Background: Lopinavir/ritonavir (LPV/r) has been proposed as primary therapy in pediatrics, but infants started on LPV/r 300 mg/m² prior to 6 weeks of age have low LPV exposure measured after 2 weeks on treatment. The clinical relevance of these low LPV concentrations is dependent on how fast young infants acquire therapeutic LPV exposure. We assessed longitudinal pharmacokinetics in young infants started on LPV/r therapy and their virologic response.

Methods:  A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r using a dose of 300/75 mg/m² twice daily + 2 NRTI in HIV-1-infected infants ≥2 weeks and <6 weeks of age. Subjects had a 12-hour pharmacokinetic evaluation performed after 2 weeks of LPV/r therapy and at approximately 1 year of age. Trough LPV concentrations and plasma HIV RNA were obtained at regular intervals during the first year of therapy. LPV and ritonavir concentrations were measured by high-performance liquid chromatography (HPLC). Non-compartmental pharmacokinetic analyses were performed. Doses were modified to maintain LPV pre-dose (C_pre) >1 µg/mL and AUC <170 µg·hr/mL based on week-2 pharmacokinetic results. The Wilcoxon Signed Rank test was used to evaluate if differences in the pharmacokinetic parameters normalized to a 300 mg/m² dose at 2 weeks and ~1year are significant.

Results: We enrolled 10 infants prior to 6 weeks of age (median 5.6) with median HIV-1 RNA of 5.9 log₁₀ copies/mL, 9 of which had evaluable pharmacokinetics at 2 weeks and 7 of these had repeat evaluations at 1 year of age. The median (IQR) pharmacokinetic parameter values for those 7 were: During the first year of therapy the overall median LPV C_pre was 2.3 µg/mL; 20% of levels were sub-therapeutic (<1 µg/mL). In individual subjects, C_pre <1 was seen in 0% to 50% of levels. Of the 10 subjects, 9 and 7 achieved viral suppression (<1000) at 16 weeks and 48 weeks, respectively. Intermittent HIV RNA levels > 1000 between 8 weeks and 48 weeks were associated with frequent sub-therapeutic C_pre, (r = 0.73, p = 0.016).

Conclusions: LPV exposure increases dramatically during the first year of life; so despite initially having low levels, young infants receiving LPV/r-based HAART at a dose of 300/75 mg/m² twice daily experienced in good virologic suppression.