CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

Methods: Prospective, randomized, double-blinded, multisite, safety/tolerability study of 4 regimens for HIV PrEP: (1) MVC alone; (2) MVC + emtricitabine (FTC); (3) MVC + tenofovir (TDF); (4) TDF + FTC. Study regimens consisted of 3 pills once-daily -- MVC 300 mg, FTC 200 mg, TDF 300 mg, with matching placebos. Eligible participants (pts) were adult HIV-uninfected men who reported a history of condomless anal intercourse with >1 HIV-infected or unknown-status man within 90 days, and had adequate safety laboratory parameters including calculated creatinine clearance >70 ml/min. Pts received randomized study regimens for 48 weeks with follow-up visits at weeks 2, 4, 8, and then every 8 weeks. At each study visit, interval history, physical exam, safety laboratories, blood plasma for drug levels, and HIV and adherence counseling and testing were conducted. All analyses were intent-to-treat; primary analyses used Kaplan-Meyer survival analysis and comparisons between study arms used chi-square, t-test, or log-rank testing. Results: 12 HPTN and ACTG sites enrolled 406 men with a median age of 30 (range 18-70; 30%<26), including 28% black, 62%white, and 10% other races; with 22% Latino. 340 (84%) completed study follow-up; 38 (9%) were lost to follow-up. 37 (9%) permanently discontinued the study regimen prior to 48 weeks; time to discontinuation did not differ among the study arms (p=0.6). The rates of grade 2-4 adverse events did not differ in pairwise comparisons between the study arms (p>0.5). Calculated creatinine clearance decreased 3-8 ml/min from baseline to week 48, without differences among the study arms (p=0.6). In a random subset of participants (n=122) at random study time points, 93% had detectable study drug plasma levels. 5 HIV seroconversions occurred: 2 had no detectable study drug levels at any study visit (1 on MVC alone, 1 on MVC+TDF), 3 others (all on MVC alone) had MVC levels of 0.7, 6.7, and 145 ng/ml (limit of quantification 0.5) at the documented seroconversion study visit; all had R5 virus and none had genotypic resistance. Conclusions: Given as HIV PrEP in MSM, MVC-based regimens were comparably safe and well-tolerated versus the control regimen of TDF+FTC. Of 5 seroconversions, 4 were associated with low or undetectable drug levels. MVC regimens may be alternatives for oral PrEP. 104 PrEP Impact on T-Cell Activation and Explant Infection: HPTN 069/ACTG 5305 Substudy Ian McGowan 1 ; Alexiy Nikiforov 2 ; AliciaYoung 3 ; Ross Cranston 1 ; Raphael J. Landovitz 4 ; Rahul Bakshi 5 ; Adriana Andrade 6 ; Kenneth H. Mayer 7 ;Timothy J.Wilkin 8 ; Roy Gulick 8 1 Univ of Pittsburgh Sch of Med, Pittsburgh, PA, USA; 2 Magee-Womens Hosp of the Univ of Pittsburgh Med Cntr, Pittsburgh, PA, USA; 3 SCHARP, Seattle, WA, USA; 4 David Geffen Sch of Med at Univ of California Los Angeles, Los Angeles, CA, USA; 5 Johns Hopkins Univ, Baltimore, MD, USA; 6 Johns Hopkins Univ Sch of Med, Baltimore, MD, USA; 7 The Fenway Inst, Fenway Hlth, Boston, MA, USA; 8 Weill Cornell Med Coll, New York, NY, USA Background: Studies of maraviroc (MVC) intensification in HIV-infected individuals have suggested that exposure to MVC is associated with increased gut-associated lymphoid tissue (GALT) T cell activation as well as increased HIV-coreceptor (CCR5) expression. Neither of these outcomes would be desirable for a PrEP regimen and so a tissue substudy was added to the HPTN 069/ACTG A5305 study to evaluate GALT responses to four antiretroviral (ART) regimens (MVC, MVC + emtricitabine (FTC), MVC + tenofovir (TDF), and TDF + FTC) and to determine whether ART exposure was associated with suppression of ex vivo / in vitro colorectal explant HIV infection. Methods: CCR5 genotype was characterized from blood sample derived DNA using PCR. Participants received 48 weeks of ART. Colorectal tissue was collected by flexible sigmoidoscopy at Baseline, +24 weeks, +48 weeks, and +49 weeks. Biopsies were enzymatically digested using 2-3 rounds of collagenase II and mechanical disassociation. Mucosal mononuclear cells were stained with antibodies to cell surface markers (CD45, CD3, CD4, CD8, CCR5, CXCR4, CD38, HLA-DR, and CD69) and the Ki-67 intracellular activation marker and run on a BD LSRFortessa flow cytometer. Four biopsies from each participant/per time point were challenged with 10 5 TCID 50 of HIV-1 BaL for two hours, washed, and incubated for 2 weeks with supernatant collection at Days 4, 7, 10, and 14 (± 1 day). Day 14 supernatant HIV-1 p24 was quantified using the Alliance assay. Results: Of the 55 men enrolled in the tissue substudy (MVC [n=13]; MVC + FTC [n=19]; MVC + TDF [n=13]; and TDF + FTC [n=10]), 51 participants were CCR5 wild type and four were heterozygotes (MVC + FTC [n=2]; TDF + FTC [n=2]). There were no significant differences in CD4 T cell activation phenotypes (CD38, HLA-DR, CD69, or Ki-67) between Baseline and Week 24/48 samples or in CCR5 phenotype in any study arm. While significant Day 14 explant viral suppression was seen between Baseline and Week 24 with all the PrEP study regimens, at Week 48 no significant suppression was seen in samples from those randomized to MVC alone. Conclusions: Increased GALT T cell activation or CCR5 phenotype was not seen in any of the study arms. The explant data suggest that MVC alone may be less effective than combination ART regimens. These observations need to be correlated with pharmacokinetic adherence data. It is also possible that reduced explant viral suppression with MVC may be due to previously reported limitations of testing MVC in the explant model.

Oral Abstracts

105 Cabotegravir Long-Acting Injection Protects Macaques Against Intravenous Challenge Chasity D. Andrews 1 ; Leslie St. Bernard 1 ; Amanda Poon 1 ;William Spreen 2 ; Agegnehu Gettie 1 ; Kasi Russell-Lodrigue 3 ; Zhi Hong 4 ; David D. Ho 1 ; Martin Markowitz 1 1 Aaron Diamond AIDS Rsr Cntr, New York, NY, USA; 2 ViiV Hlthcare, Research Triangle Park, NC, USA; 3 Tulane Natl Primate Rsr Cntr, Covington, LA, USA; 4 GSK, Research Triangle Park, NC, USA Background: Cabotegravir (CAB; GSK1265744 or GSK744) long-acting (LA) is an InSTI formulated as a 200 mg/mL injectable nanoparticle suspension. CAB LA is an effective pre-exposure prophylaxis (PrEP) agent against rectal and vaginal SHIV exposures in macaques. This study was performed to evaluate the effectiveness of CAB LA as PrEP against SIVmac251 on week 2. Group 1 was injected with 50 mg/ kg on week 0 and 4 to evaluate the protective efficacy of the CAB LA dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB LA for protection against IV challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. Infection status was monitored by real-time PCR amplification of viral gag sequences from plasma obtained weekly. Plasma CAB concentrations were measured by HPLC-MS/MS. Results: Plasma vRNA was detected in all five control macaques one week after challenge (see figure). Two 50 mg/kg doses of CAB LA resulted in 7 of 8 macaques remaining aviremic through week 24 (p=0.0047; Fisher’s exact test). All 8 macaques given a single 50 mg/kg CAB LA dose remained aviremic through week 17 (p=0.0008; Fisher’s exact test). Six of the 8 macaques given a 25 mg/kg dose followed by a 50 mg/kg dose of CAB LA remained aviremic through week 24 (p=0.021; Fisher’s exact test). The mean plasma CAB concentration in the macaques that remained aviremic was 2.58 (range 1.00 to 5.56; n=21) μg/mL compared with 1.17 (range 0.67 to 1.93; n=3) μg/mL for the animals that became infected (p=0.0524; t-test). Conclusions: In an IV challenge model, 21 of the 24 CAB LA-treated macaques remained aviremic resulting in 88% protection. The plasma CAB concentration at the time of challenge is more important for protection than sustaining plasma concentrations with the second CAB LA injection. These results support the clinical investigation of CAB LA as PrEP in people who inject drugs. intravenous (IV) SIV challenge in a model that mimics blood transfusions based on the per-act probability of infection. Methods: Three groups of rhesus macaques (n=8/group) were injected IM with CAB LA and challenged IV with 17 AID 50

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CROI 2016