Elicit: Resistance Mechanisms in Bictegravir Therapy
Resistance Mechanisms in Bictegravir Therapy
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.
Papers screened using: Drug Combination, Resistance Outcomes, Study Population, Resistance Evidence, Study Design, Relevant Drug Focus, Beyond PK/PD Only, Resistance Analysis Included
Screening
We screened in sources based on their abstracts that met specified criteria concerning drug combinations, resistance outcomes, study populations, evidence of resistance, study design, drug focus, and analysis inclusion.
Data extraction
We employed a large language model to extract data columns from each paper, which focus on aspects such as study design, population characteristics, pre-existing resistance, emergent resistance, treatment outcomes, risk factors, and mechanisms.
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 | Treatment Status |
|---|---|---|---|---|---|
| Pezzati et al., 2026 | Cohort study | 1414 | Real-world cohort (Italian ARCA) | 36 months | ART-experienced |
| Andreatta et al., 2020 | Randomized trial | 495 | Clinical trial | 48 weeks | Experienced |
| Acosta et al., 2020 | Phase 3 randomized | 565 | Clinical trial | 48 weeks | Experienced |
| Marcelin et al., 2024 | Retrospective analysis | 5986 | Real-world cohort (French multicentre) | 3 years | First or second-line |
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% | Not mentioned | 0.6% | Not mentioned | Not mentioned |
| Andreatta et al., 2020 | 14% | M184V/I: 10% | 2% | Not mentioned | Historical genotypes and proviral DNA genotyping |
| Acosta et al., 2020 | 24% | M184V/I: 14% | 4% | Not mentioned | Historical plasma HIV-1 RNA genotypes |
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 | No emergent resistance | No emergent resistance | No emergent resistance | 48 weeks |
| Acosta et al., 2020 | None detected | None detected | None detected | 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% |
| Andreatta et al., 2020 | Week 48: 99% | 100% | 100% | No failures with de novo resistance |
| Acosta et al., 2020 | High rates maintained | Maintained suppression | Not mentioned | Uncommon; blips in 2.7% |
Risk Factors for Virologic Failure
Prior INSTI virologic failure and the presence of major INSTI resistance mutations emerged as 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 | aRH 2.68 (95% CI: 1.40-5.12) |
| Andreatta et al., 2020 | Pre-existing NRTI-R, NNRTI-R, and PI-R detected in 14%, 21%, and 13% respectively | Not mentioned |
| Acosta et al., 2020 | Pre-existing NRTI-R mutations (24%) | Not mentioned |
Resistance Mechanisms
Limited mechanistic data on resistance to B/F/TAF components were available across the included studies. One study indicated that Q148H+G140S combination in integrase retained sensitivity to bictegravir with a fold-change of 2.14. This demonstrates that bictegravir’s structural properties allow it to maintain effectiveness, even with the presence of resistance mutations.
Synthesis
The evidence demonstrates low rates of treatment-emergent resistance to B/F/TAF across diverse populations. Treatment-naive populations exhibited zero emergent resistance, while treatment-experienced cohorts showed emergent resistance rates of 3-4%. B/F/TAF maintains activity against archived NRTI resistance, providing important insights into resistance management in HIV treatment.