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BACKGROUNDThe antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out.METHODSParticipants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158-266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3-12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls.RESULTSNineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5-12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0-120hr:123% (pCONCLUSIONSNevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4-12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.

© 2019 Rossetto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. In locations with a high rate of tuberculosis (TB) and HIV infection, there are a number of strategies to prevent negative outcomes such as opportunistic infections, hospitalizations and death, and this article investigates risk factors for the occurrence of hospitalization and death in cases of TB/HIV co-infection in the south of Brazil. The data are taken from a population-based retrospective cohort study on cases of TB/HIV co-infection from 2009 to 2013 in Porto Alegre, Brazil. Sociodemographic, epidemiological and clinical variables were analyzed. Relative risk (RR) estimates for hospitalization and death were determined by regression models. There were 2,419 co-infection cases, of which 1,527 (63.1%) corresponded to hospitalizations, and 662 (27.4%) to death. The occurrence of hospitalization was associated with 7 years of schooling (RR = 3.47, 95%CI: 1.97–6.29), 8–11 years of schooling (RR = 2.56, 95%CI: 1.44–4.69), place of origin—district health authorities Northwest/ Humaitá/Navegantes/Ilhas (RR = 2.01, 95%CI: 1.44–2.82), type of entry into the surveillance system as in cases of reentry after withdrawal (RR = 1,35, 95%CI: 1.07–1.70), closure in surveillance as in withdrawal of treatment (RR = 1.47, 95%CI: 1.18–1.83) and multidrug-resistant tuberculosis (RR = 3.94, 95%CI: 1.97–8.81). The occurrence of death was associated with age (RR = 1.07, 95%CI: 1,01–1,14), 7 years of schooling (RR = 3.94, 95%CI: 2.26–7.09), 8–11 years of schooling (RR = 2.84, 95%CI: 1.61–5.16), place of origin—district health authorities Baltazar (RR = 2.05, 95%CI: 1.48–2.86), type of entry in the surveillance system as cases of re-entry after withdrawal (RR = 1.53, 95%CI: 1.22–1.91), relapse (RR = 1.33, 95%CI: 1.03–1.73). The occurrence of hospitalizations and deaths is high among coinfected patients. Our estimation approach is important in order to identify, from the surveillance data, the risk factors for hospitalization and death in co-infected patients, so that they may receive more attention from the Brazilian national healthcare system.