Background
A 4-month rifapentine (RPT)-based regimen is recommended as an alternative treatment for drug-susceptible pulmonary tuberculosis (TB). A drug-drug interaction between RPT and the first-line antiretroviral drug dolutegravir (DTG) may potentially reduce DTG exposure and risk HIV viral rebound. We aimed to quantify this drug-drug interaction and describe the safety and efficacy of twice-daily DTG among individuals receiving RPT-based treatment for HIV-associated TB.
Methods
A5406 was a phase II, open-label, single-arm PK study conducted in South Africa and Thailand. Participants received antiretroviral therapy with twice-daily DTG plus TB treatment with a RPT-based regimen, dosed at 1200 mg daily, for 17 weeks. DTG was switched to daily dosing 2 weeks after RPT discontinuation. Intensive PK sampling was done at week 8 (twice-daily DTG with RPT) and week 21 (DTG daily without RPT). DTG concentrations were described with non-compartmental analysis and pharmacokinetic parameters estimated using non-linear mixed effects modelling. The primary outcome was simulated DTG trough concentrations above a target of 0.158 µg/mL, the lowest exposure leading to HIV virologic suppression in a Phase 2 trial.
Results
Thirty participants were enrolled; 13 (43%) were female, median (IQR) age 35 (32–38) years, baseline CD4 count 185(135–357) cells/µL, and HIV-1 RNA 96,911 (15,345-237,538) cp/mL. The DTG geometric mean area under the concentration-time curve over 24 hours (AUC0-24) was 34.2 µg·h/mL and 48.8 µg·h/mL for twice- and once-daily dosing, respectively (geometric mean ratio 0.70; 90% CI 0.61–0.80; Fig. 1). DTG clearance was 0.98 L/h (95% CI 0.82-1.20) when provided alone and increased 2.97-fold (95% CI 2.45-3.60) when co-administered with RPT. The proportion of individuals predicted to remain above the efficacy threshold of 0.158 µg/mL was 94% when DTG is dosed twice daily together with RPT. This was predicted to drop to 19% with standard once-daily dosing. All participants who remained on treatment achieved virologic suppression at Week 21. Grade ≥3 adverse events occurred in 20.7% (n=6; 95% CI 8.0–39.7) while on both antituberculosis and HIV treatment; one event, C. difficile colitis, resulted in treatment discontinuation.
Conclusions
DTG clearance was markedly increased by RPT co-administration. Twice-daily DTG dosing provided therapeutic exposures in most individuals, was safe, and achieved virologic suppression. These findings support DTG use during RPT-based TB therapy.
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