# 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.