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J. Boyd Francis, M.D. Lectureship HIV Primary Care: an Update on Management and Prevention

J. Boyd Francis, M.D. Lectureship HIV Primary Care: an Update on Management and Prevention

J. Boyd Francis, M.D. Lectureship HIV Primary Care: An Update on Management and Prevention

Jason R. Faulhaber, M.D. Assistant Professor, VTC-SOM Carilion Infectious Diseases, Fellowship Program Director

23 April 2021 Disclosures

I have no relevant financial disclosures Objectives

• Develop management plans for newly- and previously- diagnosed patients with HIV

• Review basic principles of antiretroviral therapy, including initiation and side effects

• Identify methods of HIV prevention and how to utilize them Case

A 24yo man presents with a 2-day history of rash, fever, and sore throat. He denies any sick contacts. He is sexually active; he endorses a total of 3 lifetime partners, 2 male and 1 female. He denies ever having any prior STI. His last sexual encounter was ~1 month ago. He engaged in receptive anal intercourse with a condom, which was found to be broken, at which point the partner disclosed he was HIV+.

Case

o PE: T 101.6 F, HR 100, BP 110/70, RR 14, SaO2=100% on RA. Mild conjunctivitis b/l 2+ tonsillar hypertrophy without exudate Tender enlarged cervical LAD b/l Diffuse maculopapular rash involving the trunk, abdomen, and proximal arms. Case

Which of the following tests would be the most appropriate for this patient? A. HIV-1/2 Ag/Ab test B. RPR C. HIV RNA D. Rapid Strep test E. Throat culture

CDC 2014 HIV Tests Available

Test What is being Utility Can detect tested as early as Monitoring Nucleic Acid Test therapy HIV RNA or DNA 7-10 days (Viral Load) Diagnose acute infection HIV p24 Ag Antigen-Antibody Screening 10-14 days HIV Ab

Antibody HIV Ab Screening 20-25 days

HIV Testing Algorithm

CDC 2018 Case (continued)

HIV-1/2 Ag/Ab test results positive with HIV-1 antibodies

Plasma HIV RNA = 845,000 copies/mL Case (continued)

Which of the following is the most appropriate next step in managing this patient? A. Obtain standard labs but start potent ART while lab results are pending B. Obtain standard labs, including genotype, and start ART after results return C. Panic and call ID Initial HIV Evaluation

• Genotype • Pregnancy test

• CD4 count • Urinalysis • CBC, CMP • Lipid profile • HAV, HBV, HCV • HbA1c • RPR • Pap smear • GC/C from all sites • Toxoplasma Ab • QuantiFERON • HLA-B*5701

Thompson 2020 Rapid Start ART

• Initiating ART at earliest possible time, including same-day and in acute infection • Rationale for treating acute/early infection: – Accelerate resolution of symptoms – Minimize immunologic damage – Diminish size of latent HIV reservoir pool – Prevent transmission to others – Improve engagement in care

Thompson 2020 Martin 2020 Bacon 2020 60.5%

CDC, MMWR 12/2019 https://www.cdc.gov/vitalsigns/test-treat-prevent/index.html Current Antiretrovirals by Class

•Nucleosides (NRTIs) •Protease Inhibitors (PIs) – (ABC) – (ATV) – (ddI) – (DRV) – (FTC) – (FPV) – (3TC) – (IDV) – (d4T) – (LPV) – Tenofovir (TDF, TAF) – (NFV) – (AZT, ZDV) •Non-Nucleosides (NNRTIs) – (SQV) – – (EFV) (TPV) – (ETR) •Entry Inhibitors – (NVP) – (ENF) – (RPV) – (MVC) – (DOR) – (IBA) •Integrase Inhibitors (INSTIs) – (FOS) – (DTG) •Pharmacokinetic Enhancers – (EVG) – (r) – (RAL) – (BIC) – (cobi) – (CAB)

https://www.poz.com/pdfs/POZ_2020_HIV_Drug_Chart_high.pdf Pearls of Starting ART

• 3-drug combination – Only class that can double up is NRTIs – 2 NRTIs + InSTI/bPI/NNRTI – *DTG-3TC is possible but with restrictions • Rapid start – Avoid ABC (uncertain HLA-B*5701 status) – Avoid NNRTIs (uncertain VL)

– Avoid 2-drug combo (uncertain CD4/VL)

DHHS 2021 Selecting an Initial Regimen

2 NRTI BACKBONE: FTC/TAF FTC/TDF 3TC/ABC

InSTI Boosted PI NNRTI Bictegravir Darunavir Rilpivirine Dolutegravir Atazanavir Doravirine Raltegravir + (ritonavir OR cobi) Efavirenz Elvitegravir/cobicistat Additional ART Considerations

• Ease of administration • Single-tablet regimen • Pill size • Pill burden • Food requirements • Co- (e.g., HBV, HCV, TB, OIs) • Renal function • Pregnancy • Drug-drug interactions • PPIs, Statins, Polyvalent cations • Pharmacokinetic booster (CYP3A4, UGT1A1, etc.)

DHHS 2021 Thompson 2020 Monitoring on ART

• Assess adherence at each visit • Vital signs (including weight) at each visit • Plasma HIV RNA • q4-6 wks after initiation until UD, then • q3-4 mos • If consistently UD >2yrs, then q6 mos

• CD4 cell count • q3-6 mos after initiation x 2yrs, or if viremic, or if <300/mL • If 300-500 and UD x 2y, then annually • If >500 and UD x 2y, then optional • CMP with each HIV RNA • Lipids at 1-3mos after starting or changing ART • Depression and substance use screening at each visit

UD=undetectable

Thompson 2020 Lab Initial Q3mo Q6mo Annually CBC     CMP    

CD4  * *  Viral Load  * *  (VL) STI testing  ** **  TB screening   Lipids    Mental     health Substance     use Adherence    

* = if still detectable VL or CD4 <300 ** = dependent on risk  = either initially or at 3 months Routine Screening

• STIs—at least annually, up to q3mo if high risk • Cancer • CVD • DM • Osteoporosis • Mental health • Substance use, including tobacco • Vaccine-preventable diseases

• Avoid live vaccines if CD4 <200/14%

Thompson 2020 Switching ART

• Rationale • Simplification of regimen (pill or ARV burden) • Drug-drug interactions • Tolerability due to SEs • Decrease short- or long-term toxicity • Resistance • Options • 3-drug to 2-drug • DTG/RPV or DTG/3TC (as long as HBV-uninfected) • Removing boosting agent • Class-switching

Major Side Effects of ART

• Hyperglycemia1 • 2.5% overall; InSTIs 22% more likely; DTG >> EVG • Weight gain2,3,4,5 • 1.5kg mean increase in weight after 1y new InSTI • Highest RFs—black, female, TDFTAF • More weight gain with DTG-3TC vs DTG-FTC-TDF • InSTI if <8mo post-switch, TAF continued gain • Older age and higher baseline BMI a/w more rapid gain • Dyslipidemia6,7 • TAF > TDF but no change in CV events • PIs and EFV

1 O’Halloran 5 Bourgi 2 McComsey 6 Arribas 3 Palella 7 Grundy 4 Orkin Major Side Effects of ART

• Bone Mineral Density1,2,3,4,5,6 • TDF > bPIs • Greatest within 1yr of ART and stabilizes after 2y • RAL a/w inferior loss (or possibly increased) • Renal7,8 • TDF: proximal tubulopathy • ATV: nephrolithiasis • DTG, BIC: mild Cr bump (less tubular secretion) • Cardiovascular9 • InSTIs had 2.5x incidence of CVD <6mo but comparable to unexposed thereafter

1 Delpino 4 Compston 7 Alfano 2 Han 5 Bedimo 8 Wearne 3 Hoy 6 Brown 9 Neesgaard Major Side Effects of ART: ADVANCE Trial

• Johannesburg • 1053 participants • TAF-FTC/DTG vs TDF-FTC/DTG vs TDF/FTC/EFV • Weight • 7.1kg vs 4.3kg vs 2.3kg • New obesity in women: 28% vs 18% vs 12% • Visceral Fat • Increased for all 3 groups, most w/TAF, women > men • BMD • Higher in TAF vs other TDF groups

Venter Projected Burden of Multi-Morbidity

• PEARL (ProjEctingAge, multimoRbidity, and poLypharmacy) simulation for 2009-2030 • Based on data from NA-ACCORD • 9 major comorbidities: depression, anxiety, treated HTN, DM, HL, CKD, Ca, MI, ESLD • Modeled in presence/absence of 3 underlying RFs: smoking, HCV infection, BMI change @2y • Projected 928,000 ART users by 2030 • Projected increase from 30% to 36% for those with >2 physical comorbidities

Kasaie Kasaie New ART • Cabotegravir-Rilpivirine LA (approved) • InSTI + NNRTI • Oral lead-in x 1mo, then IM injection q4wk • (Phase III) • Translocation inhibitor • Oral once monthly • (Phase II/III) • Capsid inhibitor • Oral lead-in x 2wks, then SC injection q6mo • MK-8507 (Phase IIb) • NNRTI • Oral once weekly • GSK3640254 (Phase IIa) • • Oral once daily

ART for Prevention

• Treatment as Prevention (TasP) • Prevention of mother-to-child transmission (PMTCT) • Post-exposure prophylaxis (PEP) • Pre-exposure prophylaxis (PrEP)

TasP

STUDY SUBJECTS RESULTS HPTN 0521 1763 heterosexual discordant couples Early had 96% reduced (Africa, 9 countries) Early vs Delayed-start ART transmission vs Delayed

PARTNER2 1166 discordant couples, HIV+ partner 0 linked transmissions after (Europe, 14 countries) on ART and UD, condomless sex >58,000 condomless sex acts over a 4-year period PARTNER23 972 discordant MSM couples 0 linked transmissions after (extension with new >76,000 condomless sex acts enrollment) over 8-year period Opposites Attract4 358 discordant MSM couples 0 linked transmissions after (Australia, Rio, Bangkok) >16,000 condomless sex acts over a 4-year period

1 Cohen 2016 2 Rodger 2016 3 Rodger 2019 4 Bavinton 2018 U = U

NIH. Available at https://www.niaid.nih.gov/diseases- conditions/10-things-know-about--suppression PrEP

• ~1.2 million Americans likely eligible1 – 1 in 4 sexually active MSM (814,000) – 1 in 5 PWIDs (73,000) – 1 in 200 heterosexual adults (258,000) • CDC reported PrEP coverage2 – 2016: 9% – 2017: 13% – 2018: 18%

1 Smith 2015 2 Harris 2019 PrEP

• Multiple studies have demonstrated PrEP is highly effective when taken as prescribed1 – Sexual transmission: ~99% effective – IDU transmission: ~80% effective • Studies only looked at using TDF alone • Daily vs On-Demand PrEP2 – CDC only recommends daily at this time – ANRS Prévenir: both regimens highly effective

1 Chou 2 Molina PrEP Options

TDF/FTC (TruvadaTM) TAF/FTC (DescovyTM) Approved for ALL persons seeking NOT approved for use in cisgender PrEP women (at risk of acquiring through vaginal sex)

Carries rare renal toxicity risk, No real risk of significant renal requiring regular Cr monitoring toxicity

Location Time to Maximal Concentration of TDF Rectal tissue 7 days Cervicovaginal tissue 20 days Blood 20 days

Recommended lead-in time is 7 days Other Options?

• Dapivirine (ASPIRE-HOPE, Ring-DREAM)1,2 – Use of a monthly vaginal ring decreased HIV incidence by 27-31% – Decreased by up to 63% with higher adherence • Cabotegravir (HPTN 083/084)3 – Long-acting injectable, every 8 weeks – Outperformed TDF/FTC • 0.4% vs 1.22% in cisMSM and TGWSM • 0.21% vs 1.79% in cis women

1 Baeten 2 Rosenberg 3 Marzinke Other Options?

• Islatravir1,2 – Translocation inhibitor – High potency, long intracellular half-life, high tissue penetration, favorable resistance profile – Once monthly pill, implantable cartridge • bNAbs – Need mix/combination to be effective – Only available by IV, possibly q3-6mo

1 Matthews 2 Patel How to Do PrEP

• Assess risk of acquiring HIV • Evaluate clinical eligibility – Assess for possible acute HIV infection and STIs – Document negative HIV test result (ideally <1 week) before initiating PrEP – Verify patient has normal baseline renal function (CrCl >60 mL/min) – Serologies for HBV and HCV – Pregnancy test for women

How to Do PrEP

• Education – Encourage PrEP as a component of comprehensive safer sex practices – Emphasize that PrEP does NOT protect against other STIs; encourage consistent condom use – Remind patient that PrEP is NOT 100% effective; efficacy increases with increased adherence CDC. Available at https://www.cdc.gov/vitalsigns/hivprep/infographic.html Providing Care within the PrEP Care System

CDC. Available at https://www.cdc.gov/hiv/effective-interventions/prevent/prep/index.html How to Do PrEP—Monitoring

National HIV Curriculum. Available at https://www.hiv.uw.edu/go/prevention/preexposure-prophylaxis-prep/core-concept/all Discontinuing PrEP

• PrEP should not be viewed as a lifelong prevention strategy • Should be used during periods of high behavioral risk • Repeat HIV testing • Document reason for discontinuation • Continue PrEP until ~28d after last high-risk exposure prior to stopping • Consider treatment in those with HBV Take-Home Points

• Earlier is better: screening, diagnosis, treatment, viral suppression, and prevention • Aging happens, putting patients at risk for other comorbidities (if not already present) • PrEP is an effective option for HIV prevention in high-risk patients; however, it is not 100% effective and does not prevent STIs • Adherence is key; the higher it is, the better the outcome

References

• Alfano G, Cappelli G, Fontana F, et al. “Kidney Disease in HIV Infection,” Journal of Clinical Medicine. 2019;8(8):1254 • Ambrosioni J, Petit E, Ligeon G, Laguno M, Miro JM. “Primary HIV-1 infection in users of pre-exposure prophylaxis,” The Lancet HIV. 2021;8(3):e166-174 • Arribas JR, Thompson M, Sax PE, et al. “Brief Report: Randomized, Double-Blind Comparison of (TAF) vs Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results,” Journal of the Acquired Immune Deficiency Syndrome. 2017;75(2):211-218 • Bacon O, Chin J, Cohen SE, et al. “Decreased Time From Human Immunodeficiency Virus Diagnosis to Care, Antiretroviral Therapy Initiation, and Virologic Suppression during the Citywide RAPID Initiative in San Francisco,” Clinical Infectious Diseases. Published online 5/25/2020. doi.org/10.1093/cid/ciaa620 • Baeten JM for the MTN-020-ASPIRE Study Team, et al. “Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women,” New England Journal of Medicine. 2016;375(22):2121-2132 • Bavinton B, Pinto A, Phanuphak N, et al. “Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study,” Lancet HIV. 2018;5:e38-47 • Bedimo RJ, Drechsler H, Jain M, et al. “The RADAR Study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naïve patients. Impact on bone health,” PLoS One. 2014;9(8):e106221 • Bourgi K, Jenkins CA, Rebeiro PF, et al. “Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada,” Journal of the International AIDS Society. 2020;23:e25484 References

• Brown TT, Moser C, Currier JS, et al. “Changes in bone mineral density after initiation of antiretroviral treatment with Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir,” Journal of Infectious Diseases. 2015;212(8):1241-1249 • Byonanebye DM for the RESPOND Study Group, et al. “Incidence of dyslipidemia in people with HIV who are treated with integrase inhibitors versus other antiretroviral agents,” AIDS. 2021;35(6):869-882 • CDC. “2018 Quick reference guide: Recommended laboratory HIV testing algorithm for serum or plasma specimens,” 2018. Available at https://stacks.cdc.gov/view/cdc/50872. Last accessed 4/12/21 • CDC. “Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations,” 2014. Available at https://stacks.cdc.gov/view/cc/23447. Last accessed 4/12/21 • Carr A, Grund B, Schwartz AV, et al. “The rate of bone loss slows after 1-2 years of initial antiretroviral therapy: final results of the Strategic Timing of Antiretroviral Therapy (START) bone mineral density substudy,” HIV Medicine. 2020;21(1):64-70 • Chou R, Evans C, Hoverman A, et al. “Preexposure Prophylaxis for the Prevention of HIV Infection: Evidence Report and Systematic Review for the US Preventive Services Task Force,” JAMA. 2019;321(22):2214-2230 • Cohen MS for the HPTN 052 Study Team, et al. “Antiretroviral Therapy for the Prevention of HIV-1 Transmission,” New England Journal of Medicine. 2016;375:830-839 • Compston J. “HIV infection and bone disease,” Journal of Internal Medicine. 2016;280(4):350-358 • Delpino MV, Quarleri J. “Influence of HIV Infection and Antiretroviral Therapy on Bone Homeostasis,” Frontiers in Endocrinology. 2020;11:502 References

• 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.” Available at https://clinicalinfo.hiv.gov/sites/default/files/inline- files/AdultandAdolescentGL.pdf • Grundy SM, Stone NJ, Bailey AL, et al. “2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Reports of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines,” Circulation. 2019;139:e1082-e1143 • Han WM, Wattanachanya L, Apornpong T, et al. “Bone mineral density changes among people living with HIV who have started with TDF-containing regimen: A five-year prospective study,” PLoS One. 15(3):e0230368 • Harris NS, et al. “Vital Signs: Status of Human Immunodeficiency Virus Testing, Viral Suppression, and HIV Preexposure Prophylaxis—United States, 2013-2018,” Morbidity and Mortality Weekly Report (MMWR). 2019;68(48):1117-1123 • Hoy JF, Grund B, Roediger M, et al. “Immediate Initiation of Antiretroviral Therapy for HIV Infection Accelerates Bone Loss Relative to Deferring Therapy: Findings from the START Bone Mineral Density Substudy, a Randomized Trial,” Journal of Bone and Mineral Research. 2017;32(9):1945-1955 • Kasaie P, Stewart C, Humes E, et al. “Multimorbidity in people with HIV using ART in the US: Projections to 2030.” Program and abstracts from the 28th Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021. Abstract 102. • Martin TCS, Abrams M, Anderson C, Little SJ. “Rapid Antiretroviral Therapy Among Individuals With Acute and Early HIV,” Clinical Infectious Diseases. Published online 8/10/2020. doi.org/10.1093/cid/ciaa1174 • Marzinke M, Grinsztejn B, Fogel J, et al. “Laboratory analysis of HIV infections in HPTN 083: Injectable CAB for PrEP,” Abstract 153LB. 28th Conference on Retroviruses and Opportunistic Infections (CROI), March 6-10, 2021

References

• Matthews RP, Zang X, Barrett S, et al. “Next-generation islatravir implants projected to provide yearly HIV prophylaxis,” Abstract 88LB. 28th CROI, March 6-10, 2021 • McComsey GA, Sax P, Althoff KN, et al. “Weight gain after switching different integrase strand transfer inhibitors (InSTIs),” Abstract 503. 28th CROI, March 6-10, 2021 • Molina J-M, for ANRS Prevenir Study Group, et al. “Incidence of HIV infection with daily or on-demand oral PrEP with TDF/FTC in France,” Abstract 148. 28th CROI, March 6-10, 2021 • Neesgaard B, for the RESPOND Study Group, et al. “Association between integrase inhibitors (InSTIs) and cardiovascular disease (CVD),” Abstract 488. 28th CROI, March 6-10, 2021 • O’Halloran J, Sahrmann J, Olsen M, et al. “Incident diabetes associated with integrase strand transfer inhibitor initiation,” Abstract 516. 28th CROI, March 6-10, 2021 • Orkin C, Porteiro N, Berhe M, et al. “Durable Efficacy of DTG+3TC in GEMINI-1&2: Year 3 Subgroup Analyses,” Abstract 414. 28th CROI, March 6-10, 2021 • Palella F, Hou Q, Li J, et al. “Weight gain among PWH who switch to ART-containing InSTIs or TAF,” Abstract 504. 28th CROI, March 6-10, 2021 • Patel M, Zang X, Cao Y, et al. “Islatravir PK threshold & dose selection for monthly oral HIV-1 PrEP,” Abstract 87. 28th CROI, March 6-10, 2021 • Rodger AJ, Cambiano V, Bruun T, et al. “Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy,” JAMA. 2016;316(2):171-181 References • Rodger AJ, Cambiano V, Bruun T, et al. “Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV- positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study,” The Lancet. 2019;393:2428-2438 • Rosenberg ZF, for the DREAM trial group, et al. “HIV Incidence and Adherence in DREAM: An Open-Label Trial of Dapivirine Vaginal Ring,” Abstract 143LB. 26th CROI, March 4-7, 2018 • Shiau S, Arpadi SM, Yin MT. “Bone Update: Is It Still an Issue Without Tenofovir Disoproxil Fumarate?” Current HIV/AIDS Reports. 2020;17:1-5 • Smith D, Van Handel M, Wolitski R, et al. “Vital Signs: Estimated Percentages and Numbers of Adults with Indications for Preexposure Prophylaxis to Prevent HIV Acquisition—United States, 2015.” MMWR 2015;64(46):1291-1295 • Surial B, for the Swiss HIV Cohort Study, “Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV,” Annals of Internal Medicine. Published online 3/16/21. doi:10.7326/M20-4853 • Thompson MA, Horberg MA, Agwu AL, et al. “Primary Care Guidance for Persons With Human Immunodeficiency Virus: 2020 Update by the HIV Medicine Association of the Infectious Diseases Society of America,” Clinical Infectious Diseases. Published online 11/6/2020. doi.org/10.1093/cid/ciaa1391 • Venter WDF, Sokhela S, Simmons B, et al. “Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results form a randomized, phase 3, non-inferiority trial,” Lancet HIV. 2020;7:e666-76 • Wearne N, Davidson B, Blockman M, Swart A, Jones ESW. “HIV, drugs and the kidney,” Drugs in Context. 2020;9:2019-11-1

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