Abstract Body

Background:

People with HIV (PWH) living in areas of high TB endemicity have high potential to benefit from short-course tuberculosis (TB) preventive therapy (TPT) with weekly isoniazid and rifapentine for 3 months (3HP). 3HP given to virally suppressed PWH on dolutegravir (DTG)-based regimens has been found to be safe and to maintain virologic suppression with adequate DTG levels. No data yet supports simultaneous 3HP with DTG-based ART initiation among ART-naïve people.

Methods:

A phase 1/2 comparative trial of simultaneous initiation of 3HP or 6 months isoniazid (6H) with DTG-based ART was performed among antiretroviral (ART)-naïve adults with HIV in South Africa. Participants were sequentially enrolled and assigned to 6H (N=25) and 3HP (N=50). PK sampling for DTG trough was performed at: day 1 (prior to first HP dose), day 17 (3 days after 3rd HP dose), and day 52 (3 days after 8th HP dose) in both groups. Primary endpoints were safety and DTG pharmacokinetics during 3HP/DTG coadministration. Safety and the secondary endpoint of HIV viral load at TPT completion were previously reported.

Results:

By week 8, viral suppression (VL < 50 copies/mL) was achieved in 100% of participants in both groups. At week 12, viral suppression (VL < 50 copies/mL) was present in 44/50 (88%) and 23/25 (92%) participants in the 3HP and 6H groups, respectively. Nonlinear mixed-effects modeling showed that there was a 72% induction effect of rifapentine on DTG clearance, from 0.95 L/hr to 1.64 L/hr. DTG trough concentration was above the PA-IC90 (64 ng/mL) in all participants at all timepoints, and >158 ng/mL (the lower 5th percentile confidence bound of concentrations achieved with fully suppressive 10 mg daily dosing in the SPRING-1 trial) in all but 2 individuals at week 3 and in all individuals at week 8. The 2 individuals w DTG concentrations below 158 ng/mL at week 3 both suppressed by week 8.

Conclusions:

Simultaneous initiation of 3HP for LTBI treatment and DTG-based ART resulted in rapid viral suppression among ART-naïve PWH. Despite a 72% induction of DTG clearance in the 3HP group, DTG concentrations enabled viral suppression < 50 copies/mL in all individuals in both groups at 8 weeks. This information is critical to informing global guidelines around LTBI treatment in ART-naïve individuals.