Update on ARV based PrEP

Transcription

1 Update on ARV based PrEP Z Mike Chirenje MD FRCOG University of Zimbabwe, College of Health Sciences, Dept. of Obstetrics and Gynaecology Avondale, Harare, Zimbabwe chirenje@uz-ucsf.co.zw

2 Controlling HIV Epidemic Despite widespread promotion of behavioral modification that include abstinence, correct and persistent use of M or F condom the spread of new HIV infections continues mostly in high risk populations. High risk populations: discordant couples, MSM, sex workers, cross-border traders, truck drivers, refugees

3 What Do We Have to Address the Epidemic? Education and behavior modification Condoms, and other barrier methods Treatment/prevention of drug/alcohol abuse Clean syringes, i.e. needle exchange programs Interruption of mother-to-child transmission Circumcision for female-to-male transmission HIV/STI Testing Antiretroviral treatment as prevention Post-exposure prophylaxis (PEP) Pre-exposure prophylaxis (PrEP)* Topical microbicides ⱡ Intra vaginal rings ⱡ Vaccination ⱡ Vaccine - *Daily Truvada ; alternate regimens still in research ⱡ Still in research With thanks to Carl Dieffenbach & Jeff Schouten 3

4 About half of all new HIV infections in 2014 occurred in 8 ESA countries Country South Africa Uganda Mozambique Zimbabwe UR Tanzania Kenya Zambia Malawi Number of new HIV infections in % new infections occurred in women Over all Decline of 32% between

5 Founder virus enters through epithelium disruption Hassey,Nature 2010

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7 What increases the risk of HIV infection? Mechanism Increased amount of HIV Breakdown of natural barrier Larger pool of susceptible cells Examples Increased viral production Type of body fluid Trauma Inflammation Immune, genetic factors (?) Hormonal contraception Inflammation Genetic factors

8 Mediators of risk for sexual transmission Factor Infectiousness Susceptibility (HIV + partner) (HIV partner) Viral load Sexually transmitted diseases (e.g. HSV-2) Bleeding, trauma Circumcision (?) in hetero men (? MSM) Genetic factors (e.g., CCR5 Δ32) Immune responses Hormonal Contraception (?) Antiretrovirals (Treatment) (PrEP)

9 What is Pre-Exposure Prophylaxis(PrEP) Is a method (biomedical intervention) to protect an individual from acquiring HIV infection by taking medication before exposure of the virus Medication must be correct dose, taken correct time, protect correct place (F genital tract, rectal mucosa for MSM) all of which are affected by adherence Exposure to HIV infection is driven by behavior, is also not constant

10 What is the Ideal drug for PrEP? Drug must be safe, potent, easy to use and acceptable High barrier to resistance Ideally, no effect on future ART options Adequate concentrations and activity at all vulnerable sites of infection Vagina, cervix, rectum, bloodstream Available & affordable

11 Topical microbicides were first candidates tested for PrEP from 2 decades ago C31G, N9 BufferGel PRO2000, CS, Carraguard Tenofovir, TMC 120, UC781, MIV150

12 Hx of microbicides (topical PrEP) development 1 st generation: Surfactants 2 nd generation: Polymers 3 rd generation: ARVs 4 th generation: Co-receptor Blockers eg. N9, SAVVY eg. PRO2000, Carraguard, Cellulose Sulfate (CS) eg. Tenofovir gel, UC-781, TMC-120 eg. CD4 blocker, CCR5 Blockers MTN trial Zena Stein publishes seminal article HIV prevention: the need for methods women can use N-9 sponge trial COL-1492 trial N-9 film trial SAVVY trial Carraguard trial CS trial MDP trial HPTN trial CAPRISA trial IPM trial

13 In past 6 yrs we have seen pivotal, proof of concept PrEP trials Oral pre-exposure prophylaxis (PrEP) Involves taking an ARV tablet by mouth Truvada (combination of tenofovir and emtricitabine) tested in 6 studies Vaginal topical products 1% tenofovir gel tested in CAPRISA 004, VOICE, FACTS Vaginal ring containing dapavirine tested in ASPIRE and ongoing RING Study

14 2010 was a very good year! Two studies provided proof of concept for ARV-based prevention CAPRISA 004 1% tenofovir gel resulted in 39% (CI 6-60) reduction HIV infection among high-risk women Women inserted gel up to 12 hrs BEFORE sex and another insertion WITHIN 12 hrs after sex, less than Two doses in 24 hrs

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20 Biomedical Interventions Behavior and Adherence

21 Study, population HPTN 052 Couples ( & ) Multicountry (n=1753) CAPRISA 004 Women South Africa (n=889) iprex MSM & TGW Multicountry (n=2499) Partners PrEP Couples ( & ) Kenya, Uganda (n=4747) TDF2 Heterosexuals ( & ) Botswana (n=1219) BTS IDUs ( & ) Thailand (n=2413) PROUD MSM Britain (n=545) IPERGAY MSM France & Canada (n=400) Strategy ART at CD4 >350 vs. <250 PrEP TFV gel PrEP FTC/TDF PrEP FTC/TDF, TDF PrEP FTC/TDF PrEP TDF PrEP FTC/TDF PrEP (BA) FTC/TDF Efficacy (95% CI) publication 96% (73-99%) Cohen et al. N Engl J Med % (6-60%) Abdool Karim et al. Science % (15-63%) Grant et al. N Engl J Med %, 67% (55-87%), (44-81%) Baeten et al. N Engl J Med % (16-83%) Thigpen et al. N Engl J Med % (10-72%) Choopanya et al. Lancet % (90% CI: 62-96%) McCormack et al CROI 2015 #22LB 86% (39-99%) Molina et al CROI 2015 #23LB

22 Study Population N Results iprex MSM % efficacy FTC/TDF Partners PrEP Study TDF2 Study Heterosexual couples Men and women % efficacy TDF 75% efficacy FTC/TDF % efficacy FTC/TDF FEM-PrEP Women % efficacy FTC/TDF VOICE Women 3021 (oral arms) No efficacy TDF No efficacy FTC/TDF FACTS 001 Women 2029 No efficacy PROUD MSM % efficacy FTC/TDF

23 The importance of being adherent Efficacy in randomized comparison % of blood samples with tenofovir detected Partners PrEP 75% 81% TDF2 62% 79% iprex 44% 51% FEM-PrEP 6% 26% VOICE - 29% FACTS % reported >80% use of gel Baeten et al N Engl J Med 2012; Grant et al N Engl J Med 2010; Van Damme et al N Engl J Med 2012; Thigpen et al N Engl J Med 2012; Marrazzo et al CROI 2013 #26LB; Rees et al CROI 2015 #26LB

24 The PrEP Landscape Oral PrEP works if used Data in heterosexual women are inconsistent: some studies showed benefit (CAPRISA 004, TDF2, Partners) other studies were negative (VOICE, FEM-PrEP, FACTS) Possible reasons for this: Varying adherence, Varying levels of genital inflammation Suboptimal vaginal tenofovir levels Increasing availability: US South Africa MSM, Female sex workers Canada Kenya France Israel

25 On the Horizon (ASPIRE and RING Study Results are encouraging Phase III safety and effectiveness trial of a vaginal ring containing the ARV dapivirine, replaced every 4 weeks. Both studies observed among 2629 women high level of protection (56% in ASPIRE) women > 21yrs Lower adherence and no protection women yrs

26 Rectal Microbicide Research Agenda Nonoxynol-9 tested (HIVNET-008) as Phase 1 Phase 1/2 studies Tenofovir 1% gel completed Maraviroc (CHARM-03) Phase 1 Phase 2 study (Proof of Concept) MTN 017 Dapivirine gel being evaluated prior Phase 3 initiation A rectal microbicide has potential use HIV prevention for women who engage in anal sex

27 The HVTN 703/HPTN 081 AMP Study: Filling the Gap AMP = Antibody Mediated Prevention This is the idea of using an antibody made by scientists and giving it to people directly, i.e. using an intravenous (IV) infusion, to prevent HIV infections. 27

28 Who is Doing the AMP Study? The study is being conducted by two groups, the HIV Vaccine Trials Network and the HIV Prevention Trials Network. Another name for The AMP Study in SSA is HVTN 703/HPTN

29 AMP Study Design: HVTN 703/HPTN 081, version 1 REGIMEN MSM & TG in the Americas Women in sub-saharan Africa TOTAL VRC01 10 mg/kg VRC01 30 mg/kg Control Total infusions total & Infusions every 8 weeks Study duration: ~22 months 29

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32 Sexually Transmitted Infections PrEP does not prevent most common STI like chlamydia, syphilis, gonorrhea, trichomoniasis Anal cancer is common among MSM, PrEP does not protect HPV Must advocate for HPV vaccination We have a long way before HIV vaccine is available

33 Acknowledgements Study Participants NIH (Grant Number U01AI069436) UZ-UCSF All our international Collaborators.