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

Abstract

Background: Sulfadoxine-pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap. Methods: Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays. Results: Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5-25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3-87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7-47.2%). The dhfr I164L mutation was found in one sample. Conclusions: The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.

Effect of Drug Pressure on Promoting the Emergence of Antimalarial-Resistant Parasites among Pregnant Women in Ghana

“…pfdhps genes that confer increased resistance to SP, for example, pfdhps K540E, A581G, and A613S/T mutations, which have been previously correlated with high levels of SP resistance (12). However, the prevalence of these mutations is lower in west and central Africa compared to eastern and southern Africa.…”

Assessment of the Feasibility, Acceptability, and Impact of Implementing Seasonal Malaria Chemoprevention in Nampula Province, Mozambique: Protocol for a Hybrid Effectiveness-Implementation Study

“…Resistance to SP or AQ may reduce the efficacy of SMC in protecting children against clinical malaria, although the relationship between the degree of resistance and the effectiveness of SMC has not yet been clearly defined. SP efficacy is threatened by drug resistance due to mutations in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthetase ( dhps ) genes [ 17 ]. According to a study conducted in Mozambique, the prevalence of dhfr and dhps mutations was 5%-6% [ 18 ], with more recent research suggesting this may be as high as >80% [ 19 ].…”

Model-informed target product profiles of long acting-injectables for use as seasonal malaria prevention

“…Investigation of the adherence to the 3x AQ regimen within one treatment course in a clinical trial in Niger showed that only 20% of children received the full regimen 10 . Additionally, the spread of resistance markers against SP was reported with increasing SMC deployment 11,12 , impacting the eligibility of regions for SMC 13 as well as the protective efficacy after implementation 14 .…”