Elicit: Resistance Mechanisms in Bictegravir Therapy
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:
- 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 | Study type | Sample size | Setting | Duration | Treatment status |
|---|---|---|---|---|---|
| Pezzati et al., 2026 | Cohort study | 1414 (973 in viral rebound analysis) | Real-world cohort | 36 months | ART-experienced |
| Andreatta et al., 2020 (BRAAVE) | Randomized trial | 495 | Clinical trial | 48 weeks | Experienced, virologically suppressed |
| Acosta et al., 2020 (Study 4030) | Phase 3 randomized, double-blind | 565 | Clinical trial | 48 weeks | Experienced, switching |
| Marcelin et al., 2024 (Virostar-1) | Retrospective analysis | 5986 | Real-world cohort | 3 years | First-line or second-line |
| Acosta et al., 2019 (Studies 1489/1490) | Randomized trial | 1274 | Clinical trial | 48 weeks | Treatment-naive |
| D’Antoni et al., 2020 | Pooled analysis | 1907 | Phase 3 clinical trials | 48 weeks | Mixed |
| D’Antoni et al., 2021 | Retrospective analysis | 20 | Clinical trials | 48 weeks | Mixed |
| Acosta et al., 2021 (Studies 1489/1490) | Phase 3 randomized, double-blind | 1274 | Clinical trial | 144 weeks | Treatment-naive |
| Marcelin et al., 2025 | Noninterventional, retrospective, observational | 6523 | Real-world cohort | 3 years | Experienced |
| Andreatta et al., 2019 (Studies 1878/1844) | Clinical trial | 570 | Clinical trial | 48 weeks | Experienced, switching |
Pre-existing Resistance Mutations
Pre-existing NRTI resistance mutations were common across studies, while INSTI resistance mutations were rare.
| 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) | 2% (11/495) | Not mentioned | Historical genotypes and proviral DNA genotyping |
| Acosta et al., 2020 (Study 4030) | 24% (138/565) | M184V/I: 14% (81/565), K65R/E/N or ≥3 TAMs: 5% (30/565) | 4% (20/565) | Not mentioned | Historical plasma HIV-1 RNA genotypes and baseline proviral DNA genotypes |
| Acosta et al., 2019 (Studies 1489/1490) | 2.7% | M41L, K219E/N/Q/R | 1.3% | T97A, Q148H (with G140S) | Retrospective deep-sequencing using deepType HIV assay |
| D’Antoni et al., 2020 | Not mentioned | Not mentioned | 1.0% (20/1907) | Various identified | Historical genotypes and/or deepType HIV assay, GenoSure IN, GenoSure Archive |
| D’Antoni et al., 2021 | Not mentioned | Not mentioned | 1.0% (20/1907) | Various identified | Historical genotypes and/or baseline RNA or DNA sequencing |
| Acosta et al., 2021 (Studies 1489/1490) | 2.7% (35/1274) | M41L, K219E/N/Q/R, K65R/E | 1.3% (17/1270) | T97A, Q148H with G140S | Retrospective baseline next-generation sequencing |
| Andreatta et al., 2019 (Studies 1878/1844) | 16% (89/543) | M184V/I: 10% (54/543) | Not mentioned | Not mentioned | Historical genotypes and proviral DNA |
Treatment-Emergent Resistance
Treatment-emergent resistance to B/F/TAF components was rare across all studies.
| 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 |
| Andreatta et al., 2020 (BRAAVE) | No emergent resistance | No emergent resistance | No emergent resistance | 48 weeks |
| Acosta et al., 2020 (Study 4030) | None detected | None detected | None detected | 48 weeks |
| Marcelin et al., 2024 (Virostar-1) | 4% emergent INSTI or NRTI RAMs | 4% emergent INSTI or NRTI RAMs | Complete absence of dual NRTI and INSTI resistance | 3 years |
| Acosta et al., 2019 (Studies 1489/1490) | None observed | None observed | None observed | 48 weeks |
| D’Antoni et al., 2020 | Not mentioned | Not mentioned | Not mentioned | 48 weeks |
| D’Antoni et al., 2021 | Not mentioned | Not mentioned | Not mentioned | 48 weeks |
| Acosta et al., 2021 (Studies 1489/1490) | None | None | None | 144 weeks |
| Marcelin et al., 2025 | 3% treatment-emergent RAMs | 3% treatment-emergent RAMs | Dual INSTI and NRTI RAMs observed | 3 years |
| Andreatta et al., 2019 (Studies 1878/1844) | No emergent resistance | No emergent resistance | No emergent resistance | 48 weeks |
Virologic Outcomes
High rates of viral suppression were maintained across studies, including among participants with pre-existing resistance mutations.
| 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% |
| Andreatta et al., 2020 (BRAAVE) | Week 48: 99% (324/327) B/F/TAF | 100% (68/68) with NRTI-R | 100% (11/11) with INSTI-R | No failures with de novo resistance |
| Acosta et al., 2020 (Study 4030) | High rates maintained through Week 48 | Maintained suppression | Not mentioned | Uncommon; blips in 2.7% |
| Marcelin et al., 2024 (Virostar-1) | Not mentioned | Not mentioned | Not mentioned | 6.8% |
| Acosta et al., 2019 (Studies 1489/1490) | High rates through week 48 | Maintained suppression | Not mentioned | 13 participants (1.0%) met criteria for analysis |
| D’Antoni et al., 2020 | Week 48: All achieved virologic success | Not mentioned | All achieved suppression | Not mentioned |
| D’Antoni et al., 2021 | 19 suppressed at baseline maintained suppression | Not mentioned | All maintained suppression without viral blips | Not mentioned |
| Acosta et al., 2021 (Studies 1489/1490) | Week 144: 98% with transmitted DRS | Maintained suppression | Not mentioned | No emergent resistance |
| Marcelin et al., 2025 | Not mentioned | Not mentioned | Not mentioned | 6% |
| Andreatta et al., 2019 (Studies 1878/1844) | 98% overall | 98% with pre-existing resistance | Not mentioned | Not mentioned |
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.
| Study | Risk factors identified | Statistical associations |
|---|---|---|
| Pezzati et al., 2026 | History of INSTI virological failure; Major INSTI-DRMs | 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) |
| Andreatta et al., 2020 (BRAAVE) | Pre-existing NRTI-R, NNRTI-R, and PI-R present | Not mentioned |
| Acosta et al., 2020 (Study 4030) | Pre-existing NRTI-R mutations | Not mentioned |
| Marcelin et al., 2024 (Virostar-1) | Not mentioned | Not mentioned |
| Acosta et al., 2019 (Studies 1489/1490) | Low adherence (<95%) and missed doses | No statistical significance |
| D’Antoni et al., 2020 | Pre-existing primary INSTI-R substitutions | Not mentioned |
| D’Antoni et al., 2021 | Baseline resistance | Not mentioned |
| Acosta et al., 2021 (Studies 1489/1490) | Pre-existing resistance substitutions | No statistical significance |
| Marcelin et al., 2025 | Not mentioned | Not mentioned |
| Andreatta et al., 2019 (Studies 1878/1844) | Pre-existing primary resistance substitutions | Not mentioned |
Resistance Mechanisms
Limited mechanistic data on resistance to B/F/TAF components were available across the included studies. One study provided phenotypic resistance data for specific mutations. 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. Potential resistance mechanisms for bictegravir were identified, including mutations that conferred low-level reduced susceptibility. Also noted were cross-resistance patterns that indicated bictegravir maintained activity against some INSTI resistance mutations.
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.