Independent Origin of<i>Plasmodium falciparum</i>Antifolate Super-Resistance, Uganda, Tanzania, and Ethiopia

Alifrangis, Michael; Nag, Sidsel; Schousboe, Mette L; Ishengoma, Deus S.; Lusingu, John; Pota, Hirva; Kavishe, Reginald A.; Pearce, R. P.; Ord, Rosalynn; Lynch, Caroline A.; Dejene, Seyoum; Cox, Jonathan; Rwakimari, John Bosco; Minja, Daniel T. R.; Lemnge, Martha; Roper, Cally

doi:10.3201/eid2008.131897

Cited by 27 publications

(28 citation statements)

References 33 publications

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“…This drug possesses only mild antimalarial potency but is a common prophylactic prescription against opportunistic respiratory tract infections among HIV infections [12] hence may also have perpetuated the mutant population. This study has observed that the high prevalence of quintuple mutants and supported by other studies [12,[58][59] confers high-level SP resistance. In Tanzania for example, a study observed that the prevalence of Pfdhps 540E mutation was generally varying in all regions with the lowest in Mtwara 63.9% and the highest 98% in Mbeya.…”

Section: Discussionsupporting

confidence: 86%

Clinical efficacy of artemisinin-lumefantrine and status of antifolate drug resistance markers in western Kenya

Kishoyian

Njagi

Orinda

et al. 2019

Preprint

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Background: The development of Plasmodium falciparum resistance to sulfadoxine-pyrimethamine (SP) necessitated its replacement with artemether-lumefantrine (AL) in Kenya. However, the delayed parasite clearance following treatment with artemisinin derivatives has now spread in the Greater Mekong Sub region and may emerge or spread to other malaria endemic regions. Since parasites resistance to drugs is correlated with specific gene mutations, molecular markers associated with antimalarial drugs offer a powerful tool to monitor the emergence and spread of resistance. In this study, we assessed the clinical efficacy of AL following its adoption and the current levels of antifolate drug resistant markers after its ban in Kenyan health facilities. Methods: We conducted a therapeutic efficacy study between May and November 2015 in Chulaimbo sub-County, Kisumu, Kenya. A total of 76 patients ≥6 and ≤60 months of age with confirmed Plasmodium falciparum mono-infection were enrolled, treated with AL and followed up for a period of 28 days. Study endpoints were adequate clinical and parasitological response (ACPR) on the 28 day and known SP molecular markers of resistance were also determined. Results: The study showed that 97% of the participants had cleared parasitemia within 48 hours with an adequate clinical and parasitological response (ACPR) of 100% clearance on day 3. On Pfdhfr/Pfdhps mutants, N51I was identified in the P. falciparum isolates with a prevalence of 94% while C59R and S108N had 92% each. The prevalence of mutation at Pfdhps codons A437G and K540E stood at 94% and 91% respectively. Conclusion: AL was found to be highly efficacious since no plasmodium falciparum parasites were observed after day 3 making it a drug of choice in Kenya. Evidence of quintuple mutations frequency is high in the study population threatening the future use of SP.

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Section: Discussionsupporting

confidence: 86%

Clinical efficacy of artemisinin-lumefantrine and status of antifolate drug resistance markers in western Kenya

Kishoyian

Njagi

Orinda

et al. 2019

Preprint

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“…Although concerning, our analysis also suggests that IPTp-SP remains associated with improvements in birth weight and maternal hemoglobin level in areas where the prevalence of the Pfdhps -K540E mutation was >90%, but where the additional Pfdhps -A581G mutation was still rare. Although parasites harboring the Pfdhfr – Pfdhps quintuple mutant are now highly prevalent in areas across eastern and southern Africa, the sextuple mutant parasites are still uncommon, but are spreading [36–38]. Our data underline the need for studying alternative drugs for IPTp and alternative strategies to IPTp, such as intermittent screening and treatment during pregnancy.…”

Section: Discussionmentioning

confidence: 90%

Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight

et al. 2015

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Background Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub-Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial. Methods Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birth weight (LBW) were assessed among human immunodeficiency virus–uninfected participants in 8 sites in 6 countries. Sites were classified as high, medium, or low resistance after measuring parasite mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. Results Among 1222 parasitemic pregnant women, overall polymerase chain reaction–uncorrected and –corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69–.88; P < .001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with high SP resistance (PR, 0.81; 95% CI, .67–.97; P = .02). Conclusions The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high-resistance areas, IPTp-SP use remains associated with increases in birth weight and maternal hemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy.

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“…This study is consistent with a sequential build-up of resistance markers for SP. The A581G mutation almost exclusively occurred in the presence of K540E mutations [31]. The prevalence of I164L mutation on the dhfr gene was still very low, detected in only one of 333 samples.…”

Section: Discussionmentioning

confidence: 91%

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

Lenthe

Meulen

Lassovski³

et al. 2019

Malar J

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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.

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Independent Origin ofPlasmodium falciparumAntifolate Super-Resistance, Uganda, Tanzania, and Ethiopia

Abstract: Comprehensive surveillance is needed to support sulfadoxine–pyrimethamine intermittent preventive treatment in pregnant women.

Cited by 27 publications

References 33 publications

Clinical efficacy of artemisinin-lumefantrine and status of antifolate drug resistance markers in western Kenya

Clinical efficacy of artemisinin-lumefantrine and status of antifolate drug resistance markers in western Kenya

Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight

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

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