Malaria chemoprevention and drug resistance: a review of the literature and policy implications

Abstract

Chemoprevention strategies reduce malaria disease and death, but the efficacy of anti-malarial drugs used for chemoprevention is perennially threatened by drug resistance. This review examines the current impact of chemoprevention on the emergence and spread of drug resistant malaria, and the impact of drug resistance on the efficacy of each of the chemoprevention strategies currently recommended by the World Health Organization, namely, intermittent preventive treatment in pregnancy (IPTp); intermittent preventive treatment in infants (IPTi); seasonal malaria chemoprevention (SMC); and mass drug administration (MDA) for the reduction of disease burden in emergency situations. While the use of drugs to prevent malaria often results in increased prevalence of genetic mutations associated with resistance, malaria chemoprevention interventions do not inevitably lead to meaningful increases in resistance, and even high rates of resistance do not necessarily impair chemoprevention efficacy. At the same time, it can reasonably be anticipated that, over time, as drugs are widely used, resistance will generally increase and efficacy will eventually be lost. Decisions about whether, where and when chemoprevention strategies should be deployed or changed will continue to need to be made on the basis of imperfect evidence, but practical considerations such as prevalence patterns of resistance markers can help guide policy recommendations.

Fig. 1

Global map of the prevalence of sulfadoxine-pyrimethamine resistance marker dihydrofolate reductase A581G. Data are from published sources and available at http://wwwarn.org/dhfr-dhps-surveyor/#0 (accessed 12 April 2021)

Fig. 2

Frequency distributions of prevalence estimates of dhps K540E (L) and A581G (R) mutations measured in studies completed in sub-Saharan Africa from 2015–2021. Data were downloaded from http://www.wwarn.org/dhfr-dhps-surveyor and studies completed before 2015 and outside of Africa were excluded. Recent measures of K540E prevalence tend to cluster below 20% and above 50%, while A581G prevalence estimates lack an obvious break point

Fig. 3

Re-analysis of data purportedly showing selection of resistance markers by monthly seasonal malaria chemoprevention in school-age Ugandan children. For each resistance marker, the three bars represent proportion of infections containing mutant genotypes at increasingly distant times from last drug treatment with Dihydroartemisinin-piperaquine. Panel A shows the original analysis, depicted here in graph form, and showing apparent selection of “pure mutant” genotypes of pfmdr1 N86Y and pfcrt K76T based on their increasing in prevalence after drug treatment. Panel B depicts a re-analysis of the same data showing no evidence of positive selection for mutant genotypes when all infections containing the mutation in question are considered to have resistant parasites. Data from Nankabirwa et al. Antimicrob Agents Chemother 2016, 60:5649–54