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.

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.

• Authors: Michael T Bretscher, Prabin Dahal, Jamie Griffin, Kasia Stepniewska, Quique Bassat, Elisabeth Baudin, Umberto D'Alessandro, Abdoulaye A Djimde, Grant Dorsey, Emmanuelle Espié, Bakary Fofana, Raquel González, Elizabeth Juma, Corine Karema, Estrella Lasry, Bertrand Lell, Nines Lima, Clara Menéndez, Ghyslain Mombo-Ngoma, Clarissa Moreira, Frederic Nikiema, Jean B Ouédraogo, Sarah G Staedke, Halidou Tinto, Innocent Valea, Adoke Yeka, Azra C Ghani, Philippe J Guerin, Lucy C Okell
• Journal: BMC medicine (BMC Med) Vol. 18 Issue 1 Pg. 47 (02 25 2020) ISSN: 1741-7015 [Electronic] England
• PMID: 32098634 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Artemether, Lumefantrine Drug Combination
• Artemisinins
• Drug Combinations
• amodiaquine, artesunate drug combination
• Amodiaquine

Topics

• Amodiaquine (pharmacology, therapeutic use)
• Antimalarials (pharmacology, therapeutic use)
• Artemether, Lumefantrine Drug Combination (pharmacology, therapeutic use)
• Artemisinins (pharmacology, therapeutic use)
• Child, Preschool
• Drug Combinations
• Female
• Humans
• Infant
• Malaria, Falciparum (drug therapy)
• Male
• Plasmodium falciparum (pathogenicity)