CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

985 Frequent Dapivirine Cross-Resistance of HIV from 1 st -line ART Failures in S. Africa Kerri J. Penrose 1 ; Kristen A. Hamanishi 1 ; Kelley C. Gordon 1 ; RaquelV.Viana 2 ; Carole L.Wallis 3 ; JohnW. Mellors 1 ; Urvi M. Parikh 1 1 University of Pittsburgh, Pittsburgh, PA, US; 2 Lancet Laboratories, Johannesburg, South Africa; 3 Lancet Laboratories/BARC-SA, Johannesburg, South Africa

Background: Two Phase III studies (IPM Ring Study and MTN ASPIRE) are currently evaluating whether monthly use of a vaginal ring containing dapivirine (DPV) prevents HIV infection in women. The rise of transmitted EFV- and NVP-resistant virus could reduce the protective efficacy of DPV. This study investigated DPV cross-resistance among recombinant subtype C viruses derived from individuals failing 1st-line NVP- or EFV-containing ART regimens in South Africa (SA). Methods: Residual plasma samples, sent for routine HIV drug resistance testing, were collected from HIV-1 subtype C-infected individuals in SA failing EFV- or NVP-containing 1st-line ART after 6 months of treatment with HIV RNA >10000 c/mL and with ≥ 1 NNRTI drug resistance mutation (DRM) detected by population sequencing. Recombinant HIV-1 LAI containing bulk-cloned full-length RT sequences from 60 plasma samples had susceptibility determined for NVP, EFV and DPV in TZM-bl cells. Fold-change (FC) values were calculated using a composite IC 50 from 13 HIV subtype C treatment-naïve samples from SA. Calculated in vitro IC 90 values were compared to in vivo maximum plasma and vaginal fluid DPV concentrations with monthly ring use (C max ) and those achieved on day 28 of ring use (C 28 ) based on published data (Nel et al. AIDS 2014). Results: 47/60 (78%) samples showed ≥ 10 fold resistance to DPV compared to treatment naïve samples and exhibited a median IC 50 of 16 ng/mL (Table). 9/60 (15%) samples displayed 3 to 9 fold resistance with median IC 50 of 1.0 ng/mL. Only 4/60 (7%) samples containing NNRTI DRM were susceptible to DPV. The median IC 90 of all viruses with ≥ 3-fold DPV resistance (10,800pg/mL) exceeded observed plasma C max during 1 month of ring use (355 pg/mL). By contrast, the DPV C 28 in vaginal fluid (29 m g/mL) was 900X higher than median IC 90 of viruses with ≥ 10-fold DPV resistance (0.031 m g/mL). The most common DRM found in the ≥ 10 fold resistant category were K103N (27/47, 57%), V106M (14/47, 30%), and L100I (9/47,19%).

Conclusions: 78% of HIV-1 from 1st-line treatment failures in SA exhibit ≥ 10-fold cross-resistance to DPV. This level of resistance exceeds expected plasma concentrations, but very high genital tract DPV concentrations from DPV ring use may be sufficient to block both wild type and resistant virus. Nevertheless, it is critically important to assess the frequency of transmitted and selected DPV resistance following DPV ring use. 986 Effect of TDF Monotherapy PrEP on Immune Function in Seroconverting Individuals Marcel E. Curlin 1 ; MichaelT. Martin 1 ; PunneepornWasinrapee 2 ;Wanna Leelawiwat 2 ; Boonyos Raengsakulrach 2 ; Janet McNicholl 1 ; Pravan Suntharasamai 3 ; Udomsak Sangkum 3 ; SuphakVanichseni 3 ; Kachit Choopanya 3 1 US Centers for Disease Control and Prevention (CDC), Apo, US; 2 Thailand Ministry of Public Health-Centers for Disease Control and Prevention Collaboration, Nothaburi, Thailand; 3 Bangkok Tenofovir Study Group, Bangkok, Thailand Background: Tenofovir disoproxil fumarate (TDF) has been used in all major published clinical trials of HIV pre-exposure prophylaxis (PrEP), and is a component of the only drug (TDF/emtricitabine) currently approved for PrEP. However, little is known about the effect of TDF monotherapy on individuals seroconverting while receiving PrEP. We examined immune functions in Bangkok Tenofovir Study (BTS) participants randomized to placebo or TDF who seroconverted during the study. Methods: All available post-infection blood specimens from all seroconverting participants were analyzed. We performed flow cytometry using standard antibody (Ab) panels to characterize differentiation and activation status of circulating CD4+ and CD8+ T cells, and intracellular cytokine staining (ICS) using overlapping HIV-1 peptides spanning Gag to characterize HIV-specific T lymphocyte responses. We measured HIV-1 NAb titers in blood against two tier-1 laboratory strains (SS1196.1 [subtype B] and Th023 [CRF01-AE]) using a luciferase reporter assay in TZM-bl cells. Treatment groups were compared using the Wilcoxon rank sum test. Results: Forty-eight seroconverters (TDF = 14, placebo = 34) provided 128 specimens collected a median of 221 days (r 40-1159) post infection and 121 days (r 41-1159) after cessation of TDF use. In TDF recipients, CD8+ T cells had significantly lower expression of intermediate, transitional effector and central effector memory cell markers compared with placebo recipients ( p < 0.02). TDF and placebo recipients did not differ in the distribution of CD4+ cells ( p > 0.05). In TDF recipients, CD8+ and CD4+ T-cells had lower expression of activation markers (CCR5 +/- HLA-DR and CD38) and programmed cell death protein 1 ( p < 0.02). There was no difference between groups in ICS responses, neutralizing Ab titers, plasma viral load (PVL), or CD4 count. Conclusions: TDF PrEP was associated with a significant skewing of CD8+ differentiation from transitional and central memory states towards an effector phenotype, In addition, TDF recipients had reduced activation of CD4 and CD8 cells, and lower expression of one marker associated with programmed cell death on activated cells. However, we did not detect significant differences in functional cellular or humoral responses, absolute peripherally circulating CD8+ or CD4+ cell counts, or PVL between groups. These data indicate that TDF PrEP could have lasting effects on T cell differentiation and cellular exhaustion in individuals becoming HIV infected while on therapy. 987 The Impact of Preexposure Prophylaxis on Antibody Maturation in HIV-InfectedWomen Oliver B. Laeyendecker 1 ; Andrew D. Redd 1 ; Martha Nason 3 ; Andrew Longosz 1 ; Quarraisha Abdool Karim 2 ;Vivek Naranbhai 2 ; Nigel Garrett 2 ; Salim S. Abdool Karim 2 ;Thomas C. Quinn 1 1 National Institute of Allergy and Infectious Diseases, Baltimore, MD, US; 2 CAPRISA, University of KwaZulu-Natal, Congella, South Africa; 3 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, US Background: The CAPRISA 004 pre-exposure prophylaxis (PrEP) randomized trial demonstrated that women who used a vaginal gel containing the antiretroviral drug Tenofovir (TFV) had a 39% lower chance of acquiring HIV. It is not known if topical TFV alters the antibody response to breakthrough HIV infection, although a previous study of TFV PrEP treated rhesus macaques demonstrated a delay in antibody avidity maturation but not in titer. Methods: Using the BED capture enzyme immune and Bio-Plex assays, anti-HIV antibody titers were measured in stored serum samples collected at 3, 6, 9, 12, 24, 36, 48, and >48 months post-infection from 35 women assigned to TFV gel and 60 assigned to placebo gel, who acquired HIV during the trial. Additionally, anti-HIV antibody avidity maturation was assessed by the Bio-Rad avidity, and Bio-Plex assays. Kaplan Meier survival analysis and log rank test was used to determine differences between treatment arms. The slope and intercepts of the increase of antibody avidity or titer, as determined by the Bio-Plex assay, was compared. A linear mixed effects model was used to examine antibody titer and avidity by treatment group. Cox proportional hazard analysis examined time to avidity cut-off.

Poster Abstracts

583

CROI 2015