Background: Concurrent treatment of tuberculosis (TB) and HIV is challenging owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) in adults with HIV/TB co-infection was assessed.
Methods: INSPIRING (NCT02178592) is a Phase 3b, non-comparative, active control, randomised, open-label study in HIV-1-infected ART-naïve adults (CD4+ ³50 cells/µL) with drug-sensitive TB. Subjects on rifampicin-based TB treatment ≤8 weeks were randomised (3:2) to receive DTG (50mg twice daily during and 2 weeks post-TB therapy, followed by 50mg once daily) or EFV (600mg once daily), with two NRTIs for 52 weeks. The Week 48 primary endpoint was the proportion of DTG subjects with plasma HIV-1-RNA < 50c/mL (responders) using the FDA Snapshot algorithm (intent-to-treat exposed [ITT-E] population). An independent committee adjudicated IRIS episodes. The study was not powered to show a difference between arms; no formal statistical hypothesis was tested.
Results: Subjects were randomised to DTG (n=69) or EFV (n=44). Median baseline HIV-1-RNA and CD4+ counts were 5.10 log10c/mL and 208 cells/µL for DTG and 5.24 log10c/mL and 202 cells/µL for EFV. The proportions of Week 48 responders (ITT-E) were 52/69 (75%) (95%CI: 65%, 86%) for DTG and 36/44 (82%) (95%CI: 70%, 93%) for EFV. The DTG non-response rate was primarily driven by non-treatment-related discontinuations: eleven subjects (16%) for DTG and three (7%) for EFV discontinued due to non-treatment-related reasons whilst suppressed (mainly loss to follow-up). There were two protocol-defined virological failures (PDVF) and no treatment-emergent resistance-associated mutations (RAMs) for DTG and one PDVF in EFV with NRTI and NNRTI RAMs. Week 48 median CD4+ increases were 220 cells/µL (IQR: 111, 271) for DTG and 190 cells/µL (IQR: 104, 252) for EFV. Two EFV subjects discontinued due to AEs. TB-associated IRIS rates were low (DTG, n=4[6%]; EFV, n=4[9%]). No subjects discontinued due to IRIS or liver events. TB treatment success was 61/69 (88%) and 39/44 (89%) in DTG and EFV, respectively. Median DTG trough concentrations during twice daily dosing with rifampicin was like that with DTG once daily without rifampicin.
Conclusions: These results show that DTG is effective and well-tolerated in HIV/TB co-infected adults receiving rifampicin-based TB treatment.