Changing antimalarial drug resistance patterns identified by surveillance at three sites in Uganda

Tumwebaze, Patrick K; Tukwasibwe, Stephen; Taylor, Aimee R; Conrad, Melissa D.; Ruhamyankaka, Emmanuel; Asua, Victor; Walakira, Andrew; Nankabirwa, Joaniter I.; Yeka, Adoke; Staedke, Sarah G.; Greenhouse, Bryan; Nsobya, Samuel L.; Kamya, Moses R.; Dorsey, Grant; Rosenthal, Philip J.

doi:10.1093/infdis/jiw614

Cited by 48 publications

(76 citation statements)

References 17 publications

(3 reference statements)

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“…Prevalences of polymorphisms in putative transporters that are associated with sensitivity to a number of antimalarials were compared between P. falciparum isolates from 2010 to 2013 and isolates from 2016. Consistent with previous trends (7,8,12,32), genotypes have changed markedly in recent years, with reversion to wild-type sequences at pfcrt K76T (P Ͻ 0.001) and pfmdr1 N86Y (P Ͻ 0.01) and D1246Y (P ϭ 0.095) (Fig. 2).…”

Section: Resultssupporting

confidence: 89%

“…The A578S mutation has been described in isolates from Uganda and other African countries, and it has not been associated with artemisinin resistance (29,32,33). Recent reports have identified amplification of a gene encoding plasmepsin 2 and a SNP in an exonuclease gene (PF3D7_1362500) that encodes an E415G mutation as markers of piperaquine resistance in Southeast Asia (24,25).…”

Section: Resultsmentioning

confidence: 99%

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Changing Antimalarial Drug Sensitivities in Uganda

Rasmussen

Ceja

Conrad

et al. 2017

Antimicrob Agents Chemother

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Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, ex vivo sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda, from subjects presenting in 2016 with malaria from the community or as part of a clinical trial comparing DP chemoprevention regimens. Compared to community isolates, those from trial subjects had lower sensitivities to the aminoquinolines chloroquine, monodesethyl amodiaquine, and piperaquine and greater sensitivities to lumefantrine and mefloquine, an observation consistent with DP selection pressure. Compared to results for isolates from 2010 to 2013, the sensitivities of 2016 community isolates to chloroquine, amodiaquine, and piperaquine improved (geometric mean 50% inhibitory concentrations [IC 50 ] ϭ 248, 76.9, and 19.1 nM in 2010 to 2013 and 33.4, 14.9, and 7.5 nM in 2016, respectively [P Ͻ 0.001 for all comparisons]), the sensitivity to lumefantrine decreased (IC 50 ϭ 3.0 nM in 2010 to 2013 and 5.4 nM in 2016 [P Ͻ 0.001]), and the sensitivity to dihydroartemisinin was unchanged (IC 50 ϭ 1.4 nM). These changes were accompanied by decreased prevalence of transporter mutations associated with aminoquinoline resistance and low prevalence of polymorphisms recently associated with resistance to artemisinins or piperaquine. Antimalarial drug sensitivities are changing in Uganda, but novel genotypes associated with DP treatment failure in Asia are not prevalent.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Changing Antimalarial Drug Sensitivities in Uganda

Rasmussen

Ceja

Conrad

et al. 2017

Antimicrob Agents Chemother

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“…It is of note that recovery of chloroquine sensitivity after its withdrawal occurred much earlier in Gulu than in other regions in Uganda [9,[22][23][24]41]. In 2013, as much as 65% of parasites displayed ex vivo chloroquine resistance [24] and 60-80% carried K76T allele in Tororo, Eastern Uganda [42]. In contrast, present results revealed that prevalence of ex vivo chloroquine-resistance and K76T alleles were already 6% and 29%, respectively, in 2013, indicating a faster recovery or re-emergence of chloroquine sensitive strains in the region.…”

Section: Discussionmentioning

confidence: 99%

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda

Balikagala

Sakurai-Yatsushiro

Tachibana

et al. 2020

Malar J

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Background: Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods.Methods: Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda, where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed.Results: Chloroquine resistance (≥ 100 nM) was observed in only 3 (1.3%) samples. Average IC 50 values for chloroquine were persistently low throughout the study period (17.4-24.9 nM). Parasites harbouring pfcrt K76 alleles showed significantly lower IC 50 s to chloroquine than the parasites harbouring K76T alleles (21.4 nM vs. 43.1 nM, p-value = 3.9 × 10 −8 ). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. Conclusion:This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

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“…Ideally, such combinations would exert opposing selective pressures on mutant and wild-type PfMDR1, in an effort to stall the emergence and spread of multidrug resistance. This approach is currently being used in clinical trials where artemether + LMF is being combined with ADQ (see Clinical Trials NCT02453308), based on earlier reports that LMF and ADQ exert opposing selective pressures on wild-type and mutant forms of both pfmdr1 and pfcrt 40,50 . In addition, the potent activity of HHQs against both ABS parasites and GAMs highlights the promise of developing this chemical class into a partner for future antimalarial combination therapies with transmission-blocking activity.…”

Section: Discussionmentioning

confidence: 99%

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Vanaerschot

Lucantoni

et al. 2017

Nat Microbiol

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Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress P. berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR/Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 as a determinant of parasite resistance to HHQs. Hemoglobin and heme fractionation assays suggest a mode of action that results in reduced hemozoin levels and might involve inhibition of host hemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs including lumefantrine, confirming that HHQs have a different mode of action than other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

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Changing antimalarial drug resistance patterns identified by surveillance at three sites in Uganda

Cited by 48 publications

References 17 publications

Changing Antimalarial Drug Sensitivities in Uganda

Changing Antimalarial Drug Sensitivities in Uganda

Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

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