Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa

Abstract

Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.

Markers of sulfadoxine–pyrimethamine resistance in Eastern Democratic Republic of Congo; implications for malaria chemoprevention

“…A high level of the dhps K540E mutation was observed in this region and this is consistent with studies that reviewed and mapped all publicly available data on 540E in Africa [9,25,26]. At all sites, the prevalence of dhps K540E mutant exceeds 50%, the threshold level defined by WHO to determine whether or not to introduce IPTi [27].…”

“…When this triple mutation in dhfr is combined with double-mutant dhps (A437G and K540E) the risk of SP treatment failure is up to 75% [7,8]. A 'sextuple mutant' genotype in which these five key mutations in dhfr and dhps gene are accompanied by dhps A581G is increasingly reported [9].…”

“…The World Health Organization (WHO) has specified that IPTi-SP should only be implemented in areas where the prevalence of the dhps K540E mutation (a proxy measure for the presence of all 5 key mutations) is under 50% [10]. Molecular surveillance reports up to 2016 have recorded prevalence of K540E exceeding the 50% threshold in 12 countries: most in East Africa (Sudan, Somalia, the Republic of the Congo, Tanzania, Malawi, Kenya, DRC, Mozambique, Ethiopia, Rwanda, Uganda, Zambia) [9], with relevant within-country variation. In the case of IPTp, SP continues to provide protection in pregnancy in all these areas except within restricted geographic areas where the dhps 581G is also present at high prevalence [4,[11][12][13][14].…”

“…There are indications that the range and prevalence of the sextuple genotype is increasing [9]. This study aimed to update molecular surveillance data from North and South Kivu with more substantial sample sizes and examine the geographic heterogeneity in prevalence of 540E and 581G in order to determine if IPTi could be a preventive strategy used in MSF mission sites within these provinces of Eastern DRC.…”

First‐in‐human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection

“…4 However, resistance to the combination is now widespread; mutations in dihydrofolate reductase (Pfdhfr gene) confer resistance to pyrimethamine while mutations in the dihydropteroate synthetase (Pfdhps gene) confer resistance to sulphadoxine. 19 Malaria treatment was compromised with the emergence in East Africa of the quintuple mutant comprising a triple F I G U R E 2 Geometric mean (±SD) plasma concentration-time profiles for P218 compared to metabolites following single P218 doses of 10-1000 mg. Note: Data plotted for P218 and metabolites shown individually for all doses are given in Supporting Information Fig.…”