The 28-day regimen of daily rifapentine (RPT) + isoniazid (INH) known as 1HP is an effective, ultrashort option for latent TB treatment in people with HIV (PWH). RPT is a known inducer of drug metabolizing enzymes and may decrease dolutegravir (DTG) concentrations and increase the risk of virologic failure. A5372 evaluates the effect of 1HP on the pharmacokinetics (PK) of DTG.
A5372 is a multicenter, PK study in which adult PWH on DTG-containing ART with HIV viral load <50 copies/mL and an indication for latent TB treatment received daily RPT/INH (600mg/300mg) for 28 days. DTG was increased to 50mg twice daily during 1HP treatment. Intensive PK sampling was performed on day 0 (before RPT/INH) with participants on standard DTG 50mg once daily, and on day 28 with participants taking 1HP and DTG 50mg twice daily. Plasma was collected pre-dose, 1, 2, 4, 8, 12, 13, 14, 23, and 24 hours post-DTG dose. Sparse trough sampling occurred on days 3, 14, and 21. Participants were followed for a total of 42 days. DTG concentrations were analyzed by a validated LC-MS/MS method. PK and demographics were summarized as median (Q1, Q3).
Thirty-seven participants enrolled between February and November 2021. At the time of this interim analysis, twenty-five participants (44% cisgender female; 56% Black/African; median age 41 (32, 49) years) had PK concentrations available. The median observed DTG trough concentration was 1745 ng/mL (1099, 2694) on day 0 vs. 2146 (1412, 2484) on day 28. Median DTG trough concentrations at days 3, 14, and 21 were 4454, 2127, and 2593 ng/mL, respectively (Figure). Twenty-four of 25 had HIV RNA levels <50 copies/mL at day 28. One participant had an HIV viral load of 160 copies/mL at day 28 (DTG concentration was 2162 ng/mL), with repeat viral load of <50 copies/mL on day 42. One participant exhibited grade 3 ALT and AST on study treatment. No one experienced hypersensitivity. No serious adverse events were reported.
DTG trough concentrations with 50mg twice daily dosing during 28 days of daily RPT/INH were higher, not lower, than those with standard dose DTG once daily alone. A decrease in trough concentrations from day 3 to 28 is suggestive of a time dependent induction of DTG metabolism by RPT/INH. These interim PK, virologic suppression, and safety data provide evidence for twice daily DTG in combination with the 1HP regimen.