Abstract
Concurrent use of rifampicin (RIF) and dolutegravir (DTG) reduces DTG exposure, thus, DTG 50 mg twice-daily is currently recommended. Food increased DTG concentrations in healthy volunteers by 33 – 66%. We therefore investigated the effect of RIF on DTG exposure when dosed at 50 mg once daily with food, which would be more convenient than 50 mg twice daily in resource limited settings, where generic fixed dosed combination of TDF/ 3TC/DTG (TLD) is widely available. Method: We conducted a single-center, randomized control trial study in Bangkok, Thailand to evaluate efficacy, safety and pharmacokinetics of dolutegravir 50 mg once daily with food versus dolutegravir 50 mg twice daily in HIV/TB co-infected patients receiving rifampin based antituberculosis therapy. TB/HIV coinfected adults, ART naïve, stable on RIF containing regimen for drug-susceptible TB were randomly assigned to receive DTG 50 mg OD with food (study arm; TLD 1 pill/day) or DTG 50 mg twice-daily (control arm; TLD 1 pill plus additional DTG). Intensive PK was scheduled at week 4. Blood samples were collected pre-dose, 1, 2, 4, 6, 8, 12, and 24-hour post-dose (by study arm). HIV-RNA, liver and renal function tests were monitored. DTG concentrations were determined by validated LC-MS/MS. PK parameters were estimated (nonparametric; WinNonLin). The primary endpoint was DTG geometric mean ratios (GMRs) of DTG 50 mg QD vs DTG 50 mg BID (90%CI) and percent of participants with DTG minimum concentrations (Cmin) above the required protein-adjusted 90% inhibitory concentration (IC90) of 0.064 μg/mL. Results: Totally 20 study arm and 20 control arm participants completed PK analysis. The majority were male (87.5%); with median age 35.6 years, and median body weight 57.5 kg. At baseline, median CD4 was 170 (IQR 45.5-302) cells/μL and median HIV RNA was 4.96 (IQR 4.23-5.61) log10 copies/mL; 43% had HIV-RNA> 100,000 copies/mL. GMR (90%CI) maximum concentration (Cmax) and area under curve (AUC0-τ) not within the bioequivalence range of 0.8-1.25: 0.84 (0.57-1.25) and 1.07 (0.72-1.59), respectively (Table 1). Cmin GMR was 0.3 (0.18-0.49); however, the geometric means in both arms were above the required IC90: 0.18 (0.11-0.28) in study arm and 0.59 (0.44-0.79) in control arm. At week 12, 83% and 83% of participants in study arm and control arm, respectively had HIV-RNA <50 copies/mL. At week 24, 83% and 100% of participants in study arm and control arm, respectively had HIV-RNA <50 copies/mL Both arms were well-tolerated. Conclusion: Although there were substantial reductions in DTG concentrations when co-administered with RIF, Cmin levels were mostly above the protein-binding-adjusted IC90 of 0.064 μg/mL and majority of participants had high efficacy and >85% had VL suppression at week 12 and 24. Dolutegravir based ART can be used safely with rifampin based antituberculosis.
