Simultaneous initiation of dolutegravir-based antiretroviral therapy and once-weekly rifapentine and isoniazid for tuberculosis prevention in antiretroviral-naive people with HIV: an open-label, non-randomised, phase 1/2 trial.

BACKGROUND Tuberculosis preventive treatment with 3 months of once-weekly isoniazid (900 mg) and rifapentine (900 mg; 3HP) is a recommended option for people with HIV; among adults with virological suppression, the 3HP regimen given with dolutegravir-based antiretroviral therapy (ART) is safe and maintained virological suppression. The DOLPHIN-TOO study assessed safety, dolutegravir pharmacokinetics, and virological efficacy of concurrent initiation of dolutegravir-based ART and 3HP among antiretroviral-naive adults with HIV. METHODS DOLPHIN-TOO was a non-randomised, open-label, pragmatic phase 1/2 trial done at The Aurum Institute Tembisa Clinical Research Site (Tembisa, South Africa). Antiretroviral-naive adults (aged ≥18 years) with HIV and no symptoms of tuberculosis disease or microbiologically confirmed absence of tuberculosis disease were sequentially enrolled and assigned to 6 months of once-daily isoniazid 300 mg (6H; n=25) or to 3HP (n=50). Once-daily dolutegravir 50 mg with tenofovir disoproxil fumarate 300 mg and lamivudine 300 mg was initiated on day 0 and tuberculosis preventive treatments were initiated on day 1; sparse pharmacokinetic sampling for dolutegravir was done on day 1 (before starting 3HP or 6H), and in week 3 (day 17) and week 8 (day 52) of treatment. HIV-1 RNA viral loads were measured serially by PCR. The primary endpoints were adverse events (grade 3 or worse per the Division of AIDS Adverse Event Grading Table version 2.1) and population pharmacokinetics of dolutegravir with and without 3HP, using 6H as a pharmacokinetic control. Non-linear mixed-effects modelling was used for pharmacokinetic analysis. The analysis population for both safety and pharmacokinetics was the intention-to-treat population. The trial is registered with the South African National Clinical Trials Register, DOH-27-1217-5770, and ClinicalTrials.gov, NCT03435146, and is completed. FINDINGS 75 participants were sequentially enrolled from Aug 31, 2021, to June 28, 2022, and assigned to 6H (n=25) or 3HP (n=50). Overall median age of participants was 35 years (IQR 27-41), all participants were Black African, and 37 (49%) were female and 38 (51%) were male. At baseline, overall median HIV viral load was 27 056 copies per mL (IQR 7088-111 620), and 20 (27%) participants had HIV viral loads higher than 100 000 copies per mL; median baseline CD4 count was 283 cells per μL. One grade 3 or worse adverse event was reported: a grade 3 cutaneous abscess requiring hospitalisation (unrelated to treatment) in a participant in the 6H group. No treatment-related grade 3 adverse events occurred. Coadministered 3HP increased dolutegravir clearance by 72% (relative standard error 12%), from 0·95 L/h before 3HP treatment to 1·64 L/h during 3HP treatment. Median dolutegravir trough concentrations were significantly lower in the 3HP group than in the 6H group at week 3 (720 ng/mL [range 92-4250] vs 1310 ng/mL [431-2980]; Wilcoxon rank-sum p=0·0006) and week 8 (669 ng/mL [184-4440] vs 1285 ng/mL [475-2890]; p=0·0066). All dolutegravir trough values were higher than the in-vitro protein-adjusted 90% maximal inhibitory concentration for dolutegravir of 64 ng/mL. INTERPRETATION Our results indicate that simultaneous initiation of 3HP tuberculosis preventive treatment and dolutegravir-based ART was safe and achieved therapeutic concentrations among antiretroviral-naive individuals with HIV, and dolutegravir dose adjustments are not needed. FUNDING Unitaid, ViiV Healthcare. TRANSLATIONS For the Afrikaans, Xhosa and Zulu translations of the abstract see Supplementary Materials section.