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

Abstract

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.