Infectious Disease Special Edition - Spring 2022 by McMahon Group

Volume 26 • Spring 2022

Casualties of War: COVID-19 & Other Communicable Diseases

COVID-19: Bad Actors Flu Update Is Kaposi Sarcoma Still a Problem?

+ Editorial Reviews From ID Experts: HIV Guidelines, Transplant Medicine, and More

In patients with cIAI... WHEN CHOOSING AN EMPIRIC ANTIMICROBIAL THERAPY

CHOOSE WITH CONFIDENCE The first fully synthetic fluorocycline antibacterial for cIAI1,2 • Broad-spectrum activity against key Gram-negative, Gram-positive, and anaerobic bacteria, including isolates expressing a variety of multidrug resistance mechanisms1 • Maintains activity against certain tetracycline-specific resistance mechanisms3 • Low rates of infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%), as seen in 2 large clinical trials1

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

a wholly owned subsidiary of

La Jolla Pharmaceutical Company

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 or to 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. ©2021 Tetraphase Pharmaceuticals, Inc. All rights reserved. 12/21 PM-ERV-00109-US

Proven as effective as carbapenems in cIAI Efficacy demonstrated as monotherapy1,4-6

Clinical cure rate, %

Non-inferior to ertapenem (IGNITE1) and meropenem (IGNITE4) Clinical cure in micro-ITT population at the TOC visit

100 90 80 70 60 50 40 30 20 10 0

Difference (95% CI) -0.7 (-4.9, 3.6)

88.7

89.3 9

368/415

XERAVA

Difference (95% CI) -0.8 (-7.1, 5.5)

90.8

91.2

198/226

177/195

187/205

Ertapenem

XERAVA

Meropenem

86.8

87.6

385/431 /

191/220

Comparators

XERAVA

POOLED ANALYSIS

Difference (95% CI) -0.5 (-6.3, 5.3)

IGNITE1

IGNITE4

• Concurrent bacteremia was present in 32 patients in the XERAVA® group and 31 patients in the comparator group in the pooled micro-ITT population; the rates of clinical responses were 87.5% for XERAVA and 77.0% for comparators7

XERAVA is a carbapenem-sparing choice for ESBL-related resistance1,8 LEARN MORE AT WWW.XERAVA.COM Study Design: XERAVA was compared with carbapenems in 2 phase 3, randomized, double-blind, active-controlled, multinational, multicenter, prospective studies in 1,041 adult patients with cIAI to demonstrate non-inferiority. Treatment was for 4 to 14 days. The primary efficacy endpoint was clinical response at the TOC visit.1 IGNITE1 compared XERAVA (N=220) 1 mg/kg IV q12h with ertapenem (N=226) 1 g IV q24h.1,5 IGNITE4 compared XERAVA (N=195) 1 mg/kg IV q12h with meropenem (N=205) 1 g IV q8h.1,6

Recommended dosage: 1 mg/kg IV every 12 hours over approximately 60 minutes for 4 to 14 days • No need for dosage adjustments in patients with renal impairment or mild to moderate hepatic impairment (Child Pugh A and Child Pugh B)1 • See full Prescribing Information for dosage adjustments in specific patient populations

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. 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. cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta-lactamase; IGNITE, Investigating Gram-Negative Infections Treated with Eravacycline; ITT, intent-to-treat; IV, intravenous; 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 invformation. Tetraphase Pharmaceuticals, Inc.; Rev. 06/2020. 2. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588. doi:10.1007/s40265-016-0545-8 3. Grossman TH, Starosta AL, Fyfe C, et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob Agents Chemother. 2012;56(5):2559-2564. doi:10.1128/AAC.06187-11 4. Data on file. Watertown, MA: Tetraphase Pharmaceuticals, Inc.; 2018. 5. 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 (IGNITE1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237 6. Solomkin JS, Gardovskis J, Lawrence K, et al. IGNITE4: results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections. Clin Infect Dis. 2019;69(6):921-929. doi:10.1093/cid/ciy1029 7. Felice VG, Efimova E, Izmailyan S, Napolitano LM, Chopra T. Efficacy and tolerability of eravacycline in bacteremic patients with complicated intra-abdominal infection: a pooled analysis from the IGNITE1 and IGNITE4 studies. Surg Infect (Larchmt). 2021;22(5):556-561. doi:10.1089/sur.2020.241 8. Zalacain M, Biedenbach DJ, Badal RE, Young K, Motyl M, Sahm DF. Pathogen prevalence and antimicrobial susceptibility among Enterobacteriaceae causing hospital-associated intraabdominal infections in adults in the United States (2012-2013). Clin Ther. 2016;38(6):1510-1521. doi:10.1016/j.clinthera.2016.04.035

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 XERAVA® (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 or with 5 mL of 0.9% Sodium Chloride Injection, USP, which will deliver the following: a. XERAVA 50 mg vial will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents). b. XERAVA 100 mg vial will deliver 100 mg (20 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. The stability of the solution after reconstitution in the vial has been demonstrated for 1 hour at room temperature (not to exceed 25°C/77°F). If the reconstituted solution in the vial is not diluted in the infusion bag within 1 hour, the reconstituted vial content must be discarded. 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 diluted solutions must be infused within 24 hours if stored at room temperature (not to exceed 25°C/77°F) or within 10 days if stored refrigerated at 2°C to 8°C (36°F to 46°F). 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 Known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or any of the excipients in XERAVA. 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 is 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 +ost-)atal ay 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.

a wholly owned subsidiary of

La Jolla Pharmaceutical Company

Distributed by: Tetraphase Pharmaceuticals, Inc. Waltham, MA 02451 XERAVA® is a registered trademark *! Tetraphase Pharmaceuticals, Inc. ©2021 Tetraphase Pharmaceuticals, Inc. All rights reserved. 1Ɲ/21 PM-ERV-00ƛƜƝ-US

Spring 2022 8

Editorial: Casualties of War

COVID-19 Resurgence, Other Infections and the Loss of Healthcare for 3 Million People

COVID-19 Pandemic Brings Out the Best—and the Worst

ACIP Recommends 2 Vaccines for Some Travelers

Inﬂuenza Rates Head Downward in Early 2022; Flu Season Appears Less Severe Than Anticipated

News Notes: Uncertain Future for 2 Long-Acting HIV Therapies

Novel Research Shedding Light on Fungal Infections

Engaging HIV Patients ... And Then Keeping Them Engaged

How to Manage Care for Aging Patients With HIV

Kaposi Sarcoma Still a Major Contributor to Morbidity, Mortality in Certain HIV Populations

HIV News: Risk for HIV Depends on Who You Are

42 71

5 People Died From Rabies in the U.S. in 2021 Classiﬁeds

IDSE Reviews

Implementing Rapid Diagnostic Tests to Augment Antimicrobial Stewardship Programs: The Time Is Now By Sarah M. Wieczorkiewicz, PharmD, FIDSA, BCPS, BCIDP

What’s New in CMV Prevention and Therapy for Transplant Patients? By Shmuel Shoham, MD, FIDSA

Updates to the 2021 Guidelines for ARV Use in Adults and Adolescents With HIV By Ashley Hoare, MS; Jessica Hoare, MS; and Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

A Multifaceted Strategy to Reduce HIV-Related Stigma and Disparities By Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP

IDSE.NET

2022 Annual Meeting

The Antimicrobial Stewardship Meeting May 18-21, 2022 Hyatt Regency, Orlando Featuring the highly-acclaimed optional Advanced Stewardship Training Program

Scan to learn more or visit mad-id.org/2022-annual-meeting/

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

Debra A. Goff, PharmD

Medical University of South Carolina Charleston, South Carolina

The Ohio State University Wexner Medical Center Columbus, Ohio

Philip A. Brunell, MD

Nancy D. Hanson, PhD

Emeritus, National Institutes of Health Bethesda, Maryland

Creighton University School of Medicine Omaha, Nebraska

Paul P. Cook, MD, FACP, FIDSA James S. Lewis II, PharmD, Brody School of Medicine FIDSA

East Carolina University Greenville, North Carolina

Oregon Health & Science University Portland, Oregon

Brian Currie, MD, MPH

Stuart Campbell Ray, MD, FIDSA

Emeritus, Albert Einstein College of Medicine Johns Hopkins University School of Medicine Monteﬁore Medical Center Baltimore, Maryland New York, New York Thomas M. File Jr, MD, MSc, MACP, FIDSA, FCCP

Summa Health Akron, Ohio Northeast Ohio Medical University Rootstown, Ohio Rajesh T. Gandhi, MD, FIDSA

Harvard University Center for AIDS Research Massachusetts General Hospital Boston, Massachusetts Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

Michael J. Rybak, PharmD, MPH, PhD, FCCP, FIDSA, FIDP

Wayne State University Detroit, Michigan Shmuel Shoham, MD, FIDSA,

Johns Hopkins University Medical School, Baltimore, Maryland Mark H. Wilcox, MD, FRCPath

Leeds Teaching Hospitals NHS Trust University of Leeds Leeds, United Kingdom

Ochsner Health System New Orleans, Louisiana

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EDITOR’S BLOG:

Casualties of War I am sure I am not the only person mesmerized by the images on my screen of the millions of people fleeing Ukraine after the Russian invasion, of the devastation and violence. As an American, I was raised on the story of immigrants making this country the melting pot it is, because generation after generation came to the United States to flee oppression, war and violence. But I didn’t really understand what that meant until the Mariel boatlift in the 1980s. If you don’t remember, Mariel was a mass exodus from Cuba into the United States. I was a staff sergeant in the U.S. Army Reserve at the time, and I helped to process the straggling mass of humanity that entered Florida and were sent to Fort Dix, N.J.: mothers and children, fathers and sons, brothers and sisters, lovers and friends. These were people who had left everything behind to come here, who were tired, scared and uncertain of their futures, and who must have had second thoughts after finding themselves on a military barracks surrounded by soldiers after leaving Cuba. That experience, while just a blip in my life, made a lasting impression because, for the first time, I understood the meaning of what I was taught in our history books. I don’t think I was ever prouder to be an American than during that long weekend of service. I keep being drawn back to that time as I watch the people of Ukraine fleeing the bombs and the terror. I am grateful for the nations accepting them. I feel for them. I pray for them, and I hope that they find peace wherever they land. I worry about their journey. The reports from the World Health Organization are dire. The Russians appear to be attacking civilian targets, such as hospitals, which are typically off limits. There is a lack of clean water, food and medical supplies. Many people are trapped, but others continue to pour over the borders to countries that are already stretched to capacity to handle the refugee influx. And looming over all of this is the COVID-19 pandemic. A serious outbreak could affect not only Eastern Europe but the entire world. I spoke with several experts, as well as attended a WHO virtual press briefing about the pandemic and Ukraine to write the story that begins on page 10. I hope you find the information and views as interesting as I did. Unfortunately, as everyone I spoke to reminded me, war and infections have been closely tied throughout history. Once again, George Santayana’s famous quote haunts us: “Those who cannot remember the past are condemned to repeat it.” —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 Cover Photo: WHO / Marta Soszynska

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Casualties of War

COVID-19 Resurgence, Other Infections and the Loss of Healthcare for 3 Million People BY MARIE ROSENTHAL, MS

ust as the world was taking baby steps toward a return to normal after two years of the COVID-19 pandemic, Russia invaded Ukraine, forcing a tidal wave of more than 3 million refugees into neighboring countries. Along with this humanitarian crisis comes another casualty of war: a possible resurgence of COVID-19 and other infections. “Even if the pandemic hadn’t happened, it is well known that whenever you get mass migration, this favors infectious disease transmission,” said Mark Wilcox, MD, FRCPath, a professor of medical microbiology and the Sir Edward Brotherton Chair of Bacteriology at the University of Leeds, in England, who is also a member of the editorial advisory board of Infectious Disease Special Edition (IDSE). “So, if you look at the history of influenza or the history of meningococcal disease, you get peaks whenever you have mass migration. Unfortunately, it’s very predictable, and this is a mass

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migration where we will almost certainly see a resurgence of COVID-19,” he said.

The Threats After weeks of decline, COVID-19 has started inching back up in Europe. In fact, cases around the world increased 8% by March 14, a reminder that COVID-19 is not over, according to Tedros Adhanom Ghebreyesus, MS, PhD, the director-general of the World Health Organization. “Although reported [COVID-19] cases and deaths are declining globally, and several countries have lifted restrictions, the pandemic is far from over, and it will not be over ‘anywhere’ until it’s over ‘everywhere,’” Dr. Tedros said at a media update. The big unknown is the effect the war in Ukraine will have on the pandemic. Will there be another surge, a new variant of concern, or will this mass migration just allow for efficient

Photos: WHO / Marta Soszynska

Poland

1.5M 1,412,503

transmission of omicron among a largely unvaccinated population and/or among older people with waning immunity? Only 34.5% of Ukraine’s population is fully vaccinated against COVID-19. “I have been fretting about this now for weeks, and I am concerned that the Eastern European countries are under-vaccinated both against influenza and COVID-19,” said William Schaffner, MD, a professor of health policy and preventive medicine in the Department of Health Policy at Vanderbilt University, in Nashville, Tenn. “I am very concerned that the conditions we are seeing— mass refugees, people crowded together—are ideal for the transmission of respiratory viruses and other infections,” he added. Influenza, rhinoviruses and human metapneumovirus are additional threats, Dr. Schaffner noted. Although most of these are relatively minor illnesses, they can be more severe in certain populations, such as those fleeing Ukraine. “We worry most about the very young and the very old, and this refugee population is enriched with these parts of the demographic spectrum,” Dr. Schaffner said. Testing and surveillance for COVID-19 has decreased worldwide, according to the WHO, which is another issue. As the humanitarian crisis continues, it will be harder and harder to do among the refugees. “The likelihood that they will be able to do surveillance for COVID is not great,” admitted Stuart Campbell Ray, MD, a professor of medicine at the Johns Hopkins University, in Baltimore, and a member of the IDSE editorial advisory board. “It would be smart to do some statistical sampling, at least, to detect if an outbreak started to occur because it could be a real challenge. But then whose lab is going handle all that volume? There are a bunch of logistical problems,” Dr. Ray said.

Worsening Situation The untenable situation was exacerbated by Russia’s targeting of hospitals and other medical establishments, according to the WHO. As of March 13, the WHO verified 31 reports of attacks on healthcare facilities in Ukraine since Feb. 24. “I worry about healthcare systems buckling [in Ukraine and receiving countries],” said Rajesh T. Gandhi, MD, a professor of medicine at Harvard Medical School, in Boston. “Obviously, it’s a complicated situation because the war itself is decimating the ability to provide healthcare, and then if you add to that the potential for increasing rates of severe COVID-19, I think it’s a perfect storm of potential problems.” Most healthcare systems are already stretched because of COVID-19, Dr. Wilcox reminded, who is also a consultant and the head of microbiology research and development at Leeds Teaching Hospitals NHS Trust. “In a small country like Poland, I just can image what a [serious] outbreak would do to their healthcare system,” he said.

1.2M

900K

600K

300K

Other European Countries 258,844

Hungary 214,160

Slovakia 165,199

Russian Federation 97,098

Romania 84,671

Moldova 82,762

Belarus 765

Figure. Population movement and displacement of refugees from Ukraine to surrounding countries as of March 9, 2022. Source: WHO

“Your healthcare system is designed to cater to your population, isn’t it? You build as many hospitals” as your population dictates. “The influx of refugees [in Poland] is already about 5% of the entire population, and that is only going to get worse.” The humanitarian emergency is affecting Ukraine, Slovakia, Hungary, Moldova and the rest of Europe, according to the WHO, but the country most affected besides Ukraine has to be Poland, which has taken in most of the refugees. More than 1.4 million people fled to Poland, a country of about 38 million people, between Feb. 24 and March 9, and the numbers are expected to grow exponentially. The United Nations High Commissioner for Refugees estimates that by July 2022, 4 million refugees will leave Ukraine. “We have the health risks of people on the move, mainly women and children,” said Mike Ryan, MPH, MB, BCh BAO, the executive director of the WHO Health Emergencies Programme, an epidemiologist and trauma surgeon, who has been managing acute health risks around the globe for nearly 25 years. “We also have a complex situation with many, many older persons with complex health needs who may not be able to move or cannot move so easily, and getting aid and assistance to them is very important. “We have had circulating vaccine-derived polio, COVID and other diseases previously and currently there. There have been previous epidemics of cholera in Ukraine. All of these risks remain,” Dr. Ryan reminded at the briefing.

So Many Levels of Complexity There are numerous levels of complexity when it comes to infectious disease threats and helping the refugees, according

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

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A small respite for women and children above the central train station tracks in Lviv, Ukraine.

refugees. “At the moment, we haven’t had many [Ukrainian] migrants to the U.K., but we will, and we did this for Afghanistan. We had an active TB screening program for them,” which enabled better treatment, Dr. Wilcox said. “It’s easier to manage if you can screen for it.” Meningococcal disease, as mentioned earlier, is also a concern. Although Ukraine does not have a lot of meningococcal disease, “they aren’t highly vaccinated, and so that would be something that could run through a population pretty quickly and in a devastating way,” Dr. Ray said. Norovirus and other diarrheal diseases are always a concern, according to Vanderbilt’s Dr. Schaffner. “Norovirus is extraordinarily transmissible,” he said. “You wish you were dead for three days and then you recover, but then of course, with dehydration, once again [it disproportionately] affects the very young and very old.” And looming over all of them is the pandemic. Between March 3 and 9, a total of 791,021 new cases of COVID-19 and 8,012 new deaths were reported from Ukraine and the surrounding countries, according to the WHO. However, suboptimal vaccination coverage is not just an issue for COVID-19, according to the WHO situation report. Ukraine has seen recent outbreaks of polio and measles, which could spread. The WHO called for enhanced surveillance for all of these diseases, and recommended that countries plan vaccination campaigns for COVID-19, polio and measles, and other vaccine-preventable diseases, including tetanus. But the ability to deliver these vaccines might be difficult with all that is happening. “Obviously, there is such a fluid situation on the ground right now, that it’s hard to predict a day in advance, much less weeks or months in advance,” Dr. Gandhi said. “I think war and infectious diseases sadly have gone closely together throughout history. We don’t want to see that repeat itself.” ■ The sources reported no relevant financial disclosures.

Photos: WHO / Marta Soszynska

to Dr. Ray, who is also the vice chair of medicine for data integrity and analytics in the Department of Medicine at Hopkins. “For one thing, just the human movement; we could digress and talk about a bunch of infectious diseases that have been seen when there’s large human movements. This sort of crisis is a breeding ground for both endemic and epidemic disease. “Another dimension, of course, is the healthcare system in the arriving site, which is going to be overwhelmed simply by the number of people arriving,” he said. Finally, all refugees with chronic conditions from cardiovascular disease and diabetes to cancer and HIV, who need immediate care and possibly medication and who probably will not have medical records will further increase the healthcare burden, Dr. Ray explained. “We’ve all heard about some of the kids with cancer who are arriving in some neighboring countries and needing care with very few records. That just illustrates the kind of disruption of usual care this kind of migration creates, and then you add to that the possibility of epidemic disease, and it is a very difficult situation,” he added. Dr. Gandhi, who is also the co-director and principal investigator at the Harvard Center for AIDS Research, as well as an immediate past president of the HIV Medicine Association, is particularly concerned about HIV. According to UNAIDS, Ukraine has the second-largest HIV epidemic in Eastern Europe and Central Asia, with an estimated 250,777 people living with HIV in 2019. “One of the key things about infectious diseases that distinguishes them from other diseases is disruptions in care carry the prospect of resulting drug resistance,” said Dr. Gandhi, who is also a member of the IDSE editorial advisory board. “We don’t want people with HIV to run out of medicines or to not have access to medicine, so that is just one aspect of the situation that I worry a lot about.” Another endemic disease of concern in Ukraine is tuberculosis. “Ukraine has a relatively high rate of drug-resistant tuberculosis,” Dr. Ray said. “And so, one of the concerns would be how to manage the risk that in crowded conditions, if people are stressed and possibly malnourished during transit, things like TB could crop up.” Although TB incidence rates have dropped significantly in Ukraine, from 127 cases per 100,000 people in 2005 to 42.2 cases per 100,000 in 2020, the prevalence of the disease is still high, according to the WHO, which estimates that in 2018, much of TB in the Ukraine was resistant: 29% of new patients and 46% of previously treated patients have resistant TB. Dr. Gandhi said, “Drug-resistant TB is very hard to treat under the best of circumstances, and this is now the worst of situations.” Tuberculosis is a disease that countries accepting refugees will probably want to screen for, Dr. Wilcox suggested. The United Kingdom faced a similar concern among Afghan

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COVID-19 Pandemic Brings out the Best—and the Worst BY TOM ROSENTHAL

hile the SARS-CoV-2 pandemic has brought out the best in millions of frontline healthcare workers, it has also prompted the worst to surface with a host of bogus cures and treatments, problematic tests, financial fraud and fake vaccination cards. Like the flotsam and jetsam that follow in the wake of a shipwreck, hucksters and scammers quickly surface to profit from disasters and tragedies. With snake oil salesmen and fraudsters popping up around the country, the COVID-19 pandemic is turning into another textbook case of how a crisis offers opportunities to reap ill-gotten gains. Consider the Washington State man who, as early as March 2020, posted online that he had a COVID-19 vaccine when no federally authorized vaccine existed, according to FDA investigators who caught up with him after a sting operation. Johnny T. Stine, 55, of Redmond, Wash., was sentenced in March in federal court after pleading guilty in August 2020 to introducing misbranded drugs into interstate commerce, a misdemeanor. He received five years probation and was ordered to pay $246,986 in restitution. The charges alleged he injected 50 to 100 people with fake COVID-19 vaccines at $400 to $1,000 a pop. To date, authorities have not identified what these people

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actually received. The case was investigated by the FDA Office of Criminal Investigations, Homeland Security Investigations and the Seattle Police Department. Then there’s the case brought to light in a March 2021 federal indictment of a Thai national who was charged with allegedly selling chloroquine phosphate as a COVID-19 treatment to people around the world, including in the United States. The defendant allegedly made tens of thousands of dollars from his scheme in which shipments were disguised as fish tank accessories, the government said. Chloroquine phosphate may do a good job cleaning your fish tank, but it is not indicated by the FDA as a treatment for COVID-19.

Ramping Up Efforts Federal law enforcement officials tasked with combatting fraud ramped up their efforts in February 2020 as the COVID19 outbreak emerged, said Matthew T. Charette, a special agent in charge with the Office of Inspector General at Health and Human Services, who has 20 years of experience protecting the integrity of the Medicare and Medicaid programs— favorite targets of medical fraudsters. Recognizing there would soon be increased funding from Congress to address

the outbreak, the investigators knew that technology company was where federal funding goes, scammers charged with conspiracy to follow, Mr. Charette told Infectious Disease commit health care fraud by Special Edition. allegedly “exploiting the panThe Health Care Fraud Unit’s COVIDdemic by fraudulently pro19 Interagency Working Group, which was moting an unproven COVIDformed to find these lawbreakers, got to 19 test to the market,” said work. In May 2021, the U.S. Department of Assistant Attorney General Justice (DOJ) announced criminal chargBrian A. Benczkowski of the es against 28 telemedicine company execJustice Department’s Criminal utives, physicians, marketers and mediDivision. In one case, employees allegedly stored cal business owners for alleging engag“The allure of cheap reliable COVID-19 tests in garbage bags and piled ing in various healthcare fraud schemes them up in various corners of the office alternatives to today’s standard designed to exploit the COVID-19 pan- with no semblance of organization, never blood tests panels has captured demic, which according to the indictment, to be sent to the laboratory. Source: the imagination of the health Washington State Attorney General. netted more than $143 million. care industry, making such The indictment is a good example of alternatives a prime subject for how COVID-19 fraud pans out, he explained. Multiple defen- fraudsters,” said U.S. Attorney David L. Anderson of the dants were charged with allegedly offering COVID-19 tests to Northern District of California, in a statement. “The scheme Medicare beneficiaries at senior living facilities, drive-through described in the complaint, in which the defendant allegedly COVID-19 testing sites and medical offices. The fraud alleged- leveraged this allure by appending the fear of the COVID-19 ly involved inducing the beneficiaries to give up their personal pandemic, amounts to a cynical multimillion dollar hoax.” data and a saliva or blood sample. The defendants then allegThen there’s the Center for Covid Control, an Illinois comedly misused the personal information and samples to submit pany that was offering “free COVID-19 testing for all patients” claims to Medicare for unrelated, medically unnecessary, and at its approximately 300 sites across the country, according more costly tests. In addition, “the COVID-19 test results were to its website. They then announced that since “CCC remains not provided to the beneficiaries in a timely fashion or were committed to providing the highest level of customer service not reliable, risking the further spread of the disease,” the and diagnostic quality” operations were suspended starting in indictment said. mid-January, “to train additional staff on sample collection and To increase access to care during the COVID-19 pandemic, handling, customer service and communications best practices, following the January 2020 declaration of a public health as well as compliance with regulatory guidelines.” emergency, the Centers for Medicare and Medicaid Services The company decided training was needed after a number (CMS) in March 2020 expanded telehealth regulations that of states and CMS announced investigations. enable beneficiaries to receive a wider range of services from In one of the investigations, the company, which was foundtheir doctors without having to travel to a medical facility—a ed by a 29-year-old woman whose Linked-In site says her previcrucial step with stay at home orders taking effect. ous experience included opening an axe-throwing lounge, was In what authorities called a first in the nation, the COVID- sued by Washington State Attorney General Bob Ferguson for 19 Health Care Fraud Takedown resulted in defendants being allegedly “providing invalid, false and delayed COVID-19 test charged with allegedly exploiting the liberalized rules “by results to Washingtonians, or sometimes providing no results submitting false and fraudulent claims to Medicare for sham at all,” his office said in a statement. telemedicine encounters that did not occur.” Medical profes“The company’s unlawful practices included storing tests sionals allegedly offered and paid bribes in exchange for refer- in garbage bags for over a week rather than properly refrigring unneeded testing, the indictment charged. erating them, and backdating sample collection dates so that The May indictment was followed by a September indict- stale samples would still be processed,” the AG claimed in the ment in which nine more defendants were charged with indictment. submitting more than $29 million in false billings regarding “Center for COVID Control contributed to the spread alleged fraud related to COVID-19 claims. Defendants are of COVID-19 when it provided false-negative results,” Mr. alleged to have used the expanded telehealth regulations to Ferguson said. “These sham testing centers threatened the misuse patient information to submit claims to Medicare “for health and safety of our communities. They must be held unrelated, medically unnecessary and expensive laboratory accountable.” The suit claims the company, which operated 13 tests,” the indictment charged. sites in Washington, allegedly billed the federal government continued on page 23 As COVID-19 spread, the president of a California medical

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

ACIP Recommends 2 Vaccines for Some Travelers BY MARIE ROSENTHAL, MS

he Advisory Committee on Immunization Practices (ACIP) voted to recommend two vaccines for people who travel abroad to areas with endemic disease. The first set of recommendations concern a rare disease transmitted by ticks, tickborne encephalitis (TBE). The ACIP voted to recommend TBE vaccine (TicoVac, Pfizer) for people 12 months of age and older, who may be exposed to the virus by being in TBE-endemic areas or who could be exposed through laboratory work, regardless of where they live.

TBE is caused by a rare but serious flavivirus related to the Powassan virus, which causes neuroinvasive disease. The virus is transmitted to people through the bite of the Ixodes species of tick, which is focally endemic in parts of Europe and Asia. About 5,000 to 10,000 cases are reported each year. The risk is seasonal and typically lasts from April to November. The incidence varies from country to country, within countries and year to year, according to Susan Hills, MBBS, MTH, a medical epidemiologist at the Arborviral Diseases Branch, CDC. There is no cure or specific treatment for TBE, but management of symptoms is possible. The risk is low to Americans, Ms. Hills added. Only 11 cases occurred in U.S. travelers from 2001 to 2020, and nine cases among military personnel assigned overseas between 2006 and 2020. Still, one in three people can have long-lasting effects after exposure that include cognitive changes, muscle weakur. ness or permanent paralysis, and in rare cases, death can occur. to A factor limiting exposure is that a person must come into p le contact with the ticks, so a person’s planned activities while eir exposure. visiting an endemic area are key to their ations for the vaccine: The ACIP made three recommendations eople who • TBE vaccine is recommended for people are moving to or traveling to a TBE-ve exposure to endemic area and will have extensive or activities and itinerary. itinerary ticks based on their planned outdoor • TBE vaccine may be considered for those traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of their planned activities and itinerary, risk factors for a

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poorer medical outcome, and personal perception and tolerance of risk. • TBE vaccination is recommended for laboratory workers with a potential exposure to the TBE virus. The FDA approved TicoVac on Aug. 13, 2021, for active immunization to prevent TBE in individuals 12 months of age and older. In clinical trials, the safety and immunogenicity of the TBE vaccine were assessed in two age groups (12 months to 15 years, and 16 years and older). In these studies, seropositivity rates were 99.5% in the younger group and 98.7% to 100% in people 16 years and older following three doses. The most common adverse reactions in both age groups were local tenderness, headache, local pain, fever, restlessness, fatigue and muscle pain. ACIP voting member Camielle Nelson Kotton, MD, an associate p professor of medicine at Harvard Medical School, in Boston, sa said she was glad for the recommendation, because it provided flexibility and a mechanism for shared decision m making between the healthcare provider and patient. Wilber H. Chen, MD, MS, a professor of medicine at the Cente Center for Vaccine Development and Global Health, University of Maryland School of Medicine, in Baltimore, also was glad for the recommendations, but for a different reason: global warming. “Even though we don’t perceive that the burden of TBE is large and it might be difficult to perhaps implement this vaccine because of the complexity of trying to understand where the tick habitat is, with the trend of global warming, we are seeing tick habitats and mosquito habitats and flaviviruses continue to circulate, so it’s just a reminder that flaviviruses— among which are dengue, West Nile, yellow fever—continue to scorch the world,” said Dr. Chen, who is also a voting member of ACIP. “So, I think we will see these types of vaccines becoming more and more important.” The second travel vaccine that was recommended was lyoph-

ilized CVD 103 HgR cholera vaccine (Vaxchora 103-HgR (Vaxchora, Emergent) Emergent), which is now recommended for children and adolescents 24 months to 17 years of age, who are traveling to an area with active cholera transmission. Fourteen of the 15-member panel voted in favor of the vaccine. Dr. Chen abstained because of a continued on page 18

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Vaccines for Travelers continued from page 16

potential conflict of interest: His institution received a grant from Emergent Biosolutions for a Shigella vaccine. Vaxchora, a live-attenuated bacterial vaccine, was approved in June 2016, and the ACIP had recommended it for adults ages 18 years through 64 years who are traveling to areas with active cholera transmission. It is the only cholera vaccine licensed for this use in the United States, according to Jennifer P. Collins, MD, MSc, a medical epidemiologist at the CDC. The company temporarily stopped making the vaccine in December 2020, due to the COVID-19 pandemic, but Emergent said it would have vaccine available beginning May 1, Dr. Collins said. So far, 62,179 doses of CVD 103-HgR have been sold, but Dr. Collins said it is unknown how many doses have been given. Cholera is a disease caused by the bacterium Vibrio cholerae that occurs in places where sanitation is poor and there is limited access to safe drinking water. It can be transmitted person-to-person and causes severe diarrheal disease. As of Feb. 25, there were 16 countries, mostly in Africa but also some parts of Asia, with active cholera transmission: Benin, Cameroon, Democratic Republic of Congo, Ethiopia, Kenya, Mozambique, Niger, Nigeria, Somalia and Uganda in Africa; and Afghanistan, Bangladesh, India, Nepal and Yemen in Asia, according to the CDC. “Regardless of cholera vaccination status, travelers to cholera-affected areas should use personal protective measures. That is, they should consume safe food and water; wash hands often with soap and safe water; and follow recommended sanitation practices, including using latrines or burying stool,” Dr. Collins said. “The buffer and active component packets of vaccine should be refrigerated at 36⁰ to 46⁰ Fahrenheit. Packets should not be out of refrigeration for more than 12 hours before reconstitution, and they should not be exposed to temperatures exceeding 80⁰ Fahrenheit,” Dr. Collins explained. “They should also be protected from light and moisture.” Only cold or room-temperature purified, bottled or spring water should be used to reconstitute the vaccine. Tap water should not be used because chlorine affects the vaccine’s efficacy. The buffer solution should be mixed with a disposable stirrer until it completely dissolves. For children younger than 6 years, half of the reconstituted buffer solution should be discarded after mixing. The active component packet is then added, and again, stirred until it disperses to form a slightly cloudy suspension that may contain white particles. “If the packets are reconstituted in the improper order, the vaccine must be discarded,” Dr. Collins said. The prepared vaccine must be consumed within 15 minutes. Because of the intricacies in reconstituting and giving this

IDSE.NET

vaccine, the ACIP had recommended that the vaccine be given at a travel clinic, but since many of them closed during COVID19 and may not reopen, it can be given in a medical office. An issue for children is taste. However, the vaccine cannot be mixed with medicine flavorings that contain propylene glycol, or food such as rice cereal, applesauce, juice or milk, and drugs. In fact, vaccine recipients should not eat food or drink beverages for 60 minutes before and after consuming the oral vaccine. “However, data support that the vaccine is compatible when mixed with 1 g to 4 g of sucrose, table sugar or 1 g of Stevia sweetener. Ninety-three percent [of ] vaccine recipients age 2 through 17 years in the clinical trial consumed the vaccine,” when it was sweetened, Dr. Collins noted. Data show the vaccine is effective for up to three months, and protection beyond three months is unknown, she said. This vaccine can be shed in the stool for up to seven days after vaccination, so patients may be counseled to make sure they wash their hands thoroughly after going to the bathroom. In a small study of the preliminary formulation, there was no household transmission of CVD 103-HgR, according to Dr. Collins, although stool shedding did occur in 11% of vaccine recipients. Vaccine efficacy can also be affected by antibiotics and chloroquine administered for malaria prophylaxis. “Antibiotics may be clinically necessary after [administration of] the vaccine, such as to treat an unrelated infection. Nearly all vaccine recipients and clinical trials had zero conversion by 10 days, suggesting administration of antibiotics after this may not affect protection,” Dr. Collins said. “Chloroquine may diminish the immune response to CVD 103-HgR, therefore CVD 103-HgR should be administered at least 10 days before starting chloroquine,” she added. There are no data on administering cholera vaccine with other vaccines. “CVD 103-HgR is not licensed for children aged less than 24 months or adults aged more than 65 years, and no data exist about the safety and effectiveness of the vaccine in these populations,” she noted. “I think that having a cholera vaccine is terrific, but this also just reminds me to mention that there are a lot of other diarrheal agents throughout the world, and these are diseases that afflict vulnerable populations like very young children, but also low- and middle-income countries—countries that don’t have clean water, sanitation and hygiene,” Dr. Chen said, causing large inequities among populations in these countries. “I am happy to see this kind of vaccine being available here in the U.S., but I continue to want to aspire to see these types of vaccines be available in the countries in which these dis■ eases are endemic.” Dr. Chen reported the conflict listed above. The other sources reported no relevant financial disclosures.

AVYCAZ® (ceftazidime and avibactam) for injection, for intravenous use INDICATIONS AND USAGE Complicated Intra-abdominal Infections (cIAI) AVYCAZ (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients 3 months or older caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients 3 months or older caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa. Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus inﬂuenzae. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated 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. CONTRAINDICATIONS AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactamcontaining products, or other members of the cephalosporin class [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Decreased Clinical Response in Adult cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min In a Phase 3 cIAI trial in adult patients, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 1). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Adverse Reactions]. Table 1. Clinical Cure Rate at Test of Cure in a Phase 3 cIAI Trial, by Baseline Renal Function – mMITT Populationa AVYCAZ + Metronidazole % (n/N) Normal function / mild impairment (CrCl greater than 50 mL/min) Moderate impairment (CrCl 30 to less than or equal to 50 mL/min) a

85% (322/379)

Meropenem % (n/N)

Development of Drug-Resistant Bacteria Prescribing AVYCAZ 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 drug-resistant bacteria [see Indications and Usage]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: t Hypersensitivity Reactions [see Warnings and Precautions] t Clostridium difficile-Associated Diarrhea [see Warnings and Precautions] t Central Nervous System Reactions [see Warnings and Precautions] 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. Clinical Trials Experience in Adult Patients AVYCAZ was evaluated in six active-controlled clinical trials in patients with cIAI, cUTI, including pyelonephritis, or HABP/VABP. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as four Phase 3 trials, one in cIAI, one in cUTI (Trial 1), one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2) and one in HABP/VABP. Data from cUTI Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. cUTI Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The six clinical trials included a total of 1809 adult patients treated with AVYCAZ and 1809 patients treated with comparators. Complicated Intra-abdominal Infections The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%). Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation. Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting. Table 2 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial. Table 2. Incidence of Selected Adverse Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cIAI Trial Preferred term

74% (26/35)

Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. Clostridium difficile-associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs 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 drugs. 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. Central Nervous System Reactions Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance.

Meropenemb (N=529)

Headache

Dizziness

Diarrhea

Nausea

Vomiting

Abdominal Pain

Gastrointestinal disorders

86% (321/373)

Microbiological modiﬁed intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug.

AVYCAZ plus metronidazolea (N=529)

Nervous system disorders

45% (14/31)

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours (with metronidazole 0.5 grams IV every 8 hours) 1 gram IV over 30 minutes every 8 hours

Increased Mortality In the Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ plus metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min [see Warnings and Precautions]. In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Complicated Urinary Tract Infections, Including Pyelonephritis The Phase 3 cUTI Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years) and 30.7% of patients were 65 years of age or older. Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded. There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. There was no speciﬁc adverse reaction leading to discontinuation. The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea. Table 3 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.

Table 3. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cUTI Trial 1 AVYCAZa (N=511)

Doripenemb (N=509)

Nausea

Diarrhea

Constipation

Upper abdominal pain

< 1%

Preferred Term Gastrointestinal disorders

a b

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours 0.5 grams IV over 60 minutes every 8 hours

Hospital-acquired Bacterial Pneumonia/Ventilator-associated Bacterial Pneumonia The Phase 3 HABP/VABP trial included 436 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes and 434 patients treated with meropenem. The median age of patients treated with AVYCAZ was 66 years (range 18 to 89 years) and 54.1% of patients were 65 years of age or older. Patients were predominantly male (74.5%) and Asian (56.2%). Death occurred in 9.6% (42/ 436) of patients who received AVYCAZ and in 8.3% (36/434) of patients who received meropenem. Treatment discontinuation due to an adverse reaction occurred in 3.7% (16/436) of patients receiving AVYCAZ and 3% (13/434) of patients receiving meropenem. There was no speciﬁc adverse reaction leading to discontinuation. Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ were diarrhea and vomiting. Table 4 lists selected adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 3 HABP/VABP clinical trial. Table 4. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 HABP/VABP Trial Preferred Term

AVYCAZa (N=436)

Meropenemb (N=434)

Gastrointestinal disorders Nausea Skin and subcutaneous tissue disorders Pruritus a b

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours 1 gram IV over 30 minutes every 8 hours

Other Adverse Reactions of AVYCAZ and Ceftazidime in Adults The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials and are not described elsewhere in the labeling. Blood and lymphatic disorders - Thrombocytopenia, Thrombocytosis, Leukopenia General disorders and administration site conditions - Injection site phlebitis Infections and infestations - Candidiasis Investigations - Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase Metabolism and nutrition disorders - Hypokalemia Nervous system disorders - Dysgeusia Renal and urinary disorders - Acute kidney injury, Renal impairment, Nephrolithiasis Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria Psychiatric disorders - Anxiety Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below: Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Lymphocytosis, Neutropenia, Eosinophilia General disorders and administration site conditions - Infusion site inﬂammation, Injection site hematoma, Injection site thrombosis Hepatobiliary disorders – Jaundice Investigations - Increased blood lactate dehydrogenase, Prolonged prothrombin time Nervous system disorders - Paresthesia Renal and urinary disorders - Tubulointerstitial nephritis Reproductive and breast disorders - Vaginal inﬂammation Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis Laboratory Changes in Adults In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3.0% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator. No adverse reactions representing hemolytic anemia were reported in any treatment group. Clinical Trials Experience in Pediatric Patients AVYCAZ was evaluated in 128 pediatric patients aged 3 months to < 18 years in two single-blind, randomized, active-controlled clinical trials, one in patients with cUTI and the other in patients with cIAI. Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in each

trial with a mean treatment duration of 6 days, and a maximum of 14 days. The regimen was selected to result in pediatric drug exposure comparable to that of adults, and in the cIAI trial, metronidazole was administered concurrently with AVYCAZ. Patients were randomized 3:1 to receive AVYCAZ or comparator, which was meropenem or cefepime in the cIAI and cUTI trials, respectively. The median age of patients treated with AVYCAZ was 8.6 years, and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%). The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI, treated with AVYCAZ. There were no deaths reported in either trial. Treatment discontinuation due to adverse reactions occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs. The most common adverse reactions occurring in greater than 3% of pediatric patients treated with AVYCAZ were vomiting, diarrhea, rash, and infusion site phlebitis. DRUG INTERACTIONS Probenecid In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended. Drug/Laboratory Test Interactions The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam. The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Data Animal Data Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults. Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. Lactation Risk Summary Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats. No information is available on the effects of ceftazidime and avibactam on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVYCAZ and any potential adverse effects on the breastfed child from AVYCAZ or from the underlying maternal conditions. Data In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams. Exposure to avibactam was observed in both pups and milk on PND 7. Pediatric Use The safety and effectiveness of AVYCAZ in the treatment of cUTI and cIAI have been established in pediatric patients 3 months to less than 18 years. Use of AVYCAZ in these age groups is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials. The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI, treated with AVYCAZ [see Adverse Reactions]. Safety and effectiveness in pediatric patients below the age of 3 months with cUTI or cIAI have not been established. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 2 years of age with cIAI and cUTI and renal impairment. Safety and effectiveness in pediatric patients less than 18 years of age with HABP/VABP have not been established. Geriatric Use Of the 1809 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 621 (34.5%) were 65 years of age and older, including 302 (16.7 %) patients 75 years of age and older.

In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm. In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm. In the Phase 3 HABP/VABP trial, 54.1% (236/436) of patients treated with AVYCAZ were 65 years of age or older, including 129 (29.6%) patients 75 years of age or older. The incidence of adverse reactions in patients ≥ 65 years of age was similar to patients < 65 years of age. The 28-day all-cause mortality was similar between treatment groups for patients 65 years of age or older (12.7% [29/229] for patients in the AVYCAZ arm and 11.3% [26/230] for patients in the meropenem arm). Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased 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. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function. Renal Impairment Dosage adjustment is required in adult patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days. Dosage adjustment is also required in pediatric patients with cIAI or cUTI and renal impairment from 2 years to < 18 years with eGFR 50 mL/min/1.73 m2 or less. There is insufﬁcient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with cIAI or cUTI and renal impairment. OVERDOSAGE In the event of overdose, discontinue AVYCAZ and institute general supportive treatment. Ceftazidime and avibactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose. In subjects with ESRD administered 100 mg avibactam, the mean total recovery in dialysate following a 4-hour hemodialysis session started 1 hour after dosing was approximately 55% of the dose. No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage. Distributed By: Allergan USA, Inc., Madison, NJ 07940 Manufactured by: GlaxoSmithKline Manufacturing S.p.A., Verona, 37135 Italy AVYCAZ® is a registered trademark of Allergan Sales, LLC. Allergan® and its design are trademarks of Allergan, Inc. All other trademarks are the property of their respective owners. © 2020 Allergan. All rights reserved. Ref: v1.1USPI2700 Revised: December 2020 US-AVY-210260 MASTER US-AVY-210253

COVID-19 Fraud continued from page 15

for $124 million for tests for uninsured residents in his state. The site now says it is closed indefinitely. “We take seriously any allegations of fraud or misbehavior by COVID-19 testing sites. CMS’s Center for Clinical Standards and Quality investigates these kinds of complaints and is aware of several alleged instances of misconduct by this company’s labs. We know that people want to feel confident that the testing sites they visit are reputable and the results they receive are accurate,” Lee Fleisher, MD, the chief medical officer and director of the Center for Clinical Standards and Quality at CMS, told Infectious Disease Special Edition. Dr. Fleisher added, “CMS is actively investigating numerous complaints about multiple laboratories and testing sites. CMS continues its investigations and will take compliance and enforcement actions as appropriate.” However, CMS said it has “no further information about any complaints received or investigated by the state agency or the CMS Location offices for these laboratories. Until a complaint has been received, a survey has been completed, and the laboratory has the opportunity to respond to any findings, there are no reports to release.” CMS also said it cannot comment on the nature of complaints received to safeguard the anonymity of complainants. Along with problems with tests, questionable cures also popped up. The FDA has been kept busy sending warning letters to such companies as natural health and herbal medicine

Report Fraud There are numerous resources to identify and stop COVID-19 health care fraud. • HHS Office of the Inspector General website offers details: https://oig.hhs.gov/fraud/consumer-alerts/fraud-alertcovid-19-scams/ • The FDA offers information on fraudulent COVID-19 tests, vaccines and treatments at: https://www.fda.gov/consumers/health-equity-forumpodcast/health-fraud-covid-19-what-you-need-know • The FTC launched a new platform for reporting consumer fraud, including those related to COVID-19: https://reportfraud.ftc.gov/#/ • The Report any Medicare/Medicaid fraud to the Centers for Medicare and Medicaid Services at: https://www.medicare.gov/basics/reporting-medicarefraud-and-abuse

purveyors from Florida to California telling them their products are not approved to treat COVID-19 and their claims on their websites were misleading. The Federal Trade Commission in 2021 sued a nasal spray manufacturer, alleging it falsely promoted its saline nasal sprays as an effective way to prevent and treat COVID-19. The FTC alleged that without conducting any clinical trials to support its COVID-19 related claims, the company sold its products on a large web retailer, as well as well-known brickand-mortar shops. The products’ COVID-19 properties are no longer promoted on the company’s website, but it is still marketed as a nasal spray. “Companies can’t make unsupported health claims, no matter what form a product takes or what it supposedly prevents or treats,” said Samuel Levine, the director of the FTC’s Bureau of Consumer Protection. “That’s the lesson of this case and many others like it, and it’s why people should continue to rely on medical professionals over ads.” The U.S. Department of Justice, the agency spearheading the effort to combat fraud, said it has brought actions against dozens of other defendants for allegedly selling products, such as industrial bleach, ozone gas, vitamin supplements and colloidal silver ointments, with false or unapproved claims about their ability to prevent or treat COVID-19 infections. With all the controversy over COVID-19 vaccination, especially in places that would not allow an unvaccinated person to attend public venues or eat in local restaurants, fake vaccine cards were bound to surface—and they did with abundance. The epidemic of fake vaccine verification cards isn’t as ubiquitous as the COVID-19 pandemic, but it is widespread. Incidents of people manufacturing the fake cards and using them to get into events litter the internet. These are not just random acts by people seeking a fast buck. How to forge a fake vax card is appearing on conspiracy and anti-vaccination websites and blog posts in an apparent concerted effort to undermine the vaccination campaign. It is a federal offense to misuse an authorized government seal—specifically, the CDC emblem that appears on authentic cards. Although it is impossible to put a price tag on the total cost of COVID-19 fraud to both individuals and the government, the DOJ reported that as of March 2021, the amount that schemes had attempted to obtain from the government had already reached $569 million. By September, that number grew exponentially. In just one indictment, the DOJ said the money allegedly lost as of a result of the activities by the 136 defendants discussed earlier was $1.4 billion. For the fiscal year ending September 30, 2021, the DOJ reported the amount it had obtained from settlements for all medical fraud—not just COVID-19—involving the government was ■ $5 billion. The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

Influenza Rates Head Downward in Early 2022; Flu Season Appears Less Severe Than Anticipated BY NEAL LEARNER

ontrary to some projections, cases of seasonal influenza peaked at the end of last year and started to decline in early 2022. Some experts had expected a more robust 20212022 flu season in the United States, as COVID-19 pandemic restrictions eased and students headed back to the classrooms. But data so far have not borne that out. Overall, influenza activity has decreased in recent weeks, while sporadic activity continues across the country, and some areas are seeing an increase, the CDC said in its March 18 influenza surveillance report. As of March 12, the CDC estimates 2.9 million flulike illnesses, 28,000 hospitalizations and 1,700 deaths due to influenza this season, with influenza A(H3N2) being the dominant strain. Thirteen deaths were in children, more than last year, but well below pre-COVID seasons. Accompanying the decline in cases was a drop in the percentage of outpatient visits due to respiratory illnesses. Those cases are now below baseline, the agency added. The overall cumulative hospitalization rate this season is 4.4 per 100,000 population. While higher than last year, the current rate is significantly lower than pre–COVID-19 levels. The hospitalization rates ranged from 16.9 to 51.4 per 100,000 people during the seasons from 2016-2017 through 2019-2020, the CDC noted. By Feb. 12, 3% of specimens submitted to clinical laboratories were positive after peaking at 6% earlier in the season, according to Lisa Grohskopf, MD, MPH, of the CDC’s Influenza Division, who updated the Advisory Committee on

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Immunization Practices (ACIP) on Feb. 23. Most specimens that were subtyped were H3N2 viruses, she added, and so far these viruses are “genetically closely related to the vaccine virus, but there are some antigenic differences that have developed as H3N2 viruses continue to evolve,” she explained. The number of B/Victoria viruses is low, and they are antigenically similar to the vaccine. The cumulative hospitalization rate (FluSurv-NET) is higher than that for the entire 2020-2021 season, but lower than that observed at this time during the four seasons preceding the pandemic, she added. The ACIP is reviewing the approved enhanced seasonal influenza vaccines to decide whether to make a recommendation for adults who are 65 years of age and older. At the meeting, the panel acknowledged the benefits of an enhanced influenza vaccine compared with standard egg-based flu shots. Three vaccines are being reviewed: Fluad Quadrivalent (Seqirus), Fluzone (Sanofi Pasteur) and Flublok Quadrivalent (Protein Sciences Corp.). “According to the CDC, older adults have an increased risk of influenza-related complications and severe outcomes. Data from the recent ACIP systematic review support the benefit of an enhanced influenza vaccine for this population,” said Gregg Sylvester, the chief medical officer of Seqirus.

Did COVID-19 Mitigation Help? The numbers are heading in a positive direction, even if the reason isn’t exactly clear. What first looked to be a “moderate or moderately severe” influenza season may be tapering off,

said William Schaffner, MD, a professor of infectious diseases at Vanderbilt University Medical Center, in Nashville, Tenn. While encouraged by the trend, he also cautioned that cases often rise through February and March, and no one is entirely sure what the influx of refugees from the Ukraine will add to the global mix (see cover story on page 10). “Flu is fickle, and we could have a second wave,” Dr. Schaffner noted. Dr. Schaffner acknowledged that he cannot explain why flu rates are trending downward, especially as people are out and about and children are in school. But it probably is related to some of the mitigation strategies, which were just lifted. “There’s still a substantial amount of mask-wearing, and g he that may have an impact on what we’re seeing,” speculated. terSuch reports are good, if somewhat counterintuitive, based on earlier projections. Becausee there was so few flu cases last season, influenza experts had postulated the possibility that our collective influenza immunity might have waned, Dr. Schaffner said. “In this case, we might have anticipated a brisker influenza season with more severe disease,” he said. acOther experts see additional COVID-19 factors influencing this year’s flu season. Influenza likely is milder due to the circulating SARS-CoV-2 omicron variant, which may be competing with the current A(H3N2) strain, postulated Paul G. Auwaerter, MD, a clinical director in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine, in Baltimore.

Drs. Schaffner and Auwaerter stressed the importance of receiving the vaccine, even if the H3N2 vaccine component is a bit off target against the current strain. “It’s not a tight match,” Dr. Schaffner said. “But—and this is hugely important—even when we’re not exactly on target with the vaccine, vaccination still provides notable protection against severe disease. You’re less likely to require admission to the hospital, less likely to have to go to intensive care unit and less likely to die. That’s part of the story that often gets lost.” Dr. Auwaerter also underscored the vaccine’s protection against the less dominate influenza B strain: “Getting an influenza vaccine is still helpful in people to help reduce the lik likelihood of infection, especially as influenza B te tends to occur later in the winter or early sp spring—and flu shots help lessen the chances of progressing to severe infection, even with a mismatch.”

174.5 million

‘Oh, Yeah, the Flu’

Coinfections With COVID-19

The burning question on everyone’s mind is the possibility of influenza/COVID-19 ccoinfection, and whether that might predispo pose patients to more serious disease of one kind or another. So far, there hasn’t been an avalanche of reports, but the season is not yet over, Dr. Schaffner reminded. “We have to wait for this to play out.” In the meantime, providers are busy testing their patients with respiratory illnesses to determine whether they might have influenza or COVID-19. Distinguishing between infections will determine the course of treatment, Dr. Schaffner said. Physicians have new monoclonal antibodies and antivirals to prevent mild COVID-19 from progressing to something more serious. They also have long available antivirals to treat influenza. “If you’re going to provide treatment, you really have to distinguish [between] the two infections,” he said.

Flu shots given by Feb. 4. Coverage similar to last season.

Each year, public health officials urge people to get their flu shots. That message may have gotten lost this year in the ongoing focus on COVID-19 vaccinations and boosters. Flu vaccination coverage among children, for example, is lower than last season, Dr. Auwaerter said. Vaccination rates among adults vary depending on the state, he added. Dr. Schaffner attributed the lower flu vaccination rates to two things: 1. general vaccine fatigue and 2. everyone’s preoccupation with COVID-19 versus influenza. “As I’ve been out there beating the drums trying to stimulate interest in vaccinations against flu, I’ve almost had to reintroduce people to flu, and say, ‘Remember there’s another nasty respiratory virus out there,’” Dr. Schaffner said. “And it’s a bit like, ‘Oh, yeah, I remember that.’ It’s not entirely surprising that vaccination rates have lagged behind what we might have expected at this time of year.”

Future Influenza Seasons Going forward, Dr. Schaffner expects to see more routine public health recommendations during flu season to wear masks, maintain social distancing and even rent a movie rather than go to a theater. “A lot of people have learned those lessons, so they’ll start doing that on their own,” he predicted. “People no longer ■ think you’re crazy if you’re out there wearing a mask.” The sources reported no relevant financial conflicts of interest.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

IDNews Uncertain Future for 2 Long-Acting HIV Therapies BY GINA SHAW

he approvals have been put on hold for two major new long-acting HIV therapies, lenacapavir (LEN, Gilead) and islatravir (ISL, Merck)—for two very different reasons, and likely with very different long-term results. On March 3, 2022, the FDA issued a complete response letter for the New Drug Application for LEN, an investigational, longacting treatment for people with multidrug-resistant HIV infection that is administered subcutaneously every six months. The FDA cited issues with chemistry manufacturing and controls for the drug, specifically that the medication is not compatible with the proposed borosilicate glass vial, which contains boron trioxide to prevent cracking. The ongoing CAPELLA trial had been suspended in December 2021 because of these concerns. The most recent clinical data on LEN, presented at CROI 2022 in February, indicated that LEN, in combination with other antiretrovirals, achieved high rates of virologic suppression and clinically meaningful increases in CD4 counts in people living with HIV whose virus was no longer effectively responding to their current therapy (poster H03). There were no drug-related serious adverse events (AEs) in the study, and the most common AEs were mild to moderate injection site reactions (63%), nausea and diarrhea (13% each), and COVID-19 (11%). Gilead’s chief medical officer, Merdad Parsey, MD, PhD, said in a statement that the company will work with the FDA to identify a solution to the problem. “Gilead intends to provide FDA with a comprehensive plan and corresponding data to use a different vial type,” he said. “We look forward to discussing this further with FDA over the coming months so that we can make this investigational new therapy available to people living with multidrug-resistant HIV as soon as possible.” The vial compatibility issue is unlikely to present a longterm hurdle for LEN, said Melissa Badowski, PharmD, MPH, a clinical associate professor in the Section of Infectious Diseases Pharmacotherapy for the University of Illinois at Chicago College of Pharmacy and founding chair of the American College of Clinical Pharmacy’s HIV Practice and Research Network. “It’s reminiscent of the delay with Cabenuva [cabotegravir-rilpivirine, ViiV Healthcare], when the FDA rejected the application in December 2019 relating to chemistry and manufacturing controls, and then it took about a year for them to come back and get approval,” she told Infectious Disease Special Edition. “They just need to identify a different vial, and I think that will be very easy to navigate for them. The data look pretty good otherwise, so hopefully there will be no additional hiccups.”

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A Different Story The situation is different with Merck’s ISL, which also halted trials in December 2021. Islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor with multiple mechanisms of action, was being investigated both in HIV prevention and treatment. But after small decreases in CD4 counts were identified in the ILLUMINATE SWITCH and IMAGINE-DR treatment trials, and dose-dependent decreases in total lymphocyte counts were found in the IMPOWER phase 2 prevention trials, Merck paused enrollment studies. On Dec. 13, 2021, the company announced that the FDA had placed a full clinical hold on five trials of oral and implant formulations of ISL for prevention and a study of injectable ISL, as well as a partial clinical hold on seven trials of oncedaily ISL plus doravirine for HIV treatment. (The partial hold means that participants in the trials will still continue to receive the medication with more frequent CD4 monitoring, but no new participants will be enrolled.) “Obviously, we want the CD4 count to go up, not down,” Dr. Badowski said. “Even though the CD4 decline was only in some patients, it was enough to cause a signal that halted enrollment. “It’s still too early to know if this drug will move forward or not, if they can identify what led to the CD4 decline. This is disappointing, but it’s actually a good thing to see that the issue has been identified. This is why clinical trials are done.” Despite these setbacks, Dr. Badowski said, the injectable long-acting HIV treatment and prevention realm is poised to explode. “There are a lot of patients who would like to go on a longeracting injectable,” she said. “It’s much more discreet when you don’t have to have bottles of HIV medication with you in your bag. I think this is going to be a very important option for patients to have. “In January 2021, we had the approval of the first long-acting injectable for treatment, cabotegravir-rilpivirine, but that is for virologically suppressed patients who are taking medications and doing well already. We need to have options in the future to help those who are more treatment-experienced as well as those who are treatment-naive and looking for discreet ■ dosing options.” Dr. Badowski reported no relevant financial disclosures.

Adjuvanted to help prevent seasonal inﬂuenza in adults 65+1 Design ned to streng gthen,, broaden, engthen n the duratio on of the and le 2-4 ne resp ponse immun

Learn more at ﬂuad.com For more information, please see Important Safety Information below and the Brief Summary on adjacent page.

INDICATION and IMPORTANT SAFETY INFORMATION INDICATION AND USAGE FLUAD® QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous inﬂuenza vaccine.

WARNINGS AND PRECAUTIONS If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior inﬂuenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential beneﬁts and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against inﬂuenza disease.

ADVERSE REACTIONS The most common ( 10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). To report SUSPECTED ADVERSE REACTIONS, contact Seqirus USA Inc. at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. Before administration, please see the full US Prescribing Information for FLUAD QUADRIVALENT. FLUAD® QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.

REFERENCES: 1. FLUAD QUADRIVALENT. Package insert. Seqirus Inc; 2021. 2. O’Hagan DT, Ott GS, De Gregorio E, Seubert A. The mechanism of action of MF59—an innately attractive adjuvant formulation. Vaccine. 2012;30(29):4341-4348. doi:10.1016/j.vaccine.2011.09.061 3. O’Hagan DT, Ott GS, Nest GV, Rappuoli R, Del Giudice G. The history of MF59® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13-30. doi:10.1586/ erv.12.140 4. Banzhoff A, Pellegrini M, Del Giudice G, Fragapane E, Groth N, Podda A. MF59-adjuvanted vaccines for seasonal and pandemic inﬂuenza prophylaxis. Inﬂuenza Other Respir Viruses. 2008;2(6):243-249. doi:10.1111/j.1750-2659.2008.00059.x FLUAD QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates. Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA ©2022 Seqirus USA Inc. January 2022 USA-aQIV-21-0065

FLUAD® QUADRIVALENT (Influenza Vaccine, Adjuvanted) Injectable Emulsion for Intramuscular Use 2021-2022 Formula

BRIEF SUMMARY OF PRESCRIBING INFORMATION Consult the full US Prescribing Information for complete product information.

Table 1b. Percentages of Subjects Reporting Solicited Systemic Adverse Reactionsa in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1)

INDICATIONS AND USAGE FLUAD QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. For intramuscular injection only. CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous influenza vaccine. WARNINGS AND PRECAUTIONS Guillain-Barré Syndrome: If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. [see Reference (1)] Evidence for a causal relationship of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. Preventing and Managing Allergic Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Altered Immunocompetence: The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope: Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Limitations of Vaccine Effectiveness: Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against influenza disease. ADVERSE REACTIONS The most common (≥10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect rates observed in clinical practice. The safety of FLUAD QUADRIVALENT was evaluated in two clinical studies in 4269 elderly subjects 65 years of age and older. Study 1 (NCT02587221) was a multi-center, randomized, observer-blind, non-influenza comparator-controlled efficacy and safety study conducted in 12 countries during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons. In this study, 3381 subjects received FLUAD QUADRIVALENT and 3380 subjects received a US-licensed non-influenza comparator vaccine (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® [GlaxoSmithKline Biologicals]). The mean age of subjects at enrollment was 72 years, 62% were female, 48% White, 34% Asian, 16% Other, 2% American Indian/Alaska Native, and 18% of Hispanic/Latino ethnicity. Solicited local and systemic adverse reactions were collected for 7 days after vaccination in a subset of 665 subjects who received FLUAD QUADRIVALENT and 667 subjects who received the comparator vaccine. The percentages of subjects reporting solicited local adverse reactions are presented in Table 1a and systemic adverse reactions are presented in Table 1b. Onset usually occurred within the first 2 days after vaccination. The majority of solicited reactions resolved within 3 days. a

Table 1a. Percentages of Subjects Reporting Solicited Local Adverse Reactions in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1) Local (Injection site) Reactionsc Injection site pain Erythema ≥25mm Induration ≥25mm Ecchymosis ≥25mm

FLUAD QUADRIVALENT N=595-659 16.3 3.8 4.0 0.5

Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe definitions: Erythema, Induration and Ecchymosis = >100 mm diameter; Injection site pain = prevents daily activity.

Non-Influenza Comparator Vaccine N=607-664 11.2 1.8 2.6 0.7

Systemic Reactionsc Headache Fatigue Myalgia Arthralgia Chills Diarrhea Nausea Loss of appetite Fever ≥100.4°F (38°C) Vomiting

FLUAD QUADRIVALENT N=595-659 10.8 10.5 7.7 7.3 5.0 4.1 3.8 3.6 1.7 0.8

Non-Influenza Comparator Vaccine N=607-664 8.3 8.8 6.1 6.6 3.9 3.0 2.3 3.6 1.2 1.1

Study 1: NCT02587221 Abbreviation: N=number of subjects with solicited safety data Non-Influenza Comparator Vaccine = combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® (GlaxoSmithKline Biologicals) a All solicited systemic adverse events reported within 7 days of vaccination are included b Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data c Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe definitions: Nausea, Fatigue, Myalgia, Arthralgia, Headache, and Chills = prevents daily activity; Loss of appetite = not eating at all; Vomiting = 6 or more times in 24 hours or requires intravenous hydration; Diarrhea = 6 or more loose stools in 24 hours or requires intravenous hydration; Fever = ≥102.2°F (39°C).

Unsolicited adverse events (AEs) were collected for all subjects for 21 days after vaccination. Related unsolicited AEs were reported by 303 (9.0%) and by 261 (7.7%) of the subjects for FLUAD QUADRIVALENT and Boostrix, respectively. For FLUAD QUADRIVALENT, injection site pain and influenza-like illness were the only unsolicited adverse reactions reported in ≥ 1% of subjects (1.7% and 1.5%, respectively). Serious adverse events (SAEs) and potentially immune-mediated adverse events of special interest (AESIs) were collected up to 366 days after vaccination. SAEs were reported by 238 (7.0%) FLUAD QUADRIVALENT recipients and 234 (6.9%) comparator recipients. There were no SAEs, AESIs or deaths in this study that were related to FLUAD QUADRIVALENT. Study 2 (NCT03314662) was a multicenter, randomized, double-blind, comparator-controlled study conducted during the 2017-18 Northern Hemisphere influenza season. In this study, 888 subjects received FLUAD QUADRIVALENT, 444 subjects received the licensed adjuvanted trivalent vaccine (aTIV-1 - FLUAD® (trivalent formulation)) and 444 subjects received an adjuvanted trivalent influenza vaccine with an alternate B strain (aTIV-2). The mean age of subjects at enrollment who received FLUAD QUADRIVALENT was 72.5 years. Female subjects represented 56.6% of the study population and the racial distribution of subjects was 91.6% Caucasian, 7.0% Black or African American, and ≤ 1% each for Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native or Other. Solicited local and systemic adverse reactions reported within 7 days after vaccination were similar to those reported for Study 1. Unsolicited AEs were collected for 21 days after vaccination. Related unsolicited AEs were reported by 39 (4.4%) and by 17-19 (3.8%-4.3%) of subjects administered FLUAD QUADRIVALENT or aTIV, respectively. For FLUAD QUADRIVALENT, injection site bruising (1.0%) was the only unsolicited adverse reaction reported in ≥ 1% of subjects. Serious AEs and AESIs were collected up to 181 days after vaccination. Within 6 months after vaccination, 37 (4.2%) FLUAD QUADRIVALENT recipients and 18-28 (4.1%-6.3%) aTIV recipients experienced an SAE. There were no SAEs, AESIs or deaths in this study that were related to the study vaccine. There were no AEs leading to withdrawal from the study. Postmarketing Experience: There are no postmarketing data available for FLUAD QUADRIVALENT. However, the postmarketing experience with FLUAD (trivalent formulation) is relevant to FLUAD QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions. Because these events 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 the vaccine. Blood and lymphatic system disorders: Thrombocytopenia (some cases were severe with platelet counts less than 5,000 per mm3), lymphadenopathy General disorders and administration site conditions: Extensive swelling of injected limb lasting more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week) Immune system disorders: Allergic reactions including anaphylactic shock, anaphylaxis, and angioedema

Musculoskeletal and connective tissue disorders: Muscular weakness

Pediatric Use

Nervous systems disorders: Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, parasthesia, syncope, presyncope

Vascular disorders: Vasculitis, renal vasculitis

Safety and effectiveness of FLUAD and FLUAD QUADRIVALENT (same manufacturing process and overlapping composition with FLUAD) were evaluated in clinical trials conducted in children 6 months to <72 months of age. Data from these trials are inconclusive to demonstrate the safety and effectiveness of FLUAD QUADRIVALENT in children 6 months to <72 months of age. The safety and effectiveness of FLUAD QUADRIVALENT in infants less than 6 months of age and in children older than 72 months of age have not been evaluated.

DRUG INTERACTIONS

Geriatric Use

Concomitant Use With Other Vaccines: No clinical data on concomitant administration of FLUAD QUADRIVALENT with other vaccines is available.

Safety and immunogenicity of FLUAD QUADRIVALENT have been evaluated in adults 65 years of age and older.

Skin and subcutaneous tissue disorders: Generalized skin reactions including erythema multiforme, urticaria, pruritus or nonspecific rash

If FLUAD QUADRIVALENT is given at the same time as other injectable vaccine(s), the vaccine(s) should be administered at different injection sites. Do not mix FLUAD QUADRIVALENT with any other vaccine in the same syringe. Concurrent Use With Immunosuppressive Therapies: Immunosuppressive or corticosteroid therapies may reduce the immune response to FLUAD QUADRIVALENT.

REFERENCE 1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 19931994 influenza vaccines. N Engl J Med 1998; 339(25):1797-1802. To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. There are insufficient human data to establish whether there is a vaccine-associated risk with use of FLUAD QUADRIVALENT in pregnancy. There were no developmental toxicity studies of FLUAD QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUAD (trivalent formulation) prior to mating and during gestation. A 0.5 mL dose was injected on each occasion (a single human dose is 0.5 mL). Lactation Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. No human or animal data are available to assess the effects of FLUAD QUADRIVALENT on the breastfed infant or on milk production/excretion.

FLUAD QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates. Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA US License No. 2049 ©2021 Seqirus USA Inc. December 2021 USA-aQIV-21-0073

Novel Research Shedding Light on Fungal Infections BY DAVID WILD A Candida tropicalis fungal colony. Source: CDC/ Dr. Hardin

ovel diagnostics are helping clinicians identify fungal infections where conventional methods have proven insufficient, and new technologies are revealing that fungi interact with pathogenic bacteria in ways that can exacerbate infections. “There is an increased understanding that while many types of chronic wounds, including diabetic foot ulcers, are polymicrobial in nature, traditional culture methods might underrepresent the vast diversity of chronic wound microbiomes, including fungal populations,” explained Lindsay Kalan, PhD, an assistant professor, Departments of Medical Microbiology and Immunology and Medicine, Division of Infectious Disease, University of Wisconsin–Madison. Advanced techniques have uncovered fungi in roughly 80% of diabetic foot ulcers, whereas traditional culturing methods identify fungi in only 5% of wounds, Dr. Kalan noted (mBio 2016;7[5]:e0158-16. doi:10.1128/mBio.01058-16). Better understanding of the role that fungal populations play in these infections could help pinpoint those patients who are most likely to develop nonhealing foot wounds, she said, noting that the presence of other organisms, such as Staphylococcus aureus, has not been a very good prognostic marker in this regard.

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“We have found some interesting things by studying microbial communities instead of a single pathogen within a single wound sample and looking at how community diversity changes before and after an intervention,” Dr. Kalan said. For example, she and her colleagues found that diabetic foot wounds that heal after debridement exhibit a significant drop in the overall microbial diversity, while unhealed or amputated wounds have a much larger proportion of fungi on a community level (mBio 2016;7[5]:e0158-16. doi:10.1128/mBio.01058-16). “Additionally, looking at highly necrotic tissue, we’ve seen a really striking increase in the proportion of pathogenic fungi that grow alongside anaerobic bacteria, suggesting there are bacterial–fungal networks forming within these wounds and leading to poor outcomes,” she said. Indeed, using a diabetic foot ulcer lab model, her team demonstrated that bacteria and fungi “jointly synergize to contribute to pathogenesis,” she said. They cultured Candida albicans along with S. aureus and Citrobacter freundii, a species of anaerobic gram-negative bacteria, and found that when C. albicans colonized first, C. freundii outcompeted S. aureus by inducing growth of fungal hyphae and binding to C. albicans (ISME J 2021;15:2012-2027). They also found significantly

higher levels of neutrophil cell death in mixed fungal–bacterial biofilms, compared with when there was a single species, Dr. Kalan said, noting these insights could identify “important markers for predicting the healing trajectory and possibly finding targets for intervention as well.”

Fungal Lung Infections in COVID-19

Fungal Lung Infections in Cystic Fibrosis There is growing interest in the role of fungi in other lung infections, such as those in patients with cystic fibrosis (CF), according to Deborah Hogan, PhD, a professor in the Geisel School of Medicine at Dartmouth, in Hanover, N.H. Although lung infections in patients with CF are most often dominated by bacteria, “it’s becoming increasingly appreciated that these infections also contain fungi, such as Candida and Aspergillus,” she said. “What we’re finding is that the fungi might be under-detected through clinical laboratory practices, where selective media specific to fungi are not always used,” Dr. Hogan said.

Fungi also have gained recognition as pulmonary pathogens among patients with COVID-19, Martin Hoenigl, MD, an associate professor, Division of Infectious Diseases and Global Public Health, University of California, San Diego and the Medical University of Graz, in Austria. He noted that 3.1% of the overall COVID19 population develops COVID-19–associated pulmonary aspergillosis (CAPA), with the number rising to 8.9% among ICU patients with COVID-19 and to 10% to 15% in ICU patients with COVID-19 who require mechanical ventilation (Clin Microbiol Infect 2021 Aug 26. doi:10.1016/j.cmi.2021.08.014). While CAPA is an ominous diagnosis, associated with a 51.8% mortality rate, it can be a challenge to diagnose, Dr. Hoenigl explained. Although “the classical neutropenic patient at risk for invasive aspergillosis who Candida lusitaniae. develops primarily angioinvasive disease” can display the typical radiological signs of Indeed, advanced analytical tools have revealed that some infection, “things get a little bit more complicated once we move a little bit up the spectrum to non-neutropenic patients lung infections are dominated by fungi, and these technologies have uncovered “some interesting dynamics between bacteria who develop primary airway–invasive disease first,” he said. In these more complicated cases, the typical radiological and fungi, including increased fungal burden after antibiotics signs of infection may not be present, and bronchoalveolar are used,” Dr. Hogan said. One recent insight with important research and potenlavage (BAL) samples from the site of infection are needed to tially clinical implications is that fungi live in the lungs of CF confirm a diagnosis. Many clinicians are reluctant to employ bronchoscopy to patients chronically, she told meeting attendees. “Using banked samples in our CF center here at Dartmouth, diagnose lung infections in COVID-19 patients because the procedure generates aerosols, but recent consensus criteria we’ve been able to determine that Candida lusitaniae can be offer a number of possible alternatives to BAL-based diagno- present for months or years in some individuals with CF and that these isolates can become phenotypically heterogenous, sis, he said (Lancet Infect Dis 2021;21[6]:e149-e162). One such alternative is diagnostic lateral flow assay (LFA) with drug-resistant subpopulations,” she said. Some C. lusitaniae isolates are resistant to fluconazole while testing for galactomannan, which Dr. Hoenigl and his colleagues have studied. In a recent multicenter trial, they others are not, she said. Thus, “depending on what isolate is found “a very good predictive value for diagnosing invasive chosen for phenotyping, the clinician might choose a different aspergillosis” with the device they used (Aspergillus GM LFA; antifungal therapy. “Clinicians need to consider more than one isolate, or perIMMY) (J Clin Microbiol 2021 Oct 13. doi:10.1128/JCM.0168921). Specifically, they documented an area under the curve of haps whole populations, when thinking about drug therapies ■ greater than 0.8 for the same device for diagnosing CAPA in for particularly chronic infections,” she said. respiratory specimens, indicating a high level of accuracy. “It also seems to work very well for distinguishing CAPA Dr. Hoenigl reported receiving grant or research support from Astellas, F2G, Gilead, Pfizer and Scynexis. Dr. Hogan reported no relevant from non-CAPA,” Dr. Hoenigl noted. financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

Engaging HIV Patients ... ... And Keeping Them Engaged BY DAVID C. HOLZMAN

ost people living with HIV today—as much as 90%—are involved in care and doing very well, but it’s the remaining 10% that is the real concern. “People who are engaged in care and take their medications do really well,” said Daniel A. Solomon, MD, an internist in the Division of Infectious Disease, Brigham and Women’s Hospital, and an Instructor of medicine at Harvard Medical School, both in Boston. “They have high rates of viral suppression, and HIV becomes a chronic disease that is easily managed, often more so than diabetes and high blood pressure.” However, “those who are homeless or unstably housed, have substance use disorders [SUDs], or have psychiatric disorders are particularly vulnerable to disengaging from HIV care and may need options that differ from the conventional clinical approach,” said Julie C. Dombrowski, MD, MPH, an associate professor in the Department of Medicine, Division of Allergy and Infectious Diseases, and the deputy director of the HIV/STD Program, Public Health Seattle and King County. Not surprisingly, studies are examining the effectiveness of different strategies to get people with HIV back into care. A recent metaanalysis examined 14 interventions (AIDS 2022 Jan 12. doi: 10.1097/ QAD.0000000000003172). The investigators reported that there are several effective strategies for improving the outcomes for people with HIV who are not receiving care, including re-engaging and retaining them by data-to-care, which looks to multiple data points to identify people not receiving care, helping them navigate the health system, offering transportation, accompanying patients to appointments and providing psychosocial support. “Papers like this are laudable efforts to summarize the literature, but a lot of amazing stuff doesn’t make it into peer review,” said Dr. Dombrowski, who was the principal investigator on an earlier paper on the topic (AIDS Patient Care STDS 2020;34[6]:267-274). Many interventions designed to re-engage people in healthcare focus on changing the patient’s care-seeking behavior or helping them navigate the HIV healthcare system, instead of changing the healthcare system to meet the needs of those who are disengaged.

Striving for the ‘Max’

Figure. The HIV care continuum outlines the steps that people with HIV take from diagnosis to achieving and maintaining viral suppression. Source: HIV.gov

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A handful of clinics across the United States are working on meeting the needs of those 10% to 15% of patients with HIV who have trouble remaining in care and maintaining viral suppression. Seattle’s Max (short for Maximum Assistance) Clinic, which provides both primary care and HIV care, is taking this new approach. The Max provides “intensive case management support,” Dr. Dombrowski explained. “We do that with both medical and nonmedical continued on page 41

How to Manage Care for Aging Patients With HIV BY JILLIAN MOCK

lorida-based physician Jonathan S. Appelbaum, MD, started caring for patients with HIV in 1985, shortly after the AIDS epidemic began. As he has aged over the years, so have many of his patients, piquing his medical interest in the intersection of HIV and aging. “We’ve seen our patients do better and live longer, and we’ve also seen older patients continue to get newly infected with HIV,” said Dr. Appelbaum, a geriatrician, an internist and a professor in the Department of Clinical Sciences at the Florida State University College of Medicine, in Tallahassee. Today, effective antiretroviral therapies mean patients with HIV are living almost as long as their contemporaries without HIV. More than half of the population of people living with HIV in the United States are 50 years of age or older, according to the CDC (https://www.cdc.gov/hiv/group/age/olderamericans/index.html). “HIV in general is aging,” said Margaret Hoffman-Terry, MD, an infectious disease physician and internist with a focus on treating patients with HIV at Lehigh Valley Health Network in Allentown, Pa. Managing care for older adults with HIV presents a unique challenge for healthcare providers, who need to screen for comorbidities, implement team-based and holistic care models, watch out for polypharmacy, and consider the barriers these patients face to receiving sufficient care. Older patients with HIV are unique in several ways. For one, they tend to develop the traditional issues of aging earlier than

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the general population, Dr. Appelbaum noted. They are also more prone to multimorbidity, he said, with intersecting diseases like diabetes, hypertension and HIV interacting with one another in unique ways that can be challenging to treat. And these patients are more likely to develop geriatric syndromes, including an increased risk for falls, cognitive decline, and issues with their bones, kidneys and liver. Why these patients seem to experience age-related health problems earlier is still unknown. “There’s always been this debate about whether people with HIV [start to] age younger, or whether what we see in reality are multiple comorbidities related to the virus and its treatment along with lifestyle that make it appear that way,” Dr. Hoffman-Terry said. Providers can monitor common health risks in this patient population. In her practice, Dr. Hoffman-Terry said they aggressively screen patients for cancers, particularly lung and colorectal, which are common in people with HIV. These patients also tend to develop kidney diseases earlier and experience neurocognitive dysfunction at earlier ages, so Dr. Hoffman-Terry and her colleagues screen for those issues regularly. Heart disease and osteoporosis also are common issues to watch. Smoking is a huge issue, and it is important to encourage smoking cessation as much as possible. “While most of my patients do make it into old age, it’s often with a collection of different problems,” she said.

When treating older patients with and without HIV, it’s also geriatrician or primary care provider working in a team with important to keep in mind what matters most to each patient, physical therapists, mental health providers, pharmacists, according to Dr. Appelbaum. A patient’s goals may not be the social workers, specialists (e.g., cardiologists, urologists) and same as a provider’s goals, he said. Knowing what patients other team members to evaluate patients and devise a care want can help providers decide which screenings and medica- plan, he said. tions to prioritize for their patients. Unfortunately, patients living with HIV face significant barKeeping a close eye on prescribed medications is also an riers to receiving the kind of care they need. Insurance can important part of caring for this patient population. Older complicate which medications patients can afford and receive, patients already are going to be on more medications and Dr. Murray said. And issues like housing and food insecurity have more comorbidities to manage than younger patients, can always be a challenge for older patients, she said. said Milena Murray, PharmD, MS, an associate professor of Sometimes the barrier is getting a diagnosis in the first pharmacy practice at Midwestern University College of place. Many patients infected with HIV later in life can Pharmacy in Downers Grove, Ill., and author go through months of workups before finally of the ARTClass column on page 65, making receiving a diagnosis. “Just because somedrug–drug interactions and polypharmacy one is over 40 doesn’t mean they don’t have a particular concern. a sex life anymore,” Dr. HoffmanPharmacists need to look at Terry said. patients’ entire lists of medicaOnce diagnosed, access to comtions to treat multiple conditions petent care can also be an issue. A and do a drug interaction check, patient’s infectious disease physiDr. Murray said. Deprescribing cian may not be equipped to or changing prescriptions can provide primary care, and the quickly become complicated, patient’s primary care docshe noted. Pharmacists have to tor may not be well versed in look out for problematic drug– treating HIV, Dr. Appelbaum drug interactions, and what Dr. explained. There’s also a shortage Murray calls, “reverse drug interof geriatricians, and even fewer The 5 M’s for actions.” For example, if a patient geriatricians who can deal with the HIV-negative seniors is on an HIV medication that makes complications of HIV, he said. their blood pressure medication Patients living with HIV also face hold true for those with more effective, changing the HIV stigma from the general populaHIV, experts said. medication will reduce the effection and healthcare professionals, tiveness of the blood pressure drug. Dr. Appelbaum said. Because of Pharmacists also need to keep this stigma, older gay men living in mind that there often are not with HIV may not have solid social great data about how certain drugs support systems, and may struggle work in older groups, as people with depression, loneliness and older than 70 years of age are rarely substance abuse, he said. Mental included in clinical trials, according health is a major concern for this to Dr. Murray. When that’s the case, patient population, Dr. Hoffmanpharmacists and providers may not Terry agreed. always realize that the symptom “I think it’s really important to they are seeing is from a particular consider that this population, while medication and try to treat it with it’s different than other populations a new drug, instead of changing the living with or without HIV, it’s not original medication. different in the way that we need A collaborative, team-based to consider the entire patient,” Dr. ■ approach ensures that older Murray said. patients with HIV are treated comSource: Health in Aging Foundation. Drs. Appelbaum and Murray reported prehensively and successfully, Dr. https://www.va.gov/covidtraining/docs/HIA_TipSheet_ relationships with Merck, ViiV Healthcare Appelbaum said. A care team for Geriatric_5Ms_19.pdf and Theratechnologies, Dr. Hoffman-Terr with Gilead and ViiV. these patients should include a

5M’s

for Geriatrics Mind Mobility Medications Multicomplexity Matters Most

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

Outcome disparities need to be addressed

Kaposi Sarcoma Still a Major Contributor to Morbidity, Mortality in Certain HIV Populations BY LEAH LAWRENCE

there are outcomes disparities that need to be addressed to improve outcomes in this HIV population.”

aposi sarcoma (KS) continues to play a significant part in morbidity and mortality among Black patients with HIV living in the South. A recent study showed Black patients with HIV-associated KS had double the mortality of white or Hispanic patients with HIV-associated KS (AIDS 2021 Dec 22. doi:10.1097/ QAD.0000000000003155). “There seems to be this notion that Kaposi sarcoma is no longer a disease of interest or concern in the United States because clinicians don’t see it as much as they did in the preART [antiretroviral therapy] era, and outcomes have improved because we have such effective treatment for HIV these days,” said study author Sheena Knights, MD, of The University of Texas Southwestern Medical Center, in Dallas. “While these points are true, our study highlights the fact that not only is Kaposi sarcoma still prevalent in certain areas of the U.S., but

5-Year Survival Rate for Kaposi Sarcoma • Blacks 69% • Whites 78% • Hispanics 81% Black race was found to be independently associated with mortality. Source: AIDS. 2021 Dec 22. doi:10.1097/QAD.0000000000003155

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History of Kaposi Sarcoma In the 1980s and 1990s, before ART, the presence of KS was how AIDS was diagnosed, explained Dirk P. Dittmer, PhD, of the UNC Lineberger Comprehensive Cancer Center, in Chapel Hill. It was one of the defining conditions of AIDS. “Then came highly active ART and that led to a decline in KS,” Dr. Dittmer said. “With ART, we all of a sudden no longer had people who were severely immune suppressed.” Rates of KS were much lower but still three to five times higher than before the 1980s, Dr. Dittmer said. “Now we have a background level of KS that you cannot treat with just ART,” Dr. Dittmer said. “We now see KS in people that still have AIDS but don’t take ART, have had their ART disrupted or have become resistant, and in people who do take ART and have no detectable disease, but are older now.” Dr. Dittmer said the results of the study by Dr. Knights’ team was not surprising to him, as he sees similar trends in North Carolina. “There was an ascertainment bias that KS had gone away, which was driven by HIV providers that saw mostly white patients in San Francisco, New York City or Chicago,” Dr. Dittmer said. “That number is going down, not because there is no more KS but because many of the patients are African American and living in more rural areas.”

Differences Seen by Race and Ethnicity Dr. Knights and her colleagues reviewed the electronic health records of patients diagnosed with HIV and KS from

HI January 2009 to December 2018, and included 262 patients for analysis. Of the patients, 30% were receiving ART at the time of KS diagnosis and one-fourth were first diagnosed with HIV and KS at the same time. Regarding disease stage, 46% of patients had T1, 75% had I1 and 54% had S1 stage disease. Of the included patients with KS, 30.9% died, with a median survival duration of 11 months from KS diagnosis. Black patients had the highest mortality of all race/ethnic groups, including white and Hispanic patients. According to Dr. Knights, U.S. Surveillance, Epidemiology, and End Results program data indicate an expected five-year survival rate of about 77% in KS, but in the current study, that rate for Black patients was 69%. The five-year survival rate was 78% for white patients and 81% for Hispanic patients. A multivariable analysis showed Black patients had a mortality risk twice that of white or Hispanic patients (hazard ratio, 2.07; 95% CI, 1.12-3.82). Black race was found to be independently associated with mortality. “Although white and Hispanic patients had slightly better mortality than expected in our study, Black patients had worse mortality than expected,” Dr. Knights said.

Implications Dr. Knights and her colleagues found Black patients had more advanced KS disease at diagnosis, and often were younger than other ethnicities, which could explain the mortality difference. “What’s not clear from our study is why these patients are presenting with more advanced disease,” Dr. Knights said. “Could these patients be infected with a specific genotype of KS-associated herpesvirus that may be associated with more advanced disease? Could there be a complex combination of socioeconomic factors involved that are difficult to measure?” She said they were unable to answer this question in this study, but hope to do so in future studies. Dr. Knights said according to the CDC’s HIV Surveillance program, Black people in the southern United States have the highest death rates from HIV, too. “I suspect that whatever the underlying etiology of the mortality disparity in KS is, it is most likely related to the same factors that contribute to higher mortality in HIV deaths in the southern United States,” Dr. Knights said. “We as HIV providers still have a lot of work to do to help ■ identify and alleviate healthcare disparities.” Dr. Dittmer reported a position as an investigator with the AIDS Malignancy Consortium. Dr. Knights reported grant funding from the UT Southwestern Simmons Comprehensive Cancer Center Pilot Award.

News

Risk for HIV Depends On Who You Are BY MARIE ROSENTHAL, MS

espite the tremendous progress made in reducing new HIV transmissions in the United States, the disease continues to affect some groups more than others, according to Sonia Singh, PhD, an epidemiologist with the CDC’s Division of HIV Prevention, who calculated the lifetime risk for HIV among various groups. “Overall, the lifetime risk for an HIV diagnosis in the United States was one in 120,” Dr. Singh said, an 11% decrease from the last analysis in 2014 (CROI 2022). One in 76 males and one in 309 females will receive a diagnosis of HIV in their lifetime, but the probable risk sharply increases based on sex and race with Black and Hispanic males having a greater risk than white or Asian males. The analysis used data from the National HIV Surveillance System, the National Center for Health Statistics and census data to calculate the probability of a diagnosis of HIV at a given age, assuming 2017-2019 diagnosis rates continue. These probabilities were applied to a hypothetical cohort to obtain risk estimates. The lifetime risk is the probability of being diagnosed with HIV from birth. The lifetime risk for Black males was one in 27, whereas the lifetime risk for Hispanic males was one in 50—both higher than the overall lifetime risk for males. Asian males experienced the lowest lifetime risk at one in 187. The risk for white males was one in 171. For American Indian/Alaskan Native men, the lifetime risk was one in 116, and one in 89 for Native Hawaiian and other Pacific Islander men. Females fared better across the board. The risk for an HIV diagnosis was one in 75 for Black females; one in 287 for Hispanic females; one in 435 for American Indian/Alaskan Native females; one in 611 for Native Hawaiian and other Pacific Islander females; one in 874 for white females; and one in 1,298 for Asian females. The states with the highest lifetime risk for being diagnosed with HIV were Georgia, Florida, Louisiana, Nevada and Maryland. “Nine of the 10 areas of residence with the highest possibility of a lifetime HIV diagnosis were located in the South,” she said. The lifetime risk for a disease is used to compare the burden of disease across populations, she explained, and is frequently used to describe cancer risk but not necessarily the risk for HIV. Lifetime risk could be a “useful tool for clinicians, outreach workers and ■ policymakers when describing a burden of HIV,” she said.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

Engaging HIV Patients continued from page 32

case managers. The latter are health department staff, who help with things like getting patients bus passes and food vouchers, providing psychosocial support, and coordinating the overall clinic.” They also provide financial incentives. “It’s not enough to lower the barriers; you have to give something to draw people in,” she said. “We give cash for having a visit with blood draw and cash for remaining virally suppressed. “Financial incentives and food make a difference in people’s ability to prioritize an HIV care visit,” Dr. Dombrowski said. “If they are trying to find a place to sleep, or food, this is one way to address those needs in a small way.” The Max Clinic also coordinates with housing agencies, providers of substance use treatment, and other agencies that work with this population. The clinic also works with the local jail to ensure inmates being released will have immediate access to medications on the outside. Many patients achieved their first successful treatment at the Max Clinic. They described a “family-like environment” in a report in AIDS and Behavioral and Psychosocial Research (2020;34[6]:267-274). Good relationships with clinic staff and the ability to receive care on a walkin basis were the strongest influences on maintaining engagement. “Walk-in visits lowered the barrier to accessing care,” according to the report. They also eliminated the shame associated with missing appointments. Participants felt that Max Clinic staff attended to their social circumstances whereas others had not. That attention resulted in patients feeling that their healthcare providers treated “me, the person—not me, the disease.” Across the country, from San Francisco to Mississippi, to Boston’s Brigham and Women’s Hospital, clinics are taking similar approaches, trying to reach the “10% to 15% who are not virologically suppressed, and who, across the board, are struggling with social stressors such as [lack of] housing and food insecurity and/or mental health issues,” Dr. Solomon said. “It requires a multidisciplinary effort to keep them coming back.”

The clinic also has an embedded psychiatry team “who help tremendously in addressing mental health,” and providers with expertise treating addictions, who can prescribe buprenorphine-naloxone or buprenorphine for SUDs. “Treating substance use disorders proactively is essential to keeping these patients in care,” Dr. Solomon said. Patients whose addictions go beyond what the Infectious Disease/HIV clinic can treat are sent to the Brigham Health Bridge To Recovery Clinic. That clinic provides immediate care for SUDs, offering medications that help treat addiction and providing connections to the longer-term care and support services critical to their recovery, including help finding housing if that’s an issue. So far, few data exist comparing the multidisciplinary approach with more conventional treatments for HIV. But in a comparison of outcomes of the first 50 patients enrolled in the Max Clinic and 100 randomly selected, matched control patients at the nearby Madison Clinic, viral suppression improved in the former group from 20% to 82% (P<0.001) and from 51% to 65% in the latter group (P=0.04). “Adjusted for differences in unstable housing, substance use and psychiatric diagnoses, Max Clinic patients were [more than] three times as likely to achieve viral suppression,” Dr. Dombrowski and her co-authors wrote (2019;6[7]:ofz294). There are caveats to these findings: lack of randomization and the Max Clinic’s enrollment depending on clinician and case manager decisions to refer patients in the treatment arm and also the lower levels of instability in the control group. This kind of individualized, hands-on care is less costeffective and may not be something that other clinics can do, but those negatives need to be viewed with the necessity to end HIV/AIDS in the United States. There were an estimated 34,800 new HIV infections in 2019, bringing the total of people living with HIV to 1.2 million, according to the CDC. Although this was an 8% fall in new infections, since 2015, more is needed to end HIV as we know it, according to the National HIV/AIDS Strategy: 2022-2025 (https://hivgov-prodv3.s3.amazonaws.com/s3fs-public/NHAS-2022-2025.pdf ). The strategy calls for engaging people at risk for HIV in “traditional public health and health care delivery systems, as well as in nontraditional community settings.” Everyone caring for people with HIV really needs to evaluate how the HIV healthcare system can be modified to meet the needs of these difficult-to-reach patients, rather than expecting the patient to meet the requirements of these systems. ■

The Goal for Ending HIV: Reduce new U.S. infections by 90% by 2030.

Who Slipped Through the Cracks? The first step is identifying patients who have fallen out of the healthcare system. A registry enables tracking patients. When a patient misses an appointment, the physician works with a social worker to determine the major barrier to keeping the patient engaged, Dr. Solomon explained.

Drs. Dombrowski and Solomon reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

From

Y U

5 People Died From Rabies In the U.S. in 2021 (Left)Tadarida Brasiliensis; (below from top) Eptesicus fuscus; and Lasionycteris noctivagans

Highest Total in a Decade BY ETHAN COVEY

ive people died from rabies last year in the United States—the highest total in a decade. Four of the deaths were linked to bat exposure. Three of the deaths, which occurred in Idaho, Illinois and Texas, were included in a CDC report. They took place over a five-week period from Sept. 28 to Nov. 10, 2021 (MMWR Morb Mortal Wkly Rep 2022;71[2]:31-32). The cases included two adults and one child, all of whom had direct contact with a bat, by either collision or biting, within three to seven weeks before symptom onset. Three bat species were involved: • Lasionycteris noctivagans (silver-haired bat) • Tadarida brasiliensis (Mexican free-tailed bat) • Eptesicus fuscus (big brown bat) All three are common in the United States and have been linked to the spread of rabies. None of the patients received postexposure prophylaxis (PEP): two because they did not realize the risk for rabies infection associated with bat exposure, and the third due to anti-vaccination beliefs. The patients died within two to three weeks of developing symptoms. “This report is a sad and important reminder that direct contact with bats is a leading cause of rabies deaths in the U.S.,” said Amber Kunkel, ScD, a CDC Epidemic Intelligence Service officer. “Rabies transmission from bats to humans can be prevented,” Dr. Kunkel said. “People should avoid contact with bats whenever possible. People who have contact with a bat should consult their local health department to determine if they should receive postexposure prophylaxis and to have the

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bat tested for rabies, if possible.” One of the other cases was in an immunocompromised Minnesota man who was bitten by a bat and received PEP but still died because he could not mount an immune response to the PEP. The final case was a man who was bitten by a rabid dog while traveling and died upon return to the United States.

Is Rabies Risk Increasing? The number of cases is raising questions about whether rates of rabies are increasing in the United States. Although the three deaths investigated in the report match the total number recorded during the preceding 48 months, and the total of five is more than reported since 2011, there are differing opinions regarding whether the risk for rabies is increasing. “Although these all happened in a short time, they occurred in different states and involved different bat species,” Dr. Kunkel said. “The number of bats tested for rabies and the proportion that test positive have been relatively stable over recent years. (About 24,000 bats were tested for rabies in 2020, and about 1,400 were positive.) These data are not yet available for 2021, but so far we have not noticed any

indication that rabies in bats is increasing.” Stephen J. Scholand, MD, an infectious disease specialist in Meriden, Conn., disagreed. “Definitely, it seems the risks of contracting rabies from bats is increasing,” he told Infectious Disease Special Edition. “This is what was recognized—what came to the attention of public health authorities. There are probably a number of other cases that are occurring but remain undiagnosed and unknown, because almost two-thirds of the time, the doctors never figure out what causes a case of encephalitis. The number of rabies cases, therefore, could be higher.” According to Charles E. Rupprecht, MD, PhD, the CEO of Lyssa Inc. in Lawrenceville, Ga., the inconsistencies in CDC reports are indicative of failures with current rabies surveillance. “The state of our surveillance is not ideal,” he said. “You’d think that in the age of COVID we’d have more real-time reporting. “The bottom line,” he added, “is we don’t really have a gauge.

“We don’t know whether there are five cases or 50 cases [in the United States],” he continued, pointing out autopsies are not performed on most people who die in the United States, so the true cause of many deaths might be incorrect. “The differential diagnosis should include rabies for everybody who has an acute progressive encephalomyelitis suspected of being of viral origin,” he said. “And it’s not.” Part of the challenge of preventing rabies deaths, particularly those associated with bat contact, is that people may not know that exposure to a bat is a risk for rabies transmission. Bites and scratches also can be very small, and it can be difficult to determine what requires medical attention. “What if you wake up and there is a bat in your bedroom?” Dr. Scholand said. “What if you open your child’s bedroom door and there is a bat? “Would the average person think that is a rabies risk?” Dr. Scholand asked. “Would they call their doctor or visit the emergency department or urgent care center for that?” Dr. Rupprecht stressed that additional efforts are needed, a difficult task in America’s already-constrained healthcare system where prioritizing and maintaining education and increasing the size of the public health workforce are challenges. According to the CDC, healthcare professionals should be aware of the risks associated with bat exposure, and can turn to health departments for detailed information regarding local risk. “Rabies epidemiology varies geographically inside the United States,” Dr. Kunkel said. “Local and state health departments are very familiar with rabies dynamics in their area, and healthcare providers should not hesitate to contact them for advice on evaluating individuals for postexposure prophylaxis. Rabid bats are present in all states except Hawaii, and any person who has direct contact with a bat should be evaluated for postexposure prophylaxis.” Ryan Wallace, DVM, a veterinarian and rabies expert in the CDC’s Division of HighConsequence Pathogens and Pathology, also noted that recent cases should not overshadow progress that has been made in reducing human rabies cases. “We have come a long way in the U.S. toward reducing the number of people who become infected each year with rabies, but this recent spate of cases is a sobering reminder that contact ■ with bats poses a real health risk,” he said. Dr. Scholand reported a relationship with Grifols. Drs. Kunkel and Rupprecht reported no relevant financial relationships.

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

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IDSE Review

Implementing Rapid Diagnostic Tests to Augment Antimicrobial Stewardship Programs: The Time Is Now BY SARAH M. WIECZORKIEWICZ, PHARMD, FIDSA, BCPS, BCIDP

or hospitalized, critically ill patients with sepsis, accurate and timely administration of antimicrobial agents is essential to prevent mortality.1,2 Rapid diagnostic tests (RDTs) have revolutionized the treatment of these patients and become one of the most powerful tools for antimicrobial stewardship programs (ASPs). Although routinely used laboratory methods, such as Gram stains, can provide helpful guidance in some clinical circumstances—such as stopping gram-positive coverage when a gram-negative organism is identified for a generally monomicrobial infection, de-escalating antipseudomonal coverage if ruled out, and so forth—they do not predict antimicrobial susceptibility patterns. In addition, routine laboratory methods often result in prolonged use of unnecessarily broad-spectrum antimicrobials or, even more concerning, ineffective therapy.

RDTs provide actionable details, even those without rapid susceptibility results, such as the ability to predict resistance patterns. When combined with the use of local antibiograms, knowledge of intrinsic resistance, and genotypic resistance marker detection, RDTs allow a more rapid, targeted approach to antimicrobial therapy. The impact of RDTs can be largely attributed to reduced duration of empiric antimicrobial therapy. Prolonged broad-spectrum empiric therapy can lead to an increased burden of Clostridioides difficile infection, antimicrobial resistance, and adverse events, such as acute kidney injury. On the contrary, erroneous empiric antimicrobial coverage can delay effective therapy to detrimental effects and lead to dramatic increases in mortality among critically ill patients.1-8 A recent study found delays in antimicrobial therapy in patients with carbapenem-resistant and -susceptible Enterobacteriaceae infections are more important for mortality than multidrug resistance (MDR).7

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

IDSE Review

However, MDR had been identified as an independent predictor of delays in time to effective therapy (TTET), likely as a result of providing inadequate empiric coverage,9 highlighting the need for RDTs with either genotypic resistance marker detection or rapid antimicrobial susceptibility testing (AST) for geographic areas with problematic multidrug-resistant organisms (MDROs). When combined with ASPs, RDTs demonstrate substantial benefit on patient outcomes, including mortality10 and attributable cost.11 With the availability of many RDT options, diagnostic stewardship is an essential component of ASPs enabling the teams to select the right test, for the right patient, at the right time.12 Furthermore, practical concerns for specific sites should be considered by the ASP, ideally comprising a multidisciplinary group that includes infectious diseases physicians and pharmacists, microbiologists, nurses, infection preventionists, information technology specialists, hospital epidemiologists, and other pertinent invested frontline providers.13 Global considerations to assess when choosing RDT platforms include, but are not limited to, institutional or regional problematic pathogens, the patient population served (ie, pediatric, adult, and/ or geriatric; immunocompromised vs general community), laboratory hours, location (ie, centralized or decentralized), operations and workflow, and leadership support. Specific practical considerations for FDA-cleared RDTs are outlined in the Table. Barriers to RDT implementation and solutions that are justified by the CDC Core Elements of leadership commitment, accountability, pharmacy expertise (previously drug expertise), action, tracking, reporting, and education have been described.14 This article provides a clinically practical overview on the selection of RDTs for infectious syndromes, including bloodstream infections (BSIs), respiratory tract infections (RTIs), central nervous system (CNS) infections, and gastrointestinal (GI) infections.

Bloodstream Infections Rapid blood culture identification technologies are among the most commonly used RDTs, and are endorsed by the Infectious Diseases Society of America (IDSA) guidelines for implementing ASPs to optimize antimicrobial use.13 This endorsement is supported by a substantial number of studies that demonstrate ASPs combined with molecular RDTs have favorable clinical outcomes, including a significant reduction in mortality in a meta-analysis of 31 mostly quasi-experimental studies.10,15-23 Available technologies identify organisms through genotypic (eg, nucleic acid amplification testing [NAAT]) and/or phenotypic (eg, biochemical assays, mass spectrometry, nuclear magnetic resonance [NMR] spectrometry) methods. FDA-cleared rapid assays from various manufacturers include peptic nucleic acid fluorescent in situ hybridization,

IDSE.NET

matrix-assisted laser desorption/ionization time-offlight mass spectrometry (MALDI-TOF MS), polymerase chain reaction (PCR), multiplex PCR panels, nanoparticle probe technology, and NMR. Although most RDTs require organism isolation before identification, and previously included none or minimal genotypic resistance testing, this strategy is rapidly evolving with the need to further close the gap between broadspectrum empiric and targeted therapy. This evolution is exemplified by the T2 Magnetic Resonance (T2MR) technology by T2 Biosystems that can detect the presence of organisms directly from a whole blood specimen without prior isolation. T2Candida, T2Bacteria, T2Resistance, and T2SARSCoV-2 (T2 Biosystems) panels are rapid detection panels that use this strategy. T2Resistance is not available for clinical use in the United States but has been granted a “breakthrough device” designation by the FDA in response to combating resistant infections, and will be useful in immunocompromised patients, as well as patients or regions with a high burden of MDROs. T2Resistance can identify gram-negative markers including KPC, OXA-48, NDM/VIM/IMP, CTX-M, and 14/15AmpC (CMY/DHA), as well as gram-positive markers including vanA/B and mecA/C. The T2SARSCoV-2 test was granted emergency use authorization from the FDA in 2020 to assess patients with signs and symptoms of COVID-19 by detecting nucleic acid from SARS-CoV-2 in upper respiratory secretions and may, in theory, allow earlier discontinuation of unnecessary empiric antimicrobial use in this patient population. T2Bacteria and T2Candida are FDA-cleared, commercially available assays that use a miniaturized MR diagnostic technique that assesses the reaction of water molecules in the presence of magnetic fields, and can detect various targets in 3 to 5 hours.24 Candidemia mortality rates are as high as 30% to 40%, and increase by approximately 50% each day therapy is delayed.24 This is concerning, as prompt antifungal initiation can be inadvertently missed, given the overall sensitivity of blood cultures in diagnosing invasive candidiasis is around 50%.25 The T2Candida assay can be incredibly useful in facilities with high rates of fungal infections (eg, immunocompromised patient population), as it not only detects organisms at densities of 1 colony-forming unit (CFU)/mL compared with 100 to 1,000 CFU/mL required for PCR-based detection,24 but also has the ability to substantially reduce TTET once detected.26 Patients with positive blood cultures identified by T2Candida noted a 27-hour reduction in time to appropriate antifungal therapy (P=0.01).27 Conversely, ASPs can use negative tests to shorten antifungal therapy. Previous data demonstrate this can be associated with a 4.3-day reduction in micafungin use, resulting in a cost savings of $48,440 on antifungals.27 The T2Bacteria assay uses multiplex detection to

identify common ESKAPE organisms (ie, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli) that pose clinical challenges due to their propensity for MDR.28,29 In a performance assessment study, the T2Bacteria assay identified organism species in 3.61±0.2 to 7.7±1.38 hours, with a per-patient sensitivity of 90% (95% CI, 76%-96%), specificity of 90% (95% CI, 88%-91%), and negative predictive value of 99.7% for proven BSIs.29 Another study duplicated the negative predictive value of 99.8% and further demonstrated the mean time to detection and species identification was 5.5±1.4 hours.28 The T2Bacteria panel has demonstrated the ability to detect pathogens approximately 55 hours faster than standard methods (eg, blood culture) in patients with sepsis.30 Given the previous benefit of RDTs including reductions in TTET, time to optimal therapy, mortality, and the observation of ASP intervention being an independent predictor of survival in MDR infections,31 the T2Bacteria assay is expected to demonstrate favorable clinical outcomes. While T2MR technology reduces time to organism identification by eliminating the need for prior organism isolation, other technologies target rapid phenotypic AST to prevent delays in therapy and avoid unnecessarily prolonged broad-spectrum therapy. One such technology is the Accelerate Pheno system (Accelerate Diagnostics), which uses rapid phenotypic methods to provide AST within 7 hours. Conventional identification with AST can take as long as 90 hours.32 This is particularly important when clinicians are concerned about prolonged exposure of insufficient antimicrobial concentrations (eg, patients with unpredictable pharmacokinetics/pharmacodynamics, augmented renal clearance, or pathogens with a high minimum inhibitory concentration), as inappropriate exposure can result in poor outcomes.32,33 A recent multicenter, randomized controlled trial comparing rapid identification plus phenotypic AST (RAPID; Accelerate

Pheno) with standard of care (SOC; MALDI-TOF MS) plus AST using broth microdilution or agar dilution was conducted in patients with gram-negative BSIs.34 The primary outcome measure was time to first antimicrobial modification within 72 hours of randomization. First antimicrobial modification was 6.3 hours faster in the RAPID group compared with the SOC group for overall antimicrobials (median [interquartile range], 8.6 [2.6-27.6] vs 14.9 [3.3-41.1] hours; P=0.02), and 24.8 hours faster for antimicrobials targeted against gramnegative organisms (median [interquartile range], 17.3 [4.9-72] vs 42.1 [10.1-72] hours; P<0.001). Among a subset of 40 patients in the RAPID group and 44 in the SOC group with resistant organisms, time to antimicrobial escalation was 43.3 hours faster in the RAPID group than the SOC group (P=0.01), while no difference was observed in de-escalations. Although the study authors report no significant differences in clinical outcomes, such as length of stay (LOS) and mortality, the ability to escalate therapy more rapidly and reduce time to effective therapy is clinically meaningful nonetheless.34 One recent quasi-experimental study of 830 bacteremic cases, however, has demonstrated a shorter median LOS (6.3-6.7 vs 8.1 days) when the Accelerate Pheno is used, regardless of whether it is paired with or without real-time notification when compared with historical controls lacking rapid diagnostics or antimicrobial stewardship intervention.36 Overall, rapid blood culture identification systems demonstrate a substantial benefit when paired with ASPs for both clinical and economic outcomes.10,11 Probabilistic analyses of RDTs combined with ASPs show an 80% chance of being cost-effective versus a 41% chance without ASPs.11 These data suggest RDTs should be the SOC across all hospitals and continue to evolve with public health needs to slow the progression of resistance and ensure antimicrobial therapy is optimized. Karius testing is a blood test based on next-generation sequencing of microbial cell-free DNA, allowing it to quantify more than 1,000 clinically relevant pathogens that include viruses, bacteria, fungi, and parasites. It may be useful for patients with severe illness, those who are immunocompromised, and/or those with a lack of pathogen identification after standard attempts via other methodologies.37 A prospective pilot study explored the utility of Karius testing as a BSI prediction tool among 47 pediatric patients with relapsed or refractory cancers. Sixteen BSI episodes (15 bacterial) were available for predictive sampling, and a predictive sensitivity of 80% (n=12/15; 95% CI, 55%-93%) was identified for bacterial BSIs.37 Hogan et al performed a retrospective cohort study to determine the real-world impact of the Karius test ordered for all suspected infectious diseases indications.38 Approximately 65% of patients were immunocompromised and 52.4% were children. A total of 82 Karius tests were evaluated with a positivity rate of 61%. The Karius test results led

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IDSE Review

When combined with use of local antibiograms and other resistance data, RDTs allow a more rapid, targeted approach to antimicrobial therapy.

IDSE.NET

mPCR

PCR

PNA-FISH

Blood Cultures

Technology Type Detection Time

20 min

90 min

E. faecalis, E. faecium, Enterococcus species

E. coli, Klebsiella pneumoniae, P. aeruginosa

C. albicans, C. glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis None

Enterococcus QuickFISH (AdvanDx)

Gram-negative QuickFISH (AdvanDx)

Yeast Traffic Light (AdvanDx)

mecA XpressFISH (AdvanDx)

1h 2h

S. aureus S. aureus

A. baumannii, C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, E. coli, Enterobacter cloacae complex, Enterobacteriaceae, Enterococcus species, Haemophilus influenzae, Klebsiella oxytoca, K. pneumoniae, Listeria monocytogenes, Proteus species, P. aeruginosa, Neisseria meningitidis, S. marcescens, Staphylococcus species, S. aureus, Streptococcus species, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes

Xpert MRSA/SA BC (Cepheid)

StaphSR (BD GeneOhm)

20 min

CoNS

Staphylococcus QuickFISH (AdvanDx)

FilmArray BCID (BioFire Diagnostics)

Resistance Detection

Practical Considerations for Clinical Practice

• Limited number of targets

• Prompt differentiation between MRSA and MSSA can facilitate faster TTET

• Identifies polymicrobial infections that may be missed by other technologies

mecA, • Comprehensive number of targets vanA/B, KPC • Multiple primers allow for identification of multiple organisms

mecA

SCCmec, mecA

• Prompt identification of MRSA

mecA

• May miss MRSA with non-mecA resistance

• Useful for hospitals with high fungal infections (eg, immunocompromised)

• Useful among community hospitals with low resistance rate

• Limited number of targets per panel

• Previously associated with reduction in LOS in CoNS-positive cultures, and reduced TTET in enterococcal bacteremia

None

MRSA and • Potential benefit for patients requiring rapid ~1.5 h to macrolidePK/PD dose adjustments (eg, augmented identify, lincosamiderenal clearance) and 7 h to antimicrobial streptogramin B • Ability to rapidly detect resistance patterns susceptibility phenotypically reported • Unreliable MIC for bacteria with multiple morphologies or polymicrobial infections

(Pre-blood culture)

Staphylococcus aureus, Staphylococcus lugdunensis, CoNS, Enterococcus faecalis, Enterococcus faecium, Streptococcus species, Escherichia coli, Klebsiella species, Enterobacter species, Proteus species, Citrobacter species, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Candida albicans, Candida glabrata

Organisms on Panel

Accelerate Pheno (Accelerate Diagnostics)

Example Systems (Manufacturer)

Table. Selected FDA-Approved Rapid Diagnostic Tests and Clinical Practice Considerationsa

IDSE Review

2.5 h

S. aureus, S. epidermidis, S. lugdunensis, S. anginosus, S. agalactiae, S. pneumoniae, S. pyogenes, E. faecalis, E. faecium

VERIGENE BC-GN (Luminex)

VERIGENE BC-GP (Luminex)

Nanoparticle probe technology

Not an all-inclusive list. Table adapted and refined from reference 68.

2.5 h

Acinetobacter species, Citrobacter species, E. coli, Enterobacter species, K. oxytoca, K. pneumoniae, P. aeruginosa, Proteus species

MALDI-TOF (bioMérieux and Brucker)

MALDI-TOF

mecA, vanA/B

CTX-M, IMP, KPC, NDM, OXA, VIM

None

CTX-M, IMP, KPC, NDM, OXA (OXA23 and OXA-48), VIM

mecA, mecC, vanA/B

• Unreliable for detection in polymicrobial bacteremia

• Can reduce TTET and unnecessary antimicrobial utilization

• Lacks ability to detect resistance markers or provide susceptibility reports

• Useful for facilities with patients at risk for uncommon infections (eg, immunocompromised population, transplant centers)

• Ability to detect a vast array of bacterial and fungal microbes

• Identifies polymicrobial infections that may be missed by other technologies

• Gram-positive and gram-negative panels contain pan targets to ensure organism inclusivity

• Most comprehensive organism and resistance detection panels currently available on the market

ASP, antimicrobial stewardship program; CNS, central nervous system; CoNS, coagulase-negative Staphylococcus; GI, gastrointestinal; LOS, length of stay; MALDI-TOF, matrix-assisted laser desorption/ionization time of flight; MIC, minimum inhibitory concentration; mPCR, multiplex polymerase chain reaction; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus; NMR, nuclear magnetic resonance; PK/PD, pharmacokinetic/pharmacodynamic; PNA-FISH, peptic nucleic acid fluorescent in situ hybridization; RSV, respiratory syncytial virus; TTET, time to effective therapy

1.5 h

C. albicans, Candida auris, Candida dubliniensis, Candida famata, C. glabrata, Candida guilliermondii, Candida kefyr, C. krusei, Candida lusitaniae, C. parapsilosis, C. tropicalis, Cryptococcus gattii, Cryptococcus neoformans, Fusarium, Rhodotorula

ePlex BCID-FP panel (GenMark Diagnostics)

30 min

1.5 h

A. baumannii, Bacteroides fragilis, Citrobacter, Cronobacter sakazakii, Enterobacter (noncloacae complex), E. cloacae complex, E. coli, Fusobacterium nucleatum, Fusobacterium necrophorum, H. influenzae, K. oxytoca, K. pneumoniae group, Morganella morganii, N. meningitidis, Proteus, Proteus mirabilis, P. aeruginosa, Salmonella, Serratia, S. marcescens, Stenotrophomonas maltophilia Pan targets: pan–gram-positive and pan-Candida

ePlex BCID-GN panel (GenMark Diagnostics)

All organisms

1.5 h

Bacillus cereus group, Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Enterococcus, E. faecalis, E. faecium, Lactobacillus, Listeria, L. monocytogenes, Micrococcus, Staphylococcus, S. aureus, Staphylococcus epidermidis, S. lugdunensis, Streptococcus, S. agalactiae (Group B Streptococcus), Streptococcus anginosus group, S. pneumoniae, S. pyogenes (Group A Streptococcus), Pan targets: pan–gram-negative and pan-Candida

ePlex BCID-GP panel (GenMark Diagnostics)

IDSE Review

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T2Bacteria

NMR

mPCR

Gastrointestinal

mPCR

Campylobacter species (jejuni, coli, upsaliensis), Clostridioides difficile (toxin A/B), Plesiomonas shigelloides, Salmonella species, Yersinia enterocolitica, Vibrio species (parahaemolyticus, vulnificus), Vibrio cholerae, enteroaggregative E. coli, enteropathogenic E. coli, enterotoxigenic E. coli, Shiga-like toxin–producing E. coli stx1/ stx2, E. coli 0157, Shigella/enteroinvasive E. coli, adenovirus F 40/41, astrovirus, norovirus GI/GII, rotavirus A, Sapovirus (I, II, IV, V), Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia Campylobacter species (jejuni, coli, lari), C. difficile toxin A/B, enterohemorrhagic E. coli, enterotoxigenic E. coli, E. coli O157, Salmonella species, Shigella species (boydii, sonnei, flexneri, dysenteriae), Vibrio species (cholerae), Y. enterocolitica (not in US), adenovirus F40/41, Norovirus GI/GII, rotavirus A, Cryptosporidium species (parvum, hominis), E. histolytica, G. lamblia Campylobacter group, Salmonella species, Shigella species, Vibrio group, Yersinia enterocolitica, Shiga toxin 1 (stx1), Shiga toxin 2 (stx2), norovirus, rotavirus Rotavirus, astrovirus, adenovirus

xTAG GPP (Luminex Corp)

VERIGENE Enteric Pathogens Test in the Gastro (Luminex)

InGenius Gastrointestinal Viral Elite Panel (ELITechGroup)

E. coli (K1 serotype only), H. influenzae, L. monocytogenes, N. meningitidis (encapsulated strains only), S. agalactiae, S. pneumoniae, C. neoformans/gattii, cytomegalovirus, enterovirus, herpes simplex viruses 1 and 2, human herpesvirus 6, human parechovirus, and varicella-zoster virus

C. albicans, C. tropicalis, C. krusei, C. glabrata, C. parapsilosis

E. faecium, S. aureus, K. pneumoniae, P. aeruginosa, E. coli

Organisms on Panel

FilmArray GP (BioFire Diagnostics)

FilmArray ME (BioFire Diagnostics)

Central Nervous System

T2Candida

Example Systems (Manufacturer)

Technology Type Detection Time

2.5 h

<2 h

3-5 h

(Pre-blood culture)

None

mecA/C, vanA/B

None

Resistance Detection

• Consider implementing in high-prevalence units (eg, pediatrics)

• Can detect multiple pathogens; however, the clinical significance to polymicrobial GI infections is unknown

• Should not be used as a test of cure

• Many GI pathogens may be shed asymptomatically for prolonged periods complicating positive results

• Infants and young children <3 y likely test positive for C. difficile due to high rates of colonization; pediatric centers may blind C. difficile results or include clinical decision support to interpret positives in this population with caution

• Cannot differentiate between live and dead organisms

• Not intended to replace traditional diagnostic testing for CNS infections

• Associated with a rapid time to diagnosis of viral infections

• Implementation may be most useful for hospitals with pediatric and neonatal patients

• T2Bacteria Panel detects 90% of all ESKAPE pathogens and T2Candida detects the 5 most common sepsis-causing fungal pathogens

• Low limit of detection can detect pathogens missed by standard testing that is reliant on blood cultures.

• Detects presence of organisms directly from blood specimen (ie, prior isolation not required) substantially expediting time to identification

Practical Considerations for Clinical Practice

IDSE Review

Adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H3, influenza A/H1-2009, influenza B, parainfluenza virus 1, parainfluenza Virus 2, parainfluenza virus 3, parainfluenza virus 4, RSV, Bordetella pertussis, C. pneumoniae, M. pneumoniae; RP2 panel adds Bordetella parapertussis Adenovirus, coronavirus (229E, HKU1, NL63, OC43), human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A H1, influenza A H1-2009, influenza A H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, RSV A, RSV B, C. pneumoniae, M. pneumoniae Adenovirus, human metapneumovirus, influenza A, influenza A (subtype H1), influenza A (subtype H3), influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, rhinovirus, RSV A, RSV B, Bordetella pertussis, Bordetella parapertussis/B. bronchiseptica, Bordetella holmesii Influenza A, influenza A H1, influenza A H3, influenza B, RSV A, RSV B, rhinovirus/ enterovirus, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, human metapneumovirus, adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human bocavirus, Chlamydophila pneumoniae, M. pneumoniae

FilmArray RP and RP2 (BioFire Diagnostics)

ePlex Respiratory Pathogen Panel (GenMark Diagnostics)

VERIGENE Respiratory Pathogens Flex Test (Luminex)

NxTAG Respiratory Pathogens Panel (Luminex)

Not an all-inclusive list. Table adapted and refined from reference 68.

Adenovirus, coronavirus, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza B, parainfluenza virus, RSV, Acinetobacter calcoaceticus-baumannii complex, E. cloacae complex, E. coli, H. influenzae, Klebsiella aerogenes, K. oxytoca, K. pneumoniae group, Moraxella catarrhalis, Proteus species, P. aeruginosa, S. marcescens, S. aureus, S. agalactiae, S. pneumoniae, S. pyogenes, Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae

The BioFire FilmArray Pneumonia (PN) panel

<3 h

<2 h

90 min

None

mecA/C and MREJ KPC, NDM, OXA48-like, VIM, IMP, CTX-M

• First pneumonia panel with 15 bacterial isolated and resistance detection capabilities

• In conjunction with procalcitonin, can assist ASP in reducing antimicrobial utilization

• Can rule viral etiologies in or out

• Implementation encouraged in institutions with high rates of inappropriate prescribing for respiratory tract infections

mPCR

Respiratory

IDSE Review

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IDSE Review

to a positive clinical impact in 7.3%, negative clinical impact in 3.7%, no clinical impact 86.6%, and indeterminant in 2.4%. Cases with a positive Karius result and clinical impact, bacteria, and/or fungi were involved compared with viruses or parasites. Karius testing was evaluated in 55 patients with febrile neutropenia.39 Sensitivity and specificity were 85% (41/48) and 100% (14/14), respectively. Time to diagnosis was shorter compared with traditional blood culture methodology (87%) and could have allowed early antimicrobial optimization in 47% of patients (ie, addition of antimicrobials [20%] mostly against anaerobes [12.7%], antivirals [14.5%], and/or antifungals [3.6%] and antimicrobial de-escalation [27.3%]). These data suggest that Karius testing may have a future role in enabling prompt initiation of antimicrobials specifically in immunocompromised hosts, although a clear role including optimal patient population has yet to be fully elucidated.

diagnostic tests, as they are significantly more sensitive, resulting in more accurate and usable results.46 More recently, multiplex PCR panels for respiratory viruses have become more common, and are able to optimize anti-influenza therapy.47 Clinical and economic outcomes vary across respiratory diagnostic studies, largely due to heterogeneity and variability in the quality of currently available data. Nonetheless, reduced antimicrobial utilization with rapid viral panels has been described among pediatric48 and adult patients.49 Overall, respiratory pathogen panels play an important role in RTI diagnostics. Novel bacterial panels have become available, but clinical outcomes have yet to be assessed. The IDSA Diagnostics Committee recently released clinical and diagnostic recommendations for management of acute RTIs.50 When bacterial pneumonia is diagnosed in patients with risk factors for resistance or at high risk for mortality, grampositive coverage for MRSA is Respiratory often empirically initiated. Because Acute RTIs are most comS. aureus is a pathogen routinely monly caused by viral organisms. implicated in pneumonia, and a However, differentiating between common colonizer of the nares, a viral and bacterial pneumonia is MRSA nasal PCR can be used to a significant challenge, and often help discontinue unnecessary vanresults in unnecessary antimicomycin. A meta-analysis of 22 crobial use for viral infections,40 studies and 5,163 patients idenSource: Clin Infect Dis. especially when bacterial coinfectified a positive predictive value 2004;39(9):1267-1284. tion cannot be ruled out. To date, of 44.8% and negative predictive no single test exists to make this value of 96.5% using 10% prevadifferentiation, but several RDTs together can assist lence,51 indicating a negative result can be particularly useful to rule out MRSA pneumonia thereby decreasASPs in the clinical decision-making process such as ing days of vancomycin therapy, especially among respiratory pathogen (viral/bacterial) panels, methipatients who are not critically ill. ASPs can use a comcillin-resistant S. aureus (MRSA) nasal PCR, and biobination of these RDTs in conjunction with a patient’s marker expression (eg, procalcitonin). Procalcitonin is clinical picture to help ensure that those who require a pro-inflammatory biomarker previously associated antibiotics are treated effectively and those who with a reduction in antimicrobial therapy for lower have solely viral infections are spared unnecessary RTIs,41 and may be useful for ruling out bacterial coinfections.42 However, a clear cutoff between bacterial antimicrobials. and viral pneumonia remains to be elucidated,43 and Central Nervous System interpretation is limited among some patient populaCNS infections are medical emergencies that are tions (eg, those needing hemodialysis).44 In the future, other promising biomarker approaches assessing host associated with considerable mortality and rapid gene expression to categorize acute RTIs as either decline that requires prompt diagnostic identification viral or bacterial may become more readily available and antimicrobial administration.52 Diagnostic testing for CNS infections is particularly challenging, as more for ASPs.45 Nonetheless, when ordering respiratory diagnostic assays, it is important to consider whether than 20 available diagnostic tests exist and various testthe test will affect clinical management. For example, ing combinations are ordered in clinical practice.53 ASPs are incredibly important for such scenarios, as they can influenza is the only respiratory virus of which treathelp guide medical teams, especially when a limited ment is available, suggesting identification by NAAT amount of cerebrospinal fluid (CSF) volume is obtained. can facilitate prompt initiation or discontinuation of Low-volume yield of CSF during lumbar puncture is anti-influenza therapy during influenza season. Howcommonly seen, especially among pediatric patients. ever, ordering the same test for a mildly ill patient not Identifying viral etiologies by PCR can facilitate diagexpected to receive treatment, or during a period of nostics, reduce hospital LOS, and reduce duration of low prevalence, does not provide value. Of note, NAAT unnecessary antimicrobial therapy.54 However, rapid is favored over traditional influenza antigen–based

CNS infections require prompt diagnostic identiﬁcation and antibiotics, if appropriate.

IDSE.NET

GI Infection Cultures Acute gastroenteritis is a leading cause of morbidity and mortality and responsible for an estimated 47.8 million episodes annually in the United States.60,61 Gastroenteritis is characterized by acute onset of diarrhea with or without vomiting and caused by a wide variety of bacteria, viruses, and parasites as well as other noninfectious cases. Identification of an infectious agent is critical for patient care and infection prevention practices; however, the etiologic pathogen goes unidentified in approximately 80% of cases.60,62,63 Conventional methods of identification (eg, antigen testing, microscopic examinations, and culture) are time-consuming, expensive, and have limited sensitivity.64 Multiplex PCR-based GI panels, such as the FilmArray, have emerged as a more rapid and accurate diagnostic tool to diagnose gastroenteritis, although clinical outcomes data are limited. The BioFire

FilmArray GI panel combines 22 enteric pathogens into a single cartridge-based test with a turnaround time of less than 2 hours. Assay performance was assessed and demonstrated 100% and 94.5% or higher sensitivity for 12 of 22 and 7 of 22 targets, respectively, and 97.1% or higher specificity for all targets.65 Although symptoms are often self-limiting, some patients may benefit from antimicrobials and experience delays in therapy due to lengthy testing methods. Hospitalization and further testing such as colonoscopy or abdominal ultrasonography may be required in patients with multiple comorbidities or severe illness pending test results, leading to unnecessary patient isolation and more extensive infection prevention practices. Beal et al evaluated the clinical and economic impact of the FilmArray GI panel compared with historical controls using traditional stool culture testing methodology.66 The positivity rate of the GI panel was 32.8% compared with 6.7% for the historical controls. The GI panel resulted in faster results reported in the electronic health record (8.94 vs 54.75 hours), less additional stool tests ordered overall (0.58 vs 3.02 additional tests; P=0.0001), fewer antibiotic days per patient (1.73 [95% CI, 1.41-2.04] and 2.12 [95% CI, 1.892.35] days per patient; P=0.06), fewer imaging studies (0.18 vs 0.39 imaging studies per patient; P=0.0002), shorter LOS (5.2±3.2 vs 5.6±3.4 days; P=0.14), and a cost savings of approximately $294 per patient. A similar rate of positivity was observed in another study comparing the FilmArray GI panel with historical stool culture controls (29.2% vs 4.1%, respectively).67 Clinical outcomes were also improved with the GI panel; patients were less likely to undergo endoscopy (8.4% vs 9.6%; P=0.008) or abdominal radiology (29.4% vs 31%; P=0.002) and less likely to receive antimicrobials (36.2% vs 40.9%; P<0.001).67 The prevalence of GI coinfection in the United States is not well known compared with developing countries; however, the FilmArray GI panel commonly detects coinfection in up to 32.9%.59-61,65-67 This may be because the PCR is not able to differentiate between asymptomatic colonization and infection.

Conclusion The development and implementation of RDTs have significantly augmented ASPs and improved clinical outcomes for patients with suspected or confirmed infections. When combined with stewardship initiatives, RDTs improve the timeliness and effectiveness of antimicrobial optimization. Although outcomes data are most substantive for BSIs, RTIs, and CNS infections, GI panels are offering advances for patients suffering from these conditions. Awareness of the benefits they may provide, along with a critical assessment of institutional needs, can optimize patient care while minimizing harm associated with inappropriate antimicrobial utilization.

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bacterial identification expedites appropriate antimicrobial utilization and improves clinical outcomes.55,56 The only clinically used, FDA-approved rapid panel is the BioFire FilmArray meningitis/encephalitis (ME) panel (BioFire Diagnostics), with a turnaround time of 1 hour and only 2 minutes of hands-on time. It is a nucleic acid–based panel that requires a small volume of CSF (0.2 mL), and has 14 total targets, including E. coli (K1 serotype only), Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis (encapsulated strains only), Streptococcus agalactiae, Streptococcus pneumoniae, Cryptococcus neoformans/gattii, cytomegalovirus, enteroviruses, herpes simplex viruses 1 and 2, human herpesvirus 6, human parechovirus, and varicella-zoster virus.57 In a study of 1,560 CSF samples, the ME panel established an 84.4% positive and greater than 99% negative agreement to traditional testing methods.56,58 The ME panel also results in a faster time to diagnosis by 10.3 hours compared with pathogen-specific PCR testing.54 There have been reports of both false-positive and false-negative results leading to concerns for institutions when deciding on implementation. A recent meta-analysis was performed to determine the sensitivity and specificity of the ME panel.59 The investigators pooled data from 8 studies (N=3,059) and reported a sensitivity and specificity with confidence intervals of 90% (95% CI, 86%-93%) and 97% (95% CI, 94%-99%), respectively. The highest proportion of false positives was associated with S. pneumoniae followed by S. agalactiae, and the highest proportion of false negatives was for herpes simplex viruses 1 and 2, enteroviruses, and C. neoformans/gattii. Despite promising potential, the ME panel cannot yet replace traditional testing methods for ME diagnosis, and knowledge of limitations is essential for utilization.56,58 It may be particularly helpful in hospitals with high CNS infection prevalence (eg, pediatric and neonatal patients).

IDSE Review

References 1.

Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):1974-1982.

2. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-1248. 3. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146-155. 4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. 5. Paul M, Kariv G, Goldberg E, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2010;65(12):2658-2665. 6. Paul M, Shani V, Muchtar E, et al. Systematic review and metaanalysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. 2010;54(11):4851-4863. 7. Lodise TP, Berger A, Altincatal A, et al. Antimicrobial resistance or delayed appropriate therapy—does one influence outcomes more than the other among patients with serious infections due to carbapenem-resistant versus carbapenem-susceptible Enterobacteriaceae? Open Forum Infect Dis. 2019;6(6):ofz194. 8. Zasowski EJ, Claeys KC, Lagnf AM, et al. Time is of the essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset enterococcal bloodstream infections. Clin Infect Dis. 2016;62(10):1242-1250. 9. Beganovic M, Timbrook TT, Wieczorkiewicz SM. Predictors of time to effective and optimal antimicrobial therapy in patients with positive blood cultures identified via molecular rapid diagnostic testing. Open Forum Infect Dis. 2019;6(1):ofy350.

blood cultures in conjunction with rapid diagnostic testing. J Clin Microbiol. 2014;52(8):2849-2854. 18. Wenzler E, Wang F, Goff DA, et al. An automated, pharmacistdriven initiative improves quality of care for Staphylococcus aureus bacteremia. Clin Infect Dis. 2017;65(2):194-200. 19. Bookstaver PB, Nimmich EB, Smith TJ 3rd, et al. Cumulative effect of an antimicrobial stewardship and rapid diagnostic testing bundle on early streamlining of antimicrobial therapy in gram-negative bloodstream infections. Antimicrob Agents Chemother. 2017;61(9):e00189-17. 20. Pogue JM, Heil EL, Lephart P, et al. An antibiotic stewardship program blueprint for optimizing Verigene BC-GN within an Institution: a tale of two cities. Antimicrob Agents Chemother. 2018;62(5):e02538-17. 21. Rivard KR, Athans V, Lam SW, et al. Impact of antimicrobial stewardship and rapid microarray testing on patients with gram-negative bacteremia. Eur J Clin Microbiol Infect Dis. 2017;36(10):1879-1887. 22. Walker T, Dumadag S, Lee CJ, et al. Clinical impact of laboratory implementation of Verigene BC-GN Microarray-based assay for detection of gram-negative bacteria in positive blood cultures. J Clin Microbiol. 2016;54(7):1789-1796. 23. Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57(9):1237-1245. 24. Pfaller MA, Wolk DM, Lowery TJ. T2MR and T2Candida: novel technology for the rapid diagnosis of candidemia and invasive candidiasis. Future Microbiol. 2016;11(1):103-117. 25. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50.

10. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis. 2017;64(1):15-23.

26. Wilson NM, Alangden G, Tibbetts RJ, et al. T2 magnetic resonance assay improves timely management of candidemia. J Antimicrob Stewardship. 2017;1(1):12-18.

11. Pliakos EE, Andreatos N, Shehadeh F, et al. The cost-effectiveness of rapid diagnostic testing for the diagnosis of bloodstream infections with or without antimicrobial stewardship. Clin Microbiol Rev. 2018;31(3):e00095-17.

27. Patch ME, Weisz E, Cubillos A, et al. Impact of rapid, cultureindependent diagnosis of candidaemia and invasive candidiasis in a community health system. J Antimicrob Chemother. 2018;73(suppl 4):iv27-iv30.

12. Messacar K, Parker SK, Todd JK, et al. Implementation of rapid molecular infectious disease diagnostics: the role of diagnostic and antimicrobial stewardship. J Clin Microbiol. 2017;55(3):715-723.

28. De Angelis G, Posteraro B, De Carolis E, et al. T2Bacteria magnetic resonance assay for the rapid detection of ESKAPEc pathogens directly in whole blood. J Antimicrob Chemother. 2018;73(suppl 4):iv20-iv6.

13. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary: implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):1197-1202.

29. Nguyen MH, Clancy CJ, Pasculle AW, et al. Performance of the T2Bacteria Panel for diagnosing bloodstream infections: a diagnostic accuracy study. Ann Intern Med. 2019;170(12):845-852.

14. Wenzler E, Timbrook TT, Wong JR, et al. Implementation and optimization of molecular rapid diagnostics in bloodstream infections: a clinical review. Am J Health Syst Pharm. 2018;75(16):1191-1202. 15. Aitken SL, Hemmige VS, Koo HL, et al. Real-world performance of a microarray-based rapid diagnostic for gram-positive bloodstream infections and potential utility for antimicrobial stewardship. Diagn Microbiol Infect Dis. 2015;81(1):4-8. 16. Wong JR, Bauer KA, Mangino JE, et al. Antimicrobial stewardship pharmacist interventions for coagulase-negative staphylococci positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother. 2012;46(11):1484-1490. 17. Nagel JL, Huang AM, Kunapuli A, et al. Impact of antimicrobial stewardship intervention on coagulase-negative Staphylococcus

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30. Drevinek P, Hurych J, Antuskova M, et al. Direct detection of ESKAPEc pathogens from whole blood using the T2Bacteria Panel allows early antimicrobial stewardship intervention in patients with sepsis. Microbiologyopen. 2021;10(3):e1210. 31. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant gram-negative bacteremia. J Infect. 2014;69(3):216-225. 32. Kerremans JJ, Verboom P, Stijnen T, et al. Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use. J Antimicrob Chemother. 2008;61(2):428-435. 33. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363.

35. Banerjee R, Komarow L, Virk A, et al. Randomized trial evaluating clinical impact of RAPid IDentification and susceptibility testing for gram negative bacteremia: RAPIDS-GN. Clin Infect Dis. 2021;73(1):e39-e46.

52. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284. 53. Wootton SH, Aguilera E, Salazar L, et al. Enhancing pathogen identification in patients with meningitis and a negative Gram stain using the BioFire FilmArray Meningitis/Encephalitis panel. Ann Clin Microbiol Antimicrob. 2016;15:26.

36. Dare RK, Lusardi K, Pearson C, et al. Clincal Impact of Accelerate Pheno Rapid Blood Culture Detection System in bacteremic patients. Clin Infect Dis. 2021;73(11):e4616-e4626.

54. Messacar K, Breazeale G, Robinson CC, et al. Potential clinical impact of the film array meningitis encephalitis panel in children with suspected central nervous system infections. Diagn Microbiol Infect Dis. 2016;86(1):118-120.

37. Goggin KP, Gonzalez-Pena V, Inaba Y, et al. Evaluation of plasma microbial cell-free DNA sequencing to predict bloodstream infection in pediatric patients with relapsed or refractory cancer. JAMA Oncol. 2019;6(4):552-556.

55. Blaschke AJ, Holmberg KM, Daly JA, et al. Retrospective evaluation of infants aged 1 to 60 days with residual cerebrospinal fluid (CSF) tested using the FilmArray Meningitis/Encephalitis (ME) panel. J Clin Microbiol. 2018;56(7):e00277-18.

38. Hogan CA, Yang S, Garner OB, et al. Clinical impact of metagenomic next-generation sequencing of plasma cell-free DNA for the diagnosis of infectious diseases: a multicenter retrospective cohort study. Clin Infect Dis. 2021;72(2):239-245. 39. Benamu E, Gajurel K, Anderson JN, et al. Plasma microbial cellfree DNA next generation sequencing in the diagnosis and management of febrile neutropenia. Clin Infect Dis. 2021;ciab324. doi:10.1093/cid/ciab324 40. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864-1873. 41. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. 42. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with positive respiratory viral panel and low procalcitonin results in proven or suspected respiratory infections. Infect Dis Ther. 2015;4(3):297-306. 43. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis. 2017;65(2):183-190. 44. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis. 2014;59(12):1761-1767. 45. Tsalik EL, Henao R, Nichols M, et al. Host gene expression classifiers diagnose acute respiratory illness etiology. Sci Transl Med. 2016;8(322):322ra11. 46. Vemula SV, Zhao J, Liu J, et al. Current approaches for diagnosis of influenza virus infections in humans. Viruses. 2016;8(4):96. 47. Green DA, Hitoaliaj L, Kotansky B, et al. Clinical utility of ondemand multiplex respiratory pathogen testing among adult outpatients. J Clin Microbiol. 2016;54(12):2950-2955.

56. Leber AL, Everhart K, Balada-Llasat JM, et al. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol. 2016;54(9):2251-2261. 57. He T, Kaplan S, Kamboj M, et al. Laboratory diagnosis of central nervous system infection. Curr Infect Dis Rep. 2016;18(11):35. 58. Hanson KE, Couturier MR. Multiplexed molecular diagnostics for respiratory, gastrointestinal, and central nervous system infections. Clin Infect Dis. 2016;63(10):1361-1367. 59. Tansarli GS, Chapin KC. Diagnostic test accuracy of the BioFire FilmArray meningitis/encephalitis panel: a systematic review and meta-analysis. Clin Microbiol Infect. 2020;26(3):281-290. 60. Scallan E, Griffin PM, Angulo FJ, et al. Foodborne illness acquired in the United States—unspecified agents. Emerg Infect Dis. 2011;17(1):16-22. 61. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis. 2011;17(1):7-15. 62. Axelrad JE, Joelson A, Nobel Y, et al. The distribution of enteric infections utilizing stool microbial polymerase chain reaction testing in clinical practice. Dig Dis Sci. 2018;63(7):1900-1909. 63. Axelrad JE, Joelson A, Nobel YR, et al. Enteric infection in relapse of inflammatory bowel disease: the utility of stool microbial PCR testing. Inflamm Bowel Dis. 2017;23(6):1034-1039. 64. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol. 2016;111(5):602-622. 65. Buss SN, Leber A, Chapin K, et al. Multicenter evaluation of the BioFire FilmArray gastrointestinal panel for etiologic diagnosis of infectious gastroenteritis. J Clin Microbiol. 2015;53(3):915-925.

48. Doan Q, Enarson P, Kissoon N, et al. Rapid viral diagnosis for acute febrile respiratory illness in children in the emergency department. Cochrane Database Syst Rev. 2014;(9):CD006452.

66. Beal SG, Tremblay EE, Toffel S, et al. A gastrointestinal PCR panel improves clinical management and lowers health care costs. J Clin Microbiol. 2018;56(1):e01457-17.

49. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017;5(5):401-411.

67. Axelrad JE, Freedberg DE, Whittier S, et al. Impact of gastrointestinal panel implementation on health care utilization and outcomes. J Clin Microbiol. 2019;57(3):e01775-18.

50. Hanson KE, Azar MM, Banerjee R, et al. Molecular testing for acute respiratory tract infections: clinical and diagnostic recommendations from the IDSA’s Diagnostics Committee. Clin Infect Dis. 2020;71(10):2744-2751. 51. Parente DM, Cunha CB, Mylonakis E, et al. The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: a diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis. 2018;67(1):1-7.

68. Beganovic M, McCreary EK, Mahoney MV, et al. Interplay between rapid diagnostic tests and antimicrobial stewardship programs among patients with bloodstream and other severe infections. J Appl Lab Med. 2019;3(4):601-616.

About the author Sarah M. Wieczorkiewicz, PharmD, FIDSA, BCPS, BCIDP, is an infectious diseases clinical specialist in Chicago, Illinois, and has 15 years of clinical experience.

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34. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.

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IDSE Review

What’s New in CMV Prevention and Therapy for Transplant Patients? BY SHMUEL SHOHAM, MD, FIDSA

nfection and disease caused by the human cytomegalovirus (CMV) remains a challenge in transplant recipients. Two new drugs, letermovir (Prevymis, Merck) and maribavir (Livtencity, Takeda) are now available for prevention and treatment, respectively, of CMV disease. This article reviews the clinical role of these drugs.

Overview Prevention and treatment of CMV disease is a fundamental part of supportive care for recipients of hematopoietic stem cell transplant (HSCT) and solidorgan transplant (SOT). Prevention is mainly by chemoprophylaxis during times of highest risk, such as in the first several months after transplantation and at times of intensification of immunosuppression. CMV serology is helpful for identifying patients at higher risk for clinically significant CMV infection. In HSCT, there is a higher risk for clinically significant CMV infection in recipients who are CMV-seropositive. In SOT, the highest risk is in CMV-seronegative recipients receiving organs from CMV-seropositive donors. Until recently, the drug of choice for prevention of infection has been valganciclovir, which is the

oral prodrug of ganciclovir. Ganciclovir administered intravenously is used when oral therapy is not feasible. Oral ganciclovir is no longer used as it has low bioavailability and is associated with poorer outcomes than other therapies. Treatment of CMV (as opposed to prophylaxis) is given when the level of viremia exceeds a certain numerical threshold (preemptive therapy), when there is viremia with symptoms compatible with CMV infection (CMV syndrome), and when there is evidence for tissue-invasive CMV disease. Treatment is usually with either IV ganciclovir or oral valganciclovir, at doses higher than those used for prophylaxis.1 The main toxicity with valganciclovir and ganciclovir, which henceforth will be referred to as (val)ganciclovir, is bone marrow suppression.2 This predominantly manifests as leukopenia but also can

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Useful terms CMV disease: CMV infection with signs and be present with thrombofoscarnet are renal impairsymptoms (includes CMV syndrome and me cytopenia or anemia. Bone ment and electrolyte abnortissue-invasive CMV disease). ma marrow toxicity from (val) malities. The predominant ttoxicities with cidofovir are ganciclovir can be particCMV syndrome: detection rrenal impairment and uveularly challenging in HSCT of CMV in blood (eg, by recipients, especially earitis. In a study including polymerase chain reaction lier in the transplant process 39 transplant recipients [PCR] test) and 2 or more of when the donor stem cells treated with foscarnet for the following: fever, malaise g have not yet fully engrafted. ganciclovir-resistant or or fatigue, leukopenia, atypical --refractory CMV infection, This side effect has largely nia, a lymphocytosis, thrombocytopenia, viro curtailed use of (val)ganvirologic failure occurred in or elevated liver aminotransferases ciclovir chemoprophylaxis one-third and renal dysfunc(defined only for solid-organ transplant during such periods in HSCT tion occurred in one-half of recipients). recipients. Bone marrow supfoscarnet recipients.6 In a CMV end-organ disease: sites of infection study including 16 transplant pression may also be an issue include GI tract, liver, retina, lungs, and central recipients receiving cidofovir, at later stages of the HSCT nervous system. 50% failed to clear CMV vireprocess and in SOT recipimia. Side effects were coments with limited bone marPreemptive treatment: administration of an mon, with nephrotoxicity row reserves owing to their antiviral drug to a patient with CMV viremia occurring in 37.5% of recipiunderlying conditions and while still asymptomatic, with the goal of ents and uveitis in 25%.7 incomplete recovery from the preventing progression to CMV disease. Usually The development of transplant procedure. Addibased on sequential monitoring of an early maribavir as an alternationally, transplant recipients detection test such as quantitative CMV PCR. tive drug is a major advance are often treated with other in management for such medications, such as mycoProphylaxis: administration of an antiviral drug patients. The clinical role of phenolate, that may deplete to patients at risk for CMV. maribavir in such instances is their bone marrow reserves. Clinically significant CMV infection: CMV reviewed later in this article. Management of cytopenia disease or CMV viremia leading to preemptive arising from (val)ganciclotreatment. Letermovir vir use often requires growth Letermovir is approved factor (granulocyte colonyCMV serology: measurement of CMV by the FDA for prophylaxis stimulating factor) support immunoglobulin G antibody levels. in CMV-seropositive HSCT and/or discontinuation of the CMV, cytomegalovirus; GI, gastrointestinal; HSCT, hematopoietic recipients. The approved antiviral agent. stem cell transplant. dose is 480 mg daily (oral or Ganciclovir is a guanosine IV) through 100 days postanalog that inhibits the CMV transplant. Letermovir’s mechanism of action is by DNA polymerase. To become active, ganciclovir must interference with DNA cleavage/packaging/maturabe phosphorylated by the viral enzyme phosphotranstion within the CMV virion.8 This is facilitated by inhiferase. This enzyme is a product of the CMV UL97 bition of the viral terminase enzyme complex (UL51, gene and mutations in that gene confer resistance to UL56, and UL89). Letermovir is not active against ganciclovir. This, in turn, can lead to CMV that proves other herpesviruses (eg, herpes simplex virus [HSV] refractory to ganciclovir. Of note, refractory CMV may and varicella zoster virus [VZV]), for which purpose not be genotypically resistant. Risk factors for CMV (val)acyclovir needs to be coadministered in patients resistance include extensive exposure to ganciclovir, who require prophylaxis for HSV and VZV. Because suboptimal ganciclovir levels in the setting of intenthe hurdle to development of resistance is generally sive immunosuppression and high viral loads.2 Neither cidofovir nor foscarnet requires this viral phosphorlow, the main use of letermovir is for prevention of ylation step to be active and hence are not affected infection as either primary or secondary prophylaxis— by UL97 mutations. Mutations in the CMV UL54 gene, including the maintenance phase of therapy when viral which encodes for a viral DNA polymerase, can lead load is very low. to resistance to ganciclovir, cidofovir, and foscarnet or The most common side effects of letermovir are none of these.3 gastrointestinal (GI). It is not associated with the bone Until recently, the main treatments available for marrow toxicities of (val)ganciclovir or the renal and refractory or ganciclovir-resistant CMV were foscarnet electrolyte toxicities of foscarnet. More challenging are and cidofovir. The efficacy and safety of both drugs the various drug interactions. Letermovir is a moderate are suboptimal. Additionally, the FDA has only granted inhibitor of the cytochrome enzyme CYP3A and hence them an indication for retinitis. The main toxicities with can increase levels of drugs metabolized through that

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prophylaxis therapy after control of significant disease. Letermovir was used in a series of 37 lung and 4 heart transplants for primary and secondary prophylaxis. In that study, median duration of letermovir prophylaxis was 282 days (interquartile range, 131-433 days). The rates of adverse effects requiring letermovir discontinuation and of breakthrough CMV infection were 12% and 2.4%, respectively.15 In a study of solid-organ transplant recipients who were converted from valganciclovir to letermovir prophylaxis, there was no significant difference in the rate of CMV breakthrough between patients on letermovir (8.7%) and valganciclovir (13.5%) (P=0.7097).16 In a study of 28 lung transplant recipients treated with letermovir for ganciclovir-resistant or -refractory CMV infection, 23 patients (82.1%) had a rapid response with subsequent clearing of the virus. Among the 5 nonresponding patients, 3 were discovered to have mutations conferring resistance at the viral terminase enzyme (UL56Gen: C325Y).17 In addition, Aryal et al reported that 3 of 8 (37.5%) SOT patients receiving letermovir for prophylaxis developed CMV viremia during prophylaxis.18 A key parameter for treatment failure is viral load. Thus, care must be taken to ensure viral load at the time of letermovir initiation is low enough to avoid risk for development of resistance and treatment failure. For example, in a study of 21 HSCT and 27 SOT recipients with CMV infection who were treated with letermovir, the key parameter for success was viral load. Whereas viral load improved or remained stable (<1 log rise in viral load) in 35 of 37 letermovir recipients initiated on therapy when viral load was less than 1,000 IU/mL, this was only the case in 6 of 10 patients whose viral load exceeded 1,000 IU/mL at initiation of letermovir.19 In another study, risk factors for breakthrough infection among patients receiving letermovir prophylaxis were low-grade CMV replication (21-149

Prevention and treatment of CMV disease is a fundamental part of supportive care for transplant recipients.

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pathway (eg, cyclosporine, tacrolimus, and sirolimus). It is also an inducer of CYP2C9 and 2C19, and can decrease levels of drugs metabolized through those pathways (eg, voriconazole). Of note, coadministration of letermovir with cyclosporine (but not tacrolimus or sirolimus) leads to increased levels of letermovir. However, all of these interactions are relatively manageable with alteration of doses and monitoring of drug levels of the immunosuppressants or voriconazole. Several trials have examined the efficacy of letermovir as prophylaxis in HSCT recipients. Marty et al conducted a blinded randomized controlled trial of letermovir versus placebo in CMV-seropositive HSCT recipients. In that trial, letermovir therapy was associated with fewer episodes of clinically significant CMV infection or requirement for premature discontinuation of therapy by 24 weeks after transplantation (122/325 patients [37.5%] vs 103/170 [60.6%]; P<0.001).9 An evaluation of all-cause mortality in that trial showed letermovir prophylaxis to be associated with lower risk for mortality at 24 weeks. (hazard ratio [HR], 0.58; 95% CI, 0.35-0.98; P=0.04).10 Postmarketing surveillance of HSCT recipients receiving letermovir as prophylaxis also showed lower rates of CMV reactivation in the first 100 days after transplant compared with historical controls (20% vs 72%; P<0.001). Similarly, the rate of clinically significant CMV infection was lower in the letermovir group versus controls (4% vs 59%; P<0.001).11 In a retrospective study, use of letermovir in CMV-seropositive HSCT recipients significantly decreased mortality with an adjusted hazard ratio of 0.62 (95% CI, 0.40-0.98). The improvement in survival was most marked in recipients of T cell– depleted transplants.12 Similarly, the impact of letermovir on HSCT mortality was evaluated in retrospective analyses. In a study comparing 114 HSCT recipients who received letermovir prophylaxis for a median of 92 days with 571 patients without prophylaxis, the incidence of clinically significant CMV and mortality at 6 months were significantly reduced (44.7% vs 72.4%; P<0.001 and 80.4% vs 73.0%; P=0.033).13 Use of letermovir as a prophylaxis strategy in HSCT recipients with acute graft-versus-host disease (GVHD) was evaluated in several retrospective studies. For example, an analysis of 119 patients showed letermovir prophylaxis was associated with decreased development of clinically significant CMV infection (HR, 0.08; 95% CI, 0.03-0.27; P<0.001), nonrelapse mortality (P=0.04), and improved overall survival (P=0.04).14 Increasingly, letermovir is used off-label in solidorgan transplant recipients, and there is an ongoing randomized double-blind trial of letermovir versus valganciclovir prophylaxis in kidney transplant recipients (MK8228-002). This is often in patients who have had difficulty tolerating (val)ganciclovir but still require primary prophylaxis, maintenance, or secondary

IDSE Review

Table. Medication for Prevention and Treatment of CMV in Transplant Recipients Target ➔ Activity

Drug

Ganciclovir/ DNA polymerase  viral replication valganciclovir

Safety and Adverse Effects

Uses

Cytopenias

Prevention and treatment of CMV infection

Maribavir

Treatment of resistant/ refractory CMV. In future UL97 protein kinase  viral assembly Dysgeusia, GI upset, drug interactions this may also include uncomplicated CMV in HSCT

Letermovir

Terminase enzyme  viral maturation GI upset, drug interactions

Prevention and possibly treatment with viral load <1,000 copies/mL

Cidofovir

DNA polymerase  viral replication

Renal and ocular toxicity

Treatment of resistant/ refractory CMV infection

Foscarnet

DNA polymerase  viral replication

Renal and electrolyte toxicity

Treatment of resistant/ refractory CMV infection

CMV, cytomegalovirus; GI, gastrointestinal; HSCT, hematopoietic stem cell transplant.

IU/mL), both at the time of letermovir initiation or during prophylaxis, and development of acute GI GVHD.20

Maribavir Maribavir is approved by the FDA for the treatment of post-transplant CMV infection that is refractory to treatment with other anti-CMV agents, such as (val)ganciclovir, cidofovir, or foscarnet. The approved dose is 400 mg twice daily. Maribavir’s mechanism of action is through inhibition of UL97 protein kinase and impairment of viral DNA assembly. As with letermovir, maribavir is not active against other herpesviruses (eg, HSV and VZV), for which (val)acyclovir needs to be coadministered if prophylaxis against HSV and VZV is needed. Of note, because CMV UL97 protein kinase is needed to activate ganciclovir, the combination of maribavir and ganciclovir actually results in antagonism of the latter drug’s antiviral activity.21 The main side effects of maribavir are taste disturbances (dysgeusia) and GI upset. Dysgeusia occurs frequently, but most often has not led to discontinuation in clinical trials of maribavir. The drug is metabolized by the CYP3A4 system and is a weak inhibitor of that enzyme complex. Hence, coadministration with maribavir leads to increased levels of calcineurin inhibitors (cyclosporin and tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus). For example, maribavir 400 mg twice daily increased tacrolimus trough concentrations by 57%.22 Several trials have assessed the efficacy of maribavir for treatment of CMV infection. Maertens et al compared maribavir and valganciclovir as preemptive therapy in a phase 2, open-label trial of adult HSCT and SOT recipients with CMV reactivation (plasma CMV DNA level, 1,000-100,000 DNA copies/mL). Participants received maribavir at doses of 400, 800, or 1,200 mg twice daily or the standard dose of valganciclovir for up to 12 weeks. The study included 117 participants in the maribavir group and 39 in the valganciclovir

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group. Clinical outcomes at 6 weeks were similar in both groups (79% and 67% of patients; risk ratio, 1.20; 95% CI, 0.95-1.51). Responses to treatment were also similar among the various maribavir dose groups. The authors concluded that maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of HSCT or SOT. A higher incidence of GI adverse events—notably dysgeusia—and a lower incidence of neutropenia were found in the maribavir group.23 Maribavir was also tested as therapy in a phase 2 trial including 120 HSCT and SOT recipients with CMV that had proven refractory or resistant to available antivirals ([val]ganciclovir, foscarnet, and cidofovir). Patients with refractory or resistant CMV infections having plasma CMV DNA levels of 1,000 copies/mL or higher were randomized (1:1:1) to twice-daily, doseblinded maribavir 400, 800, or 1,200 mg for up to 24 weeks. In that study, 80 of 120 (67%) patients achieved undetectable CMV DNA levels within 6 weeks of treatment, with similar outcomes among all the dosing groups. Among the 25 patients in that study who developed recurrent infections while on treatment, 13 developed mutations conferring maribavir resistance. As with the preemptive therapy study, GI side effects, specifically dysgeusia, were the most common adverse events related to therapy (78/120; 65%) and led to maribavir discontinuation in 1 patient. The authors concluded that maribavir at a dose of 400 mg or higher twice daily was active against CMV infection in transplant recipients who were refractory or resistant to other antivirals.24 The results of this phase 2 trial led to a randomized, open-label phase 3 trial of maribavir (n=235) at a dose of 400 mg twice daily, compared with investigator-assigned therapies (n=117; [val]ganciclovir, foscarnet, cidofovir) for 8 weeks, for treatment of refractory or resistant CMV in HSCT and SOT recipients. Significantly more patients in the maribavir group achieved

Conclusion While (val)ganciclovir remains the cornerstone for treatment of CMV in both HSCT and SOT and for prophylaxis in SOT recipients, the arrival of letermovir and maribavir as therapeutic options is a major advance in the field. Letermovir is approved by the FDA for prophylaxis in CMV-seropositive HSCT recipients and maribavir is approved as treatment of CMV infection refractory to (val)ganciclovir, cidofovir, or foscarnet. The main side effects of both drugs are GI in nature, with maribavir causing dysgeusia in a substantial percentage of patients. Neither letermovir nor maribavir

is associated with the bone marrow suppression seen with (val)ganciclovir or with the renal and electrolyte toxicities seen with foscarnet and cidofovir. As more data and clinical experience accumulate, it is expected that the primary roles for these 2 drugs will expand to include a broader range of patients for whom (val) ganciclovir is proving too toxic.

References 1.

Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients—guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13512. 2

2. Sommadossi JP, Carlisle R. Toxicity of 3’-azido-3’-deoxythymidine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for normal human hematopoietic progenitor cells in vitro. Antimicrob Agents Chemother. 1987;31(3):452-454. 3. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis. 2002;35(7):866-872. 4. Fisher CE, Knudsen JL, Lease ED, et al. Risk factors and outcomes of ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients. Clin Infect Dis. 2017;65(1):57-63. 5. Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Acad Sci U S A. 2000;97(14):8039-8044. 6. Avery RK, Arav-Boger R, Marr KA, et al. Outcomes in transplant recipients treated with foscarnet for ganciclovir-resistant or refractory cytomegalovirus infection. Transplantation. 2016;100(10):e74-80. 7. Mehta Steinke SA, Alfares M, Valsamakis A, et al. Outcomes of transplant recipients treated with cidofovir for resistant or refractory cytomegalovirus infection. Transpl Infect Dis. 2021;23(3):e13521. 8. Goldner T, Hewlett G, Ettischer N, et al. The novel anticytomegalovirus compound AIC246 (letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011;85(20):10884-10893. 9. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433-2444. 10. Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70(8):1525-1533. 11. Anderson A, Raja M, Vazquez N. Clinical “real-world” experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin Transplant. 2020;34(7):e13866. 12. Su Y, Stern A, Karantoni E, et al. Impact of letermovir primary cytomegalovirus (CMV) prophylaxis on 1-year mortality after allogeneic hematopoietic cell transplantation (HCT): a retrospective cohort study. Clin Infect Dis. 2022 Jan3;ciab1064. 13. Mori Y, Jinnouchi F, Takenaka K, et al. Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data. Bone Marrow Transplant. 2021;56(4):853-862. 14. Wolfe D, Zhao Q, Siegel E, et al. Letermovir prophylaxis and cytomegalovirus reactivation in adult hematopoietic cell transplant recipients with and without acute graft versus host disease. Cancers (Basel). 2021;13(21):5572. 15. Saullo JL, Baker AW, Snyder LD, et al. Cytomegalovirus prevention in thoracic organ transplantation: a single-center evaluation of letermovir prophylaxis. J Heart Lung Transplant. 2021;S1053-2498(21)02626-7. 16. Winstead RJ, Kumar D, Brown A, et al. Letermovir prophylaxis in solid organ transplant—assessing CMV breakthrough and tacrolimus drug interaction. Transpl Infect Dis. 2021;23(4).

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clearance of CMV viremia at the end of the 8-week treatment period (55.7% vs 23.9%; adjusted difference [95% CI], 32.8% [22.80%-42.74%]; P<0.001) and also CMV clearance plus symptom control during followup out to 16 weeks were significantly more frequent in the maribavir group (18.7% vs 10.3%; adjusted difference [95% CI], 9.5% [2.02%-16.88%]; P=0.01). As would be expected, maribavir was associated with less acute kidney injury than foscarnet (8.5% vs 21.3%) and less neutropenia than (val)ganciclovir (9.4% vs 33.9%).25 Maribavir was also evaluated for CMV prophylaxis, but results have been mixed and it is not approved for that indication. The lack of efficacy for prophylaxis may be explained by inadequate dosing in some of the early clinical trials. In a phase 2 prophylaxis study involving HSCT recipients, Winston et al compared maribavir at various doses (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) with valganciclovir. Plasma CMV DNA was lower in each of the respective maribavir groups (7% [P=0.001]; 11% [P=0.007]; 19% [P=0.038]) compared with placebo (46%), and antiCMV therapy was used less often in patients receiving each respective dose of maribavir (15% [P=0.001]; 30% [P=0.051]; 15% [P=0.002]) than in those receiving placebo (57%).26 However, in a study of high-risk liver transplant recipients (CMV donor positive/recipient negative serology), maribavir at 100 mg twice daily was compared with oral ganciclovir for prevention of CMV disease. CMV infection as measured by presence of viremia, antigenemia, or CMV disease occurred in 60% of maribavir versus 20% of ganciclovir recipients (P<0.0001) at 100 days and at 6 months (72% vs 53%; P=0.0053) after transplantation. The authors concluded that at a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.27 Moreover, in a phase 3 prophylaxis study of HSCT recipients who had engrafted, outcomes with maribavir (100 mg orally twice per day) were similar to placebo. The incidences of CMV viremia and disease within 6 months were 28% versus 30% and 4% versus 5%, respectively. The authors concluded that compared with placebo, maribavir prophylaxis did not prevent CMV disease when started after engraftment.28

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17. Veit T, Munker D, Barton J, et al. Letermovir in lung transplant recipients with cytomegalovirus infection: a retrospective observational study. Am J Transplant. 2021;21(10):e13570. 18. Aryal S, Katugaha SB, Cochrane A, et al. Single-center experience with use of letermovir for CMV prophylaxis or treatment in thoracic organ transplant recipients. Transpl Infect Dis. 2019;21(6):e13166. 19. Linder KA, Kovacs C, Mullane KM, et al. Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients. Transpl Infect Dis. 2021;23(4):e13687. 20. Royston L, Royston E, Masouridi-Levrat S, et al. Predictors of breakthrough clinically significant cytomegalovirus infection during letermovir prophylaxis in high-risk hematopoietic cell transplant recipients. Immun Inflamm Dis. 2021;9(3):771-776. 21. Chou S, Marousek GI. Maribavir antagonizes the antiviral action of ganciclovir on human cytomegalovirus. Antimicrob Agents Chemother. 2006;50(10):3470-3472. 22. Pescovitz MD, Bloom R, Pirsch J, et al. A randomized, double-blind, pharmacokinetic study of oral maribavir with tacrolimus in stable renal transplant recipients. Am J Transplant. 2009;9(10):2324-2330. 23. Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med. 2019;381(12):1136-1147. 24. Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis. 2019;68(8):1255-1264.

25. Avery RK, Alain S, Alexander BD, et al. Maribavir for refractory cytomegalovirus infections with or without resistance posttransplant: results from a phase 3 randomized clinical trial. Clin Infect Dis. 2021;ciab988. 26. Winston DJ, Young JAH, Pullarkat V, et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood. 2008;111(11):5403-5410. 27. Winston DJ, Saliba F, Blumberg E, et al. Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial. Am J Transplant. 2012;12(11):3021-3030. 28. Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011;11(4):284-292.

Dr. Shoham reported research grants from Ansun, Ciara, Emergent Biosolutions, F2G, Gilead, Merck, Shire, and Zeteo, and being a paid advisor for Adagio, Adamis, Celltrion, Immunome, Intermountain Health, and Karyopharm.

About the author Shmuel Shoham, MD, FIDSA, is a professor of medicine at Johns Hopkins University School of Medicine, in Baltimore, Maryland.

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Updates to the 2021 Guidelines for ARV Use in Adults and Adolescents With HIV BY ASHLEY HOARE, MS; JESSICA HOARE, MS; AND JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI

here were almost 38,000 adults and adolescents diagnosed with HIV infection in the United States and dependent areas in 2018, a decrease compared with 2015.1 The highest rates of diagnoses were reported in the South, the Northeast, followed by the West (Figure). Although almost 80% of these new diagnoses were in men, the number of men diagnosed with HIV in the United States and dependent areas decreased by 10% between 2015 and 2019. Despite the decrease in new diagnoses, the prevalence of HIV in adults and adolescents in the United States increased to more than 1 million in 2019.2 Of those living with HIV, approximately 65% have achieved viral suppression of their HIV infection.3 Achieving viral suppression is the result of careful selection of and adherence to the appropriate treatment. Recent data from a number of ongoing clinical trials have led to several updates to the “Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV” that are important to consider when selecting the optimal treatment.4

Recommended as Initial Regimens for Most People With HIV Four regimens are currently in the category “recommended as initial regimens for most people with HIV” (Table 1).4 Three of these regimens include 1 integrase strand transfer inhibitor (INSTI) in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs). The fourth recommended regimen for initial treatment is a combination of 1 INSTI with 1 NRTI. Dolutegravirlamivudine (DTG/3TC; Dovato, ViiV Healthcare). However, DTG/3TC is only recommended for people who have already had genotypic testing for reverse transcriptase; it is not recommended for those with HIV RNA greater than 500,000 copies/mL, nor for patients with hepatitis B virus

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Table 1. Recommended as Initial Regimens for Most People With HIV Brand Name

Generic Name

Abbreviation

Biktarvy

Bictegravir 50 mg/emtricitabine 200 mg/ tenofovir alafenamide 25 mg

BIC/TAF/FTC

Triumeq

Dolutegravir 50 mg/abacavir 600 mg/ lamivudine 300 mg

DTG/ABC/3TC

Tivicay + Emtriva/Epivir + Vemlidy/Viread

Dolutegravir 50 mg + emtricitabine 200 mg/lamivudine 300 mg + tenofovir alafenamide 25 mg/tenofovir disoproxil fumarate

DTG + TAF/TDF + FTC/3TC

Dovato

Dolutegravir 50 mg/lamivudine 300 mg

DTG/3TC

1 integrase strand transfer inhibitor (INSTI) + 2 nucleoside reverse transcriptase inhibitors (NRTIs)

1 INSTI with 1 NRTI

Adapted from reference 3.

(HBV) coinfection.4 The aforementioned regimens are considered effective with high tolerability, favorable toxicity profiles, and virologic efficacy in addition to ease of use. Since the 2018 guidelines update, regimens based on raltegravir (RAL; Isentress and Isentress HD, Merck) have been removed from the “recommended initial regimens for most people with HIV”’ category and placed in the “recommended initial regimen in certain clinical situations” category. The regimens listed in this category may be more favorable for patients presenting with different clinical situations that would make the typical starting regimens less ideal. Raltegravir-based regimens may be preferred in the setting of chronic kidney disease, specifically when abacavir (ABC), tenofovir alafenamide, and tenofovir disoproxil fumarate cannot be used due to HBV coinfection. In the setting of hyperlipidemia, RAL may be a preferred treatment option because it has fewer effects on lipid levels. This regimen also may be considered in patients with high cardiac risk to avoid worsening hyperlipidemia. In addition, RAL does not require food intake to increase absorption, and can be considered for patients who find higher caloric intake challenging. Despite its usefulness in these specific patient populations, RALbased regimens are no longer recommended for most people living with HIV. This is partially due to RAL no longer being required as an alternative to DTG.4 Raltegravir was initially preferred over DTG because of preliminary results from the initial analysis of the Tsepamo study, conducted in Botswana. These results showed a prevalence of neural tube defects (NTDs) in 0.94% in those with DTG exposure during conception compared with 0.12% in those with non-DTG antiretroviral

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treatment (ART) exposure.5 The Tsepamo study looks at birth outcomes to evaluate the prevalence of NTDs associated with antiretroviral (ARV) exposure at conception. Further analysis, as of April 2020, showed a significantly reduced prevalence of 0.19% with DTG exposure compared with 0.11% in those with nonDTG ART at conception. Furthermore, the difference in prevalence between the 2 groups was not considered statistically significant.5 Due to the significant decrease in actual prevalence of NTDs associated with DTG exposure, the Panel on Antiretroviral Guidelines for Adults and Adolescents now considers DTG-based regimens appropriate for women of childbearing potential. In conjunction to no longer being needed as an alternative for DTG in women of childbearing potential, RAL also has a higher pill burden when compared with bictegravir (BIC) or DTG regimens, is not part of a single-tablet regimen, and has a lower barrier to resistance than the other INSTI-based regimens.3

Dolutegravir in Women of Childbearing Potential Because DTG has multiple advantages, the panel considers it as a “preferred ARV.” Dolutegravir is administered as a single, once-daily dose and has favorable tolerability, increasing the likelihood of patient adherence. Furthermore, studies such as DolPHIN1 have shown an association between DTG-containing regimens and rapid viral load suppression. In women of childbearing potential attempting to conceive, this is favorable, as it reduces changes of perinatal HIV transmission while maintaining maternal health.6In the randomized DolPHIN1 study, the safety and pharmacokinetics of DTG was compared

Long-Acting Injectable Cabotegravir And Rilpivirine Cabotegravir (CAB), an INSTI, was approved as an oral tablet in combination with rilpivirine (RPV), a nonNRTI, for treatment of patients living with HIV-1.4,7,8 In June 2021, the treatment guidelines for optimizing ART in the setting of virologic suppression were updated to include the long-acting injectable combination of CAB and RPV (CAB LA + RPV LA; Cabenuva, ViiV Healthcare) as an option for patients.3 This update was the result of several successful clinical trials, such as FLAIR (First Long-Acting Injectable Regimen Trial) and ATLAS (Antiretroviral Therapy as Long-Acting Suppression Trial). This and other recently approved antiretroviral therapies are highlighted in Table 2. FLAIR looked at the use of CAB LA plus RPV LA in more than 600 adults with HIV-1 who were treatment-naive. Patients with HIV-1 levels of at least 1,000 copies/mL and any CD4+ count were enrolled from centers around the world. They received 20 weeks of daily induction therapy with DTG/ABC/3TC

West (n=7,229) Urban: 88% Suburban: 9% Rural: 3%

before being randomly selected for a treatment group. If their viral loads were suppressed, they were randomly selected for either the maintenance arm, which was the continuation of oral standard-of-care therapy, or CAB LA plus RPV LA.9 As lead-in therapy, participants in the experimental arm received 4 weeks of daily oral CAB (30 mg) and RPV (25 mg). At week 4, they received injections of 600 mg of CAB and 900 mg of RPV. This was followed by an injectable 400 mg of CAB and 600 mg of RPV 21 to 28 days after the first and second injections, and 28 to 35 days later for each subsequent injection. At 48 weeks, the long-acting injectable regimen was noninferior to the oral maintenance arm. Injection site reactions were very common among participants in the long-acting injectable arm, occurring at least once in 86% of the participants. Most were injection site reactions that were mild or moderate and resolved within a week. The incidence of injection site reactions also decreased after the first injection. In the long-acting injectable arm, the most common other drug-related adverse events were headache, fatigue, and pyrexia.9 While the updates to the treatment guidelines were based on the 48-week data, the recently analyzed 124week data also were favorable. At 124 weeks, 80.2% of participants receiving CAB LA plus RPV LA had maintained virologic suppression. Less than 5% of participants had a virologic nonresponse. Virologic data for the other 15% of participants are not yet available.10 The CAB LA plus RPV LA regimen also was investigated in patients with HIV-1 who had already achieved viral suppression on oral ARV medication. ATLAS enrolled adult participants with HIV-1 RNA levels less

Midwest

(n=4,904)

Urban: 78% Suburban: 15% Rural: 7%

Northeast

(n=5,495)

Urban: 92% Suburban: 6% Rural: 2%

South (n=19,369) Figure. HIV diagnoses by region in 2018.

Based on reference 1.

Urban: 76% Suburban: 15% Rural: 9%

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with standard-of-care drugs (nevirapine) in pregnant women with untreated HIV. Suppression of HIV RNA to less than 50 copies/mL occurred twice as fast with DTG compared with the nevirapine standard-of-care treatment.6 The guidelines now recommend that DTG can be prescribed in most people with HIV, if providers fully discuss the risks and benefits of this treatment option with women of childbearing potential. On the contrary, data regarding BIC-based regimens in pregnant women remain insufficient and still should not be used in this population.4

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than 50 copies/mL and had completed 6 months of oral ART; patients who received DTG/ABC/3TC were excluded from participating. Participants who met eligibility criteria were randomly selected to either the standard-of-care maintenance arm, continuation of oral ART, or the CAB LA plus RPV LA arm.11 Similar to FLAIR, the participants were given four weeks of lead-in therapy: 30 mg of CAB and 25 mg of RPV. Once the lead-in was complete at 4 weeks, they

received injections of 600 mg of CAB and 900 mg of RPV. They then received injections of 400 mg of CAB and 600 mg of RPV every 4 weeks. At 48 weeks, CAB LA plus RPV LA met the primary end point and was noninferior to the comparator arm. Those in the CAB LA plus RPV LA arm had viral loads of 59 copies/mL or less compared with 1% of those in the oral maintenance arm. Those in the long-acting injectable arm reported injection site reactions, headache, pyrexia,

Table 2. Recently Approved Drugs for Adults With HIV Drug Class

Generic Name

Brand Name

Indication

FDA Approval Date

Ibalizumab-uiyk

Trogarzo

Approved for HIV patients who are heavily treatmentexperienced and whose HIV cannot be successfully treated with other currently available therapies to be used in combination with other ARVs

Fostemsavir

Rukobia

Approved for HIV patients who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance, or safety considerations to be used in combination with other ARVs

July 2, 2020

Cabotegravir-rilpivirine injectable formulation

Cabenuva

Injectable approved as a complete regimen for the treatment of HIV-1 in adults to replace a current ART in those who are virologically suppressed on a stable ART with no history of treatment failure and with no known/ suspected resistance to either cabotegravir or rilpivirine

Jan 21, 2021

Cabotegravir tablet formulation

Vocabria

This tablet should be taken in combination with oral rilpivirine (Edurant) for 1 mo prior to starting treatment with Cabenuva to ensure the medications are well tolerated before switching to the extended-release injectable formulation

Jan 21, 2021

Cabotegravir tablet formulation

Vocabria

Note that these formulations were approved for preexposure prophylaxis and not treatment

Dec 20, 2021

Cabotegravir extendedrelease injectable suspension

Apretude

Post-Attachment Inhibitors Post-attachment inhibitors block CD4 receptors on the surface of certain immune cells that HIV needs to enter the cells

March 6, 2018

Attachment Inhibitors Attachment inhibitors bind to glycoprotein 120 on the outer surface of HIV, preventing HIV from entering CD4 cells

New Integrase Inhibitors

Preexposure Prophylaxis

ART, antiretroviral treatment; ARVs, antiretrovirals

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Dec 20, 2021

virologic failure.15 Participants were split into 2 cohorts. The first cohort included 272 participants who were randomized in a 3:1 ratio to receive either 600 mg of FTR twice daily or placebo. In conjunction with the cohort’s regimen failure for 8 days and following day 8, the placebo group began FTR treatment while all participants initiated optimized background therapy. The nonrandomized cohort included 99 participants who were placed on FTR with optimized background therapy from the start.1 HIV RNA levels decreased by 0.79 log10 copies/ mL in the FTR group compared with a decline of 0.17 log10 copies/mL in the placebo group. In addition, HIV RNA was reduced to less than 40 copies/mL in 54% of the randomized cohort and 38% in the nonrandomized cohort.15 After 96 weeks, virologic response increased to 60% in the randomized cohort and remained unchanged in the nonrandomized cohort.16 Only 7% of participants discontinued treatment secondary to adverse events.16 The phase 2b randomized trial, Al438011, found that viral response rates among 251 treatment-experienced participants randomized in a 1:1:1:1:1 ratio across 4 different dosing regimens of FTR (400 mg twice daily, 800 mg twice daily, 600 mg once daily, and 1,200 mg once daily) and a control group receiving ritonavir-boosted atazanavir once daily remained similar through 48 weeks.17 Both groups also had similar tolerability and adverse events.16

65 Only 65% of those living with HIV in the US achieved viral suppression.

Multidrug-Resistant HIV With Virologic Failure: Fostemsavir Fostemsavir (FTR; Rukobia, ViiV Healthcare) was approved in 2020, and is a therapy option that providers can consider for patients with multidrug-resistant (MDR) HIV in the setting of a failing ARV regimen due to resistance, intolerance, or safety concerns. Fostemsavir, which is given with other ARVs, is an attachment inhibitor that binds to glycoprotein 120 on the HIV envelope, preventing it from binding to the host CD4 cell surface.14 BRIGHTE, an ongoing phase 3, randomized trial, is analyzing the efficacy of FTR in heavily ART-experienced participants with MDR HIV in

Ibalizumab-uiyk Ibalizumab-uiyk (IBA; Trogarzo, Theratechnologies), a CD4 post-attachment inhibitor, is also considered a safe, effective treatment option in MDR patients with HIV. In a phase 3 single-arm clinical trial, 40 MDR HIV participants who experienced virologic failure on their current ARV regimen were given IBA infusions every 2 weeks in addition to optimized baseline therapy.18 After 25 weeks of treatment, 27 participants continued through 96 weeks of IBA infusion. At week 25, the median viral load reduction of patients continuing long-term treatment was 2.5 log10 copies/mL. By week 96, the median viral load reduction was 2.8 log10 copies/mL. Of the 27 patients who continued 96 weeks on study, 64% had HIV RNA less than 50 copies/mL at week 25. By week 96, 14 of those 16 patients maintained viral suppression. No new safety concerns were noted through the 96 weeks, and efficacy was maintained throughout the study.19 Updated guidelines recommend providers consider IBA injections with other ARVs in heavily treatment-experienced patients whose HIV cannot be treated appropriately with other available therapy options. While IBA

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and fatigue. The injection site reactions were mostly mild or moderate and resolved within 3 days.11 After ATLAS and FLAIR established the noninferiority of an injectable regimen of CAB and RPV, different injection time lines were considered. From 2017 to 2018, participants from the ATLAS trial enrolled into the ATLAS-2M trial, a phase 3b, multicenter study. More than 1,000 eligible participants were randomly selected to receive either CAB LA plus RPV LA every 4 or every 8 weeks. There were no significant differences in safety or efficacy between the every-4-week injection arm and the every-8-week injection arm.12 FLAIR, ATLAS, and ATLAS-2M also collected surveys on participant satisfaction with their regimen.9,11,13 The large majority of participants from FLAIR and ATLAS greatly favored the CAB LA plus RPV LA regimen over continued daily oral therapy.9,11 Surveys from ATLAS2M considered a variety of participant satisfaction–specific questions including treatment satisfaction, reason for transitioning to a long-acting injectable regimen, and acceptability of injections. Similar to findings from FLAIR and ATLAS, participants reported greatly favoring the treatment schedule for the long-acting injectable regimen compared with their previous daily oral therapy regimens. Participants also reported favoring the every-8-week regimen over the every-4-week regimen.13 To maintain viral suppression, patients living with HIV-1 usually rely on oral ART medication that must be taken every day. This regimen can be time-consuming and disheartening for patients. Long-acting injectable ARVs are emerging as an effective alternative for maintaining viral suppression for these patients.11 The guideline update recommends that providers consider this option for patients who have already achieved 3 to 6 months of virologic suppression on an oral regimen and are capable and committed to make the necessary visits for the injections.4

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offers a safe, effective, and lasting treatment option for those with MDR HIV, the drug is only administered via IV infusion compared with the oral regimen of FTR.

Looking to the Future A wide array of treatment options are available for patients living with HIV. The standard regimens recommended for most patients with HIV continue to be daily oral ART. DTG, a preferred ARV, remains a promising treatment option for women with HIV who are of childbearing potential to reduce the risk for perinatal transmission. CAB LA plus RPV LA regimens offer a promising alternative to daily oral therapy for people living with HIV who are able to commit to the monthly injection visits. In individuals with MDR HIV, the FTR oral regimen and IBA infusion offer safe, effective treatment that reduces viral loads.

References 1.

CDC. HIV in the United States by region. Accessed March 14, 2022. https://www.cdc.gov/hiv/statistics/overview/geographicdistribution.html

2. CDC. Diagnoses of HIV infection in the United States and dependent areas 2019. HIV Surveillance Report. 2019;32. Published May 2021. Accessed March 14, 2022. https://www.cdc. gov/hiv/library/reports/hiv-surveillance/vol-32/index.html

3. CDC. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2019. HIV Surveillance Supplemental Report. 2021;26(2). Published May 2021. Accessed March 14, 2022. https://www.cdc.gov/hiv/library/reports/hivsurveillance/vol-26-no-2/index.html 4. 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. Updated January 20, 2022. Accessed March 14, 2022. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf 5. Zash R, Holmes L, DIseko M, et al. Update on neural tube defects with antiretroviral exposure in the Tsepamo study, Botswana. Presented at: 2020 International AIDS Conference; July 6-10, 2020. Abstract OAXLB0102. 6. Waitt C, Orrell C, Walimbwa S, et al. Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study). PLoS Med. 2019;16(9):e1002895. 7. National Institutes of Health. Cabotegravir - patient. Accessed March 14, 2022. https://clinicalinfo.hiv.gov/en/ drugs/cabotegravir-1/patient 8. National Institutes of Health. Rilpivirine - patient. Accessed March 14, 2022. https://clinicalinfo.hiv.gov/en/drugs/ ripilvirine/patient 9. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study [published correction appears in Lancet HIV. 2021;8(12):e734]. Lancet HIV. 2021;8(4):e185-e196. 10. Orkin C, Bernal Morell E, Tan DHS, et al. Initiation of longacting cabotegravir plus rilpivirine as direct-to-injection or

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with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study. Lancet HIV. 2021;8(11):e668-e678. 11. 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. 12. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. 13. Chounta V, Overton ET, Mills A, et al. Patient-reported outcomes through 1 year of an HIV-1 clinical trial evaluating long-acting cabotegravir and rilpivirine administered every 4 or 8 weeks (ATLAS-2M). Patient. 2021;14(6):849-862. 14. Lalezari JP, Latiff GH, Brinson C, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lancet HIV. 2015;2(10):e427-e437. 15. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382:1232-1243. 16. Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lancet HIV. 2020;7(11):e740-e751. 17. Lataillade M, Zhou N, Joshi SR, et al. Viral drug resistance through 48 weeks, in a phase 2b, randomized, controlled trial of the HIV-1 attachment inhibitor prodrug, fostemsavir. J Acquir Immune Defic Syndr. 2018;77(3):299-307. 18. Emu B, Fessel WJ, Schrader S, et al. Forty-eight-week safety and efficacy on-treatment analysis of ibalizumab in patients with multi-drug resistant HIV-1. Open Forum Infect Dis. 2017;4(suppl 1):S38-S39. 19. Emu B, Lalezari J, Kumar P, et al. Ibalizumab: 96 week data and efficacy in patients resistant to common antiretrovirals [CROI Abstract 485]. Top Antivir Med. 2019;27(suppl 1):179s.

About the authors Ashley Hoare, MS, is a clinical research coordinator, Ochsner Clinic Foundation, New Orleans, Louisiana. Jessica Hoare, MS, is a clinical research coordinator, Ochsner Clinical Foundation, New Orleans, Louisiana. Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI, is the director of clinical infectious diseases research, the director of medical student research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; a clinical assistant professor at Tulane University School of Medicine, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Oschner Medical Center, in New Orleans, Louisiana.

A Multifaceted Strategy to Reduce HIV-Related Stigma and Disparities BY MILENA MURRAY, PHARMD, MSC, BCIDP, AAHIVP, FCCP

ocial determinants of health are defined as the conditions in which people are born, grow, work, live, and age, as well as the wider set of forces and systems shaping the conditions of daily life.1 The 40-year HIV epidemic, in addition to the more recent COVID19 pandemic, has produced data that these factors have a role in the transmission, morbidity, and mortality of infectious diseases.1 New data emerged regarding the effect of social determinants on patient outcomes and several disease states. However, disparities have long been known to harm people with HIV. HIV-related stigma also is associated with several adverse outcomes.2 HIV transmission is related to local HIV prevalence, individual behaviors, biological factors, and social conditions.3 Disparities are found in HIV transmission, access to treatment, and disease course. It is imperative to

consider that disease is influenced by community, societal, and environmental factors.1 As part of HIV treatment, adherence to treatment and the ability to achieve undetectable HIV RNA is affected by HIV-related stigma.2 Many advances have been made in HIV treatment and prevention; however, not all people with HIV have access to the same treatment and some individuals cannot adhere to treatment for various reasons. Social support, specifically tangible support networks, is critical for linkage to care and antiretroviral therapy (ART) adherence.4 Limited health literacy also affects the relationship between the patient’s race and ART adherence. Health literacy is a modifiable factor; patient materials should be written at an appropriate reading level.5 This particular disparity may be reduced by improving patient

education materials and using more suitable communication modes. Positive reinforcement and an expression of thanks for keeping appointments may foster adherence success.6 Stigma is additionally related to the fear of discrimination and rejection by healthcare service providers. This discrimination may lead to medical mistrust, resulting in a vicious cycle of disparity.4 People who are transgender experience health disparities and discrimination across the HIV continuum of care. A case-control study compared transgender women with HIV with cisgender women and cisgender men with HIV.4 Measures of the HIV treatment cascade and correlates of HIVrelated health status (eg, depression, stress, drug use, medical mistrust, emotional and tangible social support) were assessed. Transgender women were significantly less likely to receive

INFECTIOUS DISEASE SPECIAL EDITION • SPRING 2022

and be adherent to ART, leading to lower HIV RNA suppression than in cisgender individuals.4 In a multivariate model, transgender women having less tangible social support predicted health disparities. Poor engagement in care and delayed initiation of ART have personal and public health consequences. Systematic monitoring of engagement in care allows an opportunity to follow up on missed visits and re-engage people with HIV.6 Shared decision making, especially about choice of ART, will provide a sense of empowerment and autonomy over healthcare decisions.6 Stigma and disparities related to HIV also can lead to mental health conditions. There is a clear link between environmental stress, stigma, and psychological issues.3 Stress and stigma affect health behaviors, including accessing care. Premorbid depression and trauma have been shown to influence HIV disease progression.3 The multifactorial aspects of mental health and HIV lead to disparities in health outcomes. Appropriate identification of potential mental health issues and linkage to mental health services, if applicable, should be considered in all people with HIV, especially those with an existing history of psychiatric illness.6 A systematic review and meta-analysis of sociodemographic, clinical, and service use determinants associated with stigma among people with HIV/AIDS found several risk factors for self-reported stigma.2 This study was unique in that it included clinical, demographic, and health services use in the analysis. This analysis involved 31 studies published before November 2020 and represented 10,475 participants.2 The study found significant protective associations between selfreported stigma and age older than 30 years, living with a spouse, having a CD4 T-lymphocyte count of less than 200 cells/mcL, ART adherence, time since HIV diagnosis, and accessibility to HIV care.2

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Health disparities lead to differences in the cascade of care for adolescents and young adults with HIV compared with older adults who have HIV.7 Specific transitions of care in this population introduce barriers, such as changing care providers and loss of access to social support with adult services. Youth-friendly services, including office hours, staff, and physical space, should be considered to remove obstacles to adherence.6 Gender-affirming and behavioral healthcare should be integrated with HIV care when possible.

Disparities have long been known to harm people with HIV. Appropriate messaging about HIV is needed to provide updated information on ending the HIV epidemic and reducing HIV transmission.8 Public health messaging has evolved with the epidemic. Currently, the message is that prevention and treatment could end the HIV epidemic in the United States. In addition, health equity in HIV communications should consider social and structural inequalities and focus on social justice.8 Stigma should be called out and communications should be empowering. Intentional interventions are needed to begin the elimination of disparities for people with HIV. Healthcare services should address the needs and preferences of diverse populations. Barriers to literacy and communication should be targeted and reduced to facilitate appropriate

patient care. Additionally, researchers should include racial, ethnic, religious, and gender minority groups in clinical trials by removing obstacles to participation and reducing stigma.

References 1. Hogan JW, Galai N, Davis WW. Modeling the impact of social determinants of health on HIV. AIDS Behav. 2021; 25(suppl 2):215-224. 2. Armoon B, Higgs P, Fleury MJ, et al. Socio-demographic, clinical and service use determinants associated with HIV related stigma among people living with HIV/AIDS: a systematic review and meta-analysis. BMC Health Serv Res. 2021;21(1):1004. 3. Pellowski JA, Kalichman SC, Matthews KA. A pandemic of the poor: social disadvantage and the U.S. HIV epidemic. Am Psychol. 2013;68(4):197-209. 4. Kalichman SC, Hernandez D, Finneran S. Transgender women and HIV-related health disparities: falling off the HIV treatment cascade. Sex Health. 2017;14(5):469-476. 5. Osborn CY, Paasche-Orlow MK, Davis TC. Health literacy: an overlooked factor in understanding HIV health disparities. Am J Prev Med. 2007;33(5):374-378. 6. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Accessed March 1, 2022. https://bit. ly/3oAt4xN-IDSE 7. Zanoni BC, Mayer KH. The adolescent and young adult HIV cascade of care in the United States: exaggerated health disparities. AIDS Patient Care STDS. 2014;28(3):128-135. 8. Taggart T, Ritchwood TD, Nyhan K. Messaging matters: Achieving equity in the HIV response through public health communication. Lancet HIV. 2021;8(6):e376-e386.

About the author Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP, is an associate professor, College of Pharmacy, Midwestern University, in Downers Grove, Illinois.

CLASSIFIEDS

SPRING 2022

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Interested candidates should forward their CV to: Dr. David Alland, Director, Division of Infectious Diseases; Email: allandcv@njms.rutgers.edu. Affirmative Action/Equal Employment Opportunity Statement: It is university policy to provide equal employment opportunity to all its employees and applicants for employment regardless of their race, creed, color, national origin, age, ancestry, nationality, marital or domestic partnership or civil union status, sex, pregnancy, gender identity or expression, disability status, liability for military service, protected veteran status, affectional or sexual orientation, atypical cellular or blood trait, genetic information (including the refusal to submit to genetic testing), or any other category protected by law. As an institution, we value diversity of background and opinion, and prohibit discrimination or harassment on the basis of any legally protected class in the areas of hiring, recruitment, promotion, transfer, demotion, training, compensation, pay, fringe benefits, layoff, termination or any other terms and conditions of employment.

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Infectious Disease Special Edition - Spring 2022

Articles inside

A Multifaceted Strategy to Reduce HIV-Related Stigma and Disparities

Updates to the 2021 Guidelines for ARV Use in Adults and Adolescents With HIV

What’s New in CMV Prevention and Therapy for Transplant Patients?

Implementing Rapid Diagnostic Tests to Augment Antimicrobial Stewardship Programs The Time Is Now

5 People Died From Rabies in the U.S. in 2021

HIV News: Risk for HIV Depends on Who You Are

Kaposi Sarcoma Still a Major Contributor to Morbidity Mortality in Certain HIV Populations

Engaging HIV Patients ... And Then Keeping Them Engaged

How to Manage Care for Aging Patients With HIV

ACIP Recommends 2 Vaccines for Some Travelers

Infl uenza Rates Head Downward in Early 2022 Flu Season Appears Less Severe Than Anticipated

Novel Research Shedding Light on Fungal Infections

News Notes: Uncertain Future for 2 Long-Acting HIV Therapies

COVID-19 Pandemic Brings Out the Best—and the Worst

COVID-19 Resurgence, Other Infections and the Loss of Healthcare for 3 Million People