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AimTo characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.MethodsAnalyses were implemented in NONMEM and R. Concentrations below the quantitation limit were modelled with likelihood-based approaches. Covariate relationships were evaluated using forward addition (P

배경 The 2-drug regimen of long-acting (LA) CAB and RPV dosed i.m. every 4 weeks (Q4W) was noninferior to daily oral 3-drug ART in Phase 3 studies. Long-term Phase 2 data (LATTE-2) provide the rationale for evaluation of a longer and potentially more convenient 8-week dosing interval (Q8W). 방법 ATLAS-2M is a multicenter, open-label, Phase 3b noninferiority (NI) study of CAB+RPV LA maintenance therapy administered Q8W or Q4W to treatment-experienced, HIV-infected adults. Virologically suppressed individuals on CAB+RPV LA Q4W (ATLAS study rollover) or oral ART were randomized 1:1 to receive CAB+RPV LA Q8W or Q4W. The primary endpoint at Week 48 was the proportion with plasma HIV-1 RNA ≥50 c/mL (Snapshot, ITT-exposed [ITTe]). The key secondary endpoint was the proportion with HIV-1 RNA <50 c/mL (Snapshot, ITTe). 결과 1045 participants were randomized to CAB+RPV LA Q8W (n=522) or Q4W (n=523); 27% were female; 63% were naive to CAB+RPV LA. CAB+RPV LA Q8W was noninferior to Q4W dosing in both the primary (1.7% vs 1.0%; adjusted difference [95% CI], 0.8 [−0.6, 2.2]) and secondary analysis (94.3% vs 93.5%; adjusted difference [95% CI], 0.8 [−2.1, 3.7]). There were 8 and 2 confirmed virologic failures (CVFs; 2 sequential measures ≥200 c/mL) on Q8W and Q4W dosing, respectively; 5 and 0 CVFs, respectively, had archived resistance-associated mutations (RAMs) to RPV, either alone (n=3) or with CAB RAMs (n=1) in baseline peripheral blood mononuclear cells (PBMCs). On-treatment RAMs to RPV, CAB, or both not present in baseline PBMCs were found in 6/8 Q8W CVFs and both Q4W CVFs. The safety profile was similar for Q4W and Q8W dosing, and serious adverse events were reported in 5% of participants in the Q8W group (n=26) vs 4% in the Q4W group (n=19). Injection site reactions (ISRs) were mostly mild or moderate (98% overall) with a median duration of 3 days. Discontinuation for an adverse event occurred in 2% of participants (Q8W, n=8; Q4W, n=10), with 6 (1%) and 11 (2%) in each group due to ISRs. There was 1 death (Q8W; sepsis). Of those treated Q8W in ATLAS-2M after ≥48 weeks of Q4W dosing in ATLAS, 94% (180/191) preferred Q8W dosing. 결론 Q8W dosing of CAB+RPV LA was noninferior to Q4W dosing and well tolerated. These results support the therapeutic potential of CAB+RPV LA administered every 2 months. [ABSTRACT FROM AUTHOR]