Abstract
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). 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 > or =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 microg/mL and area under the curve (AUC) <170 microg hr ml. 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) microg hr ml; predose concentration="2.2" (range, 0.99-4.9) microg ml; maximum concentration="4.76" (range, 2.84-7.28) microg 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. 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. 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). 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> or =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 microg/mL and area under the curve (AUC) <170 microg hr ml. 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) microg hr ml; predose concentration="2.2" (range, 0.99-4.9) microg ml; maximum concentration="4.76" (range, 2.84-7.28) microg 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. 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.>
