Highlight
- Switching to a bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) regimen maintains viral suppression as effectively as continued ritonavir-boosted protease inhibitor (PI) therapy in people with HIV on second-line treatment.
- The study conducted in Haiti addresses high NRTI resistance and limited access to resistance testing in low-income settings.
- Non-inferiority was demonstrated with a 0.7% virologic failure rate in the BIC group compared to 4.1% in the PI group, supporting international guideline recommendations for second-generation integrase inhibitor use in treatment-experienced patients.
- Safety profiles were comparable, with no study drug discontinuations due to adverse events.
Study Background and Disease Burden
The global HIV epidemic continues to present significant challenges, especially in low- and middle-income countries (LMICs) where treatment options and resistance testing remain limited. In patients with HIV who have experienced first-line antiretroviral therapy (ART) failure, second-line treatment typically involves ritonavir-boosted protease inhibitors combined with nucleoside reverse transcriptase inhibitors (NRTIs). However, high rates of NRTI resistance in these populations compromise treatment efficacy. Importantly, access to resistance testing in many LMICs, including Haiti, is scarce, complicating optimal regimen selection and management.
Integrase strand transfer inhibitors (INSTIs), particularly second-generation agents like bictegravir, offer a potent and well-tolerated alternative for ART. Yet, robust clinical data regarding their efficacy in treatment-experienced patients on second-line regimens in such resource-constrained settings has been limited. This trial aimed to evaluate whether switching patients with sustained viral suppression on second-line PI-based therapy to a fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide could maintain virologic control non-inferiorly.
Study Design
This was a randomized, open-label, non-inferiority trial performed at a clinical site in Port-au-Prince, Haiti. Eligible adults aged 18 years or older with HIV-1 infection had documented viral suppression (HIV-1 RNA <200 copies/mL) on second-line ART comprised of ritonavir-boosted protease inhibitors plus two NRTIs.
Participants were randomized 1:1 to either switch to a once-daily oral fixed-dose combination of bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (bictegravir group) or continue their existing regimen: either atazanavir 300 mg with ritonavir 100 mg once daily or lopinavir 400 mg with ritonavir 100 mg twice daily plus two NRTIs (boosted protease inhibitor group).
The primary endpoint was the proportion of participants with plasma HIV-1 RNA ≥200 copies/mL at 48 weeks, assessed using the FDA Snapshot algorithm to define virologic failure. Both intent-to-treat and safety populations included all randomized participants who received at least one dose of study medication. The non-inferiority margin was prespecified as 4%.
Key Findings
Between October 2020 and April 2023, 444 people were screened, and 301 eligible participants were randomized (153 to bictegravir and 148 to boosted protease inhibitors). The median age was 49.5 years in the bictegravir group and 48.0 years in the boosted PI group, with 57% female and all participants identifying as Black.
Enrollment stopped early due to restricted access to protease inhibitor regimens. At 48 weeks, virologic failure (HIV-1 RNA ≥200 copies/mL) occurred in 0.7% (1/153) in the bictegravir group versus 4.1% (6/148) in the boosted PI group. The difference in proportions was -3.4% (95% confidence interval -8.1 to 0.2), demonstrating non-inferiority of bictegravir-based therapy.
Adverse events of grade 3 or 4 severity were reported in four participants in each group, but no participant discontinued study medication due to adverse effects. This safety profile reinforces the tolerability of the bictegravir regimen.
Detailed subgroup analyses were limited due to early termination and enrollment restrictions, but efficacy and safety profiles were consistent across demographic variables.
Expert Commentary
This trial provides compelling evidence supporting the switch from boosted protease inhibitor-based second-line regimens to a bictegravir-containing single-tablet regimen in adults with HIV and sustained viral suppression in a resource-limited context. This aligns with evolving WHO and other international HIV treatment guidelines recommending integrase strand transfer inhibitors for treatment-experienced patients.
The study’s open-label design and early cessation are limitations, potentially affecting long-term outcome extrapolation and real-world applicability. However, the rigorous methodology, well-defined endpoints, and robust virologic data underscore the clinical relevance of the findings.
Importantly, the demonstration of non-inferiority despite high background NRTI resistance underscores the high genetic barrier to resistance conferred by bictegravir and the potential to simplify therapy while maintaining treatment success.
Mechanistically, bictegravir offers potent inhibition of viral integration with a favorable resistance profile compared to boosted protease inhibitors, which may explain the low failure rates despite treatment-experienced status.
Conclusion
Switching adults with HIV and viral suppression on second-line PI-based regimens to a once-daily bictegravir, emtricitabine, and tenofovir alafenamide regimen is non-inferior in maintaining viral suppression at 48 weeks. This strategy offers a simplified, well-tolerated treatment option which may improve adherence and reduce pill burden in resource-constrained settings.
These findings support current international treatment guidelines advocating second-generation integrase inhibitors for treatment-experienced patients and provide valuable evidence to inform HIV treatment programs in low- and middle-income countries with limited access to resistance testing.
Future research should explore long-term outcomes, resistance emergence, and real-world effectiveness to fully establish the role of bictegravir-based regimens in diverse populations.
References
Severe P, Pierre S, Homeus F, Marc JB, Trevisi L, Aristhomene ML, Bernadin GR, Lavoile K, Rivera V, Duchatellier CF, Joseph MJ, Wu J, Rouzier V, Preval F, Jean E, Bernadin J, Zion A, Pierre Louis Forestal G, Avila-Rios S, Garcia Morales C, Zhang A, Israelski D, Apollon A, Dumont E, Fox E, Cremieux PY, Pape JW, Collins SE, Liautaud B, Sax PE, Koenig SP. Bictegravir, emtricitabine, and tenofovir alafenamide versus ritonavir-boosted protease inhibitor-based antiretroviral therapy in people with HIV and viral suppression on second-line therapy in Haiti: an open-label, randomised, non-inferiority trial. Lancet HIV. 2025 Sep;12(9):e616-e626. doi: 10.1016/S2352-3018(25)00130-4. PMID: 40883049.
World Health Organization. Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations. 2022 update. WHO Press; 2022.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Updated 2024.
Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nat Rev Dis Primers. 2015 Mar 26;1:15035. doi: 10.1038/nrdp.2015.35.
Swanson P, Baxi SM, Henry K, et al. Resistance profile of bictegravir and its role in antiretroviral therapy. Curr Opin HIV AIDS. 2023 Sep;18(5):395-402.
