Fixed-dose combination bictegravir-emtricitabine-tenofovir alafenamide twice-daily for treatment of HIV during rifampicin-based tuberculosis treatment (INSIGHT Study): a phase 2b, open-label, randomised non-comparative trial.

BACKGROUND: The efficacy and safety of bictegravir-based antiretroviral therapy in people with HIV and tuberculosis has not been evaluated. We aimed to evaluate the efficacy, safety, and pharmacokinetics of bictegravir-emtricitabine-tenofovir alafenamide twice-daily in people with HIV receiving rifampicin-based tuberculosis treatment. METHODS: INSIGHT was a phase 2b, open-label, randomised, non-comparative controlled trial in adults aged 18 years and older with HIV (CD4 count >50 cells per μL, not on antiretroviral therapy) taking a rifampicin-based tuberculosis regimen in Durban, South Africa. Participants were recruited from the South African Department of Health clinics (n=2) and Municipal clinics (n=58) in the eThekwini district managing individuals with HIV and tuberculosis. Participants were randomly assigned 2:1 to receive twice-daily oral bictegravir-emtricitabine-tenofovir alafenamide (50-200-25 mg; the bictegravir group) or twice-daily oral dolutegravir (50 mg) with once-daily tenofovir and lamivudine (300-300 mg; the dolutegravir group) during tuberculosis treatment, then once-daily regimens through to 48 weeks. Participants were allocated into study arms by use of an electronic randomisation system generated by the study statistician. Participants underwent clinical and safety visits, including HIV viral load measurements, at baseline and weeks 4, 8, 12, 24, 40, and 48. The primary outcome was the proportion of participants in the bictegravir group with plasma HIV-1-RNA of less than 50 copies per mL at week 24 in the modified intention-to-treat population using the US Food and Drug Administration snapshot algorithm. All participants in the modified intention-to-treat population were included in the safety analyses (ie, all participants who received at least one dose of the study drug and had at least one post-baseline safety assessment). This study was registered with ClinicalTrials.gov (NCT04734652) and is completed. FINDINGS: Between Feb 18, 2022, and Aug 4, 2023, we enrolled 122 participants: 80 in the bictegravir group and 42 in the dolutegravir group. 43 (35%) participants were female, with a median baseline HIV-1 RNA of 77 302 copies per mL (IQR 25 074-392 902) in the bictegravir group and 75 545 copies per mL (21 708-559 434) in the dolutegravir group. HIV-1-RNA in the bictegravir and dolutegravir groups were <50 copies per mL in 75 (94%, 95% CI 86-98) of 80 participants and 40 (95%, 84-99) of 42 participants at week 24, and 76 (95%, 88-99) participants and 39 (93%, 81-99) participants at week 48. Grade ≥3 adverse events occurred in 36 (45%) of 80 participants in the bictegravir group and in 23 (55%) of 42 participants in the dolutegravir group. Serious adverse events were observed in 11 (14%) participants in the bictegravir group, and three (7%) participants in the dolutegravir group, with none related to study treatment. There were no treatment failures, discontinuations, or emergent resistance in the study, except for one participant (in the dolutegravir group) with an emergent M184VI mutation. INTERPRETATION: The INSIGHT trial provides evidence to support the use of twice-daily bictegravir-emtricitabine-tenofovir alafenamide in people with HIV taking rifampicin-based tuberculosis treatment. FUNDING: The National Institutes of Health and the South African Medical Research Council.