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

Michelle L. D'Antoni, PhD; Kristen Andreatta, MS; Rima Acosta, BS; Hal Martin, MD; Silvia Chang, MS; Ross Martin, MS; Kirsten L. White, PhD


J Acquir Immune Defic Syndr. 2022;89(4):433-440. 

In This Article

Abstract and Introduction


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/mm[3] 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.


Because preexisting drug resistance can limit the use of antiretroviral drugs and render them less effective, genotypic drug resistance testing is recommended before initiating treatment or when switching regimens in a person with a history of virologic failure (VF).[1,2] Integrase strand transfer inhibitor resistance (INSTI-R) testing is not recommended unless there is suspicion of transmitted INSTI-R because the prevalence of resistance in this drug class is low (approximately 1%).[3–10] Although high efficacy is observed for INSTI-based triple therapy in clinical trials,[11–15] differences exist among the various regimens, including dosing intervals, boosting requirements, and the risk of emergent resistance in the setting of VF. In clinical trials of raltegravir (RAL)-based and elvitegravir (EVG)-based triple therapy, 21%–60% of participants with VF developed INSTI-R substitutions.[11–15] With dolutegravir (DTG) triple therapy, treatment-emergent INSTI-R in clinical trials was rare.[16,17] By contrast, no treatment-emergent INSTI-R has been documented in clinical studies of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).[17–25] Cabotegravir, a long-acting injectable INSTI used as a single agent for PrEP or in combination with rilpivirine for HIV treatment, has demonstrated high efficacy in trials, but INSTI-R substitutions were observed in those with HIV acquisition or treatment failure, occurring in 33% and 67% of those individuals, respectively.[26–30]

Although INSTI-R is rare, studying resistance in this drug class remains important and relevant because INSTIs are the backbone of initial regimens for most people with HIV.[1,31] Primary INSTI drug resistance reported in surveillance studies are mainly substitutions that cause resistance to RAL and EVG (T66A/I, E92Q, Y143C/H/R, S147G, Q148H/K/R, and N155H pathways) and R263K, which confers low-level reduced susceptibility to EVG, DTG, and bictegravir (BIC).[4,6,8,10,32–34] BIC and DTG generally have good activity against many RAL-resistant and EVG-resistant variants, but with differences, because studies have found that BIC is more broadly active against INSTI-R variants than DTG.[35] Specifically, compared with DTG, BIC has greater in vitro activity against variants with G140/Q148 mutations accompanied by 1–2 additional substitutions and variants with the E92Q/N155H combination.[36] DTG dosed twice daily has been shown to provide viral suppression in individuals with primary EVG and RAL substitutions, although virologic response has been poor with certain INSTI-R patterns.[37–39] Clinical trials of BIC in viremic individuals failing therapy with INSTI-R have not been conducted.

Studies in both treatment-naive and virologically suppressed (VS) participants have demonstrated the safety and efficacy of B/F/TAF, a potent, once-daily, single-tablet regimen for treatment of HIV-1 infection.[22,40–42] This efficacy also extends to VS patients with certain nucleos(t)ide reverse transcriptase inhibitor (NRTI) substitutions, including M184V/I and thymidine analog substitutions.[43] However, the impact of INSTI-R substitutions on B/F/TAF efficacy has not been well-documented. The objective of this study was to investigate virologic outcomes after 48 weeks of B/F/TAF treatment in a pooled analysis of individuals with preexisting INSTI-R from clinical trials.