CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

551 HIGH LEVEL OF PREEXISTING NRTI RESISTANCE PRIOR TO SWITCHING TO B/F/TAF: STUDY 4030 Rima K. Acosta , Madeleine Willkom, Kristen Andreatta, Hui Liu, Ross Martin, Silvia Chang, Hal Martin, Sean Collins, Kirsten L. White Gilead Sciences, Inc, Foster City, CA, USA Background: Bictegravir (B) is coformulated with the nucleoside/tide reverse transcriptase inhibitors (NRTIs) emtricitabine (F) and tenofovir alafenamide fumarate (TAF) (B/F/TAF). Study 4030 is an ongoing, fully enrolled, phase 3, randomized, double-blinded study (n=565) of HIV-1 RNA suppressed participants on QD dolutegravir (DTG) + F/TAF or F/tenofovir disoproxil fumarate (TDF) switching 1:1 to DTG + F/TAF or B/F/TAF for 48 weeks. Documented INSTI resistance was not enrolled if known at randomization, but all NRTI, NNRTI, and PI resistance was allowed. Methods: Proviral DNA genotypes (GenoSure Archive) from baseline samples and historical plasma HIV-1 RNA genotypes were analyzed. Documented or suspected NRTI resistance was assigned to group 1) K65R/E/N or ≥3 TAMs containing M41L or L210W (TAMs: D67N, K70R, L210W, T215F/Y, and K219Q/ E/N/R), group 2) M184I/V, any other set of TAMs, K70E/G/M/Q/S/T, L74I/V, V75A/S/M/T, Y115F, T69D, or Q151M, or group 3) no major NRTI resistance. Virologic outcomes used last available on-treatment HIV-1 RNA with the blinded Week 12 IDMC data cut. Results: Historical genotypes were available from 285/565 participants (50%). Retrospective analysis of archived mutations by HIV DNA genotype were determined for 377/565 participants; 200 also had historical genotypes. In total, 82% (462/565) of participants had pre-switch genotypic data available resulting in 24%with major NRTI resistance: 5% (29/565) in group 1 (K65R or ≥3TAMs) and 18% (104/565) in group 2 (other NRTI mutations). M184V/I was present in 17% (77/462) of participants with data. HIV DNA genotyping identified previously unknown major NRTI resistance in 15% of participants (58/377). Pre-existing INSTI mutations were found in 5% of participants (19/399): T97A (n=12), N155S (N=1), Y143H (n=2), R263K (n=2), Q148H+G140S (n=1), and S147G (n=1). Primary non-nucleoside RT inhibitor and protease inhibitor resistance mutations were present in 24% (113/462) and 8% (36/462) of participants. At this interim analysis, HIV-1 RNA <50 copies/mL was maintained in 99% of participants, 97% (28/29) in group 1, 99% (103/104) in group 2, 97% (75/77) with M184V/I, and 100% (19/19) with INSTI-R. Conclusion: This study found frequent NRTI resistance in suppressed participants switching from a DTG + F/TDF or F/TAF regimen, much of which was previously undocumented. Early data show high suppression using potent triple therapy of B/F/TAF or DTG + F/TAF. 552 LONG-TERM B/F/TAF SWITCH EFFICACY IN PATIENTS WITH ARCHIVED PREEXISTING RESISTANCE Kristen Andreatta , Madeleine Willkom, Ross Martin, Silvia Chang, Hui Liu, Ya-Pei Liu, Hiba Graham, Hal Martin, Kirsten L. White Gilead Sciences, Inc, Foster City, CA, USA Background: Studies 1844 and 1878 demonstrated non-inferior efficacy of switching suppressed HIV-1-infected adults to bictegravir/emtricitabine/ tenofovir alafenamide (B/F/TAF) versus continuing dolutegravir- (DTG) or boosted protease inhibitor (PI)-based regimens. At week 48, 93% in the B/F/TAF groups versus 95% in the DTG group and 89% in the PI group had HIV-1 RNA <50 copies/mL by snapshot algorithm, after which B/F/TAF treatment continued open-label. Here, we present resistance analyses and virologic outcomes after 2 years of B/F/TAF treatment. Methods: Archived preexisting HIV-1 drug resistance was assessed by historical genotypes (documented resistance to study drugs was exclusionary) and retrospective baseline proviral DNA genotyping (Archive assay, Monogram Biosciences). Participants with resistance to study drugs detected post- randomization were allowed to continue on study. Virologic outcomes were based on last available on-treatment HIV-1 RNA. Results: Altogether, 572 participants switched to B/F/TAF and were treated for a median of 108 weeks (IQR 106-118 weeks). Pre-switch reverse transcriptase (RT) genotypic data were available for 78% (447/572) of B/F/TAF-treated participants; integrase data were available for 55% (314/572). Preexisting primary NRTI resistance (-R), NNRTI-R, and INSTI-R substitutions were observed in 16% (71/447), 21% (93/447), and 1.9% (6/314), respectively. High frequencies of NRTI-R substitutions M184V or M184I (9.8%, 44/447) and thymidine analog mutations (TAMs; 8.5%, 38/447) were detected by DNA genotyping. Substitutions associated with resistance to the NNRTI rilpivirine (RPV) were

observed in 9.6% (43/447). At the time of analysis, 99% (564/572) of B/F/ TAF-treated participants were suppressed (HIV-1 RNA <50 copies/mL), including 95% (42/44) with archived M184V/I, 95% (36/38) with TAMs, 98% (42/43) with RPV-R, and 100% (6/6) with INSTI-R. There was no resistance development in B/F/TAF-treated participants through week 48, and no participants met criteria for resistance testing after week 48. Conclusion: Preexisting RT resistance was common among suppressed participants switching to B/F/TAF, notably RPV-R and previously unidentified M184V/I and TAMs. High rates of virologic suppression were observed in the overall and drug resistant populations through 108 weeks of B/F/TAF treatment with no resistance development, indicating that B/F/TAF is a durable switch option for suppressed patients, including those with evidence of this archived NNRTI and NRTI resistance. 553 ACTIVITY OF BICTEGRAVIR AGAINST HIV-2 ISOLATES AND INI-RESISTANT HIV-2 MUTANTS Robert A. Smith 1 , Dana Raugi 1 , Vincent H. Wu 1 , Christopher Zavala 1 , Jennifer Song 1 , Moussa Seydi 2 , Geoffrey S. Gottlieb 1 , for the University of Washington- Dakar HIV-2 Study Group 1 University of Washington, Seattle, WA, USA, 2 CHU de Fann, Dakar, Senegal Background: Bictegravir (GS-9883; Gilead Sciences, Inc.) is the most recent second-generation integrase inhibitor (INI) to be approved by the FDA for use in HIV-1–infected patients. For HIV-2, published data regarding the activity of bictegravir are limited to in vitro testing of single group B isolate (Tsai et. al., Antimicrob. Agents Chemother. 60:7086). To evaluate the potential suitability of bictegravir for HIV-2 treatment, we tested the activity of the drug against a panel of group A and group B HIV-2 isolates that were originally obtained from antiretroviral-naïve individuals. HIV-1 isolates representing group M subtypes A, B, C, and D, and group O, were included for comparison. We also determined the antiviral activity of bictegravir against raltegravir-resistant mutants of HIV-2. Methods: Antiviral activity was measured in single-cycle assays using the MAGIC-5A indicator cell line (HeLa-CD4-LTR-βgal cells). Site-directed mutants of HIV-2 integrase were constructed in the pROD9 HIV-2 molecular clone using QuikChange II XL reagents and procedures (Agilent Technologies). The cytotoxicity of bictegravir was assessed via the CellTiter-Glo® assay (Promega) Results: 50% effective concentrations (EC 50 values) for bictegravir ranged from 1.2–2.4 nM for HIV-1 (n = 6 isolates), and 1.4–5.5 nM for HIV-2 (n = 15 isolates). Average EC 50 s (± SD) for HIV-1 and HIV-2 were 1.6 ± 0.4 nM and 2.4 ± 1.1 nM, respectively. HIV-2 ROD9 variants Q91R+T97A+Y143C and Q91R+T97A+Y143C+A153S were fully susceptible to bictegravir (EC 50 = 1.2 nM and 1.6 nM, respectively, versus 2.1 nM for virus from the parental pROD9 clone). Mutations G140A+Q148R, E92Q+T97A+N155H, and I84V+E92Q+T97A+A153S+N155H conferred low-level (4–5-fold) resistance to bictegravir, whereas G140S+Q148R conferred 34-fold resistance to the drug. The 50% cytotoxic concentration (CC 50 ) for bictegravir in MAGIC-5A cells was >10 µM. Conclusion: Bictegravir is highly active against HIV-2 in culture, with EC 50 values comparable to those seen for HIV-1. The available data suggest that, for HIV-2, the resistance profile for bictegravir is similar to the profiles observed for dolutegravir and cabotegravir. These findings suggest that bictegravir could be useful for HIV-2 ART and should be further assessed in clinical trials. 554 SPECIFICITY OF 4 POINT-OF-CARE RAPID HIV TESTS IN A SETTING WITH HIGH PrEP USE Pollyanna R. Chavez 1 , Laura Wesolowski 1 , Lauren Violette 2 , Lisa Niemann 2 , Vanessa M. McMahan 2 , Andy M. Cornelius-Hudson 2 , David A. Katz 2 , Steven Ethridge 1 , Joanne Stekler 2 , Kevin P. Delaney 1 1 CDC, Atlanta, GA, USA, 2 University of Washington, Seattle, WA, USA Background: In the United States, performance evaluations of recently FDA-approved rapid HIV tests have been conducted in laboratory settings using plasma and simulated whole blood. Previously published specificity estimates for newer rapid HIV tests when used in point-of-care (POC) settings have not included estimates for persons on Pre-Exposure Prophylaxis (PrEP). Methods: During September 2015 – August 2018, persons at risk for HIV and seeking HIV testing at a public health clinic in Seattle, WA were invited to participate in the study. Consenting participants completed a behavioral questionnaire that assessed history of PrEP use and were tested with four POC tests using whole blood (see table).Additional blood specimens were collected for laboratory processing and testing. Specimens with a non-reactive

Poster Abstracts

CROI 2019 207