CROI 2016 Abstract eBook

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Poster Abstracts

Results: We find that resistance to treatments with low clinical efficacy generates patterns consistent with soft sweeps, as marked by the relatively small decrease in diversity associated with resistance. In contrast, populations receiving treatments with high clinical efficacy showed large decreases in diversity associated with a drug resistance mutation taking over the population within a patient, a pattern more consistent with hard sweeps. Among patients given treatments with 30% efficacy, sequences with 3 DRMs are predicted to have marginally fewer ambiguous calls as those with 0 DRMs (0.5 fewer ambiguous reads over 1000 bases), but among those patients given treatments with 80% efficacy, sequences with 3 DRMs are predicted to have 10 fewer ambiguous calls than those with 0 DRMs over 1000 bases, a substantial decrease in genetic diversity. Conclusions: We confirm that the transition from fast to slow evolution of drug resistance was indeed accompanied with the expected transition from soft to hard selective sweeps. These results suggest that effective drugs may push HIV-1 populations into a hard sweep regime in which populations must wait long periods of time for the correct mutation. 496 PooledWeek 48 Analysis of HIV-1 Drug Resistance in E/C/F/TAF Phase 3 Studies Michael Abram ; Nicolas A. Margot; Stephanie Cox; Renee R. Ram; Danielle P. Porter; Kathryn M. Kitrinos; Marshall Fordyce; Scott McCallister; Michael Miller; Christian D. Callebaut Gilead Scis, Inc, Foster City, CA, USA Background: Seven ongoing Phase 3 studies are evaluating the efficacy and safety of the elvitegravir (E)/cobicistat (C)/emtricitabine (F)/tenofovir alafenamide (TAF) fixed dose combination (E/C/F/TAF) in ART-naive adult (GS-US-292-0104 and GS-US-292-0111) and adolescent (GS-US-292-0106) subjects, virologically suppressed subjects with (GS-US-292- 0119) or without (GS-US-292-0109) ≥2 class resistance, subjects with mild to moderate renal impairment (GS-US-292-0112), and subjects with HIV/HBV co-infection (GS-US-292- 1249). Virologic success rates of E/C/F/TAF at Week 48 using FDA snapshot analysis and HIV-1 RNA < 50 copies/mL was high and similar among all studies (86.6-97.2%) and showed non-inferiority to comparator arms. Here we present a pooled Week 48 resistance analysis for these Phase 3 studies across the different treatment populations. Methods: Genotypic analyses were performed at screening to assess HIV-1 protease (PR), reverse transcriptase (RT) and integrase (IN) susceptibility to study drugs. Confirmed virologic failure visits through Week 48 or at discontinuation with ≥400 copies/mL HIV-1 RNA were analyzed for emergent genotypic and phenotypic resistance. Results: A total of 2308 subjects were enrolled in these E/C/F/TAF studies. Among ART-naive adults, 16 of 866 were analyzed; 7 (0.8%) developed NRTI RAMs (M184V/I, n=7; K65R, n=1) and also primary INSTI RAMs (T66I/A, n=2; E92Q, n=2; Q148R, n=1, N155H, n=1). Among ART-naive adolescents, 2 of 50 subjects were analyzed and did not develop RAMs. Among virologically suppressed subjects, 4 of 959 were analyzed; 1 developed resistance (M184M/I) and resuppressed to < 50 copies/mL before treatment discontinuation. Among virologically suppressed subjects with prior ≥2 class resistance, none of the 110 subjects met the analysis criteria. Among renally impaired subjects, 2 of 248 were analyzed; both subjects had multi-class resistance detected: 1 pre-existing and 1 due to possible re-infection followed by resuppression to < 50 copies/mL. Among HBV co-infected subjects, 0 of 75 subjects met the analysis criteria. Conclusions: In these 7 Phase 3 studies, E/C/F/TAF achieved high rates of virologic suppression through 48 weeks of treatment. The presence of PI, NRTI, or NNRTI RAMs at baseline did not affect treatment response. Resistance development to ≥1 components of E/C/F/TAF was rare in all studied populations, even in highly treatment-experienced subjects switching to E/C/F/TAF. 497 HIV Drug Resistance Testing Among Patients New to HIV Care in the United States Angela L. Hernandez 1 ; EduardoValverde 1 ; JohnWeiser 1 ; Linda Beer 1 ;YunfengTie 2 ; M. Cheryl Banez Ocfemia 1 ; Alexandra M. Oster 1 1 CDC, Atlanta, GA, USA; 2 ICF Intl, Atlanta, GA, USA Background: To guide antiretroviral therapy (ART), the U.S. Department of Health and Human Services and the International Antiviral Society–USA recommend baseline genotypic HIV drug resistance testing for HIV-infected persons at entry into care or as soon as possible after diagnosis. We assessed reported HIV genotype testing of patients new to HIV care among HIV care providers in the United States. Methods: We used data collected during 06/2013–01/2014 through the Medical Monitoring Project HIV Provider Survey, which was administered to a nationally representative sample of HIV care providers in the United States. Providers were asked for what proportion of patients new to HIV care they order HIV genotype testing as part of the initial evaluation; we included responses from 1,193 providers who answered this question. We weighted the data to account for unequal selection probabilities and non-response. We performed bivariate analyses and calculated prevalence ratios (PR) and 95% confidence intervals (CI) to examine differences in genotype testing for all patients by provider, practice, and medical care characteristics, including qualifications as an HIV specialist as defined by the HIV Medicine Association or the American Academy of HIV Medicine. Results: In all, 84.5% (CI=80.4%–88.5%) of providers reported ordering genotype testing for all patients; 8.8% (CI=5.9%–11.7%) for more than half, but not all patients; and 6.7% (CI=2.8–10.6%) for half of patients or fewer. Ordering genotype testing for all patients was significantly less common among: non-specialists (PR=0.89, CI=0.80–0.99) compared with HIV specialists; providers in private practices (PR=0.91, CI=0.82–1.00) compared with those at other facility types; and providers who first prescribe ART based on CD4 count (PR=0.83, CI=0.75–0.91) compared with providers who prescribe ART regardless of CD4 count. Conclusions: Most providers in the United States reported ordering genotype testing for all patients new to HIV care. Providers in private practice and non-specialists were less likely to order genotype testing for all patients and may benefit from additional support to implement drug resistance testing guidelines. As providers move toward adopting guidelines for universal ART prescription, we may also see increasing adoption of baseline genotype testing recommendations. 498 Protease Inhibitor Resistance at 2nd-line HIV Treatment Failure in Sub-Saharan Africa Tamara Sonia Boender 1 ; Raph Hamers 1 ; Pascale Ondoa 1 ; MaureenWellington 2 ; Margaret Siwale 3 ; Cissy Kityo 4 ; Sulaimon Akanmu 5 ; Kishor Mandaliya 6 ;Tobias Rinke deWit 1 ; Kim Sigaloff 1 ; for the PanAfrican Studies to Evaluate Resistance (PASER) Study Group 1 Amsterdam Inst for Global Hlth and Develop, Amsterdam, Netherlands; 2 Newlands Clinic, Harare, Zimbabwe; 3 Lusaka Trust Hosp, Lusaka, Zambia; 4 Joint Clinical Rsr Cntr, Kampala, Uganda; 5 Lagos Univ Teaching Hosp, Lagos, Nigeria; 6 Coast Province General Hosp, Mombasa, Kenya Background: As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of HIV-positive people will experience treatment failure, and require second- or third-line ART. It is yet unclear howmany patients will develop protease inhibitor (PI) resistance and need third-line ART regimens. Methods: HIV-1 positive adults were enrolled in the PanAfrican Studies to Evaluate Resistance Monitoring (PASER-M) cohort, at the time of switch to second-line PI-based ART, and included in the analysis if they received >180 days of second-line ART. We assessed risk factors for virological failure (viral load >400 cps/ml) after up to 3 years of second-line PI-based ART using Cox models. If viral load was ≥1,000 cps/ml, pol genotyping was performed. Drug resistance mutations were scored using the 2014 IAS-USA drug mutation list and genotype susceptibility was calculated using the Stanford algorithm Version 7.0. Results: Of 227 included participants, 25.0% (n=54/216) experienced virological failure at some point during follow-up at a rate of 138.9 failures (95%CI 106.4-181.3) per 1,000 person-years. In multivariable analysis the risk factors for virological failure were: failing a non-standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimen (hazard ratio [HR] 7.10; 95%CI 3.40-14.83; p<0.001) or PI-based first-line regimen (HR 7.59; 95%CI 3.02-19.07; p=0.001) compared to ZDV/3TC/NNRTI, PI-resistance at switch (HR 6.69; 95%CI 2.49-17.98; p<0.001) and <95% adherence (HR 3.05; 95%CI 1.71-5.42; p=0.025). For 32/43 (74%) participants with VL≥1,000 cps/ml during follow-up, genotypic data was available. At least one drug resistance mutation was found among 22/32 (69%) participants. Major PI mutations were detected in 7 (21.9%). The acquired mutations conveyed reduced susceptibility to all PIs ( figure ). Conclusions: While over 85% of participants on 2 nd -line ART had viral suppression after up to 36 months, major PI resistance was detected in 22% of those failing second-line ART. This represents approximately 3% of people initiating 2 nd -line ART. Future treatment of these individuals require third-line drugs (i.e. darunavir/ritonavir, etravirine and raltegravir), which are currently unavailable in sub-Saharan Africa. To ensure long-term ART success, availability of third-line drug options, preferably guided by HIV drug resistance testing, is urgently needed.

Poster Abstracts

193

CROI 2016