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Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

ABSTRACT: Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4? cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda.Randomized clinical trial.We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ?400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12-28 weeks gestation and any CD4? cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum.The median age of the 389 study participants was 29 years; median CD4? cell count was 370 cells/?l. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P?

SUBMITTER: Cohan D

PROVIDER: S-EPMC4428759 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

Cohan Deborah D Natureeba Paul P Koss Catherine A CA Plenty Albert A Luwedde Flavia F Mwesigwa Julia J Ades Veronica V Charlebois Edwin D ED Gandhi Monica M Clark Tamara D TD Nzarubara Bridget B Achan Jane J Ruel Theodore T Kamya Moses R MR Havlir Diane V DV

AIDS (London, England) 20150101 2

<h4>Objective</h4>Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4⁺ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda.<h4>Design</h4>Randomized clinical trial.<h4>Methods</h4>We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission ...[more]

PMID: 25426808

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Project description:BackgroundCombination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART.MethodsThree hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay.ResultsEstradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases.ConclusionsCombination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority.Clinical trials registrationNCT00993031.

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:There is conflicting evidence of the impact of commonly used antiretroviral therapies (ARTs) on the pharmacokinetics of lumefantrine and the safety profile of artemether-lumefantrine. We compared the area under the concentration-time curve from 0 h to 14 days (AUC0-14 days) of lumefantrine and the safety profile of artemether-lumefantrine in malaria-negative human immunodeficiency virus (HIV)-infected adults in two steps. In step 1, a half-dose adult course of artemether-lumefantrine was administered as a safety check in four groups (n = 6/group): (i) antiretroviral naive, (ii) nevirapine-based ART, (iii) efavirenz-based ART, and (iv) ritonavir-boosted lopinavir-based ART. In step 2, a standard-dose adult course of artemether-lumefantrine was administered to a different cohort in three groups (n = 10 to 15/group): (i) antiretroviral naive, (ii) efavirenz-based ART, and (iii) ritonavir-boosted lopinavir-based ART. In step 1, lumefantrine's AUC0-14 days was 53% (95% confidence interval [CI], 0.27 to 0.82) lower in the efavirenz-based ART group than in the ART-naive group and was 2.4 (95% CI, 1.58 to 3.62) and 2.9(95% CI, 1.75 to 4.72) times higher in the nevirapine- and ritonavir-boosted lopinavir groups, respectively. In step 2, lumefantrine's AUC0-14 days was 1.9 (95% CI, 1.26 to 3.00) times higher in the ritonavir-boosted lopinavir group and not significantly different between the efavirenz- and ART-naive groups (0.99 [95% CI, 0.63 to 1.57]). Frequent cases of hematological abnormalities (thrombocytopenia and neutropenia) were observed in the nevirapine group in step 1, leading to a recommendation from the data and safety monitoring board not to include a nevirapine group in step 2. Artemether-lumefantrine was well tolerated in the other groups. The therapeutic implications of these findings need to be evaluated among HIV-malaria-coinfected adults. (This study has been registered at the Pan African Clinical Trials Registry under numbers PACTR2010030001871293 and PACTR2010030001971409.).

Dataset Information

Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

Publications

Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

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