# 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: 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

### 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 specific criteria:

- **Drug Combination**: Patients treated with bictegravir/FTC/TAF combination therapy.
- **Resistance Outcomes**: Studies reporting resistance mechanisms for INSTIs and/or NRTIs.
- **Study Population**: HIV-positive patients of any age.
- **Resistance Evidence**: Laboratory or clinical evidence of drug resistance.
- **Study Design**: Randomized controlled trial, cohort study, etc.
- **Relevant Drug Focus**: Studies including bictegravir/FTC/TAF.
- **Beyond PK/PD Only**: Studies reporting resistance outcomes.
- **Resistance Analysis Included**: Studies including 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 (Table 1).

**Study Overview**:

| 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 |
| D’Antoni et al., 2020 | No | Pooled analysis | 1907 | Phase 3 clinical trials | 48 weeks | Not mentioned | Mixed |
| D’Antoni et al., 2021 | No | Retrospective analysis | 20 | Clinical trials (7 B/F/TAF studies) | 48 weeks | Not mentioned | Mixed |
| Acosta et al., 2021 (Studies 1489/1490) | Yes | Phase 3 randomized, double-blind | 1274 | Clinical trial | 144 weeks | Australia, Europe, Latin America, North America | Treatment-naive |
| Marcelin et al., 2025 | No | 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) | No | 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.

**Pre-existing Resistance Data**:
| Study | NRTI resistance prevalence | INSTI resistance prevalence |
|-------|---------------------------|---------------------------|
| Pezzati et al., 2026 | 25% (95% CI: 22.5-27.1) | 0.6% (95% CI: 0.2-1.4) |
| Andreatta et al., 2020 (BRAAVE) | 14% (70/495) | 2% (11/495) |
| Acosta et al., 2020 (Study 4030) | 24% (138/565) | 4% (20/565) |
| Marcelin et al., 2024 (Virostar-1) | Not mentioned | Not mentioned |
| Acosta et al., 2019 (Studies 1489/1490) | 2.7% | 1.3% |
| D’Antoni et al., 2020 | Not mentioned | 1.0% (20/1907) |
| D’Antoni et al., 2021 | Not mentioned | 1.0% (20/1907) |
| Acosta et al., 2021 (Studies 1489/1490) | 2.7% | 1.3% |
| Marcelin et al., 2025 | Not mentioned | Not mentioned |
| Andreatta et al., 2019 (Studies 1878/1844) | 16% (89/543) | Not mentioned |

### Treatment-Emergent Resistance

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

**Emergent Resistance Summary**:
| Study | Emergent INSTI resistance | Emergent NRTI resistance |
|-------|--------------------------|--------------------------|
| Pezzati et al., 2026 | Not mentioned | Not mentioned |
| Andreatta et al., 2020 (BRAAVE) | No emergent resistance | No emergent resistance |
| Acosta et al., 2020 (Study 4030) | None detected | None detected |
| Marcelin et al., 2024 (Virostar-1) | 4% emergent INSTI or NRTI RAMs | 4% emergent INSTI or NRTI RAMs |
| Acosta et al., 2019 (Studies 1489/1490) | None observed | None observed |
| D’Antoni et al., 2020 | Not mentioned | Not mentioned |
| D’Antoni et al., 2021 | Not mentioned | Not mentioned |
| Acosta et al., 2021 (Studies 1489/1490) | None | None |
| Marcelin et al., 2025 | 3% treatment-emergent RAMs | 3% treatment-emergent RAMs |
| Andreatta et al., 2019 (Studies 1878/1844) | No emergent resistance | No emergent resistance |

### Virologic Outcomes

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

**Virologic Outcomes**:
| Study | Overall viral suppression | Suppression with pre-existing NRTI resistance | Suppression with pre-existing INSTI resistance |
|-------|------------------------|------------------------------|-----------------------------------|
| Pezzati et al., 2026 | Not mentioned | Effective despite NRTI-DRMs | Not mentioned |
| Andreatta et al., 2020 (BRAAVE) | Week 48: 99% | 100% | 100% |
| Acosta et al., 2020 (Study 4030) | High rates maintained through Week 48 | Maintained suppression | Not mentioned |
| Marcelin et al., 2024 (Virostar-1) | Not mentioned | Not mentioned | Not mentioned |
| Acosta et al., 2019 (Studies 1489/1490) | High rates through week 48 | Maintained suppression | Not mentioned |
| D’Antoni et al., 2020 | 100% | Not mentioned | All achieved suppression |
| D’Antoni et al., 2021 | 19 suppressed maintained | Not mentioned | All maintained suppression |
| Acosta et al., 2021 (Studies 1489/1490) | Week 144: 98% | Maintained suppression | Not mentioned |
| Marcelin et al., 2025 | Not mentioned | Not mentioned | Not mentioned |
| Andreatta et al., 2019 (Studies 1878/1844) | 98% overall | 98% with pre-existing resistance | Not mentioned |