# 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)<br>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)<br>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.