CROI 2016 Abstract eBook

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Poster Abstracts

477 HIV Pretreatment Drug Resistance in Mexico: A Nationally RepresentativeWHO Survey Santiago Avila-Rios 1 ; Claudia García-Morales 1 ; DanielaTapia-Trejo 1 ; Margarita Matías-Florentino 1 ;Verónica Quiroz-Morales 1 ; Jesús Casillas-Rodríguez 2 ; Juan Sierra-Madero 3 ; Eddie León 4 ; Carlos Magis 4 ; Gustavo ReyesTeran 1 ; for the HIV Drug Resistance Mexican Network Group 1 Natl Inst of Respiratory Diseases, Mexico City, Mexico; 2 Condesa Specialised Clinic, Mexico City, Mexico; 3 Natl Inst of Med Scis and Nutrition Salvador Zubirán, Mexico City, Mexico; 4 Natl Cntr for HIV/AIDS Prevention and Control, Mexico City, Mexico Background: To ensure sustainability of antiretroviral treatment (ART) programmes after ART scale up, the WHO has proposed a global standardized HIV drug resistance (DR) monitoring and surveillance strategy, including the assessment of pre-treatment HIVDR (PDR). Methods: We present the first nationally representative WHO HIV PDR survey performed in Mexico from February to July 2015. Twenty-five clinics were selected to contribute with participants from 136 Ministry of Health facilities by probability-proportional-to-size sampling, according to the number of ART initiators observed in each clinic during 2013. PDR was assessed from plasma virus, based on the WHO surveillance HIVDR mutation list, using the Stanford CPR tool. All samples were processed in a WHO-accredited lab by Sanger sequencing using the software RECall and by next generation sequencing (NGS) using the software HyDRA. Results: A total of 274 participants were included in the study; 84%were men. The median CD4+ T cell count was 257 cells/uL reflecting the known late presentation to clinical care in the country. PDR to any antiretroviral (ARV) drug was 12.0% (95% CI: 8.4-16.5%). NNRTI PDR was highest (6.9%), followed by NRTI PDR (5.1%) and PI PDR (2.6%). The most frequent PDR mutations were RT K103N (4.0%), M41L (1.1%) and PR L90M (1.8%). The prevalence of PDR to any ARV drug estimated with NGS at a 20% DR mutation frequency threshold was 12.2%, but increased considering lower thresholds: 14.2% at 10%; 17.3% at 5%; 30.3% at 2%. The most frequent minority variants (<5% of the viral population) included PR M46I, N88D and RT D67G, K70E. At the 2% DR mutation frequency threshold, intermediate levels of NNRTI (7.8%), NRTI (10.9%) and PI (10.1%) PDR were observed. Three putative transmission clusters were found, one including a male and a female from Baja California with M41L, one with two MSM from Sonora with Y181C and one with a female and an MSM from Veracruz with DR to two drug classes. Conclusions: PDR in Mexico remains at the intermediate level, but individual PDR level to NNRTI has also reached intermediate level with high frequency of K103N, consistent with the wide use of efavirenz-containing first line regimens in the country. Low frequency DR mutations mainly to NRTI and PI were observed. Evidence of DR mutation transmission was found in specific geographic areas involving both heterosexuals and MSM. These observations warrant continuous PDR surveillance in the country. 478 The Dynamics of Drug Resistance Detected During Acute HIV Infection Ruth M. Kanthula 1 ; JulieWeis 2 ; ChrisWarth 2 ; Nelly R. Mugo 3 ; Lisa Frenkel 4 ; Connie M. Celum 1 ; Julie M. Overbaugh 2 ; Frederick Matsen 2 ; Jared M. Baeten 1 ; Dara Lehman 2 1 Univ of Washington, Seattle, WA, USA; 2 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 3 Kenya Med Rsr Inst, Thika, Kenya; 4 Seattle Children’s Rsr Inst, Seattle, WA, USA Background: HIV drug resistance detected during acute infection may be a result of transmission from an infected partner, selection by pre-exposure prophylaxis (PrEP), or error prone replication. Here we describe the long-term dynamics of resistance detected during early acute HIV infection. Methods: The Partners PrEP Study was a randomized trial in which serodiscordant partners were assigned to emtricitibine co-formulated with tenofovir (FTC/TDF) or TDF alone compared to placebo, and monitored for HIV infection monthly. In a previous study, baseline samples from 137 HIV serocovnverters were tested for drug resistance using 454 ultra deep sequencing at the time seroconversion was first detected. Here, we conducted resistance testing by 454 on plasma samples at 6, 12 and 24 months following seroconversion from individuals with resistance mutations detected during acute infection at frequencies ≥1% that had a Stanford score ≥30 and cause resistance to non-nucleoside or nucleoside reverse-transcriptase inhibitors (NNRTIs or NRTIs), including both PrEP and non-PrEP antiretrovirals. Results: There were 35/137 (26%) individuals with resistance detected at frequencies ≥1% at the time seroconversion was first identified: 30 had resistance to non-PrEP antiretrovirals (not TDF or FTC) likely due to transmitted resistance or error-prone replication and 11 individuals had PrEP-related mutations (K65R, K70E and M184IV); of whom 6 had both PrEP-related and non-PrEP mutations. Of the 35, 31 individuals had resistance results available through 12-24 months. Resistance faded to frequencies <1% in 16/31 (52%) individuals by 6 months after seroconversion and in 21/31 (68%) by 24 months. PrEP-selected mutations did not persist. In 5 individuals, resistance persisted at low frequencies between 1-10% of the viral population and in 3 individuals, resistance mutations K103N (n=2) or Y181C (n=1) persisted at frequencies ≥ 99% throughout follow-up. Conclusions: Among individuals who acquired HIV in a PrEP trial, non-PrEP (non TDF or FTC) mutations accounted for the majority of resistance detected during acute infection. Persistence of high frequency resistance was limited to 2 NNRTI mutations that were most likely transmitted. Most of the resistance present during acute infection faded below detection by 24 months regardless of whether it was selected or transmitted. These data suggest that in the absence of antiretroviral treatment, onward transmission of resistance is most likely to occur early after HIV infection. 479LB WITHDRAWN 480 Large Cluster Clinical Isolates Show Facilitated Escape From Integrase Inhibitors Bluma G. Brenner 1 ; Maureen oliveira 1 ; Ruxandra Ilinca Ibanescu 1 ; Olga Golubkov 1 ; Bonnie A. Spira 2 ; Mark A.Wainberg 2 1 Lady Davis Inst, Montreal, QC, Canada; 2 McGill Univ AIDS Cntr, Montreal, QC, Canada Background: Integrase inhibitors (INIs), including raltegravir (RGV), elvitegravir (EVG) and dolutegravir (DTG) are a drug class of choice in first-line therapy. Emergent resistance to EVG and RGV include N155H and G140A/G148RHQ pathways, conferring RGV/EVG cross-resistance, and Y143RHC (RGV) and T66I/E92Q/G (EVG) pathways. To date, DTG shows a higher barrier to resistance with no reported mutations in first-line therapy at 96 or 148 weeks. Phylogenetics shows a metamorphosis of the Quebec HIV epidemic towards large cluster outbreaks, averaging 43 linked transmissions/cluster. “Super-transmissible” viral lineages showed facilitated development of resistance in cell culture, revealing pathways to DTG resistance that could not be otherwise ascertained. Methods: Phylogenetic analysis identified cluster group association of newly diagnosed subjects recruited into the Montreal PHI cohort. Viral stocks from representative large cluster (cluster size 44, 44, 40, 24, 23, 71) and solitary transmissions (n=6) were amplified through co-culture of patient CD8-depleted peripheral blood mononuclear cells with human cord blood mononuclear cells (CBMCs). Selections of resistance to DTG, EVG, and RGV, were performed by repeat serial passage in CBMCs in the presence of increasing drug concentrations of drugs, based on weekly RT assays. Genotyping was performed at select passages to evaluate time to the development of drug resistance. Results: Whereas viruses belonging to solitary transmissions showed no emergent drug resistance to DTG at week 30, super-cluster lineages acquired DTG resistance within 6-12 weeks. Superclusters developed DTG resistance along R263K (2), S153Y, or H51Y pathways. Parallel EVG selections led to more complex resistance pathways. Dual selections with DTG and 3TC showed R263K emergence prior to M184I/V. Whereas DTG selections failed to accumulate mutations, R263K acquired with EVG selections led to further acquisition of INI mutations. Phenotypic assays monitored relative drug susceptibility to DTG, EVG, and RGV in the context of resistance mutations and natural polymorphisms. Conclusions: Although DTG confers a high barrier to resistance, large cluster viral lineages fast forward escape from drug pressure, providing unique insights on emergent resistance to INIs. 481 An Informatics Approach to Predicting Rates of Transmitted HIV-1 Drug Resistance Joseph M. Volpe 1 ; DongmeiYang 1 ; Suqin Cai 1 ; JayTimmerman 2 ; Charles M.Walworth 1 ; Jeannette M.Whitcomb 1 1 Monogram BioScis, South San Francisco, CA, USA; 2 LabCorp Informatics, Durham, NC, USA Background: National transmitted HIV-1 drug resistance (TDR) rates are typically monitored through HIV surveillance data and this represents the gold-standard for determining TDR rates in various populations. However, it often requires several years to prepare data for presentation and publication resulting in long lag times between data accumulation and result dissemination. Here we present a computational method using de-identified clinical test results from a large commercial database to infer TDR rates in near real-time.

Poster Abstracts


CROI 2016

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