Reduced-frequency bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV: a single-centre randomised phase 2 pilot trial in Spain

Background: Reduced-frequency oral antiretroviral therapy may lessen treatment burden, but the exposure thresholds required to maintain virological suppression and the role of the HIV reservoir remain undefined. Methods: BETAF-RED was a 48-week, single-centre, randomised, open-label, controlled phase 2 pilot trial conducted at Hospital Clínic, Barcelona, Spain. Eligible participants were adults aged 18 years or older with HIV-1 RNA <50 copies per mL for at least 6 months while receiving once-daily bictegravir, emtricitabine, and tenofovir alafenamide. Key eligibility criteria included stable clinical condition and CD4 count >350 cells per μL; key exclusions included previous virological failure or documented resistance to study drugs, active hepatitis B or C infection, and conditions judged to jeopardise adherence. Participants were assigned 1:1:1:1 to receive the oral fixed-dose single-tablet regimen bictegravir, emtricitabine, and tenofovir alafenamide 50/200/25 mg once daily, three times weekly, twice weekly, or once weekly for 48 weeks. The primary endpoint was maintenance of HIV-1 RNA <50 copies per mL (virological success) at weeks 12 and 48, assessed by Food and Drug Administration Snapshot in the intention-to-treat exposed population, defined as all randomised participants receiving study drug, and in the prespecified on-treatment analysis. Secondary outcomes were virological failure and no virological data. Safety analyses included all participants who received at least one dose of study drug. This was not a non-inferiority study, and no non-inferiority margin was specified. ClinicalTrials.gov, NCT05602506. Findings: Between November 7, 2022, and July 3, 2023, 40 participants were enrolled; 39 received study medication. In the intention-to-treat exposed Food and Drug Administration Snapshot analysis, virological success was observed at week 12 in 9/9, 9/10, 10/10, and 8/10 participants in the once-daily, three-times-weekly, twice-weekly, and once-weekly arms, respectively. At week 48, virological success was observed in 8/9, 9/10, 9/10, and 7/10 participants in the once-daily, three-times-weekly, twice-weekly, and once-weekly arms, respectively. At week 12, virological failure and no virological data were observed in 0/9 and 0/9, respectively, in the once-daily arm; 1/10 and 0/10, respectively, in the three-times-weekly arm; 0/10 and 0/10, respectively, in the twice-weekly arm; and 2/10 and 0/10, respectively, in the once-weekly arm. At week 48, virological failure and no virological data were observed in 0/9 and 1/9, respectively, in the once-daily arm; 1/10 and 0/10, respectively, in the three-times-weekly arm; 0/10 and 1/10, respectively, in the twice-weekly arm; and 2/10 and 1/10, respectively, in the once-weekly arm. In the prespecified on-treatment analysis, virological success was observed in 36/37 participants at week 12 and in all 33 participants remaining on their assigned regimen at week 48; the only virological failure occurred at week 12 in the three-times-weekly arm, and no virological data were missing at either timepoint. All three participants with protocol-defined confirmed virological failure regained suppression after resuming once-daily therapy, without emergent resistance. Interpretation: Most participants met the primary endpoint of maintained virological suppression at weeks 12 and 48 in the intention-to-treat exposed FDA Snapshot analysis. Early protocol-defined confirmed virological failures occurred in the once-weekly arm, and one confirmed low-level viraemia event occurred in the three-times-weekly arm. Because the trial was not powered for formal between-arm comparisons, these findings should be interpreted descriptively. Once-weekly dosing is not supported as a maintenance strategy; twice-weekly and three-times-weekly dosing require confirmation in larger, adequately powered studies with close virological monitoring before any clinical role can be considered. Funding: Instituto de Salud Carlos III and Institut d’Investigacions Biomèdiques August Pi i Sunyer.