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BMC Med. 2020 Feb 25;18(1):47. doi: 10.1186/s12916-020-1494-3.

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 information

1
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK. mthbretscher@gmail.com.
2
WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK.
3
Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
4
School of Mathematical Sciences, Queen Mary University of London, London, UK.
5
Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
6
ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
7
ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain.
8
Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain.
9
Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
10
Epicentre, Paris, France.
11
MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia.
12
Malaria Research and Training Center, University of Science, Techniques and Technologies of Bamako, Bamako, Mali.
13
Department of Medicine, University of California San Francisco, San Francisco, USA.
14
Clinical and Epidemiology Department, GSK Vaccines, R&D Center, Wavre, Belgium.
15
Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
16
Swiss Tropical and Public Health Institute, Basel, Switzerland.
17
University of Basel, Basel, Switzerland.
18
Medecins Sans Frontieres-OCBA, Barcelona, Spain.
19
Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria.
20
Centre de Recherches Medicales de Lambarene, Lambarene, Gabon.
21
Department of Paediatrics, University of Calabar, Calabar, Nigeria.
22
Institute for Tropical Medicine, University of Tubingen, Tubingen, Germany.
23
Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
24
Institut de Recherche en Science de la Sante, Bobo-Dioulasso, Burkina Faso.
25
Department of Clinical Research, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
26
Institut de Recherche en Science de la Sante, Nanoro, Burkina Faso.
27
Uganda Malaria Surveillance Project, Kampala, Uganda.
28
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
29
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, UK. l.okell@imperial.ac.uk.

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.

KEYWORDS:

Amodiaquine; Artemisinin; Crt; Drug; Lumefantrine; Malaria; Mathematical model; Trial; mdr1

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