Dolutegravir-Based Antiretroviral Therapy for the Treatment of Patients Co-Infected with Tuberculosis and HIV: A Multicenter, Phase 3B, Noncomparative, Open-Label, Randomized Trial

Background: Concurrent treatment of tuberculosis and HIV is challenging owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir were assessed in adults with HIV and drug-susceptible tuberculosis. Methods: INSPIRING (NCT02178592) is a Phase 3b, non-comparative, active-control, randomised, open-label study in HIV-1-infected ARTcells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomised (3:2) to receive dolutegravir (50mg twice-daily during and 2 weeks post-tuberculosis therapy, then 50mg once-daily) or efavirenz (600mg once-daily), with two NRTI for 52 weeks. The primary endpoint was the proportion of dolutegravir-arm participants with plasma HIV-1-RNA <50c/mL (responders) by FDA Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. Findings: For dolutegravir (N=69), Baseline HIV-1-RNA was >100,000 c/mL in 64%, with median CD4 208 c/µL; for efavirenz (N=44), 55% had HIV-1-RNA >100,000 c/mL, median CD4 count was 202 c/µL. Week 48 response rate was 75% (52/69) (95%CI: 65%, 86%) for dolutegravir and 82% (36/44) (70%, 93%) for efavirenz. Dolutegravir non-response was driven by non-treatmentrelated discontinuations, mostly loss-to-follow-up following initial virologic suppression. There were no deaths or study drug switches in either arm; there were two discontinuations for toxicity (efavirenz).There were three protocol-defined virological failures (2 dolutegravir with no emergence of resistance, 1 efavirenz with NRTI and NNRTI emergent resistance detected). Tuberculosis treatment success was high. TBassociated IRIS was uncommon, with no discontinuations for IRIS. Interpretation: Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily dolutegravir was effective and well-tolerated. Clinical Trial Number: NCT02178592 Funding Statement: This study was funded by ViiV Healthcare. Declaration of Interests: MAK, MA, RS, CLT, KA, AT, DB and MRK are employed by and own shares in GSK. KED received salary support through her university for research effort devoted to this study. Ethics Approval Statement: The trial was approved by local ethics committees at each site, and participants gave written informed consent.