GCM Telebriefing for Global Advocates to Discuss iPrEx Download the presentation at campaign.org/iPrExTrialResources.htmhttp:// campaign.org/iPrExTrialResources.htm You can ask questions one of three ways: - Que the operator - Use the webinar chat function -

Sponsored by NIH/NIAID/DAIDS PrEP Initiative / Iniciativa PrEx with co-funding by the Bill & Melinda Gates Foundation and drug donated by Gilead Sciences

Fully enrolled as of December 2009 Lima Iquitos Guayaquil Sao Paulo Rio de Janeiro Boston San Francisco Cape Town Chiang Mai Sites11 Participants2,499

MSM bear a major burden  Throughout the Americas  In parts of Asia  Burden in Africa is increasingly appreciated Efficacy could be different  Possibly different penetration of virus and drug into rectal tissue iPrEx is the only efficacy study of PrEP in MSM

Working with MSM in South Africa African MSM & HIV: Significance

Working with MSM in South Africa: South African MSM & HIV: significance: HIV prevalence among MSM, 10 – 40 % SA Country Progress Report on declaration of commitment on HIV/AIDS (2010) 10 % prevalence UNGASS indicators – 2007, none provided

Working with MSM in Africa: MSM research Risk factors for HIV among MSM Poor condom use Poor HIV Knowledge Poor access to care Transactional sex High number of partners Substance abuse

Working with MSM in South Africa: HIV & MSM in SA Barriers to accessing health Persisting stigma Homo-negativity Non MSM sensitive services

Working with MSM in South Africa: MSM research Cape Town MSM HIV prevalence ( ) Total 14.5 % Township 25.5% City Centre 10.4%

PrEP study Cape Town: Background “Chemoprophylaxis for HIV Prevention in Men” Safety and efficacy of Truvada® in preventing HIV 200 high-risk MSM in greater Cape Town Launched in Dec 2008 Multiple recruitment strategies to reach diverse population SMS advertising campaign LGBT-venue fieldwork Community recruiters Referrals Passive Internet recruitment

Ethnicity Location

High Risk MSM 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

Comprehensive Prevention Services Given to All HIV Testing Monthly Pre- and Post-test counseling Condoms (15 or more) STI testing if any symptoms, monthly STI screening for all every 24 weeks Partner treatment PEP if recently exposed HBV vaccine

Comprehensive Prevention Services Given to All HIV Testing Monthly Pre- and Post-test counseling Condoms (15 or more) STI testing if any symptoms, monthly STI screening for all every 24 weeks Partner treatment PEP if recently exposed HBV vaccine The primary efficacy and safety analysis is based on visits between June 2007 and May 1st 2010

4,905 Screened 1,226 (98%) Followed 1,225 (98%) Followed 1,251 (50%) Randomized to FTC/TDF 1,248 (50%) Randomized to Placebo 25 No Follow Up HIV Test23 No Follow Up HIV Test 842 Eligible, Not Enrolled 1,564 (32%) Ineligible 410 HIV Positive 405 Lab Ineligible 247 Low HIV Risk 502 Other Reasons 3,341 Eligible2,499 Randomized

Baseline Characteristics of the Participants, According to Study Group Black/African American117 (9)97 (8) White223 (18)208 (17) Mixed/Other849 (68)878 (70) Asian62 (5)65 (5) Hispanic/Latino - no. (%) P= (72)906 (73) Race/Ethnicity - no. (%) P=0.40 (n=1,251)(n=1,248) CharacteristicFTC/TDFPLACEBO

Baseline Characteristics of the Participants, According to Study Group (47)662 (53) (22)241 (19) (20)224 (18) ≥40137 (11)121 (10) Age - no. (%) P=0.04 (n=1,251)(n=1,248) CharacteristicFTC/TDFPLACEBO (Median age 9 months younger in placebo than FTC/TDF arm)

Baseline Characteristics of the Participants, According to Study Group Numbers of Partners last 12 weeks-mean (SD) P= (35)18 (43) Unprotected Receptive Anal Intercourse last 12 weeks - no. (%) P= (59)753 (60) Unprotected Anal Intercourse with HIV+/ Unknown Status Partner last 6 months - no. (%) P= (79)1,009 (81) Involved in Transactional Sex last 6 months - no. (%) P= (41)510 (41) Known HIV+ Partner last 6 months - no. (%) P= (2)32 (3) History of STI last 6 months - no. (%) P= (26)307 (25) Sexual Risk Factors at screening(n=1,251)(n=1,248) CharacteristicFTC/TDFPLACEBO

110 in total (100 incident, 10 at baseline) At least one specimen with undetectable RNA for all incident seroconverters HIV Infections

Efficacy (MITT) 44% (15-63%) Infection Numbers: 64 – 36 = 28 averted

Efficacy95% CIP-Value Intention to Treat47% Modified Intention to Treat 44% As Treated (50%)50% Summary Efficacy of Oral FTC/TDF PrEP

Subgroup Analysis

Title Box HIV Incidence by 50% Pill Use and Group Bars Are SE of the Incidence Estimate

Title Box HIV Incidence by 90% Pill Use and Group Bars Are SE of the Incidence Estimate

Title Box HIV Incidence by URAI and Group Bars Are SE of the Incidence Estimate

Efficacy95% CIP Value Intention to Treat47%22-64P=0.001 Modified Intention to Treat 44%15-63P=0.005 As Treated (50%)50%18-70P=0.006 As Treated (90%)73%41-88P< Unprotected RAI at Baseline 58%32-74P< Summary Efficacy of Oral FTC/TDF PrEP

FTC TDF HIV- HIV+ Placebo 34 Samples 26 PBMC 0 Plasma 0 Both 35 Samples 1 unavailable specimen 33 Samples 2 unavailable specimens 1 control used for 2 cases 26 Samples Stopped testing after Samples 34 PBMC 33 Plasma 33 Both 1 case > 7 days after seroconvertion 31 Samples 30 PBMC 24 Plasma 23 Both 2 cases off drug Sampling for Case Control Study FTC/TDF Cases/Controls N=36

Drug Levels 17/35 Detectable TFV-DF (fmol/10 6 cells)

Drug Level And Decreased Risk Ratio Robust because case-control study is nested in a larger cohort, although not randomized comparison Strong Correlate of Protection –Odds Ratio 12.9, P<0.001 –92% reduction in risk (95% CI 40-99%) If adjusted for URAI –95% reduction in risk (95% CI 70-99%)

Plasma HIV Level

Drug Resistance Cases Case Study Arm Study Visit Plasma HIV RNA Level (copies/ml) Rapid Antibody Tests Reverse Transcriptase Nutations Conferring Resistance FTC Resistance Phenotype (Fold Change FTC IC50) Timing Resistance 1Placebo Enrollment417Non-reactive M184V, T215Y,and K103N Not done Primary W Reactive M184V, T215Y,and K103N >300 2FTC/TDF Enrollment**10,000,000Non-reactiveWild TypeNot done Secondary W43,109*ReactiveM184V>300 3FTC/TDF Enrollment***48Non-reactiveAssay FailedNot done Indeterminate W4<400*ReactiveM184I>300 *Tested at week 8 after enrollment ** Symptomatic at enrollment, with fever, runny nose, and sinus tenderness, diagnosed as “sinusitis” *** Returned for interim visit 7 days after enrollment with sore throat

Safety

Adverse Event TDF/FTCPlacebo P value n (%)Eventsn (%)Events Creatinine Elevated25 (2%)2814 (1%)15p=0.08 Headache56 (4%)6641 (3%)55p=0.10 Depression43 (3%)4662 (5%)63p=0.07 Nausea20 (2%)229 (<1%)10p=0.04 Weight Decreased27 (2%)3414 (1%)19p=0.04 Diarrhea46 (4%)4956 (4%)61p=0.36 Bone Fracture15 (1%)1611 (<1%)12p=0.41 Adverse events

Adverse Event TDF/FTCPlacebo P value n (%)Eventsn (%)Events Grade 3110 (9%) (9%)225p=065 Grade 441 (3%)5147 (4%)60p=0.57 Grade 3 or Grade 4151 (12%) (13%)285p=0.51 Death1 (<1%)14 (<1%)4p=0.18 Drug Stopped (Perm.)25 (2%)2627 (2%)33p=0.82 Drug Stopped (All)79 (6%)9972 (6%)92p=0.54 Serious AE60 (5%)7667 (5%)87p=0.57 All AE867 (69%) (70%)2,611p=0.50 Adverse events

Sexual Partners

Conclusions Oral FTC/TDF PrEP provided additional protection against the acquisition of HIV infection among MSM receiving a comprehensive package of prevention services. Detectable drug in blood strongly correlated with the prophylactic effect.

Proposed Open Label Extensión Sponsored by NIH/NIAID/DAIDS with drug donated by Gilead Sciences

Premise Risk compensation and adherence are significant determinants of PREP effects Information about PrEP safety and efficacy could affect behavior

“Next Step” Counseling For PrEP Pill Taking Separation of roles –Monitoring –Promotion Monitoring is neutral Promotion focus –On barriers and facilitators –Blind to actual reported use

Thanks CAPE TOWN You’re Gorgeous!

The iPrEx Study: Safety, Efficacy, Behavior, and Biology Gladstone Institute of Virology and Immunology Robert Grant Vanessa McMahan Pedro Goicochea K Rivet Amico David Glidden Furong Wang Kathy Mulligan Juan Guanira Maria Esther Ramírez Carmela Ganoza Javier Lama Lorena Vargas Valdilea Veloso Esper Kallás Orlando Montoya Telmo Fernández Martin Casapía Mauro Schechter Kenneth Mayer Suwat Chariyalertsak Brian Postle Linda-Gail Bekker Susan Buchbinder Stephen Becker David Burns Howard Jaffe Peter Anderson Lane Bushman Patricia Defechereux Robert Hance Jeanny Lee Jeff McConnell Jim Rooney Grace Chow Ana Martinez Albert Liu