Dataset Information

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

ABSTRACT:

Background

Preexisting drug resistance limits the utility of HIV antiretroviral therapy. Studies have demonstrated safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), including in patients with M184V/I substitutions.

Setting

We investigated virologic outcomes through 48 weeks of B/F/TAF treatment in individuals with preexisting primary integrase strand transfer inhibitor resistance (INSTI-R).

Methods

Preexisting INSTI-R was retrospectively evaluated from 7 B/F/TAF studies. INSTI-R was assessed by historical genotypes and/or baseline RNA or DNA sequencing. Viral loads were measured at all visits.

Results

Preexisting primary INSTI-R substitutions were detected in 20 of the 1907 participants (1.0%). The 20 participants were predominantly male (75%), were Black (65%), had HIV-1 subtype B (85%), and had baseline median CD4 counts of 594 cells/mm3 and median age of 52 years. Most of the participants (n = 19) were virologically suppressed at baseline and had one primary INSTI-R substitution, E92G, Y143C/H, S147G, Q148H/K/R, N155S, or R263K, +/-secondary substitutions. All suppressed participants maintained virologic suppression throughout 48 weeks without any viral blips. One treatment-naive participant had virus with Q148H+G140S that was fully sensitive to bictegravir but only partially to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). With a baseline viral load of 30,000 copies/mL, this participant was virologically suppressed by week 4 and maintained <50 copies/mL through week 48.

Conclusions

This small cohort with primary INSTI-R achieved and/or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against most INSTI-R patterns, B/F/TAF may be a potential treatment option for patients with select preexisting INSTI-R, if confirmed by further studies.

SUBMITTER: D'Antoni ML

PROVIDER: S-EPMC8860220 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

D'Antoni Michelle L ML Andreatta Kristen K Acosta Rima R Martin Hal H Chang Silvia S Martin Ross R White Kirsten L KL

Journal of acquired immune deficiency syndromes (1999) 20220401 4

<h4>Background</h4>Preexisting drug resistance limits the utility of HIV antiretroviral therapy. Studies have demonstrated safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), including in patients with M184V/I substitutions.<h4>Setting</h4>We investigated virologic outcomes through 48 weeks of B/F/TAF treatment in individuals with preexisting primary integrase strand transfer inhibitor resistance (INSTI-R).<h4>Methods</h4>Preexisting INSTI-R was retrospectively eval ...[more]

PMID: 34897227

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Project description:ObjectivesStudies 1878 and 1844 demonstrated non-inferior efficacy of switching suppressed HIV-1-infected adults to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) versus continuing boosted PI-based triple regimens or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). Here, detailed analyses of pre-existing resistance in the two BIC/FTC/TAF switch studies and efficacy at week 48 are described.MethodsPre-existing resistance was assessed from historical genotypes (documented resistance to study drugs was excluded) and by retrospective baseline proviral archive DNA genotyping from whole blood. Outcomes were based on HIV-1 RNA at week 48 with missing values imputed using the last on-treatment observation carried forward method.ResultsCumulative pre-existing resistance data from historical and proviral genotypes were obtained for 95% (543/570) of participants who switched to BIC/FTC/TAF. Altogether, 40% (217/543) had one or more pre-existing primary resistance substitutions in protease, reverse transcriptase and/or integrase. Pre-switch NRTI resistance was detected in 16% (89/543) of BIC/FTC/TAF-treated participants, with M184V or M184I detected by proviral genotyping in 10% (54/543). At week 48, 98% (561/570) of all BIC/FTC/TAF-treated participants versus 98% (213/217) with pre-existing resistance and 96% (52/54) with archived M184V/I had HIV-1 RNA <50 copies/mL. No BIC/FTC/TAF-treated participants developed treatment-emergent resistance to study drugs.ConclusionsPre-existing resistance substitutions, notably M184V/I, were unexpectedly common among suppressed participants who switched to BIC/FTC/TAF. High rates of virological suppression were maintained in the overall study population and in those with pre-existing resistance, including M184V/I, for up to 48 weeks of BIC/FTC/TAF treatment with no resistance development. These results indicate that BIC/FTC/TAF is an effective treatment option for suppressed patients, including those with evidence of archived NRTI resistance.

Project description:BackgroundIntegrase strand transfer inhibitors (INSTIs) are recommended for first-line antiretroviral therapy in combination with two nucleos(t)ide reverse transcriptase inhibitors. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF), a novel, INSTI-based regimen, is currently approved in the US and EU for the treatment of HIV-1 infection and recommended as first-line treatment in current guidelines. In our current analysis, we aimed to determine changes in patient-reported symptoms over time among HIV-1-infected adults who initiated or switched to B/F/TAF versus another INSTI-based regimen, co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC).MethodsA planned secondary analysis of patient-reported outcomes was conducted for two double-blind, randomized, phase III studies in HIV-1-infected adults comparing B/F/TAF with ABC/DTG/3TC: one in treatment-naïve individuals (GS-US-380-1489, ClinicalTrials.gov NCT02607930) and the other in virologically suppressed participants (GS-US-380-1844, ClinicalTrials.gov NCT02603120). In both studies, the HIV symptoms distress module (HIV-SI) was administered at baseline (BL) and weeks 4, 12, and 48. Responses to each of the 20 items were dichotomized as bothersome or not bothersome. Treatment differences were assessed using unadjusted and adjusted logistic regression models (adjusted for BL HIV-SI count, age, sex, BL Veterans Aging Cohort Study [VACS] Index, medical history of serious mental illness, BL Short Form [SF]-36 Physical Component Summary [PCS], BL SF-36 Mental Component Summary [MCS], and, for virologically suppressed participants only, years since HIV diagnosis). We conducted longitudinal modeling of bothersome symptoms using a generalized mixed model including treatment, time, time-by-treatment, and additional covariates from the adjusted logistic regression model as described above. The Pittsburgh Sleep Quality Index (PSQI) was administered at the same frequency as the HIV-SI, and the total score was dichotomized as good or poor sleep quality. Similar models to those used for HIV-SI were applied, using BL sleep quality and BL SF-36 MCS as covariates. Statistical significance was assessed using p < 0.05.ResultsAcross both studies, bothersome symptoms were reported by fewer participants on B/F/TAF than those on ABC/DTG/3TC. In treatment-naïve adults, fatigue/loss of energy, nausea/vomiting, dizzy/lightheadedness, and difficulty sleeping were reported significantly less with B/F/TAF at two or more time points. Fatigue and nausea were also significantly less common for those receiving B/F/TAF in longitudinal models. In virologically suppressed participants, nausea/vomiting, sad/down/depressed, nervous/anxious, and poor sleep quality (from the PSQI) were reported significantly less with B/F/TAF at two or more time points, as well as in longitudinal models.ConclusionsB/F/TAF was associated with lower prevalence of bothersome symptoms than ABC/DTG/3TC in both treatment-naïve and virologically suppressed adults.

Project description:BackgroundWe characterized the efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a broad population of pediatric/adolescent/adult/elderly females living with HIV (FWH).SettingIntegrated analysis.MethodsAvailable data from 5 trials were integrated. Week 48 virologic suppression (HIV-1 RNA <50 copies/mL), resistance, adverse events (AEs), and laboratory parameters were assessed.ResultsThree hundred and seventy-three FWH [304 virologically suppressed; 69 antiretroviral therapy (ART)-naive] received B/F/TAF [data from comparator regimens available for 306 individuals (236 virologically suppressed and 70 ART-naive participants)]. Virologic suppression rates with B/F/TAF at week 48 were high regardless of age in participants virologically suppressed at baseline (≥95%) and in ART-naive participants (≥87%). Virologic suppression rates were similar in B/F/TAF and comparator regimens (both virologically suppressed and ART-naive groups). Treatment-emergent resistance was not detected in the B/F/TAF group. AEs considered related to study drugs were experienced by 9.2% (B/F/TAF) and 5.5% (comparator regimen) of virologically suppressed participants and 15.9% (B/F/TAF) and 31.4% (comparator regimen) of ART-naive participants. For virologically suppressed and ART-naive FWH combined, only 1 of the 373 B/F/TAF-treated and 2 of the 306 comparator-regimen participants discontinued because of AEs (none were bone/renal/hepatic AEs); grade 3/4 AEs were experienced by 5.1% (B/F/TAF) and 7.8% (comparator regimen); and grade 3/4 elevation of low-density lipoprotein/total cholesterol occurred in 2.7%/0.3% (B/F/TAF) and 5.9%/2.0% (comparator regimen). At week 48, median changes from baseline estimated glomerular filtration rate in adults were <5 mL/min; results were similar in B/F/TAF and comparator-regimen groups.ConclusionB/F/TAF treatment was effective and well tolerated over 48 weeks, confirming B/F/TAF as an option for a broad population of FWH.

Project description:Abstract Background Switching to cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) administered every month (Q1M) has demonstrated non-inferiority in viral suppression versus a range of standard of care (SoC) antiretroviral regimens, including tenofovir alafenamide based regimens, in two pivotal phase 3 clinical trials (ATLAS [NCT02951052] and FLAIR [NCT02938520]). Furthermore, CAB LA + RPV LA every 2 months (Q2M) has demonstrated non-inferiority in maintaining viral suppression compared with CAB LA + RPV LA Q1M in a phase 3b study (ATLAS-2M [NCT03299049]). As bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was not widely used at study initiation, the regimen was not present in the SoC arms of ATLAS and FLAIR. The objective was to compare efficacy and safety of CAB LA + RPV LA Q2M to BIC/FTC/TAF using indirect treatment comparison. Methods Two switch studies appropriate for facilitating indirect comparison to BIC/FTC/TAF were identified via systematic literature review (Molina et al. 2018 [NCT02603120] and Sax et al. 2020 [NCT03110380]). Indirect comparison using a generalisation of Bucher’s methodology to calculate relative risk, odds ratio, and risk differences in efficacy (Week 48 HIV RNA < 50 c/mL and ≥50 c/mL per FDA Snapshot approach and CD4+ cell change from baseline) and safety (discontinuation due to adverse events [AEs] and overall and serious AEs excluding injection site reactions [ISRs]) was conducted. Results for CAB LA + RPV LA Q2M in ATLAS-2M participants with prior integrase inhibitor (INI) exposure, but without prior CAB exposure, were indirectly compared to those with prior INI use in ATLAS and FLAIR via the common CAB LA + RPV LA Q1M comparator and were then indirectly compared to BIC/FTC/TAF via the INI comparator (Figure 1). Results No statistically significant differences in virologic failure, virologic suppression, CD4+ cell change, discontinuations due to AEs, and non-ISR serious/non-serious AEs were found between CAB LA + RPV LA Q2M and BIC/FTC/TAF (Table 1). Conclusion Indirect treatment comparison indicated efficacy and safety of CAB LA + RPV LA Q2M is not different from BIC/FTC/TAF. These regimens will be further compared in a randomized head-to-head non-inferiority trial (SOLAR, NCT04542070). Disclosures Sonya J. Snedecor, PhD, ViiV Healthcare (Other Financial or Material Support, Author’s employer, OPEN Health received funding to execute this study) Melanie Schroeder, MSc, ViiV Healthcare (Employee) Nicolas Van de Velde, PhD, ViiV Healthcare (Employee)

Project description:BackgroundBictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance.MethodsIn this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%.ResultsFive hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, -0.7% [95.001% confidence interval {CI}, -2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF.ConclusionsThe single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs.Clinical trials registrationNCT03110380.

Dataset Information

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

Background

Setting

Methods

Results

Conclusions

Publications

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

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