# 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.

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
- n = 10

## 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                               | Study type                  | Sample size             | Setting                                    | Duration    | Treatment status         |
|-------------------------------------|-----------------------------|------------------------|--------------------------------------------|-------------|--------------------------|
| Pezzati et al., 2026                | Cohort study                | 1414 (973 in rebound)  | Real-world cohort (Italian ARCA)         | 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 (French multicentre)    | 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 (from 1907 total)   | Clinical trials (7 B/F/TAF studies)      | 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 (French multicentre) | 3 years     | Experienced (≥1 prior regimen) |
| Andreatta et al., 2019 (Studies 1878/1844) | Clinical trial          | 570                    | Clinical trial                             | 48 weeks    | Experienced, switching    |

The studies comprised both treatment-naive populations and treatment-experienced individuals switching to B/F/TAF. Clinical trial durations ranged from 48 weeks to 144 weeks, with real-world cohorts following participants for up to 36 months.

### Pre-existing Resistance Mutations

Pre-existing NRTI resistance mutations were common across studies, while INSTI resistance mutations were rare (Table 2).

| 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)     | Primary INSTI-R: 2%      | Not mentioned                                                   | Historical genotypes and proviral DNA   |
| Acosta et al., 2020 (Study 4030)   | 24% (138/565)              | M184V/I: 14% (81/565), K65R/E/N: 5% (30/565)  | 4% (20/565)              | Not mentioned                                                   | Historical plasma HIV-1 RNA 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            |
| D’Antoni et al., 2020               | Not mentioned               | Not mentioned                                 | 1.0% (20/1907)            | E92G, Y143C/H, S147G, Q148H/K/R, N155S, R263K, combination: Q148H + G140S | Historical genotypes                      |
| D’Antoni et al., 2021               | Not mentioned               | Not mentioned                                 | 1.0% (20/1907)            | Same as above                                                 | Historical genotypes                      |
| Acosta et al., 2021 (Studies 1489/1490) | 2.7%                    | M41L, K219E/N/Q/R, K65R/E                   | 1.3% (17/1270)            | T97A, Q148H with G140S                                       | Retrospective baseline next-generation sequencing |
| 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 all studies (Table 3).

| 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 IN ST I or NRTI RAMs | Absence of dual 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 (Table 4).

| 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: 5.3% (95% CI: 3.7-6.9%) |
| Andreatta et al., 2020 (BRAAVE)    | Week 48: 99% (324/327)   | 100% with NRTI-R                          | 100% with INSTI-R                   | No failures with de novo resistance |
| Acosta et al., 2020 (Study 4030)   | High rates maintained    | 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 | Not mentioned                  |
| Acosta et al., 2021 (Studies 1489/1490) | Week 144: 98% with transmitted DRS | 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% 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 (Table 5).

| 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 in 14%, 21%, and 13% respectively | Not mentioned           |
| Acosta et al., 2020 (Study 4030)   | Pre-existing NRTI-R mutations (24%) | 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) |
| D’Antoni et al., 2020               | Pre-existing primary INSTI-R substitutions | Not mentioned           |
| D’Antoni et al., 2021               | Baseline resistance: pre-existing primary INSTI-R substitutions | 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% | 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.