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Background:  Lopinavir (LPV)/ritonavir (r) has been proposed as primary therapy for infants, but there are no published data on its use in young infants. We hypothesized that infants would require higher than recommended dosing for older children and dose requirements may vary with age.

Methods:  A prospective open-label trial evaluated LPV/r at an initial dose of 300 mg/m² twice daily + 2 nucleoside reverse transcriptase inhibitors (NRTI) for infants < 6 months of age. Intensive pharmacokinetic studies were done at week 2 with dose adjustment if LPV/r 12-hour post-dose concentration (C12) was < 1 mg/L; C12 was drawn every 12 weeks and intensive pharmacokinetic studies were repeated if dose was adjusted and at 1 year of age. Virologic success was defined as HIV-1 RNA < 400 copies/mL (< 400) by week 16; virologic failures never achieved < 400 and late suppressors achieved < 400 after week 16. Replication-competent HIV-1 in the resting CD4+ T-cell reservoir was measured at week 24 and week 48. CD4 percentage was drawn every 12 week. 

Results:  We enrolled 14 infants; 1 withdrew at week 2 (parental decision) and 1 at week 8 (death unrelated to study). Median follow-up at analysis was 50 weeks (range 19 to 112). At entry, median (range) age was 9.4 weeks (3.6 to 25.7), log₁₀ HIV-1 RNA 5.6 (3.77 to 6.88) and CD4 percentage 37 (19 to 59); 6 of the 12 (50%) had virologic success, 2 (17%) virologic failure, and 4 (34%) late suppressors (< 400 at week 32 to 48). Non-adherence to medications contributed to poor/slow virologic response in 3 of 6 virologic failures and late successors; all improved with social service intervention. In 9 infants studied, replication competent HIV-1 was recoverable at week 24 (median frequency 3.2 [0.22 to 81.7]) per million resting CD4⁺ T cells cultured. In 3 of 3 with HIV-1 RNA < 400 at week 48, the frequency of latently infected CD4 cells decreased (median 0.22 [< 0.22 to 1.1]). In 6 infants studied through week 36, CD4 percentage showed a median increase of 8% (–9 to +20%) from baseline. No dose-limiting toxicity occurred. Median AUC and C12 were 62 (24 to 164) mg/L·h and 2.24 (0.92 to 7.30) mg/L at week 2. One infant (8%) required dose adjustment. Infants with virologic success vs virologic failure/latent suppressors were significantly younger (median 5.6 vs 15.9 weeks, p = 0.004) and had an unexpectedly lower median week 2 AUC (34 vs 91; p = 0.04). LPV oral clearance (l/h) was weakly but negatively correlated with body size (r = –0.63; p = 0.05) at week 2 and not significantly different at 1 year of age (n = 5).

Conclusions:  The dose of 300 mg/m² LPV/r twice daily was well tolerated and produced encouraging virologic responses in those adherent to therapy, but concentrations were lower than in adults. To better define age-related differences in pharmacokinetics and response to LPV/r, a second cohort of 12 infants will be studied.

Keywords: pharmacokinetics; infants; lopinavir/ritonavir