CROI 2019 Abstract eBook

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Oral Abstracts

Results: Macaques administered 10-1074 and challenged via the penis were protected against a median of 15.5 weekly challenges, as compared to controls (median=2.5; P=0.0007, Log-rank test) and exhibited a median 10-1074 plasma level of 0.50μg /ml (range=0.10-0.70μg/ml) at SHIV breakthrough. Macaques administered both bNAbs and challenged IV were protected against a median of 5 weekly challenges, as compared to controls (median=1; P=0.0143, Log-rank test) and exhibited a median 10-1074 plasma level of 1.1µg/ml (range=0.6- 1.6µg/ml), but undetectable 3BNC117, at SHIV breakthrough. Conclusion: A single subcutaneous administration of 10-1074 durably protected macaques against repeated penile SHIV challenges providing the first evidence of efficacy by a bNAb against penile infection. Significant protection also was observed against repeated IV SHIV challenges following administration of 10-074+3BNC117, which was mainly due to 10-1074 that exhibited longer persistence. Our data support the continued development of 10-1074 as a long- acting PrEP candidate for men or persons who inject drugs who may not be able to adhere to daily PrEP. 101 PROTECTION AGAINST VAGINAL SHIV INFECTION WITH AN INSERT CONTAINING TAF AND EVG Charles Dobard 1 , M. Melissa Peet 2 , Kenji Nishiura 1 , Onkar N. Singh 2 , Timothy J. McCormick 2 , James Mitchell 1 , Gerardo Garcia-Lerma 1 , Vivek Agrahari 2 , Pardeep Gupta 3 , Sriramakamal Jonnalagadda 2 , Jill Schwartz 2 , Walid Heneine 1 , Gustavo Doncel 4 , Meredith Clark 2 1 CDC, Atlanta, GA, USA, 2 CONRAD, Arlington, VA, USA, 3 University of Sciences, Philadelphia, PA, USA, 4 Eastern Virginia Medical School, Norfolk, VA, USA Background: On-demand topical PrEP for HIV prevention has several advantages over a daily oral PrEP regimen, including reduced costs, limited drug toxicity, decreased risk of resistance, and potential to increase adherence. Inserts containing tenofovir alafenamide fumarate (TAF) in combination with elvitegravir (EVG) are being developed by CONRAD/EVMS for flexible, on-demand vaginal or rectal pericoital use. We recently found in a dose-ranging pharmacokinetic assessment in macaques that vaginal administration of inserts containing 20 and 16 mgs of TAF and EVG, respectively, resulted in rapid accumulation of EVG and durable levels of tenofovir diphosphate (TFV-DP) in mucosal tissues at concentrations associated with in vivo protection. Here we used a macaque model of vaginal SHIV transmission to investigate the protective efficacy of TAF/EVG inserts. Methods: Normal cycling pigtail macaques (n=14) were exposed vaginally to SHIV162P3 once a week for up to 13 weeks. Six macaques received inserts containing a fixed-dose combination of TAF/EVG (20 mg/16 mg) and 8 received matching placebo inserts. Inserts were placed in the posterior vagina near the cervix 4 hours before each SHIV exposure. Infection was monitored weekly by serology and RT-PCR amplification of SHIV RNA in plasma. A Kaplan-Meier survival analysis was used to compare the survival distribution between the two groups and efficacy was calculated as 1-(p1 / p0), where p1 and p0 denote the proportion of infections per total challenges for TAF/EVG and placebo controls, respectively. Results: Of the 8 macaques that received placebo inserts, 7 became SHIV infected while 1 remained SHIV negative following 13 weekly challenges. The median number of challenges to infect macaques treated with placebo inserts was 3 (range 2-13). In contrast, 5 of 6 macaques that received TAF/EVG inserts remained protected after 13 challenges resulting in an estimated efficacy of 92%. Survival analysis demonstrate at least a 9-fold reduction in risk of infection in macaques that received TAF/EVG compared to placebo inserts (p=0.007; log-rank). Conclusion: Vaginal administration of inserts containing TAF and EVG was highly effective in preventing SHIV infection in a macaque model that mimics vaginal transmission of HIV in women. The data support the clinical development and first-in-human testing of TAF/EVG inserts for on-demand topical prophylaxis against vaginally acquired HIV infection. 102 MODERATE EFFICACY OF ORAL SINGLE-AGENT TAF AGAINST VAGINAL SHIV INFECTION IN MACAQUES Ivana Massud 1 , Mian-er Cong 1 , Susan Ruone 1 , Angela Holder 1 , Kenji Nishiura 1 , George Khalil 1 , Yi Pan 1 , Jonathan T. Lipscomb 1 , James F. Rooney 2 , Darius Babusis 2 , Yeojin Park 2 , Scott McCallister 2 , Christian Callebaut 2 , Walid Heneine 1 , Gerardo Garcia-Lerma 1

1 CDC, Atlanta, GA, USA, 2 Gilead Sciences, Inc, Foster City, CA, USA Background: Tenofovir alafenamide (TAF) is a prodrug of TFV that is under evaluation as oral PrEP in combination with emtricitabine (FTC), and as a long- acting single agent delivered from implants. We recently showed that oral TAF in combination with FTC was highly effective in preventing vaginal simian HIV (SHIV) infection in female pigtailed macaques. Here we investigated if TAF alone is sufficient for preventing vaginal SHIV infection. Methods: The efficacy of single agent TAF in preventing vaginal infection was investigated in an established model of vaginal SHIV exposures consisting of up to 15 once-weekly virus challenges with SHIV162p3. Nine pigtail macaques received a clinically equivalent dose of TAF (1.5 mg/kg) orally 24h before and 2h after each weekly virus exposure. Infection outcome was compared with 21 placebo animals (6 real-time and 15 historical controls). TFV-diphosphate (TFV-DP) and dATP levels in PBMCs were measured once a week at the time of virus challenge. Kaplan-Meier survival analysis and a log-rank test was used to compare time to infection in TAF-treated animals relative to controls. Infection rates were compared using the fisher exact test. TFV-DP levels were measured in vaginal and rectal biopsies from a separate group of 9 macaques. Results: Infection rates and time to SHIV RNA detection were similar in real time and historical controls (p=0.500 and p=0.319, respectively). Two of the 9 TAF-treated animals did not metabolize TAF (TFV-DP level of 15 and 16 fmols/106 cells) and were excluded from the analysis. Three of the remaining 7 TAF-treated and 19/21 control animals became infected (p=0.021). Infection in TAF-treated animals was also delayed relative to controls (p=0.036). TFV-DP levels in the 3 animals infected during TAF PrEP (median=351 fmols/106 cells; range=143-1,568) were similar to those seen in the 4 uninfected macaques (median=331; range = 236-584; p=0.359). dATP/TFV-DP ratios were also similar among infected and protected animals (median=0.685 and 1.045, respectively, p=0.982). After a single oral dose, TFV-DP was detected in 5/9 vaginal and 9/9 rectal biopsy specimens (5 and 7.9 fmols/mg, respectively). Conclusion: A clinically equivalent dose of single agent TAF administered orally 24h before and 2h after virus exposure without FTC conferred moderate protection against vaginal SHIV infection in female macaques. These data highlight the importance of defining the PBMC TFV-DP concentrations associated with complete vaginal protection from single agent TAF. 103 LYMPHOID TISSUE PHARMACOKINETICS OF TENOFOVIR-ALAFENAMIDE VS -DISOPROXIL FUMARATE Courtney V. Fletcher 1 , Ann Thorkelson 2 , Kayla Campbell 1 , Lee Winchester 1 , Timothy Mykris 1 , Jon Weinhold 1 , Jodi Anderson 2 , Jacob Zulk 2 , Puleng Moshele 2 , Siri Jorstad 2 , Anthony Podany 1 , Jason V. Baker 2 , Timothy Schacker 2 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 University of Minnesota, Minneapolis, MN, USA Background: The secondary lymphoid tissues (LT), lymph nodes (LN) and gut-associated lymphoid tissue (GALT), are the primary sites of HIV replication and where the latent pool of virus is maintained. In HIV-infected persons with undetectable plasma HIV-RNA, an association has been reported between low concentrations of antiretroviral drugs (ARVs) in LT and measures of persistent viral production. In animals, tenofovir alafenamide (TAF) has been found to have enhanced LT penetration compared with tenofovir disoproxil fumarate (TDF). No confirmatory or comparative human LT data, however, are available. The objective of this work was to compare the LT pharmacokinetics (PK) of TAF and TDF in HIV-infected persons. Methods: Participants were HIV-infected persons enrolled in clinical studies of LT compartments and receiving TAF or TDF with other ARVs. PBMCs and mononuclear cells (MNCs) from LN, ileum and rectal tissues were obtained at steady-state. Intracellular concentrations of tenofovir-diphosphate (TFV-DP) were quantified by LC-MS/MS. Summary statistics were calculated. Results: PK data were obtained from a total of 58 persons: TAF, n=13; TDF, n=45. The Table presents median and interquartile range values for TFV-DP in PBMCs (TAF, n=38; TDF, n=45), LN (TAF, n=9; TDF, n=43), ileum (TAF, n=9; TDF, n=22) and rectum (TAF, n=7; TDF, n=35). In PBMCs, median TFV-DP concentrations were 7-fold higher with TAF compared with TDF. In LN MNCs, TFV-DP concentrations were 4.7-fold higher with TAF vs. TDF. Conclusion: TAF administration in HIV-infected persons produced higher TFV-DP concentrations in LN MNCs than did TDF. This finding confirms animal studies showing LN concentrations of TFV-DP were 5.7 to 15-fold higher with TAF, depending on the anatomical site of the LN. The 7-fold higher TFV-DP concentrations in PBMCs achieved with TAF vs. TDF, is consistent with other

Oral Abstracts


CROI 2019

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