Background:  Lopinavir/ritonavir (LPV/r) has been proposed as primary therapy for infants, but there are no published data on pharmacokinetics and efficacy in infants <6 weeks of age. We hypothesized that young infants require higher doses of LPV/r than older children to achieve the target exposure, similar to that observed in other protease inhibitors.

Methods:  A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a  dose of 300/75 mg/m² twice daily plus 2 nucleoside reverse transcriptase analogs (NRTI) in HIV-1-infected infants ≥14 days and <6 weeks of age. Patients had a 12-hour pharmacokinetic evaluation performed after 2 weeks of LPV/r therapy; LPV and ritonavir (RTV) concentrations were measured by high-performance liquid chromatography (HPLC). Both compartmental (ADAPT-II) and non-compartmental pharmacokinetic analyses were performed. Doses were modified to maintain LPV pre-dose (Cpre) >1 µg/mL and AUC <170 µg*hour/mL. A virologic endpoint was reached if plasma HIV-1 RNA was >400 copies/mL at week 16 or >4000 copies/mL thereafter. All evaluations were performed as an intent-to-treat analysis.

Results:  We enrolled 8 infants at a median (range) age of 5.6 (3.6 to 5.9) weeks and all have completed ≥24 weeks of follow up. At entry, median (range) HIV-1 RNA was 5.9 (4.7 to 6.5) log₁₀ copies/mL and CD4% was 45% (29 to 59).One infant had unevaluable pharmacokinetics due to non-adherence to medications and the remaining 7 infants completed the pharmacokinetic evaluation at a median (range) age of 7.2 weeks (5.5 to 8.0) at a LPV dose of 279 (246 to 305) mg/m² every 12 hours. The median (range) parameters were:  AUC = 33.0 (27.9 to 62.0) µg*hour/mL; C_pre= 2.6 (1.1 to 4.9) µg/mL; C_max= 3.8 (2.8 to 7.2) µg/mL, and CL/F (L/hour/m²) = 9.6 (3.2 to 12.8). There were no ≥grade 3 adverse events considered definitely related to study treatment, but 2 of the 8 infants (25%) had grade 3 neutropenia at week 8, considered possibly related to NRTI. None of the 8 infants reached a virologic endpoint at week 16 but 1 of 8 (12%) reached a virologic endpoint at week 24 due to medication non-adherence. There were no significant changes in CD4 percentage from baseline to week 24 in 4 of 4 infants with data available.

Conclusions:  Although the LPV AUC in this population was significantly lower than seen in an older cohort ages 6 weeks to 6 months (median AUC = 67.5, 23.7 to 164.0) µg*hour/mL, p = 0.032), LPV/r-based HAART at a dose of 300/75 mg/m² twice daily was well tolerated and resulted in good virologic suppression with only 1 of 8 infants meeting a protocol-defined virologic endpoint at 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.