Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 – 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36–17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
CitationSupervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial., 365 (9469 Articles IntroductionWith an estimated 500 million individuals affected every year, malaria is a leading cause of morbidity and mortality in sub-Saharan Africa along with HIV/AIDS. 1Of the 1 million deaths caused by malaria worldwide, about 90% occur in African children, a situation compounded by the emergence of drug resistance. 2In Uganda, which had a population of 24·7 million in 2003, an estimated 9·8 million individuals are infected with malaria every year (John Bosco Rwakimari, Ugandan Ministry of Health, Uganda, personal communication; http://www.health.go.ug). To tackle malaria-related mortality and morbidity, the Ugandan Ministry of Health (MoH) is concentrating on early diagnosis and effective treatment of the disease. In the 1970s and the 1980s, high malaria awareness in the population and easy access to cheap and effective antimalarials such as chloroquine and sulfadoxinepyrimethamine ensured the disease was reasonably well controlled. However, resistance to these drugs is now widespread in Uganda and in other parts of east Africa, with adverse consequences for malaria control. 3-7The MoH-recommended first-line antimalarial drug in Uganda is chloroquine combined with sulfadoxinepyrimethamine, 6 though introduction of artemisininbased combination treatments (ACTs) is planned for 2005.8 Day-28 cure rates of 52%, 9 65%, 7 and 77% 10 have been reported for this combination in different parts of Uganda. ACTs are judged effective in Africa, where they improve cure rates and reduce gametocyte carriage compared with presently used monotherapies.11,12 To combat drug-resistant malaria in Africa, WHO advocates the adoption of ACTs as first-line treatment.2 The use of the non-ACT combination of amodiaquine and sulfadoxine-pyrimethamine is considered by some as an interim measure while waiting for ACTs to become widely available. Day-28 efficacy rates of this combination were 84% and 90% in two studies in Uganda. 7,9 Artemether-lumefantrine (Coartem, Novartis Pharma, Basel, Switzerland) is the only fixed-dose formulation ACT on the WHO essential drug list. However, the combination is not registered for use in pregnant women, and was not registered for children under 10 kg in weight when we did our trial. Results of studies [13][14][15] from southeast Asia show that the six-dose regimen of artemether-lumefantrine has cure rates of more than 96%, is well tolerated, and has a good safety profile when Supervised versus unsupervised intake of six-dose artemether-lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial Patrice Piola, Carole Fogg, Francis Bajunirwe, Samuel Biraro, Francesco Grandesso, Eugene Ruzagira, Joseph Babigumira, Isaac Kigozi, James Kiguli, Juliet Kyomuhendo, Laurent Ferradini, Walter Taylor, Francesco Checchi, Jean-Paul Guthmann S...
Measuring baseline levels of adherence and identifying risk factors for non-adherence are important steps before the introduction of new antimalarials. In Mbarara in southwestern Uganda, we assessed adherence to artemether-lumefantrine (Coartem) in its latest World Health Organization blister formulation. Patients with uncomplicated Plasmodium falciparum malaria were prescribed artemether-lumefantrine and received an explanation of how to take the following five doses at home. A tablet count was made and a questionnaire was completed during a home visit. Among 210 analyzable patients, 21 (10.0%) were definitely or probably non-adherent, whereas 189 (90.0%) were probably adherent. Age group was not associated with adherence. Lack of formal education was the only factor associated with non-adherence after controlling for confounders (odds ratio = 3.1, 95% confidence interval [CI] = 1.1-9.7). Mean lumefantrine blood levels were lower among non-adherent (n = 16) (2.76 microg/mL, 95% CI = 1.06-4.45) than among adherent (n = 171) (3.19 microg/mL, 95% CI = 2.84-3.54) patients, but this difference was not statistically significant. The high adherence to artemether-lumefantrine found in our study suggest that this drug is likely to be very effective in Mbarara provided that patients receive clear dosage explanations.
Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with uncomplicated Plasmodium falciparum malaria: an open-label, randomised, non-inferiority trial MSF Field Research SummaryBackground Malaria in pregnancy is associated with maternal and fetal morbidity and mortality. In 2006, WHO recommended use of artemisinin-based combination treatments during the second or third trimesters, but data on effi cacy and safety in Africa were scarce. We aimed to assess whether artemether-lumefantrine was at least as effi cacious as oral quinine for the treatment of uncomplicated falciparum malaria during the second and third trimesters of pregnancy in Mbarara, Uganda. MethodsWe did an open-label, randomised, non-inferiority trial between October, 2006, and May, 2009, at the antenatal clinics of the Mbarara University of Science and Technology Hospital in Uganda. Pregnant women were randomly assigned (1:1) by computer generated sequence to receive either quinine hydrochloride or artemetherlumefantrine, and were followed up weekly until delivery. Our primary endpoint was cure rate at day 42, confi rmed by PCR. The non-inferiority margin was a diff erence in cure rate of 5%. Analysis of effi cacy was for all randomised patients without study deviations that could have aff ected the effi cacy outcome. This study was registered with ClinicalTrials.gov, number NCT00495508.Findings 304 women were randomly assigned, 152 to each treatment group. By day 42, 16 patients were lost to followup and 25 were excluded from the analysis. At day 42, 137 (99·3%) of 138 patients taking artemether-lumefantrine and 122 (97·6%) of 125 taking quinine were cured-diff erence 1·7% (lower limit of 95% CI -0·9). There were 290 adverse events in the quinine group and 141 in the artemether-lumefantrine group.Interpretation Artemisinin derivatives are not inferior to oral quinine for the treatment of uncomplicated malaria in pregnancy and might be preferable on the basis of safety and effi cacy.Funding Médecins Sans Frontières and the European Commission.
BackgroundMalaria in pregnancy (MiP) is a major public health problem in endemic areas of sub-Saharan Africa and has important consequences on birth outcome. Because MiP is a complex phenomenon and malaria epidemiology is rapidly changing, additional evidence is still required to understand how best to control malaria. This study followed a prospective cohort of pregnant women who had access to intensive malaria screening and prompt treatment to identify factors associated with increased risk of MiP and to analyse how various characteristics of MiP affect delivery outcomes.MethodsBetween October 2006 and May 2009, 1,218 pregnant women were enrolled in a prospective cohort. After an initial assessment, they were screened weekly for malaria. At delivery, blood smears were obtained from the mother, placenta, cord and newborn. Multivariate analyses were performed to analyse the association between mothers’ characteristics and malaria risk, as well as between MiP and birth outcome, length and weight at birth. This study is a secondary analysis of a trial registered with ClinicalTrials.gov, number NCT00495508.ResultsOverall, 288/1,069 (27%) mothers had 345 peripheral malaria infections. The risk of peripheral malaria was higher in mothers who were younger, infected with HIV, had less education, lived in rural areas or reported no bed net use, whereas the risk of placental infection was associated with more frequent malaria infections and with infection during late pregnancy. The risk of pre-term delivery and of miscarriage was increased in mothers infected with HIV, living in rural areas and with MiP occurring within two weeks of delivery.In adjusted analysis, birth weight but not length was reduced in babies of mothers exposed to MiP (−60g, 95%CI: -120 to 0 for at least one infection and -150 g, 95%CI: -280 to −20 for >1 infections).ConclusionsIn this study, the timing, parasitaemia level and number of peripherally-detected malaria infections, but not the presence of fever, were associated with adverse birth outcomes. Hence, prompt malaria detection and treatment should be offered to pregnant women regardless of symptoms or other preventive measures used during pregnancy, and with increased focus on mothers living in remote areas.
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