CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

experienced patients had evidence of ≥ 1 major INI RAM, predominantly N155H (57, 22%), G140S (33, 13%), Q148H (28, 11%), and Q148R (15, 6%). 36/44 (82%) of patients with mutations Q148H/R/K had co-existing G140A/C/S. G140A/C/S and Q148H/R/K were detected in 36/209 (17%) and 42/209 (21%) subtype B infections, and 1/46 (2%, subtype G) and 2/46 (4% subtype C and G) non-B subtype infections respectively (p=0.005 and p=0.009). As a result, prevalence of predicted cross-resistance to dolutegravir was 42 (20%) vs. 2 (4%) in B vs. non-B subtypes respectively (p=0.009). In INI-naive subtype B sequences, emergence of G140S required a single nucleotide substitution (from GGC or GGT to AGC/ AGT). With all the non-B viruses sequences analysed, two substitutions were required to mutate the observed codons (GGA or GGG) to a serine codon. Conclusions: Sequence differences between HIV-1 subtypes influence the pathways of genotypic resistance to raltegravir and resulting cross-resistance to dolutegravir. Subtype B shows a higher propensity to develop the G140/Q148 pathway compared with predominant non-B subtypes circulating in Europe, which is explained by a different codon usage at the G140 position. These findings carry implications for dolutegravir use in raltegravir- and elvitegravir-experienced subjects. 595 Differences in Resistance Mutations in Non-B Subtypes at First-Line Failure in Africa Cissy M. Kityo 1 ; SarahWalker 2 ; Immaculate Nankya 1 ; Anne Hoppe 2 ; JenniferThompson 2 ; Silvia Bertagnolio 3 ; Philippa Easterbrook 3 ; Peter Mugyenyi 1 ; Nicholas Paton 4 On behalf of the EARNESTTrialTeam 1 Joint Clinical Research Centre, Kampala, Uganda; 2 MRC Clinical Trials Unit at University College London, London, United Kingdom; 3 World Health Organization, Geneva, Switzerland; 4 Yong Loo Lin School of Medicine, Singapore, Singapore Background: Resistance mutations may vary by viral subtype, although data to date are limited, especially for non-B subtypes. Understanding the common mutational patterns is important for determining the optimal standardised regimens for the public health approach to ART in settings without resistance testing or individualised therapy. Methods: Genotypes were obtained from stored baseline samples from 792 patients aged ≥ 12 years who met WHO treatment failure criteria after >12 months on NNRTI-based first-line ART in the EARNEST trial in 4 sub-Saharan African countries. Subtype and drug susceptibility were determined by REGA and Stanford algorithms respectively. Presence of specific mutations and intermediate-high level resistance was modelled using multivariable logistic regression including subtype, ART exposure at time of first-line failure, ART prior to the failing regimen, years on first-line ART, and WHO 4 events, CD4 and VL at failure. Results: Patients had advanced treatment failure (42% VL ≥ 100,000 c/ml, 63% CD4<100 cells/mm 3 ). Viral subtypes were A1 (40%; Uganda, Kenya), C (31%; Zimbabwe, Malawi) and D (25%; Uganda, Kenya) with 4% recombinants/unclassified. One or more major NRTI or NNRTI mutations were found in 774 (98%) and mutations to both classes in 747 (94%). In adjusted analyses, 4 NRTI and 7 NNRTI mutations differed significantly across the three subtypes (p<0.05; Table 1); most of these 11 mutations were significantly more common in subtype C than in A and/or D. Intermediate/high level TDF resistance (seen in 57%) was independent of subtype (adjusted p=0.38). Intermediate/high level ZDV resistance (in 71% overall) was marginally more common in subtype C (78% (adjusted) than D (76%, p=0.05) and A (76%, p=0.06). Intermediate/high level resistance to ETR or RPV (in 51% and 62% respectively overall) was more common in subtype C (adjusted 63% and 76% respectively) than D (51% and 59% respectively, p<0.02) and A (47% and 60% respectively, p<001). Just 46% patients would be switched to a second-line regimen with predicted ≥ 1 active NRTI using the WHO algorithm (based on first-line NRTI history), but genotyping would identify a more active regimen in only an additional 35 (4%).

Poster Abstracts

“Prevalence of resistance mutations by subtype” Conclusions: We found differences between subtypes in resistance mutations at first-line failure. The impact on residual NRTI drug susceptibility was modest. However, subtype C developed higher rates of ETR and RPV resistance, limiting their potential utility in salvage regimens in resource-limited settings. 596 K65R Detected More Frequently in HIV-1 Subtype C Viruses at Virological Failure Erasmus Smit 1 ; EllenWhite 7 ; Duncan Clark 4 ; Duncan Churchill 2 ; Hongyi Zhang 6 ; Simon Collins 5 ; Deenan Pillay 3 ; AnnaTostevin 7 ; David Dunn 7 UKHDRD and UKCHIC 1 Public Health England, Birmingham, United Kingdom; 2 Brighton and Sussex Hospitals NHS Trust, Brighton, United Kingdom; 3 University of KwaZulu-Nata and University College London, London, United Kingdom; 4 St Batholomew’s and the London NHS Trust, London, United Kingdom; 5 HIV i-Base, London, United Kingdom; 6 Addenbrooke’s Hospital, Cambridge, United Kingdom; 7 University College London, London, United Kingdom Background: Theoretically, HIV-1 subtype C viruses have a greater propensity to develop a K65R mutation due to silent nucleotide polymorphisms at nearby codons (64-66) and/ or TAM codons which affect the probability of G Ç A transition. Although a high prevalence of K65R has been documented in Southern Africa cohorts, it is unclear whether this is explained by subtype per se or more general characteristics of these cohorts e.g. prolonged time on a failing regimen. We have exploited the diversity of viral subtypes within the UK to undertake a direct comparative analysis of this issue. Methods: We analysed patients infected with HIV-1 subtype B or C virus who had a resistance test (1996-2013) following virological failure (VF), regardless of type or line of regimen. Sequences with no major IAS-defined mutations were excluded; for patients with ≥ 2 tests, we selected the first test if K65R was ever detected or the last test if never detected. Prevalence of K65R was related to subtype and exposure to the NRTIs that primarily select for this mutation (TDF, ABC, ddI, d4T). Exposure was considered both as “current” (regimen at time of VF) and any previous exposure. A multivariate logistic regression model quantified the effect of subtype on the prevalence of K65R, adjusting for previous and current exposure to all four specified drugs. Results: 4,242 patients (3,439 subtype B, 803 subtype C) met the inclusion criteria. Subtype B patients were mostly MSM (77%), and those with subtype C mostly heterosexual (82%, F:M ratio=1.8). Overall, K65R was detected in 7.8% subtype B patients (median 5.0 years [IQR 1.6-7.8] after initiating ART) compared with 14.5% subtype C patients (2.5

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CROI 2015