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A Pill a Day To Keep HIV Away

A Pill a Day To Keep HIV Away. Robert M Grant, April 28, 2011. Maurice Cook ( EM Designs Group, Inc .). The HIV Pandemic. 2.6 Million New HIV Infections in 2009 41% in Young People (ages 15-24). The HIV Pandemic. 1.2 Million Started Therapy in 2009

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A Pill a Day To Keep HIV Away

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

  2. The HIV Pandemic 2.6 Million New HIV Infections in 2009 41% in Young People (ages 15-24)

  3. The HIV Pandemic 1.2 Million Started Therapy in 2009 2 New Infections For Everyone Starting Therapy 3

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

  5. HIV Prevention Methods With Efficacy Demonstrated by Randomized Clinical Trialsto Lower HIV Incidence in MSM None

  6. The iPrEx Study • 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

  7. 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

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

  9. HIV Infections Before, During, and After PREP Grant et al, CROI 2011

  10. Efficacy (MITT) 44% (15-63%) Through May 1, 2010Durable Through 144 Weeks in the Final Analysis P = 0.002 Grant et al, CROI 2011

  11. 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 New England Journal of Medicine, online Nov 23, 2010

  12. Anderson et al, CROI 2010

  13. HIV Infections During PrEP TrialsIn The USA On PrEP Off PrEP • CDC Safety Study (US sites)0 6 Daily Oral TDF vs Placebo 3 in placebo arm, 3 in deferred arm. • NIH iPrEx (US Sites) 0 3 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

  14. New England Journal of Medicine, online Nov 23, 2010

  15. New England Journal of Medicine, online Nov 23, 2010

  16. New England Journal of Medicine, online Nov 23, 2010

  17. New England Journal of Medicine, online Nov 23, 2010

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

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

  20. Drug Resistance Grant et al, CROI 2011

  21. 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

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

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

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

  25. Open Label Extension Aims: 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

  26. 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

  27. Effectiveness of tenofovir gel in preventing HIV infection in women Incidence rate ratio: 0.61 (CI: 0.4 to 0.94); p = 0.017 39% lower HIV incidence in tenofovir gel group 36

  28. FEM-PrEP Facts By February 18, 2011, 3752 screened to enroll 1951 739 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

  29. 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

  30. TFV & TFV-DP by Route & SiteMTN-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 Log10 TFV & TFV-DP (fmol/mg or pmol/mL**) * CVL TFV Endocervical Cytobrush TFV-DP Tissue TFV Tissue TFV-DP Serum TFV Cmax PBMC TFV-DP Cmax * * * * %BLQ 0 0 0 0 0 71 1 56 4 3 52 3 2 34 5 1 42 3 *Median <LLOQ, assigned BLQ/2 for median; value **Molar equivalent units assumptions: gm = mL, 106 cells = 0.2uL

  31. Cost

  32. 1 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;328:1365 2 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: 306-313. 3 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: 1149-1158. 4 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;363:2587-2599 iPrEx: Number Needed to Treat Compared with Other Health Interventions 1Mandel, et al. NEJM, 1993; 2Berger, et al. JAMA, 2006; 3Sever, et al. Lancet, 2003; 4Grant, et al. NEJM, 2010.

  33. Cost-effectiveness for PrEP by efficacy, cost, age and HIV incidence Paltiel A D et al. Clin Infect Dis. 2009;48:806-815 © 2009 by the Infectious Diseases Society of America

  34. PrEP BridgesTo Better Places Robert Grant, April 2011

  35. 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

  36. Regulatory and Normative Statusof 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

  37. Open Label Extension Aims: 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

  38. Strategies for Improving PrEP Use • 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

  39. Intermittent PrEP AdherenceIAVI 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 Mutua et al, Vienna, 2010

  40. 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

  41. An Opportunity to Win the War Against HIVStop Spread to Let Treatment Catch Up Many new opportunities, a moment to invest

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