In our study, pharmacy supply was not associated with self-reported adherence. Most importantly, adherence and age were significant predictors of reaching undetectable viral loads.
Objective CYP3A5, MDR1 (ABCB1) and OATP1 (SLCO1B1) polymorphisms have been associated with variability in the pharmacokinetics (PK) of protease inhibitors. The aim of this study was to investigate the influence of CYP3A5 A6986G, ABCB1 (C3435T and G2677T), and SLCO1B1 (T521C and A388AG) polymorphisms on the PK and virologic outcome of lopinavir/ritonavir (LPV/RTV) in HIV-infected children. Design and Methods Prospective cohort study in children (4-18 yrs old) on stable antiretroviral therapy with LPV/RTV. CYP3A5, ABCB1 and SLCO1B1 genotypes were determined using PCR amplification with allelic discrimination assays. The 12 hr plasma area under the concentration-time curves (AUC) and clearances (CL) of LPV and RTV were estimated using non-compartmental models. HIV RNA viral load was evaluated every 12 weeks for a total study period of 52 weeks. Analysis of covariance models with adjustment for age and adherence, and allometric adjustment of CL were used to assess associations between studied polymorphisms and AUC, CL and HIV RNA. Results 50 children (median age 11.2 yrs) were enrolled. Allele frequencies of studied genotypes were in Hardy-Weinberg equilibrium. There was no statistically significant association between LPV or RTV AUC or CL, and CYP3A5, ABCB1 or SLCO1B1 A388G polymorphisms. There was a significant association between SLCO1B1 T521C genotype and increased LPV AUC (p=0.042) and a nearly significant association with decreased LPV CL (p=0.063). None of the studied polymorphisms including SLCO1B1 T521C were associated with virologic outcome during 52 weeks of study follow up. Conclusions There was no statistically significant influence of the CYP3A5, ABCB1 or SLCO1B1 A388AG polymorphisms on the PK and virologic outcome of LPV/RTV in HIV-infected children. SLCO1B1 T521C polymorphism was significantly associated with increase in LPV AUC, but was not associated with undetectable HIV RNA during the study period.
Our study results strongly indicate agreement between saliva and plasma NVP concentrations in pediatric patients with HIV infection, on the basis of Bland-Altman analysis. Nonstimulated NVP saliva concentrations can be used as an alternative noninvasive, reliable, cost-effective method for direct measurement of adherence and application of therapeutic drug monitoring in NVP therapy.
In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R 2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.Lopinavir/ritonavir (LPV/RTV) (Kaletra) is the first and only coformulated RTV-boosted protease inhibitor (PI) approved for use in children. The recommended doses for children who weigh more than 15 kg are 10 mg/kg of body weight or 230 mg/m 2 (body surface area) twice daily, with a maximum of 400 mg per dose unless it is combined with drugs affecting cytochrome (CYP) P450 metabolism, which require LPV dose adjustment (4, 28). Introduced as a salvage agent (22), LPV/RTV has become one of the preferred PI choices for first-line regimens in children Ͼ6 months of age in the countries with access to the drug.Despite evidence for good antiviral efficacy among children in a clinical trial setting (16,17,23), the standard dose may not be adequate for every child. Noncompartmental analysis has shown that the average LPV plasma 12-hour-postdose concentration (C trough ) in children given the currently recommended pediatric dose of LPV is 67% lower than in adults (24). Recently, Jullien et al. published a population pharmacokinetics (PK) model of LPV in children aged 0 to 18 years (15). The model was based on a retrospective analysis of LPV plasma measurements in 157 children, with a median of 3 samples (range, 1 to 14) per patient, obtained for monitoring purposes after self-reported LPV intake. In t...
Between 2000 and 2005, 84 HIV-infected children were referred to Children's National Medical Center; 28 were born to immigrant mothers, 89% of whom were of African descent. Rates of antiretroviral prophylaxis were low regardless of maternal origin. Nonimmigrant mothers (30.4%) used illicit drugs (P < 0.001), and 50% of immigrant mothers breast-fed their children (P < 0.001). These data can guide intervention strategies.
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