# 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.