1. The 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 data
- Author
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Elizabeth Juma, Azra C. Ghani, Raquel González, Michael T. Bretscher, Sarah G. Staedke, Philippe J Guerin, Bertrand Lell, Umberto D'Alessandro, Elisabeth Baudin, Kasia Stepniewska, Emmanuelle Espie, Innocent Valea, Clarissa Moreira, Halidou Tinto, Clara Menéndez, Estrella Lasry, Abdoulaye Djimde, Nines Lima, Jamie T. Griffin, Jean-Bosco Ouédraogo, Lucy C Okell, Grant Dorsey, Ghyslain Mombo-Ngoma, Frederic Nikiema, Adoke Yeka, Quique Bassat, Corine Karema, Prabin Dahal, Bakary Fofana, Medical Research Council (MRC), Medicines for Malaria Venture, The Royal Society, and Bill & Melinda Gates Foundation
- Subjects
0301 basic medicine ,Male ,SELECTION ,Artemether/lumefantrine ,lcsh:Medicine ,Trial ,chemistry.chemical_compound ,0302 clinical medicine ,Mathematical model ,mdr1 ,Artemisinin ,Malaria, Falciparum ,11 Medical and Health Sciences ,biology ,Artesunate/amodiaquine ,General Medicine ,Artemisinins ,3. Good health ,Drug Combinations ,Child, Preschool ,Chemoprophylaxis ,Crt ,Female ,Drug ,Life Sciences & Biomedicine ,PREGNANT-WOMEN ,medicine.drug ,Research Article ,CHEMOPREVENTION ,medicine.medical_specialty ,030231 tropical medicine ,030106 microbiology ,Plasmodium falciparum ,Malària ,MOLECULAR MARKERS ,Amodiaquine ,GENETIC-STRUCTURE ,Lumefantrine ,03 medical and health sciences ,Antimalarials ,Medicine, General & Internal ,Internal medicine ,General & Internal Medicine ,parasitic diseases ,medicine ,Humans ,DIHYDROARTEMISININ-PIPERAQUINE ,ANTIMALARIAL-DRUG RESISTANCE ,POLYMORPHISMS ,Science & Technology ,business.industry ,Artemether, Lumefantrine Drug Combination ,lcsh:R ,Infant ,PLASMODIUM-FALCIPARUM MALARIA ,medicine.disease ,biology.organism_classification ,Malaria ,chemistry ,business ,SULFADOXINE-PYRIMETHAMINE - Abstract
Background 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 ( 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.
- Published
- 2020