HIV Preexposure Prophylaxis (PrEP) 2019 Roy M. Gulick, MD, MPH Chief, Division of Infectious Diseases Rochelle Belfer Professor in Medicine Weill Cornell Medicine New York City, New York

Financial Relationships With Commercial Entities Dr Gulick has no relevant financial affiliations to disclose. (Updated 08/14/19)

Learning Objectives After attending this presentation, learners will be able to: Discuss the current data to support the use of HIV PrEP Discuss investigational agents for HIV PrEP

New HIV Infections: Global ↓16% since 2010 UNAIDS: http://aidsinfo.unaids.org/2019

New HIV Diagnoses, NYC, 2017 Poverty Gender Age Borough In NYC, for the last few years, HIV case numbers have been decreasing annually. This bar chart highlights groups disproportionately affected: Balcks and Hispanics, Men, esp MSM, and those with inclomes below the fed pov line. Side note: In 2014 2,718 cases were reported 48 diagnoses among transgender women & 1 among transgender men Identified as transgender by self-report, diagnosing provider or medical chart review. Transgender women were assigned male sex at birth and currently identify as female. Transgender men were assigned female sex at birth and currently identify as male. Poverty (area based) Gender Age Borough Transmission Risk Source: NYC DOHMH, Bureau of HIV Surveillance Data

Governor Cuomo’s Plan to End AIDS in New York -- 2014 1. Diagnose HIV and link to care 2. Link, retain and treat to achieve virologic suppression 3. Provide PrEP for high-risk people to keep them HIV negative http://www.governor.ny.gov/news/ October 2014

Federal Plan to End AIDS by 2030 February 2019 https://www.hiv.gov/

Oral PrEP Studies (1) Study (reference) Study population Design Results: ↓HIV Infection IPREX Grant NEJM 2010;363:2587 2499 gay men TDF/FTC vs. placebo TDF/FTC: 45% (92% if tenofovir detected) Partners PREP Baeten NEJM 2012;367:399 4758 discordant Kenya and Uganda couples TDF vs. TDF/FTC vs. placebo TDF: 67% TDF/FTC: 75% (86-90% if tenofovir detected) CDC – TDF-2 Thigpen NEJM 2012;367:423 1200 Botswana adults (45% women) TDF/FTC: 63% (84% if tenofovir detected)

PrEP Approvals In July 2012, U.S. FDA approves TDF/FTC for pre-exposure prophylaxis (PrEP) in combination with safer sex practices to reduce the risk of sexually acquired HIV-infection in adults at high risk. Additional approvals followed including: Australia, Canada, France, India, Israel, Kenya, Peru, South Africa

Oral PrEP Studies (2) Study (reference) Study population Design Results: Reduction in HIV Infection FEM-PREP Van Damme NEJM 2012;367:411 2120 women in Kenya, South Africa, Tanzania TDF/FTC vs. placebo TDF/FTC: 6% VOICE Marrazzo 2015;372:509 5029 women in South Africa, Uganda, Zimbabwe 1% TDF gel vs. placebo gel; oral TDF vs. TDF/FTC vs. placebo 0% -- no study drugs effective (adherence <40%) (adherence < 30%)

Oral PrEP Studies (3) Study (reference) Study population Design Results: Reduction in HIV Infection iPERGAY Molina NEJM 2015;373:2237 414 MSM in France and Canada TDF/FTC vs. placebo (event-driven) TDF/FTC: 86% PROUD McCormack Lancet 2016;387:53 545 men in England TDF/FTC vs. placebo

Oral TDF/FTC PrEP Trials: Effectiveness Improves With Adherence 100 iPrEx Efficacy 44% Adherence 51% Partners PrEP Efficacy 75% Adherence 81% TDF2 Efficacy 62% Adherence 80% VOICE/FEM-PrEP Efficacy 0%/6% Adherence 29%/≤ 37% PROUD Efficacy 86% Adherence ~100% 80 60 40 20 100 FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate. References 1. Marrazzo JM, et al. N Engl J Med. 2015;372:509-518. 2. Van Damme L, et al. N Engl J Med. 2012;367:411-422. 3. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 4. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 5. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 6. McCormack S, et al. Lancet. 2016;387:53-60. Overall, these randomized clinical trials of PrEP using TDF/emtricitabine have shown that HIV incidence decreases with patient adherence. The y axis depicts the effectiveness of HIV protection in each trial while the x axis documents each trial’s adherence level. Adherence was based on pill counts or the detection of study drug in plasma.   A very clear and strong linear relationship exists where greater adherence across the study population tracks with greater HIV protection. This emphasizes how important it is to be adherent to PrEP. The TDF2, Partners PrEP, and PROUD studies all demonstrated very high degrees of HIV protection in populations that took PrEP consistently. Slide 12 of 40 Adherence (%)†

Oral PrEP Studies (4) Study (reference) Study population Design Results: Reduction in HIV Infection Thai IDU Choopanya Lancet 2013;381:2083 2413 Thai injection drug users TDF vs. placebo TDF: 49% (70% if TFV detected)

WHO Evaluation of PrEP Data 2015 Efficacy: Effective across groups, genders Adherence: Heterogeneous Side effects: no more common than placebo (subclinical renal/bone issues) Drug resistance: low (0.1%) risk Risk compensation: did not increase Cost: could be cost-effective/cost-saving Logistics: significant concerns http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/

PrEP Safety: Meta Analysis 13 randomized trials of PrEP vs PrEP Safety: Meta Analysis 13 randomized trials of PrEP vs. placebo (or no treatment) (N=15,678) all grade creatinine ↑: PrEP 336 vs. control 178 (p=0.04) grade 3-4 Pilkington J Virus Erad 2018;4:215-224

Genotypic Drug Resistance (DR) to TDF or FTC in PrEP Studies Overall risk of FTC or TFV resistance is 5/9222 (0.05%) Fonner AIDS 2016;30:1973-1983

Case Reports: HIV Infection with High Adherence to PrEP (N=6) 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; MSM, men who have sex with men; NVP, nevirapine; PrEP, pre-exposure prophylaxis; RAL, raltegravir; TDF, tenofovir disoproxil fumarate. However, as illustrated by this case reported at CROI 2016, PrEP is never going to necessarily be 100% effective. This was a MSM from Toronto, Canada. His clinician had a strong index of suspicion when the patient reported substantial risks for HIV and came in with some atypical symptoms. So, the clinician ordered an acute HIV infection assessment, did an RNA testing, and at the same time saved blood to test for TDF/FTC and found that the patient, indeed, was highly adherent to the study medication.   When the RNA test came back positive, the clinician ordered resistance testing, which suggested a high level of resistance, including resistance to some of the drugs that are not contained in a PrEP regimen of TDF/FTC. For example, the patient had resistance to integrase strand inhibitors and nonnucleoside reverse transcriptase agents and protease inhibitors, suggesting that this is a case of a patient having a highly resistant strain of HIV and transmitting it despite PrEP. So, this is a case in point that makes us say that we cannot guarantee PrEP being 100% effective, but it's certainly highly effective. So, if individuals really want maximal protection, there's still a rationale for using condoms. The other rationale for using condoms even in the setting of using PrEP is to avoid other sexually transmitted infections, because PrEP only protects against HIV. Gibas Drugs 2019;79:609-619

PrEP and STIs Systematic Review and Meta-Analysis 8 studies with 4388 participants Traeger CID 2018;67:676-686

U.S. CDC HIV PrEP Guidelines (2017) “Recommended for substantial risk of HIV Infection”

CDC HIV PrEP Guidelines (2017) Rule out acute HIV infection Assess baseline renal function Prescribe 3 months of TDF/FTC Follow-up visits every 3 months for: HIV testing Adherence and risk reduction counseling Side effect assessment Sexually transmitted infection symptom assessment and routine testing (chlamydia, gonorrhea, syphilis); treat if necessary Assess renal function every 6 months

U.S. Preventive Services Task Force (UPSTF) Recommendation Summary Population Recommendation Grade Persons at high risk of HIV acquisition The USPSTF recommends that clinicians offer PrEP with effective ART to persons who are at high risk of HIV acquisition. A JAMA 2019;321:2203-2230 Federal Rule: Private Insurance and Medicare must offer A or B services without a co-pay.

ARS Question 1: Have you prescribed oral daily TDF/FTC for PrEP? Yes No I’m not a prescriber

In 2017  120,000 PrEP users In 2019  270,000 PrEP users

Mera IAS 2017 #WEPEC0919

PrEP Initiations by Country 2018 > 25,000 10,000-25,000 5,000-10,000 1,500-5,000 500-1,500 < 500 No Data PrEP Available (No Data) >300,000 PrEP starts globally >200,000 in the US Source: AVAC Global PrEP Initiation Tracker 2018

Intermittent PrEP (I-PrEP) IPREX Follow-Up: Modeling Pharmacokinetics in Men Who Have Sex With Men (MSM) Using data from a separate PK study: 7 doses/week: 99% risk reduction 4 doses/week: 97% risk reduction 2 doses/week: 76% risk reduction Anderson Sci Transl Med 2012;4:151ra125.

ARS Question 2: Have you recommended “on-demand” TDF/FTC for PrEP? Yes No I’m not a prescriber

Event-Driven PrEP: Status FDA label of TDF/FTC specifies once-daily Recommended by IAS-USA, BHIVA, EACS (2018) and WHO (2019)

Prevenir INTERIM REPORT Open-label, prospective, cohort study in Paris Cohort population: HIV- high-risk adults, inconsistent condom use, GFR >50, HBsAg negative if using on-demand (N=3057) Rx: Choose TDF/FTC daily or on-demand dosing (and can switch); f/u every 3 months Goal: Show 15% ↓ in new HIV infections in Paris Results (HIV modified ITT analysis): 2 seroconversions, both off PrEP X 7-10 weeks 3 PrEP discontiunations due to GI sx Conclusion: High efficacy of daily and on-demand PrEP Molina IAS 2019 #TUAC0202

Rates of Detectable TFV/TFV-metabolite detection in Female Mucosal Tissues – Single Dose Study TAF 25mg TDF 300mg 100% 37% Rectal Tissue DETECTABLE CONCENTRATIONS OF TFV AND TFV-DP IN FEMALE MUCOSAL TISSUES AFTER SINGLE DOSE Cottrell J Antimicrob Chemother 2017;72:1731-1740

ARS Question 3: Have you prescribed oral daily TAF/FTC for PrEP? Yes No I’m (still) not a prescriber

Newer PrEP Agents study drug mechanism dosing route dosing PrEP stage TAF NRTI oral daily phase 3 completed cabotegravir integrase inhibitor injectable, subcutaneous once every other month studies monoclonal antibodies CD4 or gp120 attachment inhibitors Injectable subcutaneous pilot studies; phase 2b/3 AMP studies

Rates of Detectable TFV/TFV-metabolite detection in Female Mucosal Tissues – Single Dose Study TAF 25mg TDF 300mg 100% 37% Rectal Tissue DETECTABLE CONCENTRATIONS OF TFV AND TFV-DP IN FEMALE MUCOSAL TISSUES AFTER SINGLE DOSE Cottrell J Antimicrob Chemother 2017;72:1731-1740

DISCOVER: TDF vs. TAF for PrEP Double-blind, non-inferiority PrEP study Study population: MSM and TGW (N=5387) median 34 yo, 84% W, 24% L, 16% non-white, 74 TGW Study rx: daily oral TDF vs. TAF Results: 22 incident infections 5 at first visit 15 with ↓ drug levels 2 with adeq. drug levels >57% with STI Improved bone, renal markers with TAF Conclusion: TAF non-inferior to TDF for PrEP Hare CROI 2019 #104

DISCOVER: TAF/FTC vs. TDF/FTC Subanalyses: No difference in number of condomless RAI partners rectal GC/chlamydia self-reported adherence, pill counts TFV-DP levels by dried blood spots: HIV cases << controls Published data: TAF achieves EC90 within 4 hrs, TDF takes 3 days Conclusions: TAF “potentially more efficacious” FDA Advisory Committee (8/7/19): TAF/FTC PrEP approval vote: men: 16-2 for ♂; women: 10-8 against Spinner IAS 2019 #TUAC0403LB

HPTN 083: PrEP with TDF/FTC oral vs. cabotegravir (CAB) intramuscular Study population: Adult MSM and transgender women at high-risk for HIV acquisition (N=4500) Study regimen: TDF/FTC daily oral vs. CAB every 2 month injections double-blind, double-dummy design Design: non-inferiority, efficacy study 4358 (97%) enrolled globally (as of 9/10/19)!

Islatravir (ISL, formerly MK-8591) Implant Matthews IAS 2019 #TUAC0401LB

Impact: Big Cities All in context of high levels of testing & ART San Francisco: 50+% ↓ in new HIV infections in the past decade SFDPH Annual Report 2017 Sydney: 32% ↓ (25% ↓ in 2 years) Grulich Lancet HIV 2018;5:e629-e637 London: 42% ↓ Nwokolo Lancet HIV 2017;4:e482-e483 New York: 37% ↓ 20112017 NYC HIV Surveillance Report 2017

New York State AIDS Institute

Acknowledgments Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious Diseases Weill Cornell Medicine AIDS Clinical Trials Group (ACTG) Division of AIDS, NIAID, NIH The patient volunteers! Demetre Daskalakis, Raphy Landovitz, Ken Mayer for slides

Question-and-Answer