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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.

ABSTRACT: OBJECTIVE:The aim of this study was to estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as a first-line therapy for HIV-infected children less than 3 years of age in resource-limited settings. DESIGN:A prospective cohort study after conclusion of the P1060 randomized clinical trials (ClinicalTrials.gov Identifier: NCT00307151), with an overall follow-up of 7 years. METHODS:Longitudinal total cholesterol and triglyceride measures were compared between 222 and 227 children randomized to initiate LPV/r and nevirapine (NVP)-based regimens, respectively. Adipokines (adiponectin and leptin) and biomarkers of inflammation [C-reactive protein and interleukin (IL)-6], microbial translocation (lipopolysaccharide) and immune activation (sCD14), measured in 117 participants at a median of 45 weeks of follow-up, were also compared by a randomized arm. RESULTS:Mean total cholesterol and the percentage of participants with borderline or high total cholesterol was higher in the LPV/r arm from years 3 to 7 of follow-up than in the NVP arm (adjusted relative differences ranging from 10.9 to 23.4?mg/dl and adjusted relative risks ranging from a 60% increased risk to a more than four-fold increased risk for cholesterol ?170?mg/dl at 7 years of follow-up). Initiation of a LPV/r-based regimen was not associated with high triglycerides over follow-up or large differences in markers of metabolic syndrome, inflammation, microbial translocation or immune activation. CONCLUSION:Given the virologic superiority of LPV/r-based regimens in young children and open questions regarding the roll-out of dolutegravir in resource-limited settings, children are currently being maintained on LPV/r-based regimens. Our results suggest continual assessment of total cholesterol among young children initiating a LPV/r-based regimen to monitor cardiometabolic health.

SUBMITTER: Patel K

PROVIDER: S-EPMC6170714 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.

Patel Kunjal K Lindsey Jane J Angelidou Konstantia K Aldrovandi Grace G Palumbo Paul P

AIDS (London, England) 20181001 16

<h4>Objective</h4>The aim of this study was to estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as a first-line therapy for HIV-infected children less than 3 years of age in resource-limited settings.<h4>Design</h4>A prospective cohort study after conclusion of the P1060 randomized clinical trials (ClinicalTrials.gov Identifier: NCT00307151), with an overall follow-up of 7 years.<h4>Methods</h4>Longitudinal total cholesterol and triglyceride meas ...[more]

PMID: 30102656

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Project description:BackgroundNevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established.MethodsIn a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24.ResultsA total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06).ConclusionsOutcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Project description:BackgroundLopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment.MethodsChildren with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment.ResultsOf 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; Cmax 3.04 mg/L [0.03-18.6 mg/L]; C8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve24 121.63 mg/h/L [2.56-487.3 mg/h/L]; Cmax 9.45 mg/L [0.39-26.4 mg/L]; C12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L.ConclusionsModified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.

Project description:BackgroundThe International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial.MethodsHuman immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP- or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring.ResultsAs of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses.ConclusionsThese findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children.Clinical trials registrationNCT00307151.

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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.

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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.

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