HIV Science Update: From Rome to Addis – Biomedical Prevention Elly T Katabira, FRCP Department of Medicine Makerere University College of Health Sciences 16 th ICASA, Addis Ababa, Ethiopia, December 6, 2011

Treatment as prevention

Population level observational data: British Columbia All receiving HIV prevention services Montaner Lancet 2010

HPTN 052: Impact of (earlier) ART on HIV transmission and disease progression 1763 HIV discordant couples (HIV+ partner CD ) HAART delayed until CD 250 1° endpoint: HIV infection in HIV-negative partner Co- 1° endpoint: HIV disease progression in HIV+ partner Immediate HAART All receiving HIV prevention services 13 sites in 9 countries: Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, United States, Zimbabwe Cohen et al NEJM 2011 and IAS 2011

Total HIV-1 Transmission Events: 39 HPTN 052: HIV transmissions Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 p < Immediate Arm: 1 Delayed Arm: 27 96% reduction in risk of HIV transmission within the partnership (95% CI 73-99%)

Prevention of HIV acquisition in those who are HIV negative

CAPRISA 004: proof of principle for microbicides Phase 2B trial in 889 women, ages ≥18 years in South Africa Coitally dependent: gel within 12 hours before & 12 hours after sex, max. 2 applications in 24 hours Study population: Young women (mean age 23), unmarried CAPRISA 004: Pericoital 1% tenofovir gel Abdool Karim et al, Science July 2010

Q Abdool Karim et al. Science 2010 HIV protection in CAPRISA 004 No HIV resistance mutations among seroconverters

iPrEx: PrEP works for MSM 2499 MSM, randomized 1:1 daily oral FTC/TDF vs placebo 11 sites (Brazil, Ecuador, Peru, South Africa, Thailand, US) 70% from Andean sites Young high risk MSM: 50% <25 yrs Median 18 partners in 12 wks prior to enrollment iPrEx: Daily oral FTC/TDF PrEP

iPrEx HIV protection 100 infections after randomization 64 on placebo Efficacy estimate (mITT): 44% reduction in HIV acquisition (95% CI 15%-63%) 36 on FTC/TDF Weeks on Study 2 cases of M184V resistance in participants in “window period” at time of PrEP initiation = avoid PrEP initiation in those who have acute HIV infection

Partners PrEP Study 4758 HIV serodiscordant couples (HIV+ partner not yet medically eligible for ART) TDF once dailyPlacebo once daily Randomize HIV- partners (normal liver, renal, hematologic function) 1° endpoint: HIV infection in HIV- partner Co- 1° endpoint: Safety Follow couples for up to 36 months FTC/TDF once daily All receiving comprehensive HIV prevention services

Primary efficacy results TDFFTC/TDFPlacebo Number of HIV infections HIV incidence, per 100 person-years HIV protection efficacy, vs placebo62%73% 95% CI(34-78%)(49-85%) p-value0.0003< Z-score, vs. H 0 = Primary analysis: modified intention-to-treat (mITT) excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo) ITT analysis results similar Effect of TDF and FTC/TDF statistically similar (p=0.18) Slides presented IAS 2011

Subgroup analysis - gender Efficacy95% CIP-valueInteraction p- value TDF Women Men 68% 55% 29-85% 4-79% p=0.01 p=0.04 p=0.54 FTC/TDF Women Men 62% 83% 19-82% 49-94% p=0.01 p=0.001 p=0.24 Both TDF and FTC/TDF significantly reduced HIV risk in both men and women Women: 42 total infections: 8 TDF, 9 FTC/TDF, 25 placebo Men: 36 infections: 10 TDF, 4 FTC/TDF, 22 placebo Slides presented IAS 2011

Safety No statistically significant difference in deaths, SAEs, key laboratory AEs Number of participants with each safety event TotalTDFFTC/TDFPlacebo Death24 (<1%) 879 SAE320 (7%) Confirmed creatinine AE49 (1%) Confirmed phosphorus AE403 (9%) Slides presented IAS 2011

Some disappointments though…….

Ongoing safety and effectiveness study of tenofovir gel, oral TDF, and oral FTC/TDF for prevention of HIV TOTAL SAMPLE (5000) Oral Pill (3000) Truvada (1000) Tenofovir (1000) Oral Placebo (1000) Vaginal Gel (2000) Tenofovir Gel (1000) Placebo Gel (1000)

Ongoing safety and effectiveness study of tenofovir gel, oral TDF, and oral FTC/TDF for prevention of HIV TOTAL SAMPLE (5000) Oral Pill (3000) Truvada (1000) Tenofovir (Discontinued) Oral Placebo (1000) Vaginal Gel (2000) Tenofovir Gel (1000) Placebo Gel (1000)

Ongoing safety and effectiveness study of tenofovir gel, oral TDF, and oral FTC/TDF for prevention of HIV TOTAL SAMPLE (5000) Oral Pill (3000) Truvada (1000) Tenofovir (Discontinued) Oral Placebo (1000) Vaginal Gel (2000) Tenofovir Gel (Discontinued) Placebo Gel (1000)

A word of caution………..

CAPRISA 004 & iPrEx: PrEP is all about adherence CAPRISA 004 High (>80% gel adherence) n=336 (38%) 54% effective Low (<50% gel adherence) n=367 (42%) 28% effective iPrEx 8% of seroconverters had detectable drug at first HIV+ visit (and only 54% of nonseroconverters)  92% estimated efficacy if drug was present

Combination HIV prevention: a package What works for HIV prevention: – Male circumcision (F  M risk) – Male condoms, female condoms (probably) – Counseling and testing, particularly as a couple (probably) – ↓ partner #, delayed sexual debut, abstinence – Treatment of STIs (probably best to decrease infectiousness in HIV+s) – Conditional cash transfer – ART – Oral/topical PrEP – ? Vaccine Multiple, integrated, biomedical and behavioral interventions Combination prevention. Coates, et al. Lancet 2009

ACKNOWLEDGEMENT Adaora A. Adimora Audrey Pettifor Dannielle Haley Jessica Justman Mara Nakagawa-Harwood Jaread Baeten Connie Celum Pedro Cahn Julio Montaner And many others behind the scene