Background:
HPTN 084, a Phase 3 randomized, placebo-controlled trial, demonstrated the superiority of long-acting injectable cabotegravir (CAB) compared to daily oral TDF/FTC for HIV prevention in individuals assigned female at birth. Injections were provided at 8-week intervals after the first two injections were separated by 4 weeks. While there were protocol-specified visit windows for injections, some participants received injections outside of the visit schedule. Although CAB correlates of protection are unknown, we evaluated CAB concentrations in those with delayed injections during the blinded phase of HPTN 084 to assess the impact of less frequent dosing on CAB pharmacology.
Methods:
Participants randomized to the CAB arm with at least one delayed injection were included in the analysis. Delayed injections were defined as type 1 (if the second injection occurred 8-14 weeks after the first injection; 4 weeks + 4-10) or type 2 (if a subsequent injection occurred 12-18 weeks after the preceding injection; 8 weeks + 4-10). CAB concentrations were measured at visits before and after an injection delay. Drug concentrations were evaluated relative to the 4x (0.664 mcg/mL) and 8x (1.33 mcg/mL) PAIC90 (1.33 mcg/mL).
Results:
One participant acquired HIV after a 16.1-week delay between injections 8 and 9; CAB concentrations were < 4x PA-IC90 at the first HIV positive visit. We identified 194 participants who had at least one delayed injection (n=224 occurrences): 19 type 1 and 205 type 2 delays. For type 1 delays, 100% and 91% of occurrences yielded CAB concentrations ≥ 4x PA-IC90 and ≥ 8x PA-IC90 when an injection was given 8-10 weeks (4 weeks + 4-6) after the first injection; 75% were < 4x PA-IC90 when the delay was 12-14 weeks (4 weeks + 8-10). For type 2 delays, when the time between injections was 12-14 weeks (8 weeks + 4-6; n=109 occurrences), 98% and 87% of CAB concentrations were ≥ 4x PA-IC90 and ≥ 8x PA-IC90, respectively; this fell to 90% and 62% when injections were delayed 16-18 weeks (8 weeks + 8-10). Up to eight weeks post-administration of a type 2 injection delay, CAB concentrations were ≥ 4x PA-IC90 and ≥ 8x PA-IC90 in 100% and 94% of occurrences, respectively.
Conclusions:
Pharmacologic analyses suggest there may be up to 6 weeks of forgiveness in persons assigned female at birth who received delayed CAB-LA injections. These data suggest that quarterly CAB-LA dosing in this population may be feasible and warrant further investigation.