CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Conclusions: In this large study among African men and women who had a median TDF-exposure of 33 months, the reduction in mean eGFR was small and returned to within baseline levels by 4 weeks after discontinuation of TDF-based PrEP.

982 Minor Drug-Resistant Variants Infrequently Detected in Seroconverters FromMTN 003 (VOICE) Constantinos Panousis 1 ; Elias K. Halvas 1 ; Cliff Kelly 2 ; Jeanne Marrazzo 3 ; Z M. Chirenje 4 ; JohnW. Mellors 1 ; Urvi M. Parikh 1 On behalf of the MTN 003 ProtocolTeam

1 University of Pittsburgh, Pittsburgh, PA, US; 2 Fred Hutchinson Cancer Research Center, Seattle, WA, US; 3 University of Washington, Seattle, WA, US; 4 UZ-UCSF Collaborative Research Programme, Harare, Zimbabwe Background: Minor (low frequency) drug-resistant variants selected by antiretroviral (ARV)-based prevention could negatively impact response to future antiretroviral therapy. We previously reported (Marrazzo et al., NEJM 2014) that acquired resistance to ARV-based products in the MTN 003 (VOICE) study was rarely detected by standard population based genotype analysis (1/212 participants receiving active product), with no cases of tenofovir (TFV) resistance and only one case of emtricitabine (FTC) resistance with M184V, but minor resistant variants were not excluded. Here, we assess the frequency of minor resistant variants among seroconverters in the VOICE study. Methods: VOICE was a safety and effectiveness study of TFV-based products for HIV prevention conducted at 15 sites in South Africa, Zimbabwe and Uganda. Participants were randomized to vaginal TFV 1% gel, oral tenofovir disoproxil fumarate (TDF), oral FTC/TDF, or oral or gel placebo. Plasma for resistance testing was collected from seroconverters on study when HIV infection was confirmed by rapid testing and Western blot. Plasma samples from 301 seroconverters with standard genotype results were analyzed by allele- specific PCR (ASPCR) to quantify %mutant frequency down to 0.1% for K65R, M184V and M184I, and 0.3% for K70E. Mutant frequency was analyzed by treatment arm and whether TFV was detectable in plasma (>0 ng/mL). Results: Of 301 women without TFV resistance by population genotyping, 3/276 had K65R (0.5-15%mutant frequency) and 0/283 had K70E detected by ASPCR. Of 300 women without FTC resistance by population genotyping, 1/288 had M184V (0.5%mutant frequency) and 11/285 had M184I (0.5-5.2%mutant frequency) detected by ASPCR. 1 participant with M184V detected by standard genotyping had resistance confirmed by ASPCR (98%mutant frequency). The detection of low frequency mutants did not differ across treatment arms or with the detection of tenofovir at any follow-up visit. Conclusions: Fifteen of 289 (5%) participants in the VOICE trial had low frequency FTC or TFV resistance detected by ASPCR but mutant detection was not associated with treatment arm or detectable TFV suggesting transmitted resistance or spontaneously arising mutants of unknown clinical significance. Low product use in the VOICE trial could explain the infrequent selection of resistance among seroconverters. 983 PrEP-Selected Drug Resistance Fades by Six Months Following Drug Cessation Julie F. Weis 1 ; Jared Baeten 2 ; Ruth Kanthula 3 ; Connor McCoy 1 ; Lisa Frenkel 2 ; Nelly Mugo 2 ; Frederick Matsen 1 ; Julie M. Overbaugh 1 ; Connie Celum 2 ; Dara A. Lehman 1 1 Fred Hutchinson Cancer Research Center, Seattle, WA, US; 2 University of Washington, Seattle, WA, US; 3 Seattle Children’s Research Institute, Seattle, WA, US; 4 Fred Hutchinson Cancer Research Center, Seattle, WA, US Background: Pre-exposure prophylaxis (PrEP) significantly reduces HIV-1 transmission. However, selection for drug resistance may occur when PrEP is initiated during unrecognized acute infection or in breakthrough infections during periods of low PrEP adherence. In these cases it remains unclear how long resistance persists after discontinuation of PrEP. Methods: The Partners PrEP Study was a randomized trial of PrEP as emtricitabine coformulated with tenofovir disproxil fumarate (FTC/TDF), or TDF alone compared to placebo. FTC is known to select for the resistance mutation M184V and TDF for K65R and K70E. We previously reported that PrEP-related mutations were detected by 454 ultra-deep sequencing in 9 of 121 HIV seroconverters tested at detection of seroconversion when study drug was stopped and/or one month later. In this current study, we used 454 sequencing to detect and quantify PrEP-related mutations at 6, 12, and 24 months after PrEP cessation in plasma samples from these 9 individuals. A sample was classified as resistant when the frequency of mutant sequences was significantly higher than what was observed in matched controls using Fisher’s exact test, correcting for a 5% false- discovery rate. Results: All PrEP-selected mutations were no longer present by 6 months and remained undetectable at 12 and 24 months after seroconversion. This included 1 individual with both TDF-selected mutations K65R and K70E present when seroconversion was detected (56% and 10% respective frequency), and 4 individuals with M184V (ranging from 1% to 99% at detection of seroconversion). Three seroconverters (2 placebo, 1 TDF) had evidence of M184I at seroconversion, which is naturally polymorphic and was not due to PrEP selection. In these 3 cases, M184I fluctuated at low levels, from undetectable up to 6% throughout follow-up. One individual was lost to follow-up. Conclusions: Using highly sensitive assays, PrEP-selected resistance in plasma decreases to below detection by six months following drug cessation and remains undetectable for at least 24 months. Even high levels of resistance mutations during acute infection decrease rapidly in the absence of ongoing PrEP exposure. 984 Randomized Controlled Trial on ART Outcomes in Tenofovir Gel Trial Seroconvertors Anushka Naidoo ; Nivashnee Naicker; LiseWerner; Nigel Garrett; Sarah Dlamini;Villeshni Asari; Nelisile Majola; Cheryl Baxter; Quarraisha Abdool Karim; Salim S. Abdool Karim Center for the AIDS Program of Research in South Africa, Durban, South Africa Background: Prior to promoting tenofovir gel for HIV prevention in women, it is important to know whether tenofovir gel users who acquire HIV infection can be treated with tenofovir containing antiretroviral treatment (ART) with good clinical outcomes. The CAPRISA009 randomised clinical trial assessed ART outcomes in women who acquired HIV during tenofovir gel trials. Methods: Seroconvertors from the CAPRISA004 tenofovir gel effectiveness trial and CAPRISA008 tenofovir gel implementation trial were recruited into the CAPRISA009 study when eligible for ART initiation (CD4 count <350 cells/ m l, pregnancy or AIDS-defining illness). Women were randomised to a tenofovir-containing or tenofovir-sparing (zidovudine-containing) regimen. CD4 counts and viral loads (VL) were monitored at baseline and follow-up visits. Clinical outcomes, virological suppression (VL <50 copies/ml), CD4 counts, adverse events and drug switches were compared between the two groups using Fisher’s exact and Wilcoxon rank sum tests. Results: From June 2011 to August 2014, 59 women were enrolled and followed-up for a median of 13 months (IQR 6-19). Twenty-nine women (7 tenofovir gel exposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed) to a tenofovir-sparing regimen. Median baseline CD4 count and VL were 361 cells/ m l (IQR 275–420) and 4.64 log copies/ml (IQR 4.01-5.11), and did not differ by ART assignment. Overall VL suppression rates were 85.7% and 76.2% at 6 months (p=0.70) and 84.2% and 76.5% at 12 months (p=0.68) in the tenofovir-containing and tenofovir-sparing groups. In women with prior tenofovir exposure, VL suppression rates were 100% and 50% at 6 months (p=0.14) and 100% and 25% at 12 months (p=0.17) in the tenofovir-containing versus tenofovir-sparing groups. Overall, median CD4 counts at 12 months were 577 cells/ m l and 541 cells/ m l (p=0.45) and 388 cells/ m l and 549 cells/ m l (p= 0.35) in tenofovir gel exposed women in the tenofovir-containing and tenofovir-sparing groups. Women randomised to a tenofovir- sparing regimen experienced a higher frequency of grade 3 or 4 AEs (33.3% vs 10.3%, p=0.06) and had more toxicity-related drug switches (26.7% vs. 0.0%, p< 0.01) compared to women receiving a tenofovir-containing regimen. There were no drug switches in women with prior tenofovir gel exposure. Conclusions: Tenofovir-containing ART was effective and safer in tenofovir gel trial seroconvertors and should be recommended as the preferred treatment option for women with prior exposure to tenofovir gel.

Poster Abstracts

582

CROI 2015