Resistance mechanisms for INSTIs and NRTIs in bictegravir/FTC/TAF therapy

Abstract

Ten studies encompassing 19,608 participants demonstrated that bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) exhibits distinct resistance patterns depending on treatment history. Pre-existing NRTI resistance was common in treatment-experienced populations, ranging from 2.7% in treatment-naive individuals to 25% in real-world cohorts, with M184V/I mutations present in 10-16% of participants. Despite this, viral suppression rates remained 96-100% among individuals with archived NRTI resistance, indicating that these mutations do not compromise B/F/TAF efficacy. Pre-existing INSTI resistance was rare (0.6-4%), and treatment-emergent resistance to any B/F/TAF component was absent in randomized trials through 144 weeks but occurred in 3-4% of real-world treatment-experienced populations. The critical resistance mechanism identified was prior INSTI virologic failure, which increased viral rebound risk 2.68-fold, while major INSTI resistance mutations increased risk 4.21-fold. Phenotypic data revealed that Q148H+G140S, which confers high-level resistance to first-generation INSTIs, maintained bictegravir sensitivity at <2.5-fold change, demonstrating bictegravir’s activity against some INSTI-resistant variants. B/F/TAF demonstrates an exceptionally high barrier to de novo resistance development in INSTI-naive populations but faces challenges in individuals with established INSTI resistance from prior treatment failures, while archived NRTI resistance does not predict virologic failure.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 7 key aspects that mattered most to the research question. More on methods

Records from Elicit search

• n = 200
• Papers screened using criteria: Drug Combination, Resistance Outcomes, Study Population, Resistance Evidence, Study Design, Relevant Drug Focus, Beyond PK/PD Only, Resistance Analysis Included.
• n = 200 Papers screened out
• n = 190 Papers included for extraction

Results

Characteristics of Included Studies

Ten studies evaluating resistance mechanisms in bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) therapy were included, encompassing 19,608 participants across clinical trials and real-world cohorts.

Pre-existing Resistance Mutations

Pre-existing NRTI resistance mutations were common across studies, while INSTI resistance mutations were rare.

Treatment-Emergent Resistance

Treatment-emergent resistance to B/F/TAF components was rare across all studies.

Virologic Outcomes

High rates of viral suppression were maintained across studies, including among participants with pre-existing resistance mutations.

Risk Factors for Virologic Failure

Prior INSTI virologic failure and the presence of major INSTI resistance mutations emerged as the primary risk factors for viral rebound on B/F/TAF therapy.

Resistance Mechanisms

Limited mechanistic data on resistance to B/F/TAF components were available across the included studies. The Q148H+G140S combination in integrase showed high-level resistance to raltegravir and elvitegravir but remained sensitive to bictegravir, with a fold-change of 2.14. This pattern demonstrated differential cross-resistance between INSTIs, with mutations conferring resistance to first-generation INSTIs not necessarily affecting bictegravir sensitivity.

Potential resistance mechanisms for bictegravir were identified, including S153F/Y or R263K substitutions, with or without M50I, which conferred low-level reduced susceptibility. Secondary INSTI resistance substitutions such as M50I, S119P/R/T, and E157K/Q were noted but did not confer resistance independently.

Cross-resistance patterns indicated that bictegravir maintained activity against some INSTI resistance mutations. In one case, virus with Q148H+G140S demonstrated full sensitivity to bictegravir but only partial sensitivity to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). Both bictegravir and dolutegravir were described as having a high barrier to resistance in vitro and in clinical studies.

Synthesis

The evidence demonstrates consistently low rates of treatment-emergent resistance to B/F/TAF across diverse populations and settings, yet reveals important distinctions in resistance patterns between treatment-naive and treatment-experienced populations, particularly those with prior INSTI exposure.