CROI 2016 Abstract eBook

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Oral Abstracts

107 Chemoprophylaxis With Oral FTC/TAF Protects Macaques From Rectal SHIV Infection Ivana Massud 1 ; James Mitchell 1 ; Darius Babusis 2 ; Frank Deyounks 1 ; Adrian Ray 2 ; James Rooney 2 ;Walid Heneine 1 ; Michael Miller 2 ; Gerardo Garcia-Lerma 1 1 CDC, Atlanta, GA, USA; 2 Gilead Scis, Inc, Foster City, CA, USA Background: Tenofovir alafenamide (TAF) is a novel oral prodrug of tenofovir (TFV) that at low doses achieves ~90% lower plasma TFV exposure and increased intracellular TFV- diphosphate (TFV-DP) levels compared with 300 mg of tenofovir disoproxil fumarate (TDF). An investigational fixed dose combination of emtricitabine (FTC) and TAF (200/25 mg) (FTC/TAF) is currently under regulatory review for HIV treatment. If FTC/TAF will be as effective as FTC/TDF for HIV pre-exposure prophylaxis (PrEP) is not known. We investigated in macaques the efficacy of FTC/TAF in preventing rectal SHIV infection to determine the potential use for PrEP. Methods: The prophylactic efficacy of FTC/TAF was investigated using a repeat low virus dose macaque model that predicted efficacy of oral FTC/TDF in humans. Rhesus macaques (n = 12) were exposed rectally once a week to low (10 TCID 50 ) doses of SHIV 162p3 for up to 19 weeks. Animals were exposed to a first stock of SHIV 162p3 for up to 5 weeks and to a second stock of the same virus isolate for up to 14 additional weeks. Six animals received FTC/TAF (20/1.5 mg/kg) orally 24h before each virus exposure and 2h thereafter and 6 received saline as a placebo. Infection was monitored by serology and RT-PCR. Intracellular TFV-DP and FTC-triphosphate (FTC-TP) concentrations in PBMCs were measured in FTC/ TAF-treated animals at first dose and 7 and 14 weeks later to evaluate drug accumulation. Results: All 6 macaques that received FTC/TAF remained seronegative and viral RNA negative during the 19 virus challenges and a follow up period of 10 weeks. In contrast, all 6 placebo controls were SHIV RNA positive after a median of 8 (range = 1-15) exposures. The median (IQR) intracellular TFV-DP and FTC-TP concentrations in PBMCs at first dose were 554 (310, 870) fmols/10 6 cells and 1065 (912, 2459) fmols/10 6 cells, respectively. Levels accumulated approximately to 2-fold after 7 to 14 weeks of dosing (median 1365 (976, 1689) and 1626 (1311, 3252) fmols/10 6 cells of TFV-DP and FTC-TP, respectively). Conclusions: We show that FTC/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with FTC/TDF but with a substantially reduced dose. As expected, low TAF doses result in high intracellular TFV-DP concentrations in PBMCs with levels that exceed those previously seen with oral TDF. Our results in macaques suggest that FTC/TAF may be a feasible alternative to FTC/TDF for PrEP against rectal HIV infection. 108LB MTN-017: Rectal Phase 2 Extended Safety and Acceptability Study of 1% Tenofovir Gel Ross Cranston 1 ; Javier Lama 2 ; Barbra A. Richardson 3 ; Alex Carballo-Diéguez 4 ; Ratiya Kunjara Na Ayudhya 5 ; Cindy Jacobson 5 ; Mark A. Marzinke 6 ; Sherri Johnson 7 ; Jeanna Piper 8 ; Ian McGowan 1 1 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA; 2 Impacta Peru, Barranco, Lima, Peru; 3 Univ of Washington, Seattle, WA, USA; 4 New York State Psychiatric Inst., New York, NY, USA; 5 Magee-Womens Rsr Inst, Pittsburgh, PA, USA; 6 Johns Hopkins Univ, Baltimore, MD, USA; 7 FHI 360, Washington DC, DC, USA; 8 NIAID, NIH, Bethesda, MD, USA Background: Men who have sex with men (MSM), and transgender women (TGW) are disproportionately affected by HIV. Safe and acceptable HIV prevention methods that target the site of initial rectal mucosal infection are needed. Methods: MTN-017 was a Phase 2, three-period, randomized sequence, open-label, expanded safety and acceptability crossover study comparing rectally applied reduced- glycerin (RG) 1% tenofovir (TFV) and oral emtricitabine/TFV disoproxil fumarate (FTC/TDF). We enrolled healthy HIV-1 uninfected MSM and TGW>18 years at 8 sites. In each 8 week study period participants were randomized to RG-TFV rectal gel daily; or RG-TFV rectal gel before and after receptive anal intercourse (RAI) (or at least twice weekly in the event of no RAI); or took daily oral FTC/TDF. Participants were seen every 4 weeks. High product adherence was defined as >80% of expected doses taken, assessed by convergence scoring of daily texts and study product returns. Additionally, qualitative plasma TFV testing was done with results provided to participants at their next clinic visit. Generalized estimating equation models with exchangeable correlation structures and robust errors were used to compare safety, acceptability, and adherence between the three regimens. Results: Participants (n=187) were recruited from the United States (4 sites, 42%), Thailand (2 sites, 29%), Peru (1 site, 19%), and South Africa (1 site, 10%) with mean age of 31.1 years (range 18-64). Twelve percent were TGW/women by self-report and 80% had a college education. There were no differences in Grade 2 or higher adverse event rates in participants using daily gel (Incidence Rate Ratio (IRR): 1.03, p=0.88) or RAI gel (IRR: 0.88, p=0.43) compared to FTC/TDF. High adherence was less likely during the daily gel regimen (Odds Ratio (OR): 0.35, p<0.001) and participants reported they would be less likely to use the daily gel regimen for HIV protection compared to FTC/TDF (OR: 0.38, p<0.001). Adherence to gel use at least twice weekly (RAI regimen) was similar to FTC/TDF (p=0.7) with no difference in intention to use product for HIV prevention (p=0.2). Conclusions: Rectal application of RG TFV gel was safe in MSM and TGW. Similar adherence and intention to use product for HIV prevention was seen with gel applied at least twice weekly and FTC/TDF. Future topical rectal product development should focus on convenient dosing regimens. 109LB A Phase III Trial of the Dapivirine Vaginal Ring for HIV-1 Prevention inWomen Jared M. Baeten 1 ;Thesla Palanee-Phillips 2 ; Elizabeth R. Brown 3 ; Katie Schwartz 4 ; Lydia E. Soto-Torres 5 ; Annalene Nel 6 ; Zeda Rosenberg 7 ; Ian McGowan 8 ; Sharon L. Hillier 9 ; for the MTN-020/ASPIRE StudyTeam 1 Univ of Washington, Seattle, WA, USA; 2 Wits Reproductive Hlth and HIV Inst, Johannesburg, South Africa; 3 Statistical Cntr for HIV/AIDS Rsr & Prevention, Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 4 FHI 360, Durham, NC, USA; 5 NIAID, NIH, Bethesda, MD, USA; 6 Intl Partnership for Microbicides, Paarl, South Africa; 7 International Partnership for Microbicides, Silver Spring, MD, USA; 8 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA; 9 Magee-Womens Hosp of the Univ of Pittsburgh Med Cntr, Pittsburgh, PA, USA Background: Antiretroviral medications used as prophlaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1). However, in clinical trials among African women, HIV-1 incidence was not reduced because of low adherence to daily- or coitally-prescribed antiretroviral-containing pills and vaginal gels. Sustained drug-delivery products, including antiretroviral-containing vaginal rings, may improve adherence and provide protection against HIV-1 with lower systemic antiretroviral exposure. Methods: We conducted a randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, among women aged 18-45 years in Malawi, South Africa, Uganda, and Zimbabwe. Dapivirine concentrations in plasma were measured in quarterly-collected samples; levels >95 pg/mL, a concentration nearly always achieved with >8 hours of use, were used to define adherence. Thus, plasma dapivirine could exclude those who were non-adherent but could potentially overestimate adherence if a ring was inserted only several hours before a visit. Results: A total of 2629 women enrolled. Their median age was 26 years, median follow-up was 1.6 years, and women attended 91% of expected monthly visits. Among women assigned to the active dapivirine vaginal ring arm, approximately 80% had dapivirine detected in plasma. A total of 168 post-randomization HIV-1 infections occurred: 71 among those assigned the dapivirine vaginal ring (incidence 3.3 per 100 person-years) and 97 among those assigned the placebo ring (incidence 4.5 per 100 person-years). Compared to those assigned placebo, women assigned the dapivirine ring had a 27% (95% CI 1 to 46, p=0.046) relative reduction in HIV-1 incidence overall, a 37% (95% CI 12 to 56, p=0.007) reduction in an analysis excluding data from two sites with lower retention and adherence, and a 56% (95% CI 31 to 71, p=0.0003) reduction in an as-randomized analysis among women older than 21 years of age. Adherence was lower in women aged 18-21 compared to women older than 21. The rate of adverse medical events was similar between study arms. Conclusions: A monthly dapivirine vaginal ring was safe and effective for HIV-1 prevention in African women. This multi-country study is the first to demonstrate HIV-1 protection for a sustained-release approach for delivery of an antiretroviral for HIV-1 prevention. HIV-1 protection was greater in as-randomized subgroups with evidence of better adherence to ring use.

Oral Abstracts

42

CROI 2016