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

BMC Medicine

Ghyslain Mombo-Ngoma¹  Elizabeth Juma²  Quique Bassat³  Raquel González³  Clara Menéndez³  Sarah G. Staedke⁴  Bertrand Lell⁵  Grant Dorsey⁶  Nines Lima⁷  Elisabeth Baudin⁸  Emmanuelle Espié⁸  Innocent Valea⁹  Halidou Tinto⁹  Frederic Nikiema⁹  Jean B. Ouédraogo⁹  Michael T. Bretscher^1,10  Lucy C. Okell^1,10  Azra C. Ghani^1,10  Umberto D’Alessandro^1,11  Abdoulaye A. Djimde^1,12  Bakary Fofana^1,12  Estrella Lasry^1,13  Jamie Griffin^1,14  Corine Karema^1,15  Adoke Yeka^1,16  Philippe J. Guerin^1,17  Prabin Dahal^1,17  Kasia Stepniewska^1,17  Clarissa Moreira^1,17 

[1] Centre de Recherches Medicales de Lambarene;Centre for Global Health Research, Kenya Medical Research Institute;Centro de Investigação em Saúde de Manhiça (CISM);Department of Clinical Research, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine;Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna;Department of Medicine, University of California San Francisco;Department of Paediatrics, University of Calabar;Epicentre;Institut de Recherche en Science de la Sante;MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London;MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine;Malaria Research and Training Center, University of Science, Techniques and Technologies of Bamako;Medecins Sans Frontieres-OCBA;School of Mathematical Sciences, Queen Mary University of London;Swiss Tropical and Public Health Institute;Uganda Malaria Surveillance Project;WorldWide Antimalarial Resistance Network (WWARN);

关键词: Malaria;    Artemisinin;    Drug;    Lumefantrine;    Amodiaquine;    Trial;   

DOI  :  10.1186/s12916-020-1494-3

来源: DOAJ

【 摘 要 】

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 (<=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.

【 授权许可】

Unknown