scholarly journals No Emergent Resistance in HIV-1 Infected Virologically-Suppressed Subjects Who Switched to R/F/TAF

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S427-S427
Author(s):  
Danielle Porter ◽  
Rima Kulkarni ◽  
Huyen Cao ◽  
Devi Sengupta ◽  
Kirsten White
Keyword(s):  
Dna Analysis ◽  
Virologic Failure ◽  
Success Rates ◽  
Resistance Mutations ◽  
Double Blind ◽  
Resistance Development ◽  
Safety And Efficacy ◽  
Proviral Dna ◽  
Tenofovir Alafenamide ◽  
Hiv 1

Abstract Background GS-US-366-1216 and GS-US-366-1160 are randomized, double-blind, phase 3b studies evaluating the safety and efficacy of switching to rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF) from R/F/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/F/TDF, respectively, in HIV-1-infected virologically-suppressed subjects. At Week 48, switching to R/F/TAF was non-inferior to staying on R/F/TDF (94% vs. 94%, respectively) or EFV/F/TDF (90% vs. 92%) for HIV-1 RNA <50 c/mL (virologic success) by FDA snapshot analysis. Here, we present integrated resistance analyses of these two studies through Week 48. Methods Historical genotypes were collected when available. Subjects in the resistance analysis population (subjects with HIV-1 RNA ≥400 c/mL at virologic failure, discontinuation, or Week 48) had genotypic/phenotypic analyses at failure for protease and reverse transcriptase (RT; PhenoSense GT, Monogram). Subjects with post-baseline resistance mutations detected had their baseline proviral DNA analyzed retrospectively (GenoSure Archive, Monogram). Results Of the 1504 randomized and treated subjects, resistance development was analyzed for 7 subjects (0.9%; 7/754) on R/F/TAF, 1 subject (0.3%; 1/313) on R/F/TDF, and 2 subjects (0.5%; 2/437) on EFV/F/TDF. No R/F/TAF (0%) or R/F/TDF (0%) subjects developed primary NNRTI or NRTI resistance mutations. One EFV/F/TDF subject (0.2%; 1/437) developed primary NNRTI and NRTI resistance mutations (NNRTI: Y188L; NRTI: M184V). Three subjects on R/F/TAF had virologic rebound with mutations also detected at baseline by proviral DNA analysis. Historical genotypes were available for 527 subjects; virologic success rates were high among subjects with pre-existing mutations (Table 1). Conclusion No emergent resistance to any of the components of R/F/TAF was detected through 48 weeks after switching. Virologic success rates were high among subjects with pre-existing mutations. Disclosures D. Porter, Gilead Sciences, Inc.: Employee and Shareholder, Salary; R. Kulkarni, Gilead Sciences, Inc.: Employee and Shareholder, Salary; H. Cao, Gilead Sciences, Inc.: Employee and Shareholder, Salary; D. Sengupta, Gilead Sciences Inc.: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary

scholarly journals 2509. Pooled Resistance Analyses of Darunavir (DRV) Once Daily (QD) Regimens and Formulations Across 10 Clinical Studies of Treatment-Naïve (TN) and Treatment-Experienced (TE) Patients with Human Immunodeficiency Virus (HIV)-1 Infection

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S870-S871 ◽  
Author(s):  
Erkki Lathouwers ◽  
Sareh Seyedkazemi ◽  
Donghan Luo ◽  
Kimberley Brown ◽  
Sandra De Meyer ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Virologic Failure ◽  
Transcriptase Inhibitor ◽  
Resistance Testing ◽  
Resistance Development ◽  
Single Tablet Regimen ◽  
Treatment Naïve ◽  
Tenofovir Alafenamide ◽  
Hiv 1 ◽  
Phenotypic Susceptibility

Abstract Background DRV has demonstrated high efficacy and barrier to resistance development across diverse populations, from TN to heavily TE patients. We evaluated resistance data from 10 clinical studies of different DRV 800 mg QD–based antiretroviral regimens and formulations. Methods The analysis included patients from 10 phase 2/3 studies (48–192 weeks in duration) of ritonavir- and cobicistat-boosted DRV 800 mg QD–based regimens in TN and virologically failing or suppressed TE patients with HIV-1 (table). Three were phase 3 studies of the DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen (STR). Post-baseline resistance was evaluated in patients experiencing protocol-defined virologic failure (PDVF); definitions and criteria for resistance testing varied slightly among studies. Resistance-associated mutations (RAMs) were based on respective International Antiviral Society–USA mutation lists over time. Results Of the 3,635 patients evaluated, 250 met PDVF criteria and 205 had post-baseline genotypes/phenotypes. Overall, 4 (0.1%) patients developed (or had identified [switch studies]) ≥1 DRV and/or primary protease inhibitor (PI) RAM (table), and only 1 (< 0.1%, ODIN) patient lost DRV phenotypic susceptibility; this TE patient had prior VF with lopinavir. Among those who used a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone (mostly emtricitabine [FTC] + tenofovir [TFV]), 12 (0.4%) patients had ≥1 NRTI RAM, including 10 with M184I/V associated with FTC resistance. No TFV RAMs were observed. Among patients receiving D/C/F/TAF (n = 1,949), none had post-baseline DRV, primary PI, or TFV RAMs; only 2 (0.1%) patients developed an FTC RAM. Conclusion Across a large, diverse population using DRV 800 mg QD–based regimens and formulations, resistance development remains rare; 0.1% of patients had ≥1 DRV and/or primary PI RAM post-baseline. Among 3 trials of the D/C/F/TAF STR, no patients developed a DRV or primary PI RAM. After > 10 years of investigating DRV 800 mg QD–based regimens in clinical trials, loss of phenotypic susceptibility to DRV has never been observed in TN or TE virologically suppressed patients and was only once observed in a TE patient with prior VF on multiple antiretrovirals, including a PI. Disclosures All authors: No reported disclosures.

scholarly journals 1448. Forgiveness of BIC/FTC/TAF: In Vitro Simulations of Intermittent Poor Adherence Find Limited HIV-1 Breakthrough and High Barrier to Resistance

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S726-S727
Author(s):  
Andrew Mulato ◽  
Rima K Acosta ◽  
Stephen R Yant ◽  
Tomas Cihlar ◽  
Kirsten L White
Keyword(s):  
Virologic Failure ◽  
Resistance Development ◽  
Drug Concentrations ◽  
Suboptimal Adherence ◽  
Trough Concentrations ◽  
Tenofovir Alafenamide ◽  
Emergence Of Resistance ◽  
Perfect Adherence ◽  
Hiv 1

Abstract Background Short lapses in adherence to ARVs can lead to virologic failure and emergence of resistance. Previous in vitro studies of regimen “forgiveness” simulated drug exposures of perfect adherence or short-term suboptimal adherence with bictegravir+emtricitabine+tenofovir alafenamide (BIC+FTC+TAF) and with dolutegravir and lamivudine (DTG+3TC). Here, viral breakthrough (VB) and resistance development were evaluated under alternating high and low drug exposures simulating variable adherence levels. Methods Wild-type HIV-1 (IIIb)-infected MT-2 cells were exposed to drug combinations and monitored for VB. Experiments alternated between high and low drug concentrations of either BIC+FTC+TAF or DTG+3TC (Table 1). Drug concentrations for each regimen were determined using human plasma-free adjusted clinical trough concentrations (Cmin), at simulated Cmin after missing 2 or 4 consecutive doses (Cmin-2 and Cmin-4) based on drug half-lives. Emergent HIV-1 were genotyped by deep sequencing and a 2% threshold. Results In these experiments, constant drug concentrations corresponding to full adherence (Cmin) did not lead to VB. Using Cmin concentrations for one week followed by constant Cmin-2 exposures for 4 weeks, DTG+3TC had VB and emergence of M184V/I in reverse transcriptase (RT) but there was no VB for BIC+FTC+TAF. Using alternating drug exposures of Cmin (weeks 1 and 3) and Cmin-2 or Cmin -4 (weeks 2, 4, and 5), VB was not observed with BIC+FTC+TAF, and VB was decreased or delayed with DTG+3TC compared to DTG+3TC held at Cmin-2 or Cmin-4. Resistance development was observed in some cultures with VB: 1 culture with BIC+FTC+TAF had G163R in IN and 19 cultures with DTG+3TC had INSTI and RT resistance including 10 with M184V/I. Table 1. Summary of Breakthrough Frequency and Resistance Development Conclusion BIC+FTC+TAF has high in vitro forgiveness and consistent protection against emergence of drug resistance during simulations of short lapses in adherence. Higher DTG+3TC exposure, whether constant or intermittent, was better at preventing or delaying VB than lower DTG+3TC exposures, but DTG+3TC was less forgiving than BIC+FTC+TAF. Prevention of viral replication and resistance development is necessary to maintain lifelong viral suppression, particularly in the real world where drug adherence is often imperfect. Disclosures Andrew Mulato, BS, MBA, Gilead Sciences, Inc. (Employee, Shareholder) Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Stephen R. Yant, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Tomas Cihlar, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc. (Employee, Shareholder)

scholarly journals Viral Blips Were Infrequent in HIV-1-Infected Virologically-Suppressed Adults Treated with Tenofovir Alafenamide or Tenofovir DF Rilpivirine-Containing Regimens

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S428-S428
Author(s):  
David A Wohl ◽  
Rima Kulkarni ◽  
Will Garner ◽  
Kirsten White ◽  
Danielle Porter
Keyword(s):  
Virologic Failure ◽  
Outcome Data ◽  
Double Blind ◽  
Treatment Groups ◽  
Low Level ◽  
Tenofovir Df ◽  
Tenofovir Alafenamide ◽  
The Impact ◽  
Hiv 1 ◽  
Research Grant

Abstract Background Differences between regimens in the frequency of transient episodes of viremia (viral blips) as well as the impact of these viral blips on the risk of virologic failure and resistance development is not fully understood. Here we investigate the frequency of viral blips in virologically-suppressed subjects switching to rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF) vs. maintaining R/F/tenofovir disoproxil fumarate (TDF) and the association of viral blips with clinical outcome through Week 48 of study GS-US-366-1216. Methods GS-US-366-1216 is a randomized, double-blind, phase 3b study evaluating the safety and efficacy of switching to R/F/TAF from R/F/TDF in HIV-1-infected virologically-suppressed subjects. For the viral blip analysis, treated subjects with ≥1 post-baseline HIV-1 RNA value were included. All on-drug HIV-1 RNA data points and FDA snapshot outcome data through Week 48 were utilized. Plasma HIV-1 RNA was measured using the Roche Taqman 2.0 assay. A viral blip was defined as any post-baseline HIV-1 RNA value ≥50 c/mL preceded and followed by HIV-1 RNA &lt;50 c/mL. Results Of the 627 subjects included in the analysis, 23 (3.7%) experienced ≥1 blip through Week 48 and were distributed similarly between treatment groups (10/315, 3.2% R/F/TAF; 13/312, 4.2% R/F/TDF; P = 0.53; median 6 viral load measurements per subject). Twenty subjects had single blips (8 R/F/TAF, 12 R/F/TDF) and 3 subjects experienced 2 blips each (2 R/F/TAF, 1 R/F/TDF). Of 26 total blip events, 19 (73%) were low-level at 50–199 c/mL. Among subjects with blips, 22/23 (96%) were virologic successes at Week 48 (9/10, 90% R/F/TAF; 13/13, 100% R/F/TDF), similar to those subjects without blips (568/604, 94% overall; 287/305, 94% R/F/TAF; 281/299, 94% R/F/TDF). One subject in the R/F/TAF group had 2 blips prior to experiencing virologic rebound with mutations also detected at baseline (determined by retrospective proviral DNA sequencing). Conclusion Viral blips were infrequent among subjects switching to R/F/TAF or maintaining R/F/TDF through Week 48 of study GS-US-366-1216. No differences in blip frequency or virologic failure post-blip were observed between treatment groups. Most blips were low-level (&lt;200 c/mL) and most subjects with blips remained suppressed through Week 48. Disclosures D. A. Wohl, Gilead Sciences Inc.: Consultant and Investigator, Consulting fee and Research grant; ViiV: Consultant and Investigator, Consulting fee and Research grant; Janssen: Consultant, Consulting fee; Bristol Myers Squibb: Consultant, Consulting fee; R. Kulkarni, Gilead Sciences, Inc.: Employee and Shareholder, Salary; W. Garner, Gilead Sciences, Inc.: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary; D. Porter, Gilead Sciences, Inc.: Employee and Shareholder, Salary

scholarly journals Proviral DNA as a Target for HIV-1 Resistance Analysis

Intervirology ◽  
2015 ◽  
Vol 58 (3) ◽  
pp. 184-189 ◽  
Author(s):  
Nadine Lübke ◽  
Veronica Di Cristanziano ◽  
Saleta Sierra ◽  
Elena Knops ◽  
Eugen Schülter ◽  
...  
Keyword(s):  
Resistance Testing ◽  
Detectable Viral Load ◽  
Resistance Mutations ◽  
Proviral Dna ◽  
Drug Resistance Mutations ◽  
Resistance Analysis ◽  
Additional Resistance ◽  
Plasma Rna ◽  
Hiv 1 ◽  
Rna And Dna

Background: Resistance analysis from viral RNA is restricted to detectable viral load. Therefore, analysis from proviral DNA could help in cases with low-level or suppressed viremia. Methods: Viral plasma RNA and the corresponding cellular proviral DNA of 78 EDTA samples from 48 therapy-naïve (TN) and 30 therapy-experienced (TE) HIV-1-infected patients were isolated and analyzed for their resistance profiles in the protease and reverse transcriptase genes. Results: Overall, 175 drug-resistance mutations (DRMs) were detected in 25/30 TE (83.3%) and 5/48 TN (10.4%) samples. The TE patients displayed a mean number of 6.68 DRMs in RNA and 5.20 in DNA. In the TN patients, a mean of 0.8 DRMs was found in RNA and 1.0 in DNA; 75% of the DRMs were detected in RNA and DNA simultaneously. In the TE samples, 76% of the DRMs were detected simultaneously in RNA and DNA, 23% exclusively in RNA and 1% in DNA only. The TN samples revealed a significantly higher frequency of DRMs in DNA than in RNA. Conclusions: Proviral DNA resistance testing provides additional resistance information for TN patients. It is also a reliable alternative for TE patients with unsuccessful RNA testing and can provide valuable information when no records are available.

scholarly journals HIV-1 resistance profile in plasma and peripheral blood lymphocytes in a group of naive patients

2012 ◽  
Vol 64 (4) ◽  
pp. 1261-1270 ◽  
Author(s):  
Marina Siljic ◽  
Dubravka Salemovic ◽  
Dj. Jevtovic ◽  
Ivana Pesic-Pavlovic ◽  
Sonja Zerjav ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Viral Rna ◽  
Resistance Mutations ◽  
Primary Resistance ◽  
Resistance Profile ◽  
Proviral Dna ◽  
Drug Resistance Mutations ◽  
Hiv 1

Transmitted HIV-1 drug resistance (TDR) is a persisting problem, even though the prevalence of primary resistance may remain stable or start to decline. Proviral DNA detectable in peripheral blood mononuclear cells (PBMCs) is a reservoir of drug resistant viral variants and could be an alternative marker to viral RNA for the detection of drug resistance mutations. The aim of this study was to compare the HIV-1 resistance profile between plasma viral RNA and proviral DNA in a group of untreated patients. Thirty-one HIV-1 seropositive patients without prior ARV treatment were included in the study. The presence of non-polymorphic drug resistance mutations was identified in 10 cases in proviral DNA and in 11 cases in plasma according to different scoring systems. Our results show a similar resistance profile between plasma RNA and proviral DNA, but with some discordances present. The sequencing of proviral DNA could provide useful additional information with regard to primary resistance.

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