Short-course preventive therapy with 12 once-weekly rifapentine/isoniazid doses (3HP) could transform TB control, but drug interactions with antiretrovirals may pose implementation challenges. In a previous trial, 3HP administered with dolutegravir (DTG) resulted in serious adverse events (AE) in 2/4 healthy subjects (fever, hypotension, elevated transaminases); the study was halted. We conducted a Phase I/II study of 3HP and DTG in adults with HIV to characterize safety, drug interactions, and viral suppression.
HIV infected adults with undetectable viral load on efavirenz (EFV)-based regimens were recruited into 3 groups. All received DTG in place of EFV for 8 weeks, then began 3HP; after 3HP completion, all participants were followed 4 more weeks. Viral loads were measured at baseline and weeks 11 and 24. Groups 1A (n=12) and 1B (n=18) had intensive DTG PK sampling performed at week 8 (pre-HP), then weeks 11 and 16 following the 3rd and 8th doses of HP. Group 2 (n=30) were treated with the same schedule and had sparse DTG PK sampling at weeks 8, 11 and 16. Primary endpoints were 1) grade >3 AE and 2) population PK parameters of DTG with or without HP. An independent Study Monitoring Committee recommended release of results following its second review.
Of the 60 participants who received 3HP, 43 (70%) were female, median (IQR) age was 40 (35-48) years, all were black African, median (IQR) CD4 was 683 (447-935) cells/mm3, and median (IQR) BMI was 28.9 (24.0-32.9) kg/m2. All participants received ≥6 HP doses at the time of this report. Three Grade 3 AE occurred (2 elevated creatinine, 1 hypertension). HIV viral loads at baseline, day 58 (pre-HP), day 72 (3rd HP dose) and day 168 (post-HP) were all <40 c/mL. Table 1 shows Group 1A and 1B PK results. The geometric mean (GM) trough concentration of DTG on Day 58 (pre-HP) was 1003 ug/mL (5th-95th %ile: 500-2080), and during HP treatment 546 (134-1616) with all trough levels but one above DTG IC90 of 64 ug/mL; Table). Overall, HP administration decreased DTG bioavailability by 29% (RSE 13%) (+18%, -37% and -35% for week 1, 3 and 8), while clearance remained unchanged.
Co-administration of DTG and HP was well-tolerated, with no HP-related Grade >3 AEs. Although HP decreased DTG bioavailability, which was associated with a modest decrease in trough levels, all trough levels but one were above the DTG IC90. All viral loads were suppressed. DTG may be co-administered with 3HP without dose adjustment.