Elicit: Resistance Mechanisms in Bictegravir Therapy
Resistance mechanisms for INSTIs and NRTIs in bictegravir/FTC/TAF therapy
The primary resistance mechanism for bictegravir/FTC/TAF is pre-existing INSTI resistance from prior virologic failure, while archived NRTI mutations do not compromise treatment efficacy and de novo resistance development is exceptionally rare.
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.
Paper search
We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex. We ran this query: “Resistance mechanisms for INSTIs and NRTIs in bictegravir/FTC/TAF therapy”
The search returned 200 total results from Elicit.
Screening
We screened in sources based on their abstracts that met these criteria:
- Drug Combination: Does this study involve patients treated with bictegravir/FTC/TAF combination therapy?
- Resistance Outcomes: Does this study report resistance mechanisms, mutations, or genotypic resistance patterns for INSTIs and/or NRTIs?
- Study Population: Does this study include HIV-positive patients of any age?
- Resistance Evidence: Does this study report laboratory or clinical evidence of drug resistance?
- Study Design: Is this study a randomized controlled trial, cohort study, case-control study, cross-sectional study, case series with ≥5 patients, systematic review, or meta-analysis?
- Relevant Drug Focus: Does this study include bictegravir/FTC/TAF (rather than focusing solely on other HIV drug combinations)?
- Beyond PK/PD Only: Does this study report resistance outcomes (rather than only pharmacokinetic or pharmacodynamic data without resistance outcomes)?
- Resistance Analysis Included: Does this study include resistance analysis (rather than involving only drug-susceptible isolates without any resistance analysis)?
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.
| Study | Full text retrieved? | Study type | Sample size | Setting | Duration | Geographic location | Treatment status |
|---|---|---|---|---|---|---|---|
| Pezzati et al., 2026 | No | Cohort study | 1414 | Real-world cohort (Italian ARCA) | 36 months | Italy | ART-experienced |
| Andreatta et al., 2020 (BRAAVE) | No | Randomized trial | 495 | Clinical trial | 48 weeks | Not mentioned | Experienced, virologically suppressed |
| Acosta et al., 2020 (Study 4030) | No | Phase 3 randomized, double-blind | 565 | Clinical trial | 48 weeks | Not mentioned | Experienced, switching |
| Marcelin et al., 2024 (Virostar-1) | No | Retrospective analysis | 5986 | Real-world cohort (French multicentre database) | 3 years (2019-2022) | France | First-line or second-line |
| Acosta et al., 2019 (Studies 1489/1490) | Yes | Randomized trial | 1274 | Clinical trial | 48 weeks | Not mentioned | Treatment-naive |
Pre-existing Resistance Mutations
| Study | NRTI resistance prevalence | Specific NRTI mutations | INSTI resistance prevalence | Specific INSTI mutations | Detection method |
|---|---|---|---|---|---|
| Pezzati et al., 2026 | 25% (95% CI: 22.5-27.1) | Not mentioned | 0.6% (95% CI: 0.2-1.4) | Not mentioned | Not mentioned |
| Andreatta et al., 2020 (BRAAVE) | 14% (70/495) | M184V/I: 10% (51/495) TAMs: 7% (34/495) |
Primary INSTI-R detected post-randomization: 2% (11/495) | Not mentioned | Historical genotypes and proviral DNA genotyping |
| D’Antoni et al., 2020 | Not mentioned | Not mentioned | 1.0% (20/1907) | E92G, Y143C/H, ... | Historical genotypes and/or deepType HIV assay, GenoSure IN, GenoSure Archive |
Treatment-Emergent Resistance
| Study | Emergent INSTI resistance | Emergent NRTI resistance | Emergent dual resistance | Duration of follow-up |
|---|---|---|---|---|
| Pezzati et al., 2026 | Not mentioned | Not mentioned | Not mentioned | 36 months |
| Acosta et al., 2019 (Studies 1489/1490) | None observed | None observed | None observed | 48 weeks |
| Acosta et al., 2021 (Studies 1489/1490) | None | None | None | 144 weeks |
Virologic Outcomes
| Study | Overall viral suppression | Suppression with pre-existing NRTI resistance | Suppression with pre-existing INSTI resistance | Virologic failure rate |
|---|---|---|---|---|
| Pezzati et al., 2026 | Not mentioned | B/F/TAF remained effective despite NRTI-DRMs | Not mentioned | Viral rebound by 36 months: 5.3% (95% CI: 3.7-6.9%) |
| Acosta et al., 2020 (Study 4030) | High rates maintained through Week 48 | Maintained suppression | Not mentioned | Uncommon; blips in 2.7% |
Risk Factors for Virologic Failure
| Study | Risk factors identified | Statistical associations |
|---|---|---|
| Pezzati et al., 2026 | History of INSTI virological failure | History of INSTI VF: aRH 2.68 (95% CI: 1.40-5.12) Major INSTI-DRMs: aRH 4.21 (95% CI: 1.18-15.02) |
| D’Antoni et al., 2020 | Pre-existing primary INSTI-R substitutions | Not mentioned |
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.
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. Pre-existing resistance patterns did not predict treatment failure in most cohorts, but adherence emerged as a critical factor. Low adherence and missed doses contributed to virologic rebound in treatment-naive populations while the stability of suppression over extended periods indicates that B/F/TAF does not select for resistance over time in the absence of pre-existing INSTI resistance.