Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: Pharmacokinetics and 24-week safety and efficacy

BACKGROUND:: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS:: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants ≥14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 μg/mL and area under the curve (AUC) <170 μg hr/mL. RESULTS:: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC ≤ 36.6 (range, 27.9-62.6) μg hr/mL; predose concentration ≤ 2.2 (range, 0.99-4.9) μg/mL; maximum concentration ≤ 4.76 (range, 2.84-7.28) μg/mL and apparent clearance (L/h/m) ≤ 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS:: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.