Browsing by Subject "Artemisinins"

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    Impact of the large-scale deployment of artemether/lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia
    (BioMed Central Ltd, 2009) Barnes, Karen; Chanda, Pascalina; Ab Barnabas, Gebre
    Malaria is one of the most significant causes of morbidity and mortality worldwide. Every year, nearly one million deaths result from malaria infection. Malaria can be controlled in endemic countries by using artemisinin-based combination therapy (ACT) in combination with indoor residual spraying (IRS) and insecticide-treated nets (ITNs). At least 40 malaria-endemic countries in sub-Saharan Africa now recommend the use of ACT as first-line treatment for uncomplicated falciparum malaria as a cornerstone of their malaria case management. The scaling up of malaria control strategies in Zambia has dramatically reduced the burden of malaria. Zambia was the first African country to adopt artemether/lumefantrine (AL; Coartem(R)) as first-line therapy in national malaria treatment guidelines in 2002. Further, the vector control with IRS and ITNs was also scaled up. By 2008, the rates of in-patient malaria cases and deaths decreased by 61% and 66%, respectively, compared with the 2001-2002 reference period.Treatment with AL as first-line therapy against a malaria epidemic in the KwaZulu-Natal province of South Africa, in combination with strengthening of vector control, caused the number of malaria-related outpatient cases and hospital admissions to each fall by 99% from 2001 to 2003, and malaria-related deaths decreased by 97% over the same period. A prospective study also showed that gametocyte development was prevented in all patients receiving AL. This reduction in malaria morbidity has been sustained over the past seven years.AL was introduced as first-line anti-malarial treatment in 2004 in the Tigray region of Ethiopia. During a major malaria epidemic from May-October 2005, the district in which local community health workers were operating had half the rate of malaria-related deaths compared with the district in which AL was only available in state health facilities. Over the two-year study period, the community-based deployment of AL significantly lowered the risk of malaria-specific mortality by 37%. Additionally, the malaria parasite reservoir was three-fold lower in the intervention district than in the control district during the 2005 high-transmission season.Artemisinin-based combination therapy has made a substantial contribution to reducing the burden of malaria in sub-Saharan Africa.
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    The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients
    (2015) Kredo, T; Mauff, K; Workman, L; Van Der Walt, J-S; Wiesner, L; Smith, P J; Maartens, G; Cohen, K; Barnes, K I
    BackgroundArtemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir–based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.MethodsAn adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.ResultsWe enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8μg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.ConclusionDespite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.Trial registrationClinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1345-1) contains supplementary material, which is available to authorized users.