et al compared the effectiveness of the Framingham Heart Study general CVD risk score (FRS), Framingham Heart Study coronary heart disease risk score (FHS-CHD), atherosclerotic cardiovascular disease risk score (ASCVD), Systematic COronary Risk Evaluation for the Netherlands (SCORE-NL), and Data Collection on Adverse Events of Anti-HIV Drugs risk score (D:A:D). Of note, the D:A:D model is the only HIV-specific risk score. In terms of overall cumulative risk, the D:A:D, ASCVD, and SCORE-NL estimated similar risk distributions, while the FRS and FHSCHD both estimated a higher overall cumulative risk. Across all risk prediction models, most PWH were categorized as low/medium risk. When comparing general risk scores with the HIV-specific D:A:D risk score, ASCVD and SCORE-NL produced similar results, but both the FRS and FHS-CHD placed more patients into a higher risk category, for a potential overestimation of CVD risk.44 Thompson-Paul et al compared the abilities of the FRS, ACC/AHA pooled cohort equation (PCE), D:A:D, and SCORE risk prediction models. The FRS, PCE, and D:A:D were all able to adequately distinguish highCVD risk PWH from those with low risk, but PCE and D:A:D estimated a lower overall CVD event risk. In contrast, SCORE was unable to categorize individuals with HIV into high- or low-risk groups.45 Raggi et al specifically assessed cardiovascular event prediction and reported that PCE and D:A:D were better at categorizing PWH without CVD events, yet FRS was better at predicting CVD events at 5 and 10 years among HIV+ people. Therefore, PCE and D:A:D may be more useful in detecting the potential for future CVD events in PWH with lower CVD risk.46

By 2035, 74% of people with HIV will be ≥50 years, and 44% will have ≥3 chronic conditions related to aging.

In 2019, the AHA suggested applying the atherosclerotic cardiovascular disease risk calculator to those living with HIV, recommending that physicians adjust the calculated risk estimate by 1 to 2 times the original risk estimate due to underestimation of CVD risk among PWH. Traditional and nontraditional CVD risk factors should be considered on an individual basis in estimating risk.2

Management and Switching ART Regimens Treating traditional CVD risk factors, such as hypertension and dyslipidemia, should be a mainstay for all patients. Appropriate choice of ART regimens for people with high CVD risk, earlier diagnosis, and treatment of HIV infection will decrease the burden of CVD and noncommunicable diseases among PWH over time.47 Multidisciplinary lifestyle interventions encouraging increased physical exercise and smoking cessation along with improved diet, which may result in lower cholesterol levels, may be best implemented in the primary care setting. In addition, medications have a role because lifestyle modification does not prevent all aspects of CVD risk, such as CIMT, or the risks associated with CVD and polypharmacy.48 The effectiveness of statins in treating dyslipidemia is well known. People living with HIV diagnosed with their first acute coronary syndrome, however, are less frequently prescribed a high-intensity statin within 3 years of follow-up than those without HIV. Even when statin therapy is prescribed to individuals with HIV, they

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achieve less of a reduction in LDL cholesterol and are less likely to reach cholesterol goals, with the exception of HDL cholesterol, at 6 months. Additional interventions need to be taken to improve the lipid profiles of PWH to make them less atherogenic and lower their increased CVD risk.49 The increased prevalence of subclinical coronary atherosclerosis found in PWH warrants attentive monitoring. For individuals with HIV who have already had a CVD event, consideration should be given to invasive procedures. Those with HIV who receive invasive coronary intervention experience no difference in mortality or cardiac death compared with those without HIV within 3 years after the procedure.47 When examining trends in percutaneous coronary intervention (PCI) from 2003 to 2013 in PWH presenting with ST-elevation MI, there has been an increase in PCI and use of drug-eluting stents, which are safe and effective in patients with and without HIV.6 A 2011 study analyzing data from 23 cardiac ICUs in France noted a 4-fold increased risk for acute coronary syndrome recurrence at 1 year and more frequent urgent PCI in HIV+ people. The recurrence was noted to occur in different coronary sites as opposed to original site rethrombosis.6 Despite this observation, HIV+ people are less likely to receive drug-eluting stents and more likely to receive bare metal stents compared with those without HIV.50-52 The use and efficacy of PCI with drug-eluting stents in the HIV+ population warrants further research. For PWH who have an undetectable viral load, careful consideration must be given to the potential negative effect on metabolic and cardiovascular health prior to switching ART regimens. Several recent studies looked at the effects of switching ART regimens in individuals with an undetectable viral load, from an NRTI regimen of tenofovir disoproxil fumarate to tenofovir alafenamide. In addition to NRTIs, recent studies also evaluated the effects of integrase strand transfer inhibitor regimens on cardiovascular health.

Conclusion People who are HIV+ have a higher risk for specific age-related health problems, especially CVD, and present with a more aggressive clinical picture. The gap in CVD care between the general population and those with HIV must be addressed—and closed—through early recognition, addressing CVD prevention, and increasing ART implementation and adherence. As the relationship between HIV, ART, traditional risk factors, and CVD becomes better understood, further research needs to focus on determining the optimal CVD screening methods, management protocols that reduce thrombotic risk, and appropriate therapeutic interventions decreasing CVD risk in PWH.

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References 1.

Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated individuals in the United States and Canada. PLoS One. 2013;8(12):e81355.

So-Armah K, Benjamin LA, Bloomfield GS, et al. HIV and cardiovascular disease. Lancet HIV. 2020;7(4):e279-e293.

Siddiqi AE, Hall HI, Hu X, et al. Population-based estimates of life expectancy after HIV diagnosis: United States 2008-2011. J Acquir Immune Defic Syndr. 2016;72(2):230-236.

Smit M, Cassidy R, Cozzi-Lepri A, et al. Projections of noncommunicable disease and health care costs among HIV+ persons in Italy and the U.S.A.: a modelling study. PLoS One. 2017;12(10):e0186638.

Feinstein MJ, Bahiru E, Achenbach C, et al. Patterns of cardiovascular mortality for HIV-infected adults in the United States: 1999 to 2013. Am J Cardiol. 2016;117(2):214-220.

Bernelli C, Danzi GB, Cerrato E, et al. Cardiovascular events recurrence and coronary artery disease in HIV patients: the price we have to pay for the chronicization of the disease. Can J Cardiol. 2020;36(1):127-134.

Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-979.

Womack JA, Chang CC, So-Armah KA, et al. HIV infection and cardiovascular disease in women. J Am Heart Assoc. 2014;3(5):e001035.

Cowell A, Shenoi SV, Kyriakides TC, et al. Trends in hospital deaths among human immunodeficiency virus-infected patients during the antiretroviral therapy era, 1995 to 2011. J Hosp Med. 2015;10(9):608-614.

10. Paisible AL, Chang CC, So-Armah KA, et al. HIV infection, cardiovascular disease risk factor profile, and risk for acute myocardial infarction. J Acquir Immune Defic Syndr. 2015;68(2):209-216. 11.

Levy ME, Greenberg AE, Hart R, et al. High burden of metabolic comorbidities in a citywide cohort of HIV outpatients: evolving health care needs of people aging with HIV in Washington, DC. HIV Med. 2017;18(10):724-735.

12. Aberg JA. Aging and HIV infection: focus on cardiovascular disease risk. Top Antivir Med. 2020;27(4):102-105. 13. Mayer KH, Loo S, Crawford PM, et al. Excess clinical comorbidity among HIV-infected patients accessing primary care in US community health centers. Public Health Rep. 2017:33354917748670. 14. Koethe JR, Jenkins CA, Lau B, et al. Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Res Hum Retroviruses. 2016;32(1):50-58. 15. Helleberg M, May MT, Ingle SM, et al. Smoking and life expectancy among HIV-infected individuals on antiretroviral therapy in Europe and North America. AIDS. 2015;29(2):221-229. 16. Fitch KV, Looby SE, Rope A, et al. Effects of aging and smoking on carotid intima-media thickness in HIV-infection. AIDS. 2013;27(1):49-57. 17. Webel AR, Perazzo J, Longenecker CT, et al. The influence of exercise on cardiovascular health in sedentary adults with human immunodeficiency virus. J Cardiovasc Nurs. 2018;33(3):239-247. 18. Hanna DB, Post WS, Deal JA, et al. HIV infection is associated with progression of subclinical carotid atherosclerosis. Clin Infect Dis. 2015;61(4):640-650. 19. Janjua SA, Staziaki PV, Szilveszter B, et al. Presence, characteristics, and prognostic associations of carotid plaque among PWH. Circ Cardiovasc Imaging. 2017;10(10):e005777. 20. O’Dwyer EJ, Bhamra-Ariza P, Rao S, et al. Lower coronary plaque burden in patients with HIV presenting with acute coronary syndrome. Open Heart. 2016;3(2):e000511. 21. Crowe SM, Westhorpe CL, Mukhamedova N, et al. The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol. 2010;87(4):589-598.

23. Maisa A, Hearps AC, Angelovich TA, et al. Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS. 2015;29(12):1445-1457.

inappropriate prescribing in older HIV+ patients. Pharmacotherapy. 2017;37(12):1498-1506. 41. Vos AG, Hulzebosch A, Grobbee DE, et al. Association between immune markers and surrogate markers of cardiovascular disease in HIV positive patients: a systematic review. PLoS One. 2017;12(1):e0169986.

24. Hsue PY, Waters DD. Heart failure in persons living with HIV infection. Curr Opin HIV AIDS. 2017;12(6):534-539.

42. Vos AG, Idris NS, Barth RE, et al. Pro-inflammatory markers in relation to cardiovascular disease in HIV infection: a systematic review. PLoS One. 2016;11(1): e0147484.

25. Ogunmodede JA, Kolo PM, Katibi IA, et al. Structural echocardiographic abnormalities seen in HIV/AIDS patients are independent of cd4 count. Niger J Clin Pract. 2017;20(6):716-723.

43. Raggi P, Zona S, Scaglioni R, et al. Epicardial adipose tissue and coronary artery calcium predict incident myocardial infarction and death in HIV-infected patients. J Cardiovasc Comput Tomogr. 2015;9(6):553-558.

26. Nduka C, Sarki A, Uthman O, et al. Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol. 2015;199:307-318.

44. Phan BAP, Weigel B, Ma Y, et al. Utility of 2013 American College of Cardiology/American Heart Association cholesterol guidelines in HIV-infected adults with carotid atherosclerosis. Circ Cardiovasc Imaging. 2017;10(7):e005995.

27. Antony I, Kannichamy V, Banerjee A, et al. An outlook on the impact of HIV infection and highly active antiretroviral therapy on the cardiovascular system — a review. Cureus. 2020;12(11):e11539. 28. Richterman A, Sax PE. Antiretroviral therapy in older PWH. Curr Opin HIV AIDS. 2020;15(2):118-125. 29. Nsagha DS, Weledji EP, Assob NJ, et al. Highly active antiretroviral therapy and dyslipidemia in PWH/AIDS in Fako Division, South West Region of Cameroon. BMC Cardiovasc Disord. 2015;15:95. 30. Abebe M, Kinde S, Belay G, et al. Antiretroviral treatment associated hyperglycemia and dyslipidemia among HIV infected patients at Burayu Health Center, Addis Ababa, Ethiopia: a cross-sectional comparative study. BMC Res Notes. 2014;7:380.

45. Krikke M, Hoogeveen RC, Hoepelman AI, et al. Cardiovascular risk prediction in HIV-infected patients: comparing the Framingham, atherosclerotic cardiovascular disease risk score (ASCVD), Systematic COronary Risk Evaluation for the Netherlands (SCORE-NL) and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models. HIV Med. 2016;17(4):289-297. 46. Thompson-Paul AM, Lichtenstein KA, Armon C, et al. Cardiovascular disease risk prediction in the HIV outpatient study. Clin Infect Dis. 2016;63(11):1508-1516. 47. Smit M, van Zoest RA, Nichols BE, et al. Cardiovascular disease prevention policy in HIV: recommendations from a modelling study. Clin Infect Dis. 2018;66(5):743-750.

31. Limas TG, Pinto Gde A, Marcato LM, et al. Analysis of the prevalence of dyslipidemia in individuals with HIV and its association with antiretroviral therapy. Rev Soc Bras Med Trop. 2014;47(5):547-551.

48. Saumoy M, Alonso-Villaverde C, Navarro A, et al. Randomized trial of a multidisciplinary lifestyle intervention in HIV-infected patients with moderate-high cardiovascular risk. Atherosclerosis. 2016;246:301-308.

32. Taramasso L, Ricci E, Menzaghi B, et al. Weight gain: a possible side effect of all antiretrovirals. Open Forum Infect Dis. 2017;4(4):ofx239.

49. Boccara F, Miantezila Basilua J, Mary-Krause M, et al. Statin therapy and low-density lipoprotein cholesterol reduction in HIV-infected individuals after acute coronary syndrome: results from the PACS-HIV lipids substudy. Am Heart J. 2017;183:91-101.

33. Abrahams Z, Levitt N, Lesosky M, et al. Changes in body fat distribution on dual-energy X-ray absorptiometry in black South Africans starting first-line antiretroviral therapy. AIDS Patient Care STDs. 2016;30(10):455-462. 34. Dorjee K, Baxi SM, Reingold AL, et al. Risk of cardiovascular events from current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study. BMC Infect Dis. 2017;17(1):708. 35. Piconi S, Pocaterra D, Rainone V, et al. Maraviroc reduces arterial stiffness in PI-treated HIV-infected patients. Sci Rep. 2016:6:28853. 36. Gatell JM, Assoumou L, Moyle G, et al. Switching from a boosted protease inhibitor (PI/r) based regimen to a dolutegravir regimen in virologically suppressed patients with high cardiovascular risk or age ≥50 years is non-inferior and decreases lipids. Presented at: 9th IAS Conference on HIV Science; July 23-26, 2017; Paris, France. Abstract TUAB0102. 37. Ladapo JA, Richards AK, DeWitt CM, et al. Disparities in the quality of cardiovascular care between HIV-infected versus HIVuninfected adults in the United States: a cross-sectional study. J Am Heart Assoc. 2017;6(11):e007107. 38. Todd JV, Cole SR, Wohl DA, et al. Underutilization of statins when indicated in HIV-seropositive and seronegative women. AIDS Patient Care STDs. 2017;31(11):447-454. 39. Molas E, Luque S, Retamero A, et al. Frequency and severity of potential drug interactions in a cohort of HIV-infected patients identified through a multidisciplinary team. HIV Clin Trials. 2018;19(1):1-7. 40. McNicholl IR, Gandhi M, Hare CB, et al. A pharmacist-led program to evaluate and reduce polypharmacy and potentially

50. Ciaffi L, Cavassini M, Genne D, et al. Switch to etravirine for HIV+ patients receiving statin treatment: a prospective study. Eur J Clin Invest. 2015;45(7):720-730. 51. Bundhun PK, Pursun M, Huang WQ. Does infection with human immunodeficiency virus have any impact on the cardiovascular outcomes following percutaneous coronary intervention?: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2017;17(1):190. 52. Albaeni A, Harris C, Eid SM, et al. HIV status and type of coronary stent placed in patients presenting with ST-elevation myocardial infarction. Coron Artery Dis. 2017;28(3):239-245.

The authors reported no relevant financial disclosures.

About the Authors Jacob Boudreaux, MD, is a 2020 graduate of the University of Queensland, Ochsner Clinical School, in Brisbane, Australia. He plans to pursue a career in anesthesiology. Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI, is the director of clinical research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Ochsner Medical Center, in New Orleans, Louisiana.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

IDSE Review

22. Khera AV, Cuchel M, de la Llera-MoyaM, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364(2):127-135.

RUKOBIA: for heavily treatment-experienced (HTE) patients with multidrug-resistant HIV-1

INDICATION RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations. IMPORTANT SAFETY INFORMATION Contraindications • Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. • Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum). Warnings and precautions Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: • Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. • Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

A first-in-class treatment with a novel mechanism of action1,2

Sustained rates of virologic suppression in patients who were previously unable to construct a viable regimen1 Robust CD4+ T-cell recovery, even in the most immunocompromised patients1 BRIGHTE is a Phase 3, partially randomized trial in HTE patients with confirmed HIV-1 RNA ≥400 copies/mL. The randomized cohort (double-blind, placebo-controlled through Day 8, then open-label) enrolled 272 patients who had 1 or 2 ARV classes remaining due to resistance, intolerability, or contraindications. At baseline, 73% had CD4+ T-cell counts of <200 cells/mm3 and 89% had HIV-1 RNA ≥1000 copies/mL. The primary endpoint was the adjusted mean decline in HIV-1 RNA at Day 8: 0.79 log10 copies/mL (RUKOBIA 600-mg BID + failing regimen, n=201) vs 0.17 log10 copies/mL (placebo + failing regimen, n=69); difference: -0.625 (95% CI: -0.810, -0.441); P<0.0001. At Week 96, 60% of patients were virologically suppressed, an increase from 53% at Week 24. The mean increase in CD4+ T-cell counts from baseline at Week 96 was 205 cells/mm3. In a subgroup summary analysis, those with a baseline CD4+ T-cell count <20 cells/mm3 had a mean increase of 240 cells/mm3. The most common adverse reaction (all grades) observed in ≥5% of patients was nausea (10%).1

Visit RUKOBIAhcp.com to learn more

Adverse reactions

Use in speciﬁc populations

• The most common adverse reaction (all grades, randomized cohort) observed in ≥5% of subjects was nausea (10%).

• Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.

• 81% of adverse reactions reported with RUKOBIA were mild or moderate in severity. Drug interactions • See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions. • Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible. • Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. • Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant. Please see Brief Summary of Prescribing Information for RUKOBIA on the following pages. ARV=antiretroviral; BID=twice daily; CI=confidence interval; HIV-1=human immunodeficiency virus type 1. References: 1. Data on file, ViiV Healthcare. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. https://clinicalinfo. hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Updated December 18, 2019. Accessed September 18, 2020.

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS RUKOBIA is contraindicated in patients: with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA; coadministered strong F\WRFKURPH 3 &<3 $ LQGXFHUV DV VLJQL¿FDQW GHFUHDVHV LQ WHPVDYLU (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to: Androgen receptor inhibitor: Enzalutamide; Anticonvulsants: Carbamazepine, phenytoin; Antimycobacterial: Rifampin; Antineoplastic: Mitotane; Herbal product: St John’s wort (Hypericum perforatum). WARNINGS AND PRECAUTIONS Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may GHYHORS DQ LQÀDPPDWRU\ UHVSRQVH WR LQGROHQW RU UHVLGXDO RSSRUWXQLVWLF infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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. QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily, WLPHV WKH UHFRPPHQGHG GDLO\ GRVH KDV EHHQ VKRZQ WR VLJQL¿FDQWO\ prolong the QTc interval of the electrocardiogram. RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of RUKOBIA and certain other drugs PD\ UHVXOW LQ NQRZQ RU SRWHQWLDOO\ VLJQL¿FDQW GUXJ LQWHUDFWLRQV VRPH RI which may lead to: Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir; possible prolongation of QTc interval from increased exposure to temsavir. See Drug Interactions for steps to prevent or manage these possible and known VLJQL¿FDQW GUXJ LQWHUDFWLRQV LQFOXGLQJ GRVLQJ UHFRPPHQGDWLRQV &RQVLGHU the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs. ADVERSE REACTIONS Clinical Trials Experience: A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial. The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatmentexperienced adult subjects. A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of VXEMHFWV DQG LQFOXGHG FDVHV RI VHYHUH LPPXQH UHFRQVWLWXWLRQ LQÀDPPDWRU\ syndrome. Data from the randomized cohort form the basis of the safety DVVHVVPHQW RI 58.2%,$ EHFDXVH WKH SUHVHQFH RI VLJQL¿FDQW FRPRUELG illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all JUDGHV UHSRUWHG LQ RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW LQ WKH :HHN 96 analysis are listed in Table 1.

Table 1. Adverse Reactionsa *UDGHV WR 5HSRUWHG LQ RI 6XEMHFWV Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis) Adverse Reaction Nausea Diarrhea Headache Abdominal painc Dyspepsia Fatigued Rashe Sleep disturbancef Immune Reconstitution ,QÀDPPDWRU\ 6\QGURPH Somnolence Vomiting

RUKOBIA plus OBT Q b 10% 4% 4% 3% 3% 3% 3% 3% 2% 2% 2%

Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving RUKOBIA in the open-label phase of the trial. c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes pooled terms: fatigue and asthenia. e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. f ,QFOXGHV SRROHG WHUPV LQVRPQLD VOHHS GH¿FLW VOHHS GLVRUGHU DEQRUPDO GUHDPV a

Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%). Less Common Adverse Reactions: The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort. – Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic. – Musculoskeletal Disorders: Myalgia. – Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy). – Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade WR[LFLW\ LQ RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW RI WKH %5,*+7( WULDO DUH presented in Table 2. 7DEOH 6HOHFWHG /DERUDWRU\ $EQRUPDOLWLHV *UDGHV WR 5HSRUWHG LQ RI 6XEMHFWV LQ WKH 5DQGRPL]HG &RKRUW 5HFHLYLQJ 58.2%,$ SOXV OBT in the BRIGHTE Trial (Week 96 Analysis) Laboratory Parameter Preferred Term ALT (>5.0 x ULN) AST (>5.0 x ULN) Direct bilirubin (>ULN)b %LOLUXELQ [ 8/1

&KROHVWHURO PJ G/ b Creatinine (>1.8 x ULN or 1.5 x baseline) &UHDWLQH NLQDVH [ 8/1

Hemoglobin (<9.0 g/dL) Hyperglycemia (>250 mg/dL) Lipase (>3.0 x ULN) /'/ &KROHVWHURO PJ G/

1HXWURSKLOV FHOOV PP3) Triglycerides (>500 mg/dL) Urate (>12 mg/dL)

RUKOBIA plus OBT Q a) 5% 4% 7% 3% 5% 19% 2% 6% 4% 5% 4% 4% 5% 3%

ULN = Upper limit of normal. a Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n = 221 for cholesterol and triglycerides, n = 216 for LDL cholesterol, and n = 268 for all other parameters). b Grade 3 only (no Grade 4 values reported).

The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% (cont’d on next page)

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use (cont’d) versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively. Changes in Serum Creatinine: Clinically relevant increases in serum FUHDWLQLQH KDYH SULPDULO\ RFFXUUHG LQ SDWLHQWV ZLWK LGHQWL¿DEOH ULVN IDFWRUV for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established. Changes in Direct Bilirubin: Increases in direct (conjugated) bilirubin have been observed following treatment with 58.2%,$ 7DEOH &DVHV RI FOLQLFDO VLJQL¿FDQFH ZHUH XQFRPPRQ DQG were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA. Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-infection: A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where antihepatitis therapy was withdrawn. DRUG INTERACTIONS Potential for RUKOBIA to Affect Other Drugs: Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition. When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol. Potential for Other Drugs to Affect RUKOBIA: Coadministration of RUKOBIA with rifampin, a strong &<3 $ LQGXFHU VLJQL¿FDQWO\ GHFUHDVHV WHPVDYLU SODVPD FRQFHQWUDWLRQV The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can VLJQL¿FDQWO\ GHFUHDVH WHPVDYLU SODVPD FRQFHQWUDWLRQV ZKLFK PD\ OHDG WR loss of virologic response. (VWDEOLVKHG DQG 2WKHU 3RWHQWLDOO\ 6LJQLÀFDQW Drug Interactions: Information regarding potential drug interactions with RUKOBIA is provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss RI HI¿FDF\ • Androgen receptor inhibitor: Enzalutamide—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Anticonvulsants: Carbamazepine, Phenytoin—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Antimycobacterial: Rifampin—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Antineoplastic: Mitotane—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Herbal product: St John’s wort (Hypericum perforatum)— Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Hepatitis C virus direct-acting antivirals: Grazoprevir, Voxilaprevir— Coadministration may increase exposures of grazoprevir or voxilaprevir; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible. • Oral contraceptive: Ethinyl estradiol—Ethinyl estradiol daily dose VKRXOG QRW H[FHHG PFJ Caution is advised particularly in patients with additional risk factors for thromboembolic events. • Statins: Rosuvastatin, Atorvastatin, Fluvastatin, Pitavastatin, Simvastatin—Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. Consult the full Prescribing Information for potential drug interactions; this list is not all-inclusive. Drugs that Prolong QT Interval: Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes. Drugs without Clinically 6LJQLÀFDQW ,QWHUDFWLRQV ZLWK 58.2%,$ Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine,

famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: 7KHUH DUH LQVXI¿FLHQW KXPDQ GDWD RQ WKH use of RUKOBIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures (see Data). Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1– infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether RUKOBIA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving RUKOBIA. Pediatric Use: The safety and effectiveness of RUKOBIA have not been established in pediatric patients. Geriatric Use: &OLQLFDO WULDOV RI 58.2%,$ GLG QRW LQFOXGH VXI¿FLHQW QXPEHUV RI VXEMHFWV aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration RI 58.2%,$ LQ HOGHUO\ SDWLHQWV UHÀHFWLQJ JUHDWHU IUHTXHQF\ RI GHFUHDVHG hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Renal Impairment: No dosage adjustment is required for patients with renal impairment or those on hemodialysis. Hepatic Impairment: No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C). OVERDOSAGE 7KHUH LV QR NQRZQ VSHFL¿F WUHDWPHQW IRU RYHUGRVH ZLWK 58.2%,$ ,I overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be VLJQL¿FDQWO\ UHPRYHG E\ GLDO\VLV

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GlaxoSmithKline Research Triangle Park, NC 27709

THE MORE YOU DETECT THE BETTER YOU PROTECT Improve care for more patients with ePlex® Blood Culture Identification Panels, the only BCID panels that can detect >95% of organisms that cause sepsis Sepsis is a common complication of COVID-19 and rapid diagnosis is key to effective treatment. ePlex BCID Panels rapidly detect more of the organisms that cause sepsis. Armed with this critical information, you can prescribe the right treatment within hours – rather than days – improving patient care. The ePlex BCID Panels can identify >95% of the pathogens that cause sepsis. Combine this with order-to-report integration and templated comments and you’re ready to fast-track treatment intervention, enabling earlier escalation for resistant organisms or de-escalation of empirical antimicrobials.

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IDSE Review

Rapid Diagnostic Tests: Modern-Day Tools in the Realm of Infectious Diseases BY KAREN FONG, PHARMD, BCIDP

n the modern clinical microbiology laboratory, rapid diagnostic tests (RDTs) have transformed infectious diseases management by providing more rapid and robust microbiological diagnoses. The advances in the detection of bacteria, viruses, and fungi during the management of these infections not only serve as invaluable guidance in early clinical decision making, but have had significant impact on clinical outcomes, antimicrobial use, and cost savings.1-3 In particular, direct-specimen rapid amplification and detection platforms and next-generation sequencing are the 2 major directions in the current explosion of molecular technology. These techniques present the opportunity to provide laboratory diagnoses at a speed, sensitivity, and breadth never before possible with conventional microbiology.4

RDTs are not yet a replacement for bacterial and fungal cultures with antimicrobial susceptibility testing, but they provide information about the clinical presentation and assist empiric antimicrobial selection by allowing the prediction of susceptibility patterns based on local antibiograms. However, there still may be drawbacks associated with RDTs, including cost and potential overuse, indicating stewardship strategies may offer a beneficial role.4 Within the structure of health care organizations, antimicrobial stewardship programs (ASPs) have demonstrated their immense value through the improvement of clinical outcomes and mitigation of adverse events with the optimization of antimicrobial use.5,6 Hospital ASPs have improved the rates of infection cures and combat challenges with Clostridioides difficile infections, antimicrobial resistance, adverse effects, length of stay (LOS), and costs.6-8 For new diagnostic tests, a rapid turnaround time for pathogen identification and accurate interpretation of susceptibility results are essential for appropriate selection of antimicrobial therapy.9 ASPs may be

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exploited to correctly interpret and rapidly communicate results, directing clinicians to appropriate adjustment of antimicrobial therapy.10 RDTs combined with ASP intervention, particularly for bloodstream infections (BSIs), have provided consistently meaningful results on antimicrobial optimization and patient outcomes.1,2 Additionally, ASP guidelines have deemed rapid testing for broad panels of respiratory viruses as an important intervention to reduce the inappropriate use of antibiotics.11 Since RDTs are complex interventions influenced by clinical context, patient flow, access, and timing, there should be emphasis on deriving their maximal benefit through optimizing the implementation of efficient evidence-based ASP interventions.2,12,13 Although RDTs may provide a promising level of diagnostic accuracy, combination with routine ASP efforts is imperative to observe translational outcomes.2,14-16 It is important to keep in mind that evaluations of the clinical efficacy of RDTs beyond BSIs are still evolving as we discuss novel RDTs and their performance with current diagnostic stewardship practices.12

Blood The management of BSIs and blood culture contaminants (eg, coagulase-negative staphylococci) has been fundamentally changed by molecular RDT by providing actionable information much earlier than conventional cultures. Matrix-assisted laser desorption/ionization time of flight, or MALDI-TOF (eg, bioMérieux, BD Bruker), polymerase chain reaction (PCR)-based technologies (eg, BioFire FilmArray BCID, GenMark ePlex BCID), nanoparticle probe technology (eg, Verigene BC-GP and BC-GN) have been associated with decreases in time to effective therapy, hospital LOS, and mortality when paired with ASP interventions.2 Table 1 presents a comprehensive chart of currently used blood RDTs regarding sample type required, turnaround time, pathogen identification, resistance gene detection, and susceptibility testing. In a cost-effectiveness analysis, benefits of molecular RDTs in BSIs have been observed.14 Interestingly, there is a strong synergism between stewardship and RDT being highlighted by these data, in that RDT has an 80% chance of cost-effectiveness with ASP but only 41.1% in its absence. The introduction of the Accelerate Pheno system (Accelerate Diagnostics), an automated rapid phenotypic testing system, has created further potential changes in the management of BSIs. This system can yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after a positive blood culture. Compared with routine methods, overall sensitivity and specificity for the identification of organisms and essential agreement and categorical agreement for antimicrobial

IDSE.NET

susceptibility were 95.6%, 99.5%, 95.1%, and 95.5%, respectively.17 Recently, several studies have explored the Accelerate Pheno system coupled with ASP intervention. A randomized controlled trial of patients with gram-negative BSIs combined with prospective audit and feedback demonstrated significantly faster antibiotic changes (median decrease of approximately 25 hours for gram-negative antibiotics; P<0.001) and antibiotic escalation (median decrease of about 43 hours; P=0.01) with Accelerate Pheno, but there were no differences in clinical outcomes, including hospital LOS and mortality compared with culture-based methods.18 Three quasi-experimental, before-and-after observational studies that analyzed integration of Accelerate Pheno with ASP intervention had variable results in patient outcomes. Median time to optimal or targeted therapy and step-down antimicrobial therapy were significantly shorter with the use of Accelerate Pheno, but LOS and duration of therapy (DOT) were not consistently shorter, despite ASP intervention.19-21 Nevertheless, Accelerate Pheno seems to have consistently shown no benefit on mortality compared with culture.18-21 Larger studies with ASP intervention are needed to assess its effect on clinical outcomes. A shortcoming of the Accelerate Pheno system is the lack of resistance gene testing. Bhalodi et al evaluated 40 Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis isolates to understand the correlation between ceftriaxone nonsusceptibility of Accelerate Pheno and extended-spectrum beta-lactamases (ESBL) production. Ceftriaxone categorical agreement of the Accelerate Pheno and broth microdilution was 97.5%.22 The ESBL confirmatory disk test was positive in 84.6% (22/26) of ESBL-producing isolates and negative in 92.9% (13/14) of non–ESBL ± AmpCproducing isolates, resulting in 4 false negatives and 1 false positive.22 ESBL production is well correlated with ceftriaxone nonsusceptibility. In critically ill patients, the ability to optimize therapeutic dosing to maximize pharmacokinetic and pharmacodynamic (PK/PD) parameters in the setting of a known MIC has been associated with improved outcomes.23 Moreover, prospective evaluations of critically ill patients have reflected common underdosing for PK/PD targets.24 Despite variable susceptibility interpretation due to MIC testing, the introduction of rapid phenotypic testing may be important to ASPs as it relates to PK/PD optimization.25 In the United States, candidemia is one of the most common hospital-acquired BSIs, with mortality up to 47%, a rate that can be even higher among patients with septic shock. As much as a 50% reduction in mortality has been associated with prompt initiation of appropriate antifungal therapy and source control. However, this is often delayed due to blood culture insensitivity, prolonged turnaround time (median time to positivity, 2-3 days; range, 1 to ≥7 days) needed to

yield growth, and possibility of negative growth with invasive abdominal candidiasis.26 Considering these limitations, clinicians frequently overuse empiric antifungal therapy for suspected invasive candidiasis—a practice with unproven clinical value.27 The Fungitell ß-D-glucan (BDG) detection assay (Associates of Cape Cod) and the T2Candida Panel (T2 Biosystems) are non-culture diagnostic tests with a shorter turnaround time (8-12 hours), and have entered clinical practice as adjunctive RDTs to cultures.26,28 BDG is a component of the cell wall in Candida species, Aspergillus species, and Pneumocystis jiroveci. Due to cross-reactivity with other organisms, true-positive results have limited specificity for candidemia. False positives may be caused by physiologic changes, selected antimicrobials, hemodialysis, albumin or immunoglobulin therapy, or use of surgical material containing glucan.26 A few studies explored the use of BDG in suspected candidemia and showed de-escalation of antifungal therapy through avoidance and reduction, but they did not incorporate active ASP intervention.29,30 In 2 small single-center cohort studies, BDG combined with ASP intervention showed mixed results in antifungal consumption and clinical outcomes of patients with suspected or proven invasive candidiasis. Overall antifungal use was not consistently reduced, and improvements in clinical failure rate and mortality may have been influenced by choice of antifungal, dosage adjustments, source removal, and further workup of invasive candidiasis as recommended by the respective ASP interventions.31,32 Molecular Candida platforms, such as the T2Candida Panel by T2 Biosystems and Karius Test by Karius detecting Candida species DNA from whole blood,

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IDSE Review

Rapid diagnostic tests provide a wealth of information to providers, enabling them to act more quickly than before.

have emerged. Sensitivity and specificity seem to be much more promising compared with blood cultures, at 91% and 99%, respectively, but the role of the T2Candida Panel in the early diagnosis and management of candidemia remains unclear.26,33 In 3 retrospective single-center cohort studies, the T2Candida Panel was evaluated with active ASP intervention in adults with suspected or proven candidemia. Time to appropriate therapy decreased in patients with proven candidemia, while shorter micafungin DOT and cost savings were observed in patients without microbiological evidence of invasive candidiasis. Antifungal discontinuation with negative tests was inconsistent despite antimicrobial stewardship intervention such as prospective audit and feedback being performed on negative results.34-36 Bomkamp et al found that overall antifungal DOT improved after implementation of the T2Candida Panel, but the use of micafungin continued to decline after the panel was removed, likely due to the concomitant increased stewardship resources including physician-directed prospective audit and feedback around implementation. In contrast, Steuber et al observed antifungal discontinuation with negative tests to be unexpectedly low even with pharmacist-driven prospective audit and feedback. In the regression model, in the ICU, LOS predicted failure to discontinue antifungal therapy within 48 hours of negative results (odds ratio [OR], 0.96; 95% CI, 0.94-0.99; P=0.002).35 Perhaps these findings imply that the stewardship potential of the T2Candida Panel, if any, is heavily contingent on the effectiveness of the ASP intervention, as clinicians are particularly apprehensive about de-escalation in patients already at substantially high risk for fungal infections. The performance of the T2Candida Panel on whole blood specimens for detection of intraabdominal candidiasis (IAC) was recently assessed. IAC is another indication with high mortality rates if antifungal treatment is delayed but that decision is limited by low sensitivity and slow turnaround of intraabdominal cultures.37,38 Blood cultures remain the gold standard for invasive candidiasis but are typically sterile in more than 80% of patients with IAC.37,38 In 48 highrisk patients for IAC, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the T2Candida Panel relative to blood cultures were 33%, 93%, 71%, and 74%, respectively.39 IAC was present, diagnosed by intraabdominal culture, in 100% of cases with concordant positive T2Candida/BDG but absent in 90% of concordant negative results.39 More study is needed to determine whether the T2Candida Panel has a role in the diagnosis of IAC and other types of invasive candidiasis. By detecting bacterial DNA by T2 magnetic resonance from whole blood, the T2Bacteria Panel by T2 Biosystems recently made its debut to improve early initiation of appropriate antibiotic therapy in BSIs. The

IDSE Review

Table 1. Current Blood Rapid Diagnostic Tests Blood FilmArray Blood ePlex Blood Culture Culture Identification Identification (BioFire) (GenMark)

Test Sample type Turnaround time

Positive blood culture 1h

Verigene Blood Culture Test (Luminex)

Accelerate Pheno (Accelerate Diagnostics)

T2BacteriaPanel (T2 Biosystems)

T2CandidaPanel (T2 Biosystems)

Positive blood culture

Direct from whole blood

2.5 h

Identification: 2 h Susceptibility: 7 h

3-5 h

Positive Positive blood culture blood culture 1.5 h

Gram-positive (GP) pathogen Bacillus cereus group

Bacillus subtilis group

Corynebacterium

Cutibacterium acnes

Enterococcus spp.

Enterococcus faecalis

Enterococcus faecium

Lactobacillus

Listeria spp.

Listeria monocytogenes

Micrococcus species

X X

Staphylococcus spp.

Staphylococcus aureus

Staphylococcus epidermidis

Staphylococcus lugdunensis

X X

Streptococcus spp

Streptococcus agalactiae

Streptococcus anginosus

Streptococcus pneumoniae

Streptococcus pyogenes

mecA

mecC

vanA

vanA/B

Resistance genes

GP susceptibility

Yes

Gram-negative (GN) pathogen Acinetobacter spp.

Acinetobacter baumannii

Bacteroides fragilis

X X

Citrobacter spp.

Cronobacter sakazakii

Escherichia coli

Enterobacter spp Enterobacter cloacae complex Enterobacter (non-cloacae complex)

IDSE.NET

X X

Fusobacterium nucleatum

Haemophilus influenzae

IDSE Review

Fusobacterium necrophorum

Klebsiella spp.

Klebsiella aerogenes

Klebsiella oxytoca

Klebsiella pneumoniae

Morganella morganii

Neisseria meningitidis

Proteus spp.

Proteus mirabilis

X X

Pseudomonas aeruginosa

Salmonella

Serratia marcescens

Stenotrophomonas maltophilia

CTX-M

IMP

KPC

mcr-1

NDM

OXA-48-like

Serratia spp

Resistance genes

OXA

Candida albicans

Candida auris

VIM GN susceptibility

Yes

Fungal pathogen (FP)

Candida dubliniensis

Candida famata

Candida glabrata

Candida guilliermondii

Candida kefyr Candida krusei

X X

Candida lusitaniae

Candida parapsilosis

Candida tropicalis

Cryptococcus gattii Cryptococcus neoformans

X X

Fusarium Rhodotorula FP susceptibility

X X X

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

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T2Bacteria Panel’s sensitivity and specificity, paired with a single set of blood cultures, in diagnosing BSIs caused by Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Pseudomonas aeruginosa, and E. coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%-91%), respectively.40 The NPV was 99.7%. Limited to only 5 bacteria, sensitivity and specificity for any organism was 43% (95% CI, 32%-54%) and 89% (95% CI, 87%-91%), respectively. Time from initiation of testing to detection and identification of pathogens was shorter for the T2Bacteria Panel (mean, 7.70 hours) than blood cultures (71.7 hours). Of concern, a 10% false-positive rate was observed for its targeted organisms.40 A small prospective, noninterventional T2Bacteria Panel clinical study in the emergency department demonstrated that the panel, relative to blood culture, showed a 100% positive percent agreement (PPA) and 98.4% negative percent agreement (NPA).41 Compared with blood culture, the T2Bacteria assay identified bacteria on average 56.6 hours faster with the potential to de-escalate therapy, reduce time to species-directed therapy, and reduce time to effective therapy.41 Although the T2Bacteria assay appeared to have detected 25% more positives than blood culture, deemed to be associated with evidence of infection, true positivity remains unclear.41 A recent substudy of a larger prospective, multicenter clinical trial evaluated the significance of positive T2Bacteria cases when blood culture was negative to gain a better understanding of whether these results were false positives or potentially associated with an infection. In 233 participants, 20 patients were identified with 21 (9%) discordant results. Eleven cases (52.5%) had

probable BSI, 4 (19%) had possible BSI, and 6 (28.5%) were presumptive false positives.42 Among the probable and possible BSIs, discrepancies appeared to be associated with closed space and localized infections (majority, pyelonephritis and abscess) and recent use of active antimicrobial agents.42 Further prospective, ideally interventional, studies are needed to justify its role along with ASPs in patient care.43 The Karius Test has offered a new potential tool in the antimicrobial stewardship armamentarium of microbiologist testing. This novel metagenomic microbiological diagnostic test uses next-generation sequencing (NGS) of microbial cell-free DNA in plasma, which is able to identify 1,250 bacteria, fungi, parasites, and viruses.44,45 Although currently clinical data are fairly limited, this new technology has shown promise in diagnosing and identifying causative infectious etiologies for pneumonia, bacteremia, infective endocarditis, and general sepsis, despite pretreatment with antibiotics. Its role may be useful in immunocompromised hosts with febrile neutropenia to curb delay of targeted treatment and prolonged broad-spectrum antimicrobial use where a broader range of pathogens may be associated with illness. Given its noninvasive nature, NGS has been coined with the term “liquid biopsy” for the diagnosis of invasive mold infection (IMI). The performance of NGS for specifically IMI in immunocompromised patients, the majority being hematopoietic cell transplant recipients and leukemia/lymphoma patients, was evaluated in 3 studies. NGS was able to detect both biopsy-proven/probable Aspergillus and non-Aspergillus IMI with a sensitivity of 51%.46-48 The specificity and PPV were estimated to

RDTs not only show promise in managing bacterial infection, but also for viral and fungal infections.

IDSE.NET

Respiratory Respiratory Viral Panels In the United States, pneumonia has been a major contributor to morbidity and mortality, with estimates of 63,000 deaths and 1.2 million hospitalizations annually.49,50 The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selecting agents targeted to the major treatable respiratory bacterial pathogens.51 However, systematic surveillance studies indicate that patients hospitalized for suspected CAP are more than twice as likely to harbor respiratory viruses than bacteria.52-54 There is difficulty in distinguishing between bacterial and viral etiologies in lower respiratory tract infections (LRTIs) because of similar manifestations, leading to the common overuse of antibiotics.55 In patients with isolated viral pneumonia, antibiotic therapy may be safely withheld if these infections can be easily identified from those with concomitant bacterial etiology.56 Procalcitonin (PCT) is a component of the innate proinflammatory response that is released in reaction to a bacterial challenge, discriminating between viral and bacterial infections.57 A Cochrane review demonstrated a 2.4-day reduction in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15 days; P<0.001), a lower risk for antibiotic-related adverse effects (16.3% vs 22.1%; adjusted OR, 0.68; 95% CI, 0.57-0.82; P<0.001), and significantly lower mortality (8.6% vs 10.0%; adjusted OR, 0.83; 95% CI, 0.70-0.99; P=0.037) with a PCT-guided antibiotic stewardship algorithm in adults with acute respiratory infections (ARIs) compared with usual care, respectively.58 Yet, clinicians cannot rely solely on PCT to guide antibiotic treatment decisions, based on findings from a multicenter, prospective surveillance study of adults hospitalized with CAP. A PCT threshold allowing perfect discrimination between viral and bacterial detection could not be identified.59 Results were further supported by a meta-analysis of CAP patients, demonstrating that the PCT sensitivity and specificity are too low and variable to provide reliable evidence to enable clinicians to confidently address whether the infection is bacterial and antibiotics need to be administered, or whether it is viral and antibiotics may be withheld.60 The ATS/IDSA guidelines for the diagnosis and treatment of adults with CAP recommend empiric antibiotic therapy be initiated in adults with clinically suspected and radiographically confirmed CAP regardless of initial serum

PCT level.51 Furthermore, PCT use does not consistently reduce antibiotic days in patients with LRTIs compared with usual care, likely as a consequence of subpar adherence to the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback.55 Given the mixed results on PCT efficacy, respiratory viral PCR assays, FilmArray Respiratory Panel 1 & 2 by BioFire Diagnostics, XT-8 Respiratory Viral Panel and ePlex Respiratory Pathogen Panel 1 & 2 by GenMark Diagnostics, NxTAG Respiratory Pathogen Panel and Verigene Respiratory Pathogens Flex Test by Luminex, may be useful as an adjunctive RDT. As an important intervention to reduce the use of inappropriate antibiotics, antimicrobial stewardship guidelines advocate rapid testing for broad panels of respiratory viruses.11 In a multicenter, retrospective cohort analysis of adults admitted with suspected pneumonia in 179 hospitals nationwide, only 24.5% (40,787/166,273) were tested for respiratory viruses, with the majority tested for influenza.61 Viral assays were positive in 12.6% (5,133/40,787), typically for influenza and rhinovirus.61 Antibacterial courses were significantly shorter for virus-positive versus negative patients overall (mean, 5.5 vs 6.4 days; P<0.001) but varied by bacterial testing: 8.1 versus 8.0 days (P=0.60) if bacterial tests were positive; 5.3 versus 6.1 days (P<0.001) if bacterial tests were negative; and 3.3 versus 5.2 days (P<0.001) if bacterial tests were not obtained (interaction, P<0.001).62 A minority of patients were tested for a fraction of the potential respiratory viruses. Patients with positive viral tests often received a prolonged duration of unnecessary antibacterial courses even with concurrent negative bacterial tests. Nonetheless, viral testing may have affected antibacterial use as patients with positive viral results were treated for 0.9 fewer days than those with negative viral results despite being generally older and sicker. The IDSA’s Diagnostics Committee suggests that the combination of respiratory viral testing and PCT may be more likely to exclude bacterial coinfection with confidence in a meaningful period.12 In 2 multicenter, quasi-experimental studies, the respiratory viral panel (RVP) combined with PCT and either direct or indirect (automated best practice alert) ASP intervention had a higher proportion of antibiotic discontinuation or de-escalation, and significantly reduced antibiotic days of therapy (mean, 2.2 days [5.8 vs 8.0 days; P<0.001]).62,63 In the absence of ASP intervention, previous evidence observed low rates of antibiotic discontinuation in patients with negative PCT and positive RVP.64 In particular, findings from Moradi et al emphasize the importance of its real-world implementation strategy by leveraging indirect ASP intervention through an automated alert that may be especially useful for minimal resource settings.62,65 Reduction in antibiotic DOT observed with a RVP and PCT combination with a varying level of ASP

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

IDSE Review

be 100% based on no findings of false positives in 19 controls.47 The NPV was estimated to be 81% to 99%.46 NGS combined with serum galactomannan yields an improved sensitivity of 84% for patients with proven/ probable IMI.46 Future larger studies are needed to validate the sensitivity and specificity of this approach.

IDSE Review

intervention appears to be similar, if not greater, and more consistent compared with solely PCT or RVP utilization with ASP intervention, but more robust headto-head comparisons are needed to confirm such speculations.55,58,62,63,66

Lower Respiratory Tract Infection Panels The BioFire FilmArray Pneumonia Panel and Curetis Unyvero Lower Respiratory Tract (LRT) Panel are multiplex syndromic molecular testing panels for LRTIs, recently approved by the FDA. Compared with conventional microbiology cultures, these panels provide increased sensitivity and detect the presence of resistance markers with a turnaround time of 1 to 5 hours. The BioFire FilmArray Pneumonia Panel identifies 8 viruses, 8 resistance genes, 3 atypical bacterial targets using qualitative targets, and 15 bacterial targets with semiquantitative analysis, which facilitates the evaluation of infection versus colonization. The Curetis Unyvero LRT Panel detects 29 bacterial pathogens and 19 resistance genes. Both panels are compatible with multiple specimen types (sputum, endotracheal aspirates, bronchoalveolar lavage fluid). Although clinical specificity may be improved with semiquantitative analysis, neither molecular testing panels nor culture distinguish airway colonizers from invasive pathogens. Molecular testing for bacterial pathogens was not addressed by the current CAP or hospital- or ventilator-associated pneumonia guidelines, as their potential effect on clinical decision making are not yet determined.51,67 A downstream effect of paradoxically increasing antimicrobial use should be considered as a possibility. The BioFire FilmArray Pneumonia Panel demonstrates a PPA and NPA of 98.1% and 96.2%, respectively, for the identification of bacterial targets in bronchoalveolar lavage specimens compared with culture.68 Similarly, a high overall agreement of 99.2% (95% CI, 98.4%-99.6%) for viral detection is observed between the BioFire pneumonia panel and culture.69 In 396 endotracheal or bronchoalveolar lavage specimens, Rand et al found a sensitivity of 97.8% (95% CI, 94.3%-99.4%), specificity of 80.4% (95% CI, 74.5%85.4%), PPV of 80% (95% CI, 75.5%-84%), and NPV of 97.8% (95% CI, 94.3%-99.1%) with the BioFire panel for bacterial pathogens compared with culture. The panel's semiquantitative copy numbers were strongly correlated with the report of white blood cells on initial Gram stain and conventional bacterial semiquantitation.70 Bacterial targets discovered by the panel, not found in culture, had significantly higher levels of

white blood cells reported on Gram stain, suggesting a host response and potential pathogenicity.70 Likewise, Kolenda et al observed 100% sensitivity and 88.4% to 100% specificity with the panel in 99 SARS-CoV-2 patients compared with culture.71 Of concern, 60.5% of bacterial targets reported using the panel were not recovered by culture and 76.9% of discordant results corresponded to bacteria belonging to commensal oral flora and/or report with 105 copies/mL or lower bacterial nucleic acids.71 The BioFire panel’s sensitivity may be useful to rule out bacterial coinfections and avoid inappropriate prescribing of antibiotics, but positive results should be interpreted with caution. Although the BioFire panel can detect resistance genes with concordance with results by culture, CTX-M and carbapenemase genes could not be definitively linked to the microorganism(s) detected.72 Thus, the panel results should be used with culture results to confirm susceptibility or resistance. The Curetis Unyvero LRT Panel reported comparable diagnostic accuracy. Klein et al found an overall PPA and NPA for culture of 93.4% and 98.3%, respectively, but 21.7% of specimens had additional potential pathogens identified by the panel. PPV for antibiotic resistance markers compared with antibiotic susceptibility testing ranged from 80% to 100%.74 Interpretation challenges were similarly noted for the Curetis panel; not all genes could be attributed to an organism, highlighting the essential continuation of current culture methods with antimicrobial susceptibility testing.75 Pickens et al reported an overall sensitivity of 85.7% (95% CI, 82.3%-88.7%) and specificity of 98.4% (95% CI, 98.2%-98.7%), with an NPV of 97.9% (95% CI, 97.6%-98.1%) relative to culture.76 Results predicted antibiotic de-escalation from unnecessary methicillinresistant S. aureus (MRSA) and P. aeruginosa coverage in 65.9% (405/615) of patients.76 Challenges with interpretation of newer RDTs, especially with resistance genes, may be potentially mitigated by ASP intervention, requiring further exploration.

In addition to their effect on outcomes, RDTs offer a cost savings.

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Clinical Utility of Surveillance Screening MRSA Nasal PCR The MRSA nasal PCR, Cepheid GeneXpert SA Nasal, has become a robust ASP tool for de-escalation from MRSA therapy, such as vancomycin and linezolid, mainly in patients with suspected or confirmed pneumonia. Evidence for the MRSA nasal PCR to rule out MRSA pneumonia repeatedly demonstrated an NPV of greater than 95%.77 Thus, the current CAP guidelines recommend the routine use of the MRSA nasal PCR for

Gastrointestinal Panels Syndromic panels, FilmArray Gastrointestinal Panel (BioFire), xTAG Gastrointestinal Pathogen Panel (Luminex), and Verigene Enteric Pathogens Test (Luminex), have been developed to identify causative pathogens of infectious diarrhea that may be part of the wide differential diagnosis. Conventional testing with stool cultures has subpar sensitivity with a turnaround time of 3 to 5 days.9 These rapid panels are highly sensitive; encompass a broad range of community-acquired bacterial, viral, and parasitic pathogens in the United States; and typically yield results in 1 to 5 hours. However, most infectious diarrhea is self-limiting, treatment is not recommended, and most targets lack associated antimicrobial treatment. Negative consequences of this molecular platform may be introduced through inclusion of several targets of questionable significance, including enteropathogenic E. coli (EPEC), C. difficile, and low-incidence targets, and further exacerbated by its nonquantitative nature.86 Additionally, specimens are often positive for multiple targets, creating further difficulty in treatment selection.87 EPEC is one of the most frequently positive targets, followed by C. difficile, but may represent colonization and lead to unnecessary treatment due to its prevalence in adults in the United States.87,88 The inclusion of C. difficile toxin raises serious concern as C. difficile colonizes more than half of children younger than 12 months of age and 5% to 10% of

asymptomatic adults.89 Since detection does not differentiate between infection and colonization, testing should only be performed in the appropriate clinical context, paving the way for diagnostic and ASP partnerships.4,86 Development of clinical criteria for testing, selective reporting of results, and maintenance of separate testing methods for C. difficile are potential ASP strategies to mitigate incidental detection and inappropriate subsequent treatment.90 Although data have shown a modest decrease in the number of antibiotic days, antibiotic prescriptions, imaging studies, hospital LOS, and hospitalization cost with panel testing, these studies were retrospective without ASP intervention.91,92 In a prospective observational single-center study, Keske et al reported that the panel, after ASP intervention, educational meetings and activities with providers, decreased antibiotic use compared with pre-ASP intervention (42.9% vs 25.8%, respectively; P=0.023).88 Robust studies with diagnostic stewardship are needed to fully capture the impact of these panels on hospital clinical and financial outcomes.

Central Nervous System Panel Central nervous system (CNS) infections are associated with significant morbidity and mortality, requiring timely medical management including rapid identification of infectious etiology and administration of antimicrobial therapy. Bacterial meningitis and viral encephalitis rely heavily on cerebrospinal fluid (CSF) examination performed after lumbar puncture. In bacterial meningitis, CSF cultures are positive in 70% to 85% of patients who have not received previous antimicrobial therapy, but cultures may take up to 48 hours for organism identification.93 For viral encephalitis, more than 10% of patients can have normal CSF findings, and isolation of viral causes by CSF cultures provides limited value.95 Current meningitis and encephalitis treatment guidelines support the adjunctive use of multiplex molecular diagnostics to establish the specific etiology of infection.93,94 The FilmArray Meningitis/Encephalitis Panel (BioFire) tests for 14 common community-acquired bacterial (E. coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae), viral (cytomegalovirus, enterovirus, herpes simplex virus 1 [HSV-1], HSV-2, human herpesvirus 6, human parechovirus, varicella zoster virus), and fungal (Cryptococcus neoformans/gattii) pathogens in about 1 hour. The panel may be most useful for excluding the diagnosis of bacterial meningitis with its 100% sensitivity and NPV.93,95 Despite the speed and ease of use for this panel, subpar performance issues have been raised, such as false positives particularly for S. pneumoniae,77 variable sensitivity for HSV,97 and inferior sensitivity for Cryptococcus compared with antigen testing.98,99 Patient outcomes, LOS, and antimicrobial duration

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the de-escalation of MRSA coverage.51 The implementation of this tool combined with ASP intervention has been associated with a median reduction of 2.1 days of vancomycin (P<0.01).78 Vancomycin avoidance in suspected or confirmed pneumonia with MRSA nasal screening among ICU patients has been associated with a cost avoidance of $108 per patient based on the cost of surveillance testing, vancomycin, and vancomycin therapeutic drug monitoring levels.79 During implementation, the ability of the MRSA nasal PCR to hold its NPV for 7 days after result and vancomycin exposure lacking effect on results of testing should be recognized.80,81 The clinical utility of the MRSA nasal PCR appears to extend to other indications, such as skin and soft tissue infections (SSTIs).82 A national Veterans Affairs system study supported this notion in the largest cohort to date including 561,325 clinical cultures.83 A high overall NPV was observed for all infection types (96.5%) and specific infections such as BSIs (96.5%), intraabdominal infections (98.6%), respiratory infections (96.1%), SSTIs (93.1%), and urinary tract infections (99.2%).83 Conversely, despite gramnegative resistance surveillance using rectal swab testing (eg, Streck ARM-D resistance detection kits) being standard infection prevention and control practice, its clinical utility for antimicrobial decision making has yet to be determined.84,85

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Table 2. Selected Rapid Diagnostic Test for Outpatient Respiratory Results Respiratory (Outpatient) Rapid Diagnostic Test

Method

Targets

Turnaround Time

CLIA Status

FilmArray Respiratory Panel EZ (BioFire)

PCR assay

4 bacteria, 15 viruses including SARS-CoV-2

45 min

Waived

ID NOW (Abbott)

Isothermal nucleic acid amplification

Influenza A and B RSV Strep A2

2-13 min

Waived

BinaxNOW (Abbott)

Immunochromatographic assay

Influenza A and B RSV Strep A2

6-15 min

Waived

BD Veritor Plus (BD)

Chromatographic immunoassay

Influenza A and B RSV Strep A2

<6-11 min

Waived

Cobas Liat PCR (Roche Diagnostics)

Real-time PCR amplification

Influenza A/B Influenza A/B and RSV Strep A

<15 min

Waived

Xpert Xpress (Cepheid)

Real–time PCR amplification

Flu Flu/RSV Strep A

18-20 min

Waived/ moderate

CLIA, Clinical Laboratory Improvement Amendments; PCR. polymerase chain reaction; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Strep A2, group A Streptococcus.

surrounding implementation of the panel are limited with inconsistent results.100,101 Further analytical and clinical validation, possibly with an ASP approach, may be beneficial as the panel falls short as a stand-alone test, thus requiring additional confirmation.102

Outpatient Antimicrobial Prescribing and Diagnostic Potential Respiratory Although the target for ASPs has been primarily in the inpatient setting, the importance of ASPs in the outpatient setting is increasingly recognized, leading to the release of the CDC’s Core Elements of Outpatient Antibiotic Stewardship.103 Based on population database evaluations in the United States, at least onethird of antimicrobial prescribing is considered inappropriate, attributed to mainly respiratory infections.104 Interventions such as C-reactive protein testing, shared decision making, and PCT-guided management have shown potential to influence primary care ARI prescribing behavior in a systematic review. The utility of outpatient RDTs is evolving, but conclusions cannot be drawn from studies of low or very low quality.105 Molecular point-of-care testing, with ID NOW and BinaxNOW (Abbott), Cobas Liat PCR (Roche Diagnostics), Xpert Xpress (Cepheid), BD Veritor Plus (BD), and FilmArray Respiratory Panel EZ (BioFire), is widely available in the outpatient setting, but their use is limited by regulations on testing (Clinical Laboratory Improvement Amendments [CLIA] waivers) and logistical circumstances of achieving practical turnaround time during primary care visits. Table 2 shows

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a summary of outpatient respiratory RDTs with testing method, bacterial or viral targets, turnaround time, and CLIA status. In a study comparing the performance of ID NOW 2, Cobas influenza A/B nucleic acid test, and Xpert Xpress Flu for Flu A and Flu B, the overall sensitivities were 93.2%, 100%, and 100%, and 97.2%, 94.4%, and 91.7%, respectively. The specificity for Flu A and Flu B by all methods was greater than 97%.106 These tests outperformed the sensitivity of the BD Veritor Flu A/B antigen test, which were 79.5% for Flu A and 66.7% for Flu B. In contrast, BD Veritor Flu A/B antigen test compared with BinaxNOW influenza had higher sensitivity (89.6%; 95% CI, 82.2%-94.3% vs 72.4%; 95% CI, 63.2%80.0% and 98.8%; 95% CI, 92.6%-99.9% vs 100%; 95% CI, 94.5%-100.0%) in the detection of Flu A and Flu B, respectively.107 The FilmArray Respiratory Panel EZ (RPEZ) was demonstrated to significantly influence the appropriate use of antibiotics and was associated with a decrease in clinic appointment duration in the outpatient pediatric clinic setting.108 Although promising, these results are very likely limited by its turnaround time of approximately 1 hour compared with the other tests. Additionally, there is uncertainty whether the implementation of RPEZ would reduce the use of downstream health care resources, including radiological and laboratory tests, telephone calls, and follow-up appointments.109 In the outpatient setting, the significance of rapid turnaround time cannot be overemphasized as this determines whether results are clinically actionable. Post hoc analysis of randomized controlled trial data

Conclusion As the realm of infectious diseases management continues to evolve, RDTs are increasingly recognized for their impact on clinical outcomes, antimicrobial use, and cost savings. For the management of BSIs, invasive candidiasis, respiratory infections, infectious diarrhea, CNS infections, and outpatient respiratory infections, there is a multitude of technological advances. Along with implementation of efficient evidence-based ASP interventions, many of these RDTs show promise in their potential to improve patient care.

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About the Author Karen Fong, PharmD, BCIDP, is a clinical pharmacist, Infectious Diseases and Antimicrobial Stewardship, Department of Pharmacy, at the University of Utah Health, in Salt Lake City, Utah.

Data on HIV Prevention BY SARAH MICHIENZI, PHARMD, BCPS, AAHIVP, AND ERIC WENZLER, PHARMD, BCPS, BCIDP, AAHIVP

omparisons have been made between the public health response to COVID-19 and the early days of the HIV epidemic.1 As with COVID-19, messaging regarding HIV risk and severity is of utmost importance. Many do not believe they will contract the viruses; or if they do, they will not develop severe illness. Additionally, there is not a one-size-fits-all approach to preventing infection with either virus. We know masking, handwashing, and physical distancing help prevent the spread of COVID-19.2 However, not all people are able to adequately physically distance due to factors such as crowded living environments and performing essential job functions. Similarly, we know correct and consistent condom use and adherence to oral pre-exposure prophylaxis (PrEP) with emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) or FTC-tenofovir alafenamide (FTC/TAF; Descovy, Gilead) are both highly effective in preventing HIV.3 However, not all people are willing to use condoms or able to negotiate for their use successfully. Additionally, not all people are able to adhere to daily medication, and some have contraindications to FTC/TDF and FTC/TAF. Achieving the goal of a 75% reduction in new HIV infections by 2025 and at least a 90% reduction by 2030, as set forth in the federal program “Ending the HIV Epidemic: A Plan for America,” requires a multifaceted approach that targets the highest-risk populations.4 The initiative calls for ramping up diagnosis, treatment, prevention and outbreak response efforts. It is estimated that fewer than 25% of people who could benefit from PrEP are using it. Solutions to increase PrEP uptake and adherence/persistence are many. For example, data presented at AIDS 2020 showed that a California PreExposure Prophylaxis Assistance Program contributed to PrEP expansion

by removing financial and structural barriers.5 More pharmacotherapeutic options for PrEP to meet the diverse needs of patients represent another potential solution. One such novel agent is a long-acting injectable integrase strand transfer inhibitor (INSTI), cabotegravir and rilpivirine (CAB/RPV; Cabenuva, ViiV Healthcare/ Janssen).

HPTN 083 HPTN 083 or “Pre-exposure Prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men” was a phase 2b/3 randomized, doubleblind, double-dummy clinical trial.6 The primary efficacy end point was incident HIV infections with CAB/RPV or oral FTC/TDF. The study was stopped early in May 2020 after reaching the prespecified stopping bound of accruing 25% of the end points in an interim analysis, which allowed for the final results to be presented at AIDS 2020. The study continued unblinded and all participants were offered CAB/RPV. Cisgender men and transgender women who have sex with men, at least 18 years of age who met criteria for HIV risk, were generally in good health, and did not have hepatitis or contraindications to gluteal injections

were eligible for inclusion. Notably, cisgender women were not included in HPTN 083 despite the large number of heterosexual women in the United States who could benefit from PrEP. Safety and efficacy of CAB/RPV among cisgender women of sub-Saharan Africa were investigated in a similar study, HPTN 084.7 Results of this study became available in November 2020. Data on adolescents are forthcoming from HPTN substudies 083-01 and 084-01.8 Participants were randomized 1:1 to the CAB/RPV or FTC/TDF arm. In step 1, participants received daily oral CAB or FTC/TDF. This oral lead-in is required before administering the long-acting injectable CAB to ensure tolerability, as it has a long half-life once injected. Injections began in step 2. Participants received injections of CAB/RPV (CAB arm) or matching placebo (FTC/TDF arm) at weeks 5 and 9 and every 2 months after that as well as oral FTC/TDF (FTC/TDF arm) or matching placebo (CAB arm) daily. The study planned for step 2 to last approximately 3 years, at which time injections would be discontinued. Participants in the CAB/RPV arm would receive oral daily FTC/TDF for 1 year in step 3 to reduce the risk for HIV acquisition in the presence of subtherapeutic levels of CAB/RPV.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2021

The primary efficacy cohort included 2,243 and 2,247 participants in the CAB/RPV and FTC/TDF arms, respectively. Transgender women represented 12.4% of the total study population, and most were between the ages of 18 and 29 years. There were study sites in the United States, Latin America, Asia, and Africa, and nearly 50% of the U.S. participants were Black.

A multifaceted approach is needed to reach the U.S. goal of a

75% reduction in new HIV cases by 2025, and at least a

90% reduction by 2030. In 6,389 person-years of followup, with a median per-participant follow-up time of 1.4 years (interquartile range [IQR], 0.8-1.9), there were 52 HIV infections: 13 in the CAB arm and 39 in the FTC/TDF arm. Only 5 of the 13 HIV infections in the CAB arm occurred despite continuous ontime CAB/RPV injections. The others occurred after prolonged nonadherence to CAB/RPV (n=5) and during the oral lead-in phase (n=3). Of note, the pooled HIV incidence of 0.81 (95% CI, 0.61-1.07) per 100 person-years observed in the study was considerably lower than the target background HIV incidence of about 4.5%. Although designed as a noninferiority trial, CAB/ RPV met criteria for superiority, with a 66% reduction in HIV acquisition risk compared with FTC/TDF. Similarly, CAB/RPV was shown to be superior to FTC/TDF in women in HPTN 084.7 CAB/RPV was well tolerated overall. Injection site reactions (ISRs) were the primary adverse event (AE), with 80.9% of participants in the CAB arm

IDSE.NET

reporting an ISR. Most were classified as mild (grade 1) or moderate (grade 2), and lasted a median of 3 days (IQR, 2-5 days). There was a strong association between ISR severity and odds of permanent discontinuation, with 27 participants (2.2%) in the CAB arm permanently discontinuing the injection due to an injection-related AE. Grade 2 or higher AEs reported in at least 5% of participants and more frequently in the CAB arm were nasopharyngitis (19.3%), increased blood glucose (9.0%), and pyrexia (5.4%). In contrast, grade 2 or higher decreased creatinine clearance occurred more frequently in the FTC/TDF arm (72.0%), which is an expected result of TDF therapy. Results of HPTN 083 demonstrated the superiority of a novel long-acting injectable INSTI, CAB/RPV, given every 2 months after the initial 2 injections compared with the standard combination of 2 nucleotide reverse transcriptase inhibitors, FTC/TDF, taken orally once daily. It is important to remember that FTC/TDF still performed well in this study and remains a highly effective means of HIV prevention.

Implantable Device At CROI 2021, Merck presented some exciting, but very early results from a phase 1, double-blind, placebo-controlled study of an investigational islatravir subdermal implant for PrEP.9 Twelve people received the implant with 48, 52, or 56 mg of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for 12 weeks. After 12 weeks, the patients were evaluated for an additional 8 weeks. The implant demonstrated a prespecified pharmacokinetic threshhold at 12 weeks across all 3 drug concentrations. The company said it plans to initiate a phase 2 trial to see if the implant could provide long-acting PrEP for up to 12 months.

References

1. Dunleavy BP. Fauci sees similarities between HIV, COVID-19 in public health response. Accessed February 10, 2021. http://bit.ly/3uHstOF-IDSE

2. CDC. COVID-19 vaccination. Accessed February 10, 2021. https://www.cdc.gov/vaccines/ covid-19/index.html 3. CDC. HIV prevention. Accessed February 10, 2021. http://bit.ly/3r8KALl-idse 4. CDC. Ending the HIV Epidemic: A Plan for America. Accessed February 10, 2021. https:// www.cdc.gov/endhiv/index.html 5. Peters P, Nakamur A, Barraza A, et al. The California pre-exposure prophylaxis assistance program: lessons learned during an initial expansion of services. Presented at: AIDS 2020: Virtual; July 6-10, 2020. Abstract PEC0622. Accessed February 17, 2021. http://bit.ly/3uKj3Cc-IDSE 6. Landovitz R, Donnell D, Clement M, et al. HPTN083 interim results: pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is safe and highly effective for cisgender men and transgender women who have sex with men (MSM, TGW). Presented at: AIDS 2020: Virtual; July 6-10, 2020. Abstract OAXLB01010. Accessed February 10, 2021. http://bit.ly/30kOJjL-idse 7. HIV Prevention Trials Network. HPTN 084 study demonstrates superiority of CAB LA to oral FTC/TDF for the prevention of HIV. Accessed February 10, 2021. http://bit.ly/2OEK6hu-IDSE 8. HIV Prevention Trials Network. HPTN studies. Accessed February 10, 2021. https://www. hptn.org/index.php/research/studies 9. Patel M, Zang X, Youfang C, et al. Islatravir (ISL) PK threshold & dose selection for monthly (QM) oral HIV-1 PrEP. CROI 2021 Virtual. March 6-10. Presentation 1167. https:// www.vcroi2021.org/live-stream/19762731/ HIV-TREATMENT-AND-PREVENTIONNEW-OPPORTUNITIES-TO-OPTIMIZEDRUG-DOSING-ADHERENCE-AND-ANTIRETROVIRAL-THERAPY

The authors reported no relevant financial relationships.

About the authors: Sarah Michienzi, PharmD, BCPS, AAHIVP, is a clinical assistant professor and clinical infectious disease pharmacist in the Pharmacotherapy Section, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois. Eric Wenzler, PharmD, BCPS, BCIDP, AAHIVP, is an assistant professor in the Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.

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