Are Prophylactic and Therapeutic Target Concentrations Different? The Case of Lopinavir/ritonavir or Lamivudine Administered to Infants for the Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding [PublishAheadOfPrint]

The ANRS 12174 trial assessed the efficacy and tolerance of LPV/r versus 3TC prophylaxis administered to breastfed infants, whose HIV-infected mothers were not on ART. In this sub-study, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at week 6, 26 and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters based on previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered as missing doses and discarded from Bayesian analysis. The overall population analysis shows that 30 to 40% of infants did not reach therapeutic targets, regardless of treatment group. Median[IQR] LPV C_trough at week 6, 26 and 38 were 2.8[1.7-4.4], 5.6[3.2-7.7] and 3.4[2.3–7.3] mg/L, respectively. Median[IQR] 3TC AUC_0-12 were 5.6[4.1-7.8], 5.9[5.1-7.5] and 7.3[4.9-8.5] mg.h/Lat week 6, 26 and 38, respectively. The therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain most infants above therapeutic pharmacokinetic targets.

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