# 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

**Papers screened**: 200

**Papers screened out**: 190

**Papers included for extraction**: 10

## Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of [Semantic Scholar](https://www.semanticscholar.org/) and [OpenAlex](https://openalex.org/).

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**: Involves patients treated with bictegravir/FTC/TAF combination therapy?
- **Resistance Outcomes**: Reports resistance mechanisms, mutations, or genotypic resistance patterns for INSTIs and/or NRTIs?
- **Study Population**: Includes HIV-positive patients of any age?
- **Resistance Evidence**: Reports laboratory or clinical evidence of drug resistance?
- **Study Design**: Type is 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**: Study includes bictegravir/FTC/TAF?
- **Beyond PK/PD Only**: Reports on resistance outcomes? 
- **Resistance Analysis Included**: Includes 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 | Geographic Location | Treatment Status |
|-------|------------|-------------|---------|----------|--------------------|------------------|
| Pezzati et al., 2026 | Cohort study | 1414 | Real-world cohort (Italian ARCA) | 36 months | Italy | ART-experienced |
| Andreatta et al., 2020 (BRAAVE) | Randomized trial | 495 | Clinical trial | 48 weeks | Not mentioned | Experienced, virologically suppressed |
| Acosta et al., 2020 (Study 4030) | Phase 3 randomized, double-blind | 565 | Clinical trial | 48 weeks | Not mentioned | Experienced, switching |
| Marcelin et al., 2024 (Virostar-1) | 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) | Randomized trial | 1274 | Clinical trial | 48 weeks | Not mentioned | Treatment-naive |
| D’Antoni et al., 2020 | Pooled analysis | 1907 | Phase 3 clinical trials | 48 weeks | Not mentioned | Mixed (1 naive, 19 suppressed in resistance subset) |
| D’Antoni et al., 2021 | Retrospective analysis | 20 | Clinical trials (7 B/F/TAF studies) | 48 weeks | Not mentioned | Mixed (1 naive, 19 suppressed) |
| Acosta et al., 2021 (Studies 1489/1490) | Phase 3 randomized, double-blind | 1274 | Clinical trial | 144 weeks | Australia, Europe, Latin America, North America | Treatment-naive |
| Marcelin et al., 2025 | Noninterventional, retrospective, observational | 6523 | Real-world cohort (French multicentre database) | 3 years (2022-2024) | France | Experienced (≥1 prior regimen) |
| Andreatta et al., 2019 (Studies 1878/1844) | Clinical trial | 570 | Clinical trial | 48 weeks | Not mentioned | 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)<br>TAMs: 7% (34/495) | Primary INSTI-R detected post-randomization: 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)<br>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 |
| Marcelin et al., 2024 (Virostar-1) | Not mentioned | Not mentioned | Not mentioned | Not mentioned | Not mentioned |
| 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) | E92G, Y143C, Y143H, S147G, N155S, Q148H, Q148K, Q148R, R263K<br>Combination: Q148H + G140S | Historical genotypes and/or deepType HIV assay, GenoSure IN, GenoSure Archive |
| D’Antoni et al., 2021 | Not mentioned | Not mentioned | 1.0% (20/1907) | E92G, Y143C/H, S147G, Q148H/K/R, N155S, R263K | 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 (≥15% cutoff) |
| Marcelin et al., 2025 | Not mentioned | Not mentioned | Not mentioned | Not mentioned | Not mentioned |
| 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 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 (2019-2022) |
| 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 (2022-2024) |
| 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% (95% CI: 3.7-6.9%) |
| Andreatta et al., 2020 (BRAAVE) | Week 48: 99% (324/327) B/F/TAF, 100% (162/162) SBR to 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 (HIV RNA <50 copies/mL) | Not mentioned | All achieved suppression | Not mentioned |
| D’Antoni et al., 2021 | 19 suppressed at baseline maintained suppression throughout 48 weeks | Not mentioned | All maintained suppression without viral blips | Not mentioned |
| Acosta et al., 2021 (Studies 1489/1490) | Week 144: 98% with transmitted DRS, 97% without | Maintained suppression similar to those without | Not mentioned | No emergent resistance |
| Marcelin et al., 2025 | Not mentioned | Not mentioned | Not mentioned | 6% |
| Andreatta et al., 2019 (Studies 1878/1844) | 98% (561/570) overall | 98% (213/217) 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<br>Major INSTI-DRMs | History of INSTI VF: aRH 2.68 (95% CI: 1.40-5.12)<br>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 in 14%, 21%, and 13% respectively<br>M184V/I and TAMs detected in 10% and 7% | Not mentioned |
| Acosta et al., 2020 (Study 4030) | Pre-existing NRTI-R mutations (24%)<br>K65R/E/N or ≥3 TAMs (5%) | 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 (P >0.05) for preexisting resistance or subtype |
| D’Antoni et al., 2020 | Pre-existing primary INSTI-R substitutions<br>Patient characteristics: 75% male, 30% white, 85% HIV-1 subtype B | Not mentioned |
| D’Antoni et al., 2021 | Baseline resistance: preexisting primary INSTI-R substitutions<br>Demographics: predominantly male (75%), Black (65%), HIV-1 subtype B (85%) | Not mentioned |
| Acosta et al., 2021 (Studies 1489/1490) | Pre-existing resistance substitutions did not affect treatment outcomes | No statistical significance (P >0.05) |
| Marcelin et al., 2025 | Not mentioned | Not mentioned |
| Andreatta et al., 2019 (Studies 1878/1844) | Pre-existing primary resistance substitutions in 40%<br>Pre-switch NRTI resistance in 16%<br>M184V/I mutations in 10% | Not mentioned |

### Resistance Mechanisms

Limited mechanistic data on resistance to B/F/TAF components were available across the included studies. One study with full-text availability 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. This pattern demonstrated differential cross-resistance between INSTIs, with mutations conferring resistance to first-generation INSTIs not necessarily affecting bictegravir sensitivity.

Most studies did not report detailed mechanistic data on phenotypic resistance levels, compensatory mutations, or fitness costs associated with resistance to B/F/TAF components.

## 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.