Maurice Cook ( EM Designs Group, Inc.) A Pill a Day To Keep HIV Away Robert M Grant, April 28, 2011

The HIV Pandemic 2.6 Million New HIV Infections in % in Young People (ages 15-24)

3 The HIV Pandemic 1.2 Million Started Therapy in New Infections For Everyone Starting Therapy

MSM Have 19.3 Higher Odds of HIV Infection Baral S, Plos Med 2007

HIV Prevention Methods With Efficacy Demonstrated by Randomized Clinical Trials to Lower HIV Incidence in MSM None

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MSM and Trans Women Randomized 1:1 Daily Oral PREP FTC/TDF vs Placebo Followed on Drug for:  HIV seroconversion  Adverse Events (especially renal & liver)  Metabolic Effects (Bone, Fat, Lipids)  HBV Flares among HBsAg+  Risk Behavior & STIs  Adherence  If infected ‣ Drug Resistance ‣ Viral load ‣ Immune responses & CD4 Count The iPrEx Study

8 Used PEP After High-Risk Sex No PEP After High-Risk Sex No PEP No High-Risk N HIV Infections1100 Incidence1.5%11.6%0% 200 MSM given a AZT/3TC PEP starter pack Followed for 24 months Main reasons for not starting PEP – Sex with primary partner, friends advised against, concerned about side effect, thought exposure was low risk

Fully enrolled as of December 2009 Lima Iquitos Guayaquil Sao Paulo Rio de Janeiro Boston San Francisco Cape Town Chiang Mai Sites11 Participants2499 New England Journal of Medicine, online Nov 23, 2010

FTC/TDFPlaceboTotalDifferenceSignificance Before PrEP2810-6P=0.06 During PrEP P=0.002 After PrEP426+2P=0.NS Total P=0.001 HIV Infections Before, During, and After PREP Grant et al, CROI 2011

Efficacy (MITT) 44% (15-63%) Through May 1, 2010 Durable Through 144 Weeks in the Final Analysis P = Grant et al, CROI 2011

New England Journal of Medicine, online Nov 23, 2010 Drug Levels Cases matched to controls by site and time on study Drug Detection Correlated with Seronegative Status (OR 12.9, P<0.001) 92% reduction in HIV risk 95% if controlled for Unprotected Receptive Anal Intercourse

17 Anderson et al, CROI 2010

HIV Infections During PrEP Trials In The USA On PrEPOff PrEP CDC Safety Study (US sites)06 Daily Oral TDF vs Placebo 3 in placebo arm, 3 in deferred arm. NIH iPrEx (US Sites) 03 Daily Oral FTC/TDF vs. Placebo 2 in placebo arm 1 in active arm 9 weeks after stopped drug Grohskopf, IAS Vienna 2010; Grant NEJM 2010

New England Journal of Medicine, online Nov 23, 2010

Nausea on History New England Journal of Medicine, online Nov 23, 2010

Weight Gain New England Journal of Medicine, online Nov 23, 2010

Genotypic Resistance HIV Status at Enrollment InfectedUninfected Placebo N=8 FTC/TDF N=2 Placebo N=83 FTC/TDF N=48 65R 0 (0%) 70E 0 (0%) 184I 0 (0%)1 (50%)0 (0%) 184V 1 (13%)1 (50%)0 (0%) TDF Resistance 0 (0%) FTC Resistance 1 (13%)2 (100%)0 (0%) Drug Resistance Grant et al, CROI 2011

HIV Resistance - Results New HIV infections (91 samples tested)  No drug resistance in participants on Truvada  2 with minor variant drug resistance on placebo (1 to tenofovir, 1 to emtricitabine) HIV infections already present at enrollment  2 cases of emtricitabine resistance  Resistance dropped to undetectable levels within 6 months after stopping PrEP

HIV Cases Averted: FTC Resistance Ratio 35 HIV Infections Averted 2 Cases of FTC Resistance Ratio of 17.5

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Sexual Partners New England Journal of Medicine, online Nov 23, 2010

Condom Use with High Risk Sex New England Journal of Medicine, online Nov 23, 2010

Will pill taking increase if people are given FTC/TDF (without placebo) and know it can be effective? What will happen to sex practices? Safety and acceptability of every 12 week visits Collect more safety data over longer periods of time Open Label Extension Aims:

Stop Giving a Placebo Provide New Information About Efficacy About Safety Reassurance at week 4 Decide to Use PrEP Neutralize Visit Incentives “Next Step” Counseling Client centered, motivational Neutral Assessment Focus on barriers and facilitators Monitor and Discuss Drug Levels Strategies for Improving PrEP Use

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36 Effectiveness of tenofovir gel in preventing HIV infection in women 36 TenofovirPlacebo # HIV infections3860 Women-years (# women)680.6 (445)660.7 (444) HIV incidence (per 100 women-years) Incidence rate ratio: 0.61 (CI: 0.4 to 0.94); p = % lower HIV incidence in tenofovir gel group

By February 18, 2011, 3752 screened to enroll Bondo, Kenya; 432 Bloemfontein, South Africa; 16 in Arusha, Tanzania. 21% HIV infected at screening 90% retention, reported adherence 95% 5% annual HIV incidence 56 infections: 28 placebo arm, 28 FTC/TDF arm Hormonal contraception used by most 66% injectable, 30% oral contraception Pregnancy rates was 9%, mostly in the oral arm Pregnancy rate was higher in the FTC/TDF arm Some mild side effects in the FTC/TDF arm FEM-PrEP Facts

Possible Explanations Likely 2 or more of the following Bad luck (chance) Low adherence Poor drug penetration in vaginal tissues Sex hormone FTC interactions Not likely, but possible Unblinding by side effects Drug sharing Drug Testing and Resistance Testing Will Tell

TFV & TFV-DP by Route & Site MTN-001: Hendrix et al CROI 2011 Vaginal dosing achieves active drug (TFV-DP) concentrations in tissue >100x higher than with oral dosing No additive effect of Dual TFV-DP ~5-15% of TFV in the same compartment Effective concentrations have not been established Log 10 TFV & TFV-DP (fmol/mg or pmol/mL**) Serum TFV C max PBMC TFV-DP C max CVL TFV Endocervical Cytobrush TFV-DP Tissue TFV-DP Tissue TFV *Median <LLOQ, assigned BLQ/2 for median; value **Molar equivalent units assumptions: gm = mL, 10 6 cells = 0.2uL * * * * * %BLQ

Cost

iPrEx: Number Needed to Treat Compared with Other Health Interventions Outcome of InterestIntervention # Needed to Treat to Prevent Outcome Death from colorectal cancer Annual FOBT Colorectal Screen 1 4,551 Stroke in women with no previous CV disease Aspirin 81 mg daily Heart attack in hypertensives with average cholesterol Atorvastatin 10 mg daily HIV infection in MSMTruvada 1 pill daily Mandel JS, Bond JH, Church TR. et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328: Berger, J.S. Et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295: PS Sever et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a multirandomised trial. Lancet 2003; 361: Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363: Mandel, et al. NEJM, 1993; 2 Berger, et al. JAMA, 2006; 3 Sever, et al. Lancet, 2003; 4 Grant, et al. NEJM, 2010.

Cost-effectiveness for PrEP by efficacy, cost, age and HIV incidence Paltiel A D et al. Clin Infect Dis. 2009;48: © 2009 by the Infectious Diseases Society of America

PrEP Bridges To Better Places FromTo Denial and stigmaHIV test Negative HIV TestProtective behavior Multiple partnersIntimacy Serodiscordant couplesViral suppression on treatment Stigma and Loss to Follow-upRetention in care Don’t ask (about sex), don’t tellPrevention for positives “Treatment mortgage” with balloon payments Fixed rate to fully fund universal test and treat Robert Grant, April 2011

Collateral Benefits All observed during PrEP in iPrEx Found the epidemic with surveillance Increased HIV testing and counseling Timely identification of acute infections Decreased partners More condom use Universal HBV vaccination Routine STI screening and treatment Antiretroviral treatment or linkage to care Advocacy for state of the art therapy 687 people employed Advocacy for constitutional protections Community building Good Participatory Practices Models Could Consider Collateral Benefits

Regulatory and Normative Status of Oral FTC/TDF PrEP United States Gilead preparing supplemental NDA Pre-submission meetings with FDA CDC issues interim guidance Outside The United States “We are not ready” Looking to the US for examples Robert Grant, April 2011

Will pill taking increase if people are given FTC/TDF (without placebo) and know it can be effective? What will happen to sex practices? Safety and acceptability of every 12 week visits Collect more safety data over longer periods of time Open Label Extension Aims:

Stop Giving a Placebo Provide New Information About Efficacy About Safety Reassurance at week 4 Decide to Use PrEP Cohort benefits given to all “Next Step” Counseling Client centered, motivational Neutral Assessment Focus on barriers and facilitators Monitor and Discuss Drug Levels Strategies for Improving PrEP Use

Intermittent PrEP Adherence IAVI East African Trial 72 MSM and FSW in Kenya 72 Discordant Couples in Uganda Truvada vs. Placebo 2:1 Daily vs. twice weekly and post exposure (1:1) MEMS data adjusted for curiosity openings 48 RegimenMSM/FSW % (IQR) Couples % (IQR Daily92% (79-99%)97 (93-100%) Non-daily Fixed Doses55% (28-88%)91% (77-98%) Post Exposure Doses26% (14-50%)45% (20-63%) Mutua et al, Vienna, 2010

The ADAPT Study (HPTN 067) Alternative Dosing to Augment PrEP Pill Taking Intermittent PrEP in: –MSM (N = 180, Bangkok, Thailand) –WSM (N = 180 Cape Town, South Africa) Oral FTC/TDF in three dosage groups: –Daily dosing –Time-driven dosing group: FTC/TDF twice weekly with a post-exposure boost. –Event-driven dosing group: FTC/TDF before and after a potential exposure to HIV infection. Drug Level in Hair and PBMC

An Opportunity to Win the War Against HIV Stop Spread to Let Treatment Catch Up Many new opportunities, a moment to invest ExposureIntervention GestationalSuppressive Therapy NeedleClean Needles PenileMale Circumcision VaginalTDF 1% Gel RectalOral FTC/TDF

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