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dc.contributor.authorBretscher, M
dc.contributor.authorDahal, P
dc.contributor.authorGriffin, J
dc.contributor.authorBassat, Q
dc.contributor.authorBaudin, E
dc.contributor.authorD'Alessandro, U
dc.contributor.authorDjimde, AA
dc.contributor.authorDorsey, G
dc.contributor.authorEspié, E
dc.contributor.authorFofana, B
dc.contributor.authorGonzález, R
dc.contributor.authorJuma, E
dc.contributor.authorKarema, C
dc.contributor.authorLasry, E
dc.contributor.authorLell, B
dc.contributor.authorLima, N
dc.contributor.authorMenéndez, C
dc.contributor.authorMombo-Ngoma, G
dc.contributor.authorMoreira, C
dc.contributor.authorNikiema, F
dc.contributor.authorOuédraogo, JB
dc.contributor.authorStaedke, SG
dc.contributor.authorTinto, H
dc.contributor.authorValea, I
dc.contributor.authorYeka, A
dc.contributor.authorGhani, AC
dc.contributor.authorGuerin, PJ
dc.contributor.authorOkell, LC
dc.date.accessioned2020-03-20T18:15:51Z
dc.date.available2020-03-20T18:15:51Z
dc.date.issued2020-02-25
dc.date.submitted2020-03-06
dc.identifier.pmid32098634
dc.identifier.doi10.1186/s12916-020-1494-3
dc.identifier.urihttp://hdl.handle.net/10144/619612
dc.description.abstractBACKGROUND: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. METHODS: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. RESULTS: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. CONCLUSION: Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.en_US
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.rightsWith thanks to BMC.en_US
dc.subjectAmodiaquine
dc.subjectArtemisinin
dc.subjectCrt
dc.subjectDrug
dc.subjectLumefantrine
dc.subjectMalaria
dc.subjectMathematical model
dc.subjectTrial
dc.subjectmdr1
dc.titleThe duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient dataen_US
dc.typeArticle
dc.identifier.eissn1741-7015
dc.identifier.journalBMC Medicineen_US
dc.source.journaltitleBMC medicine
dc.source.volume18
dc.source.issue1
dc.source.beginpage47
dc.source.endpage
refterms.dateFOA2020-03-20T18:15:52Z
dc.source.countryEngland


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