1. Daily oral antiretroviral use for the prevention of HIV infection in heterosexually active young adults in Botswana: results from the TDF2 study MC Thigpen, PM Kebaabetswe, DK Smith, TM Segolodi, FA Soud, K Chillag, LI Chirwa, M Kasonde, R Mutanhaurwa, FL Henderson, S Pathak, R Gvetadze, CE Rose, LA Paxton for the TDF2 Study Team 1

2. Background Preexposure Prophylaxis Initiative (iPrEX) study among men who have sex with men –Tenofovir-emtricitabine (TDF-FTC) reduced HIV transmission by 44% [95% Confidence Interval (95% CI) 15% to 63%, p=0.005] Interim data from FemPrEP study among high risk women showed no such protective effect Additional safety and efficacy data among heterosexual men and women are needed 2

3. TDF2 Methods Study Design: –Double-blind placebo-controlled randomized clinical trial TDF-FTC vs. matching placebo –≥ 1200 male and female Botswana citizens –Followed for ≥ 12 months –Eligibility criteria: 18-39 years old HIV uninfected Sexually active within past 3 months Healthy –Normal baseline laboratory tests –No chronic medical conditions –Not pregnant or breast feeding –Willing to use hormonal contraception 3

4. TDF2 Methods (2) Study procedures: –Tested for HIV infection every month Dual rapid fingerstick tests at screening Monthly oral transudate (Oraquick) thereafter Positives confirmed by additional testing –EIA, Plasma viral load, ARV resistance testing –Monitored for illness and side effects –Lab testing at Month 1 & 2 then every 3 months –Individualized HIV risk reduction and medication adherence counseling –Assessed adherence using multiple measures Self-report, Pill counts, Drug levels 4

5. Preliminary Results

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8. Demographic Characteristic TDF-FTC group n=601 Placebo group n=599 P value Age group:18-20 years 21-29 years 30-39 years 1.7% 90.3% 8.0% 2.5% 87.3% 10.2% 0.23 Female Gender45.6%45.1%0.86 Education:Primary or less Secondary Postsecondary 3.0% 73.4% 23.6% 3.3% 73.2% 23.5% 0.62 Marital status:Single Married Divorced/Widowed 94.7% 5.2% 0.1% 93.3% 6.2% 0.5% 0.45 Baseline Characteristics among TDF2 Study Participants 8

9. Efficacy – Intention-to-Treat Analysis 9 HIV-infected in TDF-FTC group and 24 HIV-infected in placebo group Overall protective efficacy 62.6% (95% CI 21.5 to 83.4, p=0.0133) 9

10. Efficacy – Participants on Study 4 HIV-infected in TDF-FTC group and 19 HIV-infected in placebo group Overall protective efficacy 77.9% (95% CI 41.2 to 93.6, p=0.0053) 10

11. HIV Infection By Gender Using 33 Seroconverters TDF-FTCPlaceboEfficacy95% CIP-value Female71449.4-21.7, 80.80.107 Male21080.124.6, 96.90.026 Using 23 Seroconverters TDF-FTCPlaceboEfficacy95% CIP-value Female31375.523.8, 94.40.021 Male1682.4-2.8, 99.10.065 11

12. Drug Resistance One participant with unrecognized acute wild-type HIV infection at enrollment started on TDF-FTC –All mutations emerged to high levels K65R M184V Also A62V conferring cross-NRTI resistance One participant in placebo group –K65R only in very low levels (<1%) 12

13. Safety TDF-FTC group (n=601) Placebo group (n=599) P value Any adverse event535 (89.0%)513 (85.6%)0.019 Common Cold229 (38.1%)239 (39.9%)0.78 Fatigue52 (8.7%)45 (7.5%)0.44 Headache227 (37.8%)224 (37.4%)0.75 Dizziness92 (15.3%)64 (10.7%)0.019 Abdominal pain154 (25.6%)152 (25.4%)0.69 Nausea113 (18.8%)43 (7.2%)<0.0001 Vomiting69 (11.5%)41 (6.8%)0.005 Diarrhea76 (12.6%)65 (10.9%)0.24 Back Pain56 (9.3%)67 (11.2%)0.35 Rash39 (6.5%)41 (6.8%)0.87 Fracture5 (0.8%)4 (0.7%)0.69 Any serious adverse event55 (9.2%)51 (8.5%)0.58 Death2 (0.3%)4 (0.7%)0.46 Number (%) Participants with Clinical adverse events by treatment group 13

14. Safety (2) TDF-FTC groupPlacebo groupP value Grade 1-4 events Hypophosphatemia2182400.31 Hyperamylasemia99110110.96 Elevated SGOT43390.70 Elevated SGPT48630.43 Hyperbilirubinemia70720.97 Elevated Creatinine10- Grade 3-4 events Hypophosphatemia21240.66 Hyperamylasemia12180.92 Number Abnormal Laboratory Values by treatment group 14

15. Adherence/Behavioral Data TDF-FTC group Placebo group P value Medication adherence by pill count Overall84.1%83.7%0.79 Among 33 seroconverters89.9%92.9%0.65 Among 23 seroconverters85.5%93.1%0.33 Sexual behavior % with > 1 sexual partner in the prior month 14.2%14.1%0.86 % of vaginal episodes with condom use 81.9%79.7%0.21 15

16. Conclusions Daily TDF-FTC effective and safe for prevention of HIV infection among heterosexual men and women overall compared to placebo Data suggests efficacy for men and women separately, but study not large enough to draw definitive conclusions by gender Overall safety and efficacy findings consistent with Partners PrEP data 16

17. Next steps Other planned analyses include –Efficacy among participants with varying levels of self-reported adherence –Drug level testing for efficacy and adherence –Change in bone mineral density –Trends in risk behavior over time Open label provision of TDF-FTC for 12 months for all study participants CDC & partners will fully review all heterosexual trial data & develop specific guidance for use among heterosexual men and women 17

18. Acknowledgements Botswana Study Team Sandra Johnson Thomas Sukalac Daniel Abebe Evans Buliva Neo Tamuhla Joyce Kgampi Lionah Ockhuizen Thapelo Rampebana Bonny Moapare Bakgaki Ratshaa Onkabetse Matlhaba Nkumbuludzi Ndwapi Kabo Pilane Kabo Kagiso Keodiretseng Moloi CDC and BOTUSA Staff Debra Byrd Paula Casillas Lisa Harper Brandi Collins Vasavi Thomas Sherri Pals John T. Brooks Lisa Grohskopf Peter Kilmarx Margarett Davis Kathleen Toomey Clyde Hart Kevin Malotte Craig Hendrix Eugene Jooste The TDF2 Participants U.S. National Institutes of Health Gilead for providing the study medication 18