Antiretroviral Drugs for HIV Seronegative People: It works in trials, what about the real world?

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1 Antiretroviral Drugs for HIV Seronegative People: It works in trials, what about the real world? Lut Van Damme 11 Oct Disclaimer Gilead donated the study product for the FEM-PrEP trial I participated with Gilead at the FDA hearing, no payment or any reimbursement or incentive received 2 1

2 HIV Prevention: not only biomedical interventions Approach Risk reduction counseling Counseling & Education Cost per infection averted Treatment, PrEP, Microbicides Clinical interventions Addressing housing, Poverty Addressing Stigma Circumcision, Vaccines, Healthcare, Human rights, Gender equality Long-lasting prevention interventions Changing the context Socioeconomic factors Structural interventions 3 Microbicides for women Abdool Karim Q, Science 2010 Oral pre-exposure prophylaxis Grant R, NEJM 2010 (MSM) Baeten J, NEJM 2012 (couples) Thigpen, NEJM, 2012 (Heterosexuals) Male circumcision Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007 HIV PREVENTION combined interventions Treatment of STIs Grosskurth H, Lancet 2000 Male & female condoms HIV Counselling and Testing Coates T, Lancet 2000 Post Exposure prophylaxis (PEP) Scheckter M, 2002 Treatment for prevention Cohen M, NEJM 2011 Behavioural Intervention 4 2

3 16 July 2012: FDA Approves First Drug for Reducing the Risk of Sexually Acquired HIV Infection Truvada, taken daily, is to be used for pre-exposure prophylaxis (PrEP) in combination with safer sex practices to reduce the risk of sexually-acquired HIV infection in adults at high risk. Risk Evaluation and Mitigation Strategy available It is still better to prevent HIV than to treat a life-long disease (D. Birnkrant, director of FDA division of antiretroviral products) 5 July 2010: ARV microbicide (topical PrEP) prevents HIV & HSV-2 in women - CAPRISA

4 Nov 2010: Oral TDF/FTC PrEP prevents HIV in MSM iprex trial 7 11 July 2012: Oral PrEP among heterosexuals 8 4

5 Partners PrEP 9 TDF2 Time to Event Analysis of Seroconverter Data Analysis using all 33 Seroconverters Failure years TRT FTC/TDF Placebo 10 5

6 FEM-PrEP 11 Sep- Nov 2011: MTN Stops the VOICE trial Tenofovir Arms (gel and oral tablet) VOICE - Vaginal and Oral Interventions to Control the Epidemic TOTAL SAMPLE (5000) Truvada (1000) ORAL (3000) Tenofovir tablet (1000) DSMB recommends halting tenofovir tablet (VIREAD) arm due to futility Placebo tablet (1000) TOPICAL (2000) Tenofovir Gel Placebo Gel (1000) (1000) DSMB recommends halting tenofovir gel arm due to futility 12 6

7 Resistance in PrEP trials Study iprex TDF2 Partners PrEP FEM-PrEP Result Two FTC resistant infections (M184V and M184I) among two participants infected at enrollment (and 1/8 in placebo group acute infections) One TFV and FTC resistant infection (K65R and M184V) in a participant with acute infection at enrollment One TFV resistant infection (K65R ) in a participant in TDF group and one FTC resistant infection (M184V) in a participant in TDF/FTC group both participants had acute infection at enrollment Four resistant infections in TDF/FTC arm (3 M184V and 1 M184I) and one in placebo group (M184V) 13 Safety in PrEP trials 14 7

8 iprex: Adverse Events 15 iprex: Percent changes from baseline in BMD 16 8

9 Partners PrEP (1) No statistically significant difference in deaths, SAEs, key laboratory AEs Number of participants with each safety event Death 24 (<1%) SAE 320 (7%) Confirmed creatinine AE 49 (1%) Confirmed phosphorus AE 403 (9%) Total TDF FTC/TDF Placebo Partners PrEP (2) Monthly 19-item symptom questionnaire % of participants reporting symptom Nausea TDF FTC/TDF Placebo P-value TDF vs. Placebo P-value FTC/TDF vs. Placebo All visits 1.6% 1.7% 1.5% p=0.23 p=0.18 Month 1 Diarrhea 6.3% 5.9% 4.5% p=0.03 p=0.07 All visits 1.6% 1.8% 1.4% p=0.18 p=0.02 Month 1 4.1% 4.5% 2.8% p=0.06 p=

10 TDF2 TDF/FTC (N=601) (%) Placebo (N=599) (%) Nausea 113 (18.8) 43 (7.2) < Diarrhea 76 (12.6) 65 (10.9) 0.24 Fracture 5 (0.8) 4 (0.7) 0.69 Any SAE 55 (9.2) 51 (8.5) 0.58 Death 2 (0.3) 4 (0.7) 0.46 Elevated creatinine 1 (0.2) 0 - p Hypophosphatemia (grade 3-4) 21 (3.5) 24 (4.0) PrEP and Risk of Disinhibition 20 10

11 iprex: Sexual Practices 21 ADHERENCE 22 11

12 Effectiveness and adherence in oral PrEP trials Study Population N % HIV protection Partners PrEP TDF2 Serodiscordant heterosexual couples Young men and women (TDF/FTC arm) % of plasma samples with TFV detection iprex MSM FEM-PrEP Young women Adherence in FEM-PrEP Study Design 2120 HIV-negative women, years, randomized to daily oral TDF/FTC (Truvada ) or matching placebo in Tanzania, Kenya, and South Africa One year of follow-up, with visits every 4 weeks, 52 weeks on product Highly effective contraception required at enrollment. Continued use of effective method strongly encouraged (but not required) at follow-up Adherence Data at Every Visit Pill counts Structured interviews (unless product not previously dispensed) Plasma and cells for possible drug level testing 24 12

13 Primary Effectiveness Analysis TDF/FTC (N=1024) Placebo (N=1032) HIV Infections Incidence rate 4.7 per 100 P-Y 5.0 per 100 P-Y Estimated effectiveness: 6% reduction in risk Hazard Ratio = 0.94 (0.59, 1.52); p-value = Adherence: Self-Report and Pill Counts TDF/FTC Placebo Usually/always took study pill 95% 95% Easy/very easy to take pills 97% 96% Days covered by pills (based on pill counts) 86% 89% 26 13

14 % of women 10/9/2012 Infected Cases and Matched Controls with 10 ng/ml Tenofovir in Plasma at Visits Defining Infection Windows 100 Cases Controls % % 38.0% %?? Time of infection 21.2% 14.8% 25.7% 0 Window Start P=0.63 Window End P=0.12 Both Visits P= Exploring the low adherence in FEM-PrEP Contraceptive use Risk perception 28 14

15 Contraceptive Method Used at Enrollment New initiators (N=1077) Existing users (N=1043) Oral pills 43.1% 16.7% Injectables 55.0% 77.6% IUD/Implant/FS 2.0% 5.8% 29 Demographics New initiators (N=1077) Existing users (N=1043) Age in years: mean Education in years: mean Married 21.9% 40.2% Previously pregnant 59.2% 85.8% STI at baseline 16.6% 16.7% BV at baseline 38.7% 35.3% Vaginal sex acts per week: mean Sex partners in past 4 weeks: mean

16 Contraceptive Method Discontinuation Enrollment method New initiators Existing users p-value Pooled 6.1% 2.3% 0.02 Oral pills 12.7% 8.0% Injectables 1.2% 1.1% 31 Maximum Days with Truvada/Placebo use (Pill Counts) Enrollment method New initiators Existing users p-value Pooled 85.7% 90.0% 0.04 Oral pills 81.1% 85.0% Injectables 89.0% 91.2% 32 16

17 Pregnancy Rates per 100 woman-years (95% CI) Enrollment method New initiators Existing users p-value Pooled 13.8 (11.1, 16.9) 5.0 (3.4, 7.0) 0.09 Oral pills 32.1 (25.5, 39.7) 20.8 (12.8, 31.7) Injectables 2.1 (0.9, 4.1) 2.4 (1.3, 4.1) 33 Conclusions New initiators of effective contraception in FEM-PrEP: More likely to choose oral contraceptive pills than existing method users Generally younger, less likely to be married and less likely to have previously been pregnant More likely to switch contraceptive methods or stop using contraception all-together Exhibited modestly lower adherence to Truvada/placebo by pill count Had higher loss to follow-up, missed visit and pregnancy rates, but effects modified by age, marital status and parity status 34 17

18 HIV Risk Perception: Methods Quantitative data Face-to-face interview at enrollment and quarterly follow-up visits, asked to all participants Question: What do you think are your chances of becoming infected with HIV in the next 4 weeks? Options: no, small, moderate or high chance Qualitative data Repeated in-depth interviews (IDIs) with participants who seroconverted, conducted at week 1, 4, and 8 after HIV diagnosis in Bondo (n=24) and Pretoria (n=32) 35 Results (1): Risk Perceptions are Generally Low but Vary Among Sites Site Risk Perception Baseline N=530 Week 12 N=324 Week 24 N=210 Week 36 N=61 Bloem No 66% 64% 70% 75% -- Small 25% 26% 22% 23% -- Moderate 5% 8% 6% 0 -- High 4% 2% 2% 2% -- Week 52 N=0 Site Risk Perception Baseline N=748 Week 12 N=652 Week 24 N=559 Week 36 N=395 Week 52 N=176 Pretoria No 61% 67% 71% 74% 73% Small 21% 17% 15% 12% 15% Moderate 16% 13% 10% 11% 9% High 3% 3% 4% 3% 3% 36 18

19 Results (1b): Risk Perceptions are Generally Low but Vary Among Sites Site Risk Perception Baseline N=720 Week 12 N=657 Week 24 N=605 Week 36 N=459 Week 52 N=319 Bondo No 20% 27% 21% 16% 19% Small 24% 24% 29% 32% 34% Moderate 36% 34% 37% 36% 36% High 20% 16% 13% 16% 12% 37 Results (2): Behavioral and Perception Factors Associated with HIV Risk Perceptions at Baseline Variable OR (95% CI) P Having more than 1 sexual partner 2.4 (2.0, 3.0) <.0001 Having sex without a condom 1.8 (1.5, 2.2) <.0001 Does not know or does not want to answer about partners HIV status 2.0 (1.7, 2.5) <

20 Results (3): Risk Perceptions are Associated with HIV Infection Risk Perception Participant who seroconverted (n=68) No 47% Small 16% Moderate 16% High 21% Adjusted hazard ratio for HIV infection -- high versus no chance Hazard (95% CI) 3.12 (1.58, 6.17).0011 P 39 Could biology also play a role? 40 20

21 Effectiveness in rectal sex % HIV risk reduction (95 % CI) 2 doses/week 76% (56 to 96%) 4 doses/week 96% (90 to 99%) 7 doses/week 99% (96 to 99%) P. Anderson, ScTranslMed Sep TNF Concentration (ng/ml or ng/g) Tenofovir Rectal Tissue Vaginal Tissue Blood Plasma Time Post Single Truvada Dose (days) Patterson et al WAC

22 Other potential biological reasons Cytokines High viral load in infecting partner 43 Where are we now? Ongoing trials for daily oral PrEP Partners PrEP VOICE CDC among IDU in Bangkok Existing Guidelines CDC: guidelines for MSM and heterosexuals South Africa: guidelines for MSM FDA approval for label change Ongoing/planned demonstration projects Ongoing/planned trials for intermittent use 44 22

23 Variables to consider for program implementation Acceptability Will people agree to be tested? Is there stigma related to PrEP? Compliance Will people take their drugs? Impact Does it reduce transmission? Will there be risk compensation? Can we manage drug resistance? Cost-effectiveness Generic version only available in developing countries Will health insurance plans cover this expense? 45 Specific questions to be addressed for oral PrEP Which population? How to obtain and sustain a high adherence? Which level of adherence gives protection? How to test at baseline for HIV infection? How often to repeat HIV testing? Where to go for follow-up? OTC or prescription? How often to test for potential side effects e.g., renal function, bone density? Will there be behavior changes off setting the benefit? 46 23

24 Demonstration & Implementation Projects for Oral PrEP WHO Framework for country level protocol development Implementation stakeholder project with GWU funded by BMGF iprex Olé ongoing Demonstration project among MSM in San Francisco & Miami Partners PrEP: serodiscordant couples in Kenya and Uganda in whom PrEP will be used to bridge the time until the infected partner goes on treatment and is suppressed Plans for CHOICE 47 Intermittent PrEP (1) HPTN 066: PK study Randomized to one tablet TDF/FTC (1) once weekly (2) twice weekly (3) double dose twice weekly (4) daily 5 weeks - DOT Men and women in US (N=32 ) Fully enrolled 48 24

25 Intermittent PrEP (2) HPTN 067: Behavioral study to evaluate intermittent dosing MSM (N=180) in Bangkok, high-risk women (N=180) in Cape Town, enrolling. Six weeks lead-in period with DOT, followed by one week without dosing to determine individual steady-state PK. Then 24 weeks of self-administration and randomized to (1) daily dosing (2) time driven dosing (3) event driven dosing 49 Intermittent PrEP (3) ANRS IPERGAY study: Phase III trial among MSM in France and Canada and TBD Peri-coital use of Truvada (TDF/FTC) vs placebo Enrolling, N=300 in first phase, if enrollment OK: increase to 1900 MRC PROUD: Determine the feasibility of a big clinical trial to assess if inclusion of PrEP in HIV prevention package is clinically effective and cost-effective MSM (N=500) attending GUD clinics in UK One-year delay vs. immediate peri-coital PrEP use Enrollment planned to start in Nov

26 NEXT PrEP HPTN 069: Safety and tolerability phase II study Each participant takes three pills a day for 48 weeks: placebo pill(s) plus: Maraviroc (300 mg MVC) MVC-FTC MVC-TDF TDF-FTC 400 U.S. MSM Long acting products: TMC 278: injectable in early stage of clinical testing 51 HIV prevention: we have the tools, we need the will and the investment Knowledge of HIV status Behavioral interventions Condoms Clean injection equipment for IDUs Blood supply screening Prevention of unwanted pregnancy Treatment of STIs PMTCT Male circumcision Structural interventions Medication assisted therapy for drug users ARVs: PrEP and ART 52 26