CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

491LB Large-Scale Transmission and Clustering of HIV Protease Resistance in Ontario, Canada P. Richard Harrigan 1 ; Ashleigh B. Sullivan 2 ; Jeffrey B. Joy 1 ; Kevin Gough 3 ;Vanessa G. Allen 4 ;Tony Mazzulli 4 ; Doug Sider 5 1 BC Cntr for Excellence in HIV/AIDS, Vancouver, BC, Canada; 2 Public Hlth Agency of Canada, Toronto, ON, Canada; 3 St. Michael’s Hosp/Univ of Toronto, Toronto, ON, Canada; 4 Ontario Agency for Hlth Protection and Promotion, Toronto, ON, Canada; 5 Public Hlth Ontario, Toronto, ON, Canada Background: Transmitted HIV drug resistance has important potential clinical and public health implications. Transmission of signficant resistance to HIV protease inhibitors is particularly uncommon. Pre-therapy HIV drug resistance genotyping has been recommended as standard of care in Ontario, Canada since 2005, and subsequent to 2014, performed automatically on “new” viral load requests. Since the implementation of “reflex” genotyping, an unusual pattern of HIV drug resistance (very high PI resistance without substantial nRTI or NNRTI resistance) was observed in multiple patients sent for routine pre-treatment testing. Methods: We reviewed the epidemiologic and clinical characteristics of all HIV-positive individuals in care in the province of Ontario, Canada. Phylogenetic trees were inferred for HIV pol sequences from the first sample for each patient for whom testing was available (N=11,550 patients). Tip-to-tip distances (patristic distance < 0.02) between sequences from different individuals on the phylogeny were used to define clusters. Resistance data and patient characteristics were super-imposed on phylogenetic trees to identify clusters of transmitted protease resistance. Results: There were 49 untreated patients with PI resistance identified in a single large cluster. Typically each patient had at least seven PI mutations detected at the first pre-treatment genotype (all of 10I,33F,48V,54T,71V,74S and 82A), conferring significant levels of inferred resistance to most PIs except darunavir. These mutations were usually observed in combination with nRTI “revertant” mutations (41L and 215L or S). Resistant patients were observed from 2005 (N=4) to present, with the majority observed in recent years (N=9 in 2014 and 17 in 2015). All sequences clustered closely together in a phylogenetic tree. All patients were male, and the median age was 29 years at the time of sampling. The majority of cases (80%) were observed in Toronto. Isolated cases with a similar resistance profile have also been observed in other provinces; however the vast majority have been in Ontario. Conclusions: High level protease inhibitor resistance can occur with sufficient replicative fitness to circulate for more than a decade in the community, suggesting the potential for transmission of extensively drug resistant HIV, which could threaten our treatment paradigms. Systematic surveillance of HIV resistance in untreated individuals remains important even as the incidence of resistance in treated populations declines overall. 492LB Prevalence and Incidence of Integrase Drug Resistance in BC, Canada, 2009–2015 Katherine Lepik ; BenitaYip; Marjorie A. Robbins; Conan K.Woods;Viviane D. Lima; Rachel A. McGovern;WendyW Zhang; Rolando A. Barrios; Julio Montaner; P. Richard Harrigan BC Cntr for Excellence in HIV/AIDS, Vancouver, BC, Canada

Background: In British Columbia (BC), use of the integrase inhibitors (INI) raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) in antiretroviral (ART) regimens has increased from 10% of ART-treated persons in 2009 (540 RAL-treated) to 32% in 2015 (978 RAL, 500 EVG and 1011 DTG). This study characterizes the evolution of incident and prevalent INI resistance from 2009 to Oct. 2015 and tests the hypothesis that prevalence of INI drug resistance mutations is increasing over time. Methods: HIV-1-infected persons age ≥19 years were included if they received ART and drug resistance testing through BC Centre for Excellence in HIV/AIDS programs between Jan-2009 and Oct-2015. Persons with INI or other (reverse transcriptase, protease) resistance were defined as those having at least one sample with a score ≥30 (intermediate or high level resistance) by the Stanford HIV drug resistance algorithm v7.0.1. Incident cases of INI resistance were counted in the first year they appeared and were categorized by the INI temporally associated with new resistance: RAL, EVG, DTG, or Unclassifiable (resistance predated INI use in BC). Prevalent cases of INI and other resistance and INI mutations were counted in each year they appeared. Annual prevalence/1000 ART-treated persons was calculated at year end (31-Oct in 2015). Changes in prevalent resistance over time were tested for trend (generalized additive model, R© v3.2.2). Results: A total of 57 persons had intermediate or high level INI resistance. Prevalence of INI resistance/1000 ART- treated persons increased from 1.07 in 2009 to 6.8 in 2015, see Figure 1a (trend p<0.001, R 2 0.99). During this period, other ART resistance declined from 331 to 285/1000 (trend p<0.001, R 2 0.98). Figure 1a depicts evolution of prevalent INI resistance mutations. Until 2013, most new cases of INI resistance were associated with RAL use (Figure 1b). In 2014 and 2015, 8/19 (42%) of new INI resistance followed EVG or DTG use: Five cases were associated with EVG (mutations: two 66A/I and one each 92Q, 145S, 147G) and three emerged during DTG therapy (mutations: 66I and two 263K). Seven persons were ART experienced and one (DTG, 66I) was ART naïve. Conclusions: The prevalence of INI resistance remains low compared to other ART resistance, but is increasing with expanded INI use. Emergent INI resistance has been observed during treatment with RAL, EVG and DTG in ART naïve and experienced patients.

Poster Abstracts

493LB Divergent ARV Resistance at Screening for ACTG A5288 Study of 3rd-Line ART in RLS Carole L. Wallis 1 ; Beatriz Grinsztejn 2 ; SaranVardhanabhuti 3 ; Robert A. Salata 4 ; Peter Mugyenyi 5 ; Catherine Godfrey 6 ; Michael Hughes 7 ; Ann Collier 8 ; JohnW. Mellors 9 ; for the A5288 Team 1 BARC-SA and Lancet Lab, Johannesburg, South Africa; 2 Inst de Pesquisa Clínica Evandro Chagas (IPEC)/Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil; 3 Statistical and Data Analysis Cntr, Harvard School of Public Hlth, Boston, MA, USA; 4 Case Western Reserve Univ, Cleveland, OH, USA; 5 Joint Clinical Rsr Cntr, Kampala, Uganda; 6 DAIDS, NIAID, NIH, Rockville, MD, USA; 7 Harvard Sch of PH, Boston, MA, USA; 8 Univ of Washington, Seattle, WA, USA; 9 Univ of Pittsburgh, Pittsburgh, PA, USA Background: HIV-1 drug resistance remains an important cause of failure of 2nd-line antiretroviral therapy (ART) but limited resistance data exist from resource-limited settings (RLS). We analyzed the frequency and patterns of resistance at screening for ACTG A5288: a study of 3 rd -line ART after prior exposure to NRTI, NNRTI and PI in RLS. Methods: Plasma samples from a screening visit for enrollment into A5288 had protease and reverse transcriptase genotyped in real time by DAIDS-certified laboratories in RLS. Resistance mutations and scores were determined using the Stanford algorithm (v6.2). Subtype was determined by phylogenetic analysis. Associations of drug class resistance with HIV-1 subtype, screening HIV RNA, and nadir CD4 were evaluated. Results: 665 plasma samples were available for analysis from Asia (171, 26%), South America (138; 21%), Eastern Africa (180; 27%), Southern Africa (170, 26%) and other locations (6; <1%). Median age was 41, 48% female, median HIV RNA 4.5 log 10 cps/ml and median nadir CD4 65 cells/mm 3 . HIV subtype C (48%), B (20%) and A1 (18%) were most common. Prior exposure to NVP (63%) was more common than EFV (56%). At time of screening, TDF (67%) and 3TC (90%) were the most commonly prescribed NRTIs with either LPV/r (55%) or ATV/r (43%); 6% had RAL exposure. High-level or intermediate resistance was common (Table): 519 candidates (78%) had resistance to one or more drugs. 137 samples (21%) had resistance to 1 drug class, 207 (31%) to 2 drug classes, and 175 (26%) to all 3 drug classes (NRTI, NNRTI, PI). However, 461 (69%) showed susceptibility to 2 nd -line regimens (1

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CROI 2016