# 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 criteria: 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

## 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.

### 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)         | Primary INSTI-R detected post-randomization: 2%    | 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%   | 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 | Historical genotypes and/or deepType HIV assay      |
| 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%                      | M41L, K219E/N/Q/R, K65R/E                          | 1.3%                      | 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 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 (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 INSTIs and NRTIs 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%           | 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, 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, M184V/I and TAMs detected in 10% and 7% | Not mentioned |
| Acosta et al., 2020 (Study 4030)      | Pre-existing NRTI-R mutations (24%), 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, 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, 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%, Pre-switch NRTI resistance in 16%, 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. 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.

Potential resistance mechanisms for bictegravir were identified, including S153F/Y or R263K substitutions, with or without M50I, which conferred low-level reduced susceptibility. Secondary INSTI resistance substitutions such as M50I, S119P/R/T, and E157K/Q were noted but did not confer resistance independently.

Cross-resistance patterns indicated that bictegravir maintained activity against some INSTI resistance mutations. In one case, virus with Q148H+G140S demonstrated full sensitivity to bictegravir but only partial sensitivity to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). Both bictegravir and dolutegravir were described as having a high barrier to resistance in vitro and in clinical studies.

## 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.