CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Methods: A HIPAA-compliant unique Patient ID was assigned to each test result in the LabCorp Clinical Database. New cases of HIV diagnosis were inferred using the linked results from HIV diagnosis, viral load and drug resistance tests. We developed a novel inference model which employs a successive series of filters to derive a subset of resistance assays that were likely to have been performed at the time of initial HIV diagnosis. We used the 2009 surveillance drug resistance mutations (SDRM) list from the Stanford University HIV Drug Resistance Database to determine mutational frequencies. We validated the model by comparing the predicted 2008-2011 NRTI, NNRTI, and PI frequencies to ranges established from prior TDR surveillance studies. We then used our model to calculate rates of TDR for 2012-2014 per drug class, including INIs. This model allows us to assess prevalence rates according to age group, gender, and geography. Results: We identified 8612 putative baseline resistance tests from 2008-2011. The rates for NRTI (7.6%), NNRTI (11.2%), and PI (2.9%) SDRMs compared favorably with previously reported TDR rates, as did the overall rates for any SDRM (17%). For 2012-2014, we analyzed 14,325 putative baseline resistance tests and observed an overall rate for TDR mutations of 17.2%. We observed prevalence rates of 6.3%, 12.3%, 2.7%, and 0.6% for the NRTIs, NNRTIs, PIs, and INIs, respectively. Conclusions: Our model demonstrates a novel real-time method for inferring the prevalence of TDR by drug class. This model suggests that national TDR rates for NRTI, NNRTI, and PIs from 2012-2014 have not decreased relative to prior years and that INI TDR rates were surprisingly low, possibly reflective of the efficacy of current antiretroviral regimens which incorporate this class. Near real-time TDR data can facilitate early detection of new drug resistance strains should they arise, such as in response to PrEP. Analysis of 2015 rates will be included for presentation. 482 Impact of Transmitted Thymidine Analogue Mutations on Responses to First-Line ART Anna Maria Geretti 1 ; EllenWhite 2 ; Apostolos Beloukas 3 ; Chloe Orkin 4 ; AnnaTostevin 2 ; PeterTilston 5 ; David Chadwick 6 ; Caroline Sabin 7 ; David Dunn 2 ; for the HIV Drug Resistance Database and CHIC Study 1 Inst of Infection & Global Hlth, Univ of Liverpool, Liverpool, UK; 2 Med Rsr Council Clinical Trials Unit at Univ Coll London, London, UK; 3 Univ of Liverpool, Liverpool, UK; 4 Barts Hlth NHS Trust, London, UK; 5 Manchester Royal Infirmary, Manchester, UK; 6 South Tees Hosp NHS Fndn Trust, Middlesbrough, UK; 7 Univ Coll London, London, UK Background: Thymidine analogue mutations (TAMs; RT codons 41, 67, 70, 210, 215, 219) are a prevalent form of transmitted drug resistance (TDR) in Europe and North America, commonly occurring as singleton revertants of T215Y/F (e.g., T215E), and thought to often represent onward transmission from ART-naive subjects. Although PI/r-based therapy is recommended for patients with transmitted TAMs, it is not known whether alternative regimens carry an increased risk of virologic failure (VF). The study aimwas to analyze ART outcomes in subjects with ≥1 TAM (and no other resistance) vs. subjects without evidence of resistance. Methods: Subjects underwent genotypic resistance testing in 1998-2012 prior to starting TDF or ABC + 3TC or FTC + PI/r (ATV, DRV, FPV, LPV) or NNRTI (EFV, NVP, RPV). VF definition: confirmed viral load >50 (or 200) cps/mL after ≥6 months of ART, or one viral load >50 (or 200) cps/mL followed by a treatment change. Time to VF was analyzed using Kaplan Meier plots (figure) and Cox models adjusted for age, ethnicity, risk group, pre-ART viral load and CD4 count, and ABC use. Results: Of 6926 patients evaluated before ART initiation, 6345 (92%) had no resistance; 271 (4%) had ≥1 TAM, including 204/271 (75%) with singleton TAMs, most commonly T215 revertants (112/271, 41%). VF risks at the 50 cps cut-off were 808/6345 (13%) in subjects with no resistance vs. 33/271 (12%) in subjects with ≥1TAM (P=0.53, log rank test). VF risks in subjects with no resistance were 304/1591 (19%) for PI/r use vs. 504/4754 (11%) for NNRTI use ( adj HR=2.2; 95% CI 1.9-2.5; P<0.001). The same direction of effect was observed with ≥1TAM: 16% (21/131) for PI/r vs. 9% (12/140) for NNRTI ( adj HR=1.7; 0.8-3.4, P=0.15). At the 200 cps cut-off, VF risks were 401/6345 (6%) in subjects with no resistance vs. 12/271 (4%) in subjects with ≥1TAM (P=0.14, log rank test). VF risks in subjects with no resistance were 149/1591 (9%) for PI/r use vs. 252/4754 (5%) for NNRTI use ( adj HR=1.9; 1.6-2.4, P<0.001). With ≥1TAM, VF risks were 6/131 (5%) for PI/r vs. 6/140 (4%) for NNRTI ( adj HR=0.9; 0.3-2.8, P=0.87). Conclusions: This cohort analysis supports the hypothesis that in patients with ≥1 TAM as the sole form of TDR (predominantly singleton T215 revertants), there was no apparent virologic advantage of starting ART with a PI/r-based regimen. As the influence of confounding factors cannot be excluded, the data should be regarded as providing a framework for designing a controlled trial.

Poster Abstracts

483 Increasing Prevalence of Silent Mutations in HIV-1 Subtype B RT Which Alter Fitness

Sushama Telwatte 1 ; Chanson J. Brumme 2 ; Anna C. Hearps 1 ; Catherine F. Latham 1 ; Con Sonza 3 ; P. Richard Harrigan 2 ; GildaTachedjian 1 1 Burnet Inst, Melbourne, Australia; 2 BC Cntr for Excellence in HIV/AIDS, Vancouver, BC, Canada; 3 Univ of Melbourne, Melbourne, Australia

Background: Resistance to combination antiretroviral therapy (cART) in HIV-1 infected individuals is typically due to non-synonymous mutations that change the protein sequence; yet, the selection of synonymous or ‘silent’ mutations in HIV-1 has been reported 1 . Silent K65K and K66K mutations in HIV-1 reverse transcriptase (RT) are associated with thymidine analog mutations (TAMs) D67N and K70R, which confer decreased susceptibility to most HIV-1 nucleoside RT inhibitors. We previously showed that D67N/K70R in HIV-1 RT increase indel frequency by 100-fold, contributing to impaired viral fitness, and that either K65K or K66K reversed these defects 2 . However, the impact of the silent mutations in clinically-relevant virus backbones and their prevalence in a population over time are unknown. Methods: A retrospective analysis of all drug-naïve HIV-infected individuals enrolled in the Drug Treatment Program (DTP) at the British Columbia Centre for Excellence in HIV/ AIDS between 1997 and 2014 examined the prevalence of K65K/K66K in this population. A longitudinal analysis of HIV-1 RT sequences from 2131 individuals from the same cohort assessed the temporal appearance of K65K/K66K relative to TAMs. Growth competition assays evaluated the fitness of multidrug-resistant (MDR) HIV-1 variants ± K65K or K66K derived from a patient isolate. Results: A retrospective analysis of all drug-naïve HIV-infected individuals in the DTP cohort revealed that K65K and K66K increased in prevalence in drug-naïve individuals from 11% in 1997 to 36% in 2014 [p=9.9x10 -14 (Cochran-Armitage test), n=5221] (Fig.1). K65K and K66K were selected in 316 individuals (15%) followed longitudinally. In 95% of

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CROI 2016