Presented at HIVR4P 2018 – (OA15.06LB) Tail-phase Safety, Tolerability and Pharmacokinetics of Long-acting Injectable Cabotegravir in HIV-uninfected Individuals: HPTN 077 Final Results
Raphael J Landovitz, Sue Li, Joseph J Eron, Beatriz Grinsztejn, Halima Dawood, Albert Y Liu, Manya Magnus, Mina C Hosseinipour, Ravindre Panchia, Leslie Cottle, Paul Richardson, Mark A Marzinke, Susan H Eshleman, Ryan Kofron, Adeola Adeyeye, David Burns, Alex R Rinehart, David Margolis, Marybeth McCauley, Craig W Hendrix
Background: Long-acting injectable Cabotegravir (CAB LA) is an INSTI in development for PrEP. HPTN 077 evaluated CAB LA 800 mg intramuscular (IM) injection every 12 weeks (Q12W) and 600 mg IM every 8 weeks (Q8W) after an initial 4-week interval. Prolonged exposure (the pharmacokinetic [PK] “tail”) after terminal injection results from slow absorption from the injection site depot.
Methods: HPTN 077 was a Phase 2a multicenter study in low-risk HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the US. 199 participants were randomized 3:1 to CAB or placebo (PBO) and received oral CAB 30 mg or PBO daily for 4 weeks followed by 800 mg Q12W IM (Cohort 1 [C1], 2x2mL, n=82) or PBO (n=28), or 600 mg Q8W IM (Cohort 2 [C2], 1x3mL, n=69) or PBO (n=20) over 41 weeks. Participants were followed for 52-76 weeks after the final injection for evaluation of adverse events (AE), tolerability and PK.
Results: Retention was 91% and 95% (C1 and C2) at 52 weeks after last injection, and 92% and 93% (respectively) at 76 weeks. Overall in the tail phase, grade 2 or higher AEs were reported by 91% of CAB recipients (87.8% in C1; 95% in C2), compared to 69.8% of PBO participants (76% in C1; 61.1% in C2). Geometric means of apparent terminal half lives (T½app) for males and females will be presented. T½appsignificantly associated with sex and BMI with 1.5 times higher in females than males (p=0.009) and 1.02 times higher per unit BMI increase (p=0.01). Detectable plasma CAB (>25ng/mL) results 52 weeks and 76 weeks after the last injection bye cohort and sex will be presented.
Conclusions: Exposure to decreasing CAB plasma concentrations following the last injection was well tolerated. The T½app of CAB LA for females was significantly increased compared to males. In at-risk persons who discontinue CAB LA, the PK tail phase may represent a period of risk for selection of CAB-resistant virus should HIV infection occur. Data from ongoing Phase 3 studies will help evaluate this risk.