CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

964 Oral Single-Dose Maraviroc Does Not Prevent Ex Vivo HIV Infection of Rectal Mucosa in Healthy HIV-1 – Negative Human Volunteers in Tissue Explants. Josep Coll 2 ; José Moltó 2 ; Jaume Boix 3 ; Laura Else 4 ; Elisabet Garcia 1 ; Roger Paredes 2 ; David Back 4 ; Bonaventura Clotet 5 ; Cecilia Cabrera 1 1 Institut de Recerca de la Sida IrsiCaixa, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain; 2 Fundació Lluita Contra la SIDA, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain; 3 Unidad de Endoscopia Digestiva. Hospital Universitario Germans Trias i Pujol, Barcelona, Spain; 4 Pharmacology Research Laboratories, Liverpool, United Kingdom; 5 Fundació Lluita Contra la SIDA-IRSICAIXA, VIC-UCC (Universitat de Vic-Universitat Central de Catalunya), Barcelona, Spain Background: Maraviroc (MVC) is a potential candidate for pre-exposure prophylaxis (PreP). We have explored the efficacy of an oral single-dose of MVC to prevent ex vivo HIV infection. Methods: Ten HIV-negative, healthy male volunteers were enrolled in this study. Rectal infection with C. trachomatis or N. gonorrhoeae as well as infection with T. pallidum , HBV, HCV and HIV-1 were ruled out. Participants received a witnessed single oral dose of MVC (300 mg in 6 and 600 mg in 2 volunteers) on day 7 after enrollment. Rectal biopsies (16-20 per session) were performed at baseline (without MVC) and at day 7 (4 hours after MVC dosing). Additionally, 2 individuals received tenofovir/emtricitabine 300/200 mg qd within 10 days before the rectal biopsy, as a control group. Rectal tissue was incubated with a R5 isolate (6x10 4 TCID 50 ) for 1h at 370C and washed before transferring onto gelfoam rafts. Culture mediumwas collected and replaced every 2 days during 18 days and the p24 production was measured. Three replicates were performed for each infection to account for differences in cellularity between biopsies. MVC concentration was measured in plasma and in rectal tissue by validated LC-MS/MS, and normalized to the 300 mg dose. Results: Overall, MVC was well tolerated and there were no serious adverse events during the study. Median dose-normalized concentration of MVC in plasma and in rectal tissue was 155 ng/mL and 561 ng/mL (p= 0.0006). Despite MVC concentrations in rectum being above the IC 50 reported in colorectal tissue infections (56.4 ng/mL), ex-vivo HIV infection occurred in all participants specimens, both at baseline and at day 7, even after administration of double MVC dose. Conversely, a complete inhibition of the infection was observed in cultures from the two volunteers who received Truvada. Conclusions: In our experimental model, a single oral dose of MVC 300 mg or 600 mg did not prevent ex vivo infection of human rectal mucosa 4 hours after dosing, even though the drug concentration achieved in tissue was above the IC 50 reported in rectal tissue. The lack of prophylactic efficacy observed in our study suggests that MVC could not prevent rectal HIV transmission when used as a “on demand” pre-exposure prophylaxis strategy. 965 CCR5 BlockadeWith Maraviroc Does Not Prevent SIVmac Oral Transmission to Macaques Egidio Brocca-Cofano 1 ; Cuiling Xu 1 ; Dongzhu Ma 1 ; Benjamin Policicchio 1 ; Kevin Raehtz 1 ;Tammy Dunsmore 1 ; George Richter-Haret 1 ; Brandon F. Keele 2 ; Ivona Pandrea 1 ; Cristian Apetrei 1 1 University of Pittsburgh, Pittsburgh, PA, US; 2 National Cancer Institute (NCI), Frederick, MD, US Background: HIV maternal-to-infant-transmission (MTIT) accounts for >300,000 cases of infection annually. Current prevention strategies cannot eliminate MTIT, and new prevention paradigms are badly needed. We reported that the availability of SIV target cell (i.e., CCR5 + CD4 + T cells) availability at mucosal sites may drive virus transmission efficacy in natural hosts of SIVs, particularly during MTIT. Our goal was to investigate if CCR5 blockade with Maraviroc (MVC) impacts the efficacy of oral SIV transmission to infant rhesus macaques (RMs). Methods: Nine RMs aged six months were included. Five received MVC (150 mg/kg, bid, orally) for up to 6 months, during which coreceptor occupancy was closely monitored. After one month, treated infant RMs and 4 untreated controls were orally exposed to 10,000 TCID50 of SIVmac766XII (a mixture of 12 barcoded SIVmac251 transmitted/founder clones) every two weeks, for up to 6 times. Plasma viral loads were monitored by real-time single genome amplification. Changes in the immune cells were monitored by flow cytometry. Results: Coreceptor occupancy testing revealed that MVC effectively blocked CCR5 expression in infant RMs. MVC was well tolerated, with no adverse reaction. At the end of the study, all infant RMs in the control group (4/4) and 60% of those receiving MVC (3/5) became infected with SIVmac766XII, the difference being not significant. There were no differences in the number of exposures needed to infect infant RMs in the two groups (1, 3, 5 and 6 inoculations for controls versus 2,3 and 4 inoculation for the RMs receiving MVC). None of the treated or control infant RMs were infected with more than one viral variant, suggesting that the animals were not overexposed to virus, which might have offset the protective effect of MVC. The only difference observed between the two groups consisted of a significant delay of ramp-up viremia in the MVC-treated infants. However, peak and postpeak VLs were similar in the two groups. No significant differences in CD4 + T cells or in the levels of immune activation were observed between the two groups. Conclusions: MVC was efficient in blocking CCR5 and was well tolerated in infant RMs. Blocking CCR5 with MVC does not significantly impact SIV oral transmission. Since SIVmac is more promiscuous than HIV-1 with regard to coreceptor usage (i.e., being able to use alternative coreceptors, such as BOB/GPR15 and Bonzo/STRL33), CCR5 blockade in humans might be more effective in preventing MTIT. 966LB Correlation of In Vivo Cabotegravir Concentration and Prevention of SIV in Macaques William R. Spreen 4 ; Anabel Lowry 1 ; Ranajit Pal 2 ;Yun LanYueh 4 ; Susan Ford 4 ; Nicola Richardson-Harman 3 ; Jim A.Turpin 1 ; FulviaVeronese 1 ; James E. Cummins 1 ABL/BIOQUAL NHPTeam 1 National Institutes of Health, Bethesda, MD, US; 2 Advanced Bioscience Laboratories, Inc, Rockville, MD, US; 3 Alpha StatConsult LLC, Damascus, MD, US; 4 GlaxoSmithKline, Durham, NC, US Background: Previous studies with long-acting cabotegravir (CAB LA, GSK1265744) demonstrated protection against repeated intrarectal and intravaginal SHIV 162p3 challenges in nonhuman primates. In one study, evaluation of the “window of protection” was performed using a single dose level of CAB LA in male macaques undergoing repeated intrarectal SHIV 162p3 challenges. In order to determine if there is a relationship between the plasma drug concentration (as related to Protein Adjusted IC 90 , PA-IC 90 ) and protection against intravaginal SIV transmission, we assessed plasma PK and longitudinal breakthrough infections in rhesus macaques following multi-exposure intravaginal challenge. Methods: Twenty-seven Chinese rhesus macaques were injected intramuscularly with CAB LA at three dose levels (10, 30, and 50 mg/kg; n=9) at days -7 and -1 prior to initiation of weekly intravaginal SIV mac251 challenges (1000 TCID 50 ). Nine untreated (i.e., no CAB LA injection) macaques served as virus controls. Macaques resisting infection after each weekly exposure were continually challenged for a maximum of 20 times and monitored for breakthrough infections. Plasma drug concentration measured by mass spectrophotometry and viral load measured by NASBA were monitored weekly until infection and then for an additional 16 weeks post infection. Results: Significant protection from virus acquisition was noted in macaques dosed with 30 and 50 mg/kg CAB LA with a median of 9-11 challenges required for infection of drug-treated macaques compared to 3 (2-4 inter-quartile range) for untreated controls ( P <0.05; Log rank analysis) . There were no statistical differences between the 30 and 50 mg/kg doses for protection from infection or between the 10 mg/kg dose (median of 4 protected challenges) and the untreated controls. Analysis of plasma drug concentrations demonstrated a significant correlation between plasma CAB LA concentration and virus acquisition ( P =0.0004). A CAB LA plasma concentration of 711 ng/mL (~4x PA-IC 90 ) was predicted by logistic regression analysis to provide a 90% probability of in vivo protection after 7 SIV challenges. Conclusions: These results may further elucidate the “window of protection” for cabotegravir and suggest that targeting 4x PA-IC 90 in plasma may be sufficient to protect against vaginal SIV transmission in macaques, thus supporting a relationship between plasma drug concentration and in vivo efficacy.

Poster Abstracts

573

CROI 2015