Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Abstract

The use of antimalarial drugs is an effective strategy in the fight against malaria. However, selection of drug resistant parasites is a constant threat to the continued use of this approach. Antimalarial drugs are used not only to treat infections but also as part of population-level strategies to reduce malaria transmission toward elimination. While there is strong evidence that the ongoing use of antimalarial drugs increases the risk of the emergence and spread of drug-resistant parasites, it is less clear how population-level use of drug-based interventions like seasonal malaria chemoprevention (SMC) or mass drug administration (MDA) may contribute to drug resistance or loss of drug efficacy. Critical to sustained use of drug-based strategies for reducing the burden of malaria is the surveillance of population-level signals related to transmission reduction and resistance selection. Here we focus on Plasmodium falciparum and discuss the genetic signatures of a parasite population that are correlated with changes in transmission and related to drug pressure and resistance as a result of drug use. We review the evidence for MDA and SMC contributing to malaria burden reduction and drug resistance selection and examine the use and impact of these interventions in Senegal. Throughout we consider best strategies for ongoing surveillance of both population and resistance signals in the context of different parasite population parameters. Finally, we propose a roadmap for ongoing surveillance during population-level drug-based interventions to reduce the global malaria burden.

Keywords: Genetic surveillance; Mass drug administration (MDA); Population genetics; Seasonal malaria chemoprevention (SMC); Selective sweep; Therapeutic efficacy study (TES).

Graphical abstract

Fig. 1

Population Genetic Indicators of Decreasing Transmission. As transmission decreases, there are fewer infected individuals (i.e., decreased incidence), represented by the silhouettes on the right with colored dots representing different parasite genotypes in the population. At high transmission levels (left), many individuals are infected, a substantial proportion of which are infected with multiple strains (black silhouettes). Elevated complexity of infection (COI) at high transmission levels decreases with reduced transmission intensity. A few individuals are infected with only one parasite type, represented by shading matching the parasite color, while a few individuals are uninfected (gray silhouettes). As transmission levels decrease, the proportion of uninfected individuals increases. In addition, more infections are monogenomic (infected with only one strain, silhouettes with only one colored dot). Finally, specific parasite types (represented by red and blue silhouettes) may be shared between transmission seasons.

Fig. 2

Population Genetic Signatures of Hard and Soft Selective Sweeps. (A) Hard selective sweeps result from the appearance of a new drug-resistance locus (red) on a given background haplotype (yellow) that increases in frequency. The surrounding background (yellow) will also increase in frequency in the population along with the drug-resistance allele due to genetic hitchhiking. The result is the fixation of the advantageous drug resistant allele under drug pressure. A survey of the genetic region around the advantageous allele (star) shows decreased genetic diversity that produces the pattern expected of a hard selective sweep. (B) Soft selective sweeps result when the drug-resistance allele arises on multiple backgrounds (yellow and green). Under drug pressure, the drug-resistance allele will increase in frequency; however, because there are multiple genetic backgrounds, the overall diversity in the genomic region surrounding the advantageous allele differs and there is only a small reduction in genetic diversity in the region surrounding the drug resistant allele (star).

Fig. 3

Impact and Stratification of Malaria Interventions in Senegal. (A) Proportional mortality (red line) and morbidity (blue line) between 2001 and 2019 in Senegal is shown with proportion on the y-axis and year on the x-axis. The vertical and horizontal arrows indicate the initiation and duration of various interventions, respectively. These interventions or strategies include intermittent preventive therapy in pregnancy (IPTp); artemisinin-based combination therapy (ACT); indoor residual spraying (IRS); rapid diagnostic test (RDT); long-lasting insecticide-treated nets (LLINs); home-based management of malaria (HBMM); focal test and treat (FTAT); focal screen and treat (FSAT); focal drug administration (FDA); seasonal malaria chemoprevention (SMC); integrated community case management (ICCM); and, universal coverage (UC). (B) Map showing the use of antimalarial interventions in Senegal based upon incidence: <5/1000 (green); 5/1000 to <15/1000 (yellow); 15/1000 to <25/1000 (red stippled); and ≥25/1000 (red). The interventions described in the corresponding colored boxes and abbreviations or translations include: scaled up for impact (SUFI); MILDA (long-lasting insecticide-treated nets, LLINs); AID in riposte (responsive indoor residual spraying); PECADOM (person in charge of the domicile (house); PECADOM+ (PECADOM strategy with active surveillance); case and outbreak investigation (‘investigation des cas et des foyers’); ultrasensitive RDT (TDR Ultrasensible); primaquine treatment (primaquine); AID standard (standard indoor residual spraying); seasonal malaria chemoprevention (CPS) sometimes carried out in ‘hot spots’; case documentation from January to June (‘documentation des cas de janvier a juin’); mass drug administration (MDA); intermittent preventive therapy in pregnant women (TPIg).