Once-Daily Dolutegravir-Based Antiretroviral Therapy Among Adults With Advanced HIV Disease Receiving 1 Month of Daily Rifapentine and Isoniazid for Tuberculosis-Preventive Therapy and Fluconazole for Treatment of Cryptococcal Meningitis: Results of a Pharmacokinetic Study.

BACKGROUND

One month of daily isoniazid and rifapentine (1HP) is an efficacious, well-tolerated, and safe tuberculosis-preventive therapy regimen. Its implementation has been slow due to concern about drug-drug interactions with rifapentine.

METHODS

This single-arm pharmacokinetic study included 15 adults with advanced human immunodeficiency virus (HIV) disease receiving once-daily 50-mg dolutegravir-based antiretroviral therapy during 1HP therapy, alongside once-daily 800-mg fluconazole for treatment of cryptococcal meningitis. Participants underwent intensive pharmacokinetic sampling on days 1, 5, and 14 of 1HP therapy; sampling was conducted before and 2, 4, 8, and 24 hours after dosing. Dolutegravir, rifapentine, and fluconazole plasma concentrations were measured by means of high-performance liquid chromatography mass spectrometry, and bioequivalence was assessed with standard 90% confidence intervals (CIs).

RESULTS

Fifteen participants were enrolled, of whom 9 (60%) were female. The median age (interquartile range) was 37 (27-41) years, and the median CD4 cell count was 11/μL (10-25/μL). Overall, 14 of 15 participants completed sampling on days 5 and 14. The day 14 geometric mean (GM) dolutegravir trough concentration (95% CI) was 0.61 (.32-1.16) mg/L, while the median (interquartile range) was 0.63 (0.34-0.87) mg/L, with 100% of samples above the dolutegravir protein-adjusted 90% inhibitory concentration of 0.064 mg/L, with a GM ratio of 0.76 (90% CI, .4-1.46) compared with day 1. The day 14 maximum plasma concentration and area under the concentration-time curve from 0 to 24 hours for fluconazole were reduced compared with day 1, with GM ratios of 0.73 (90% CI, .57-.94) and 0.77 (.64-.93), respectively. Of 14 participants alive at 12 weeks after 1HP initiation, 11 (78%) had an HIV viral load (VL) <200 copies/mL. No cases of cryptococcal meningitis relapse occurred during the 18-week follow-up.

CONCLUSIONS

Standard once-daily 50-mg dolutegravir and 800-mg fluconazole dosing may be a safe and effective option for patients receiving 1HP tuberculosis-preventive therapy. These findings support further evaluation in larger studies.