Screening for Mutations Related to Atovaquone/Proguanil Resistance in Treatment Failures and Other Imported Isolates of<i>Plasmodium falciparum</i>in Europe

Wichmann, Ole; Muehlberger, Nikolai; Jelı́nek, Tomáš; Alifrangis, Michael; Peyerl‐Hoffmann, Gabriele; Mühlen, Marion; Grobusch, Martin P.; Gascón, Joaquim; Matteelli, Alberto; Laferl, Hermann; Bisoffi, Zeno; Ehrhardt, Stephan; Cuadros, Juan; Hatz, Christoph; Gjørup, Ida; McWhinney, Paul; Beran, Jiřı́; Cunha, Saraiva da; Schulze, Marco H.; Kollaritsch, Herwig; Kern, Peter; Fry, Graham; Richter, Joachim

doi:10.1086/424469

Cited by 61 publications

(46 citation statements)

References 30 publications

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“…Atovaquone targets the parasite mitochondrial cytochrome b and is generally very effective in its use together with the antifolate proguanil (in the singletablet Malarone formulation) as prophylaxis and treatment for travelers from areas of nonendemicity. Rare cases of prophylaxis or treatment failure are caused by new point mutations in the parasite cytb gene, at key positions such as codon 268 where different mutational changes have occurred (Tyr268Ser and Tyr268Asn) (79,108,198). In many organisms, the mitochondrial genome has a higher mutation rate than the nuclear genome, so it is possible that mutations in the parasite cytochrome b are more common than in other drug targets encoded by nuclear genes.…”

Section: Surveillance and Preventionmentioning

confidence: 99%

Molecular Epidemiology of Malaria

Conway

2007

Clin Microbiol Rev

103

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SUMMARY Malaria persists as an undiminished global problem, but the resources available to address it have increased. Many tools for understanding its biology and epidemiology are well developed, with a particular richness of comparative genome sequences. Targeted genetic manipulation is now effectively combined with in vitro culture assays on the most important human parasite, Plasmodium falciparum, and with in vivo analysis of rodent and monkey malaria parasites in their laboratory hosts. Studies of the epidemiology, prevention, and treatment of human malaria have already been influenced by the availability of molecular methods, and analyses of parasite polymorphisms have long had useful and highly informative applications. However, the molecular epidemiology of malaria is currently undergoing its most substantial revolution as a result of the genomic information and technologies that are available in well-resourced centers. It is a challenge for research agendas to face the real needs presented by a disease that largely exists in extremely resource-poor settings, but it is one that there appears to be an increased willingness to undertake. To this end, developments in the molecular epidemiology of malaria are reviewed here, emphasizing aspects that may be current and future priorities.

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Section: Surveillance and Preventionmentioning

confidence: 99%

Molecular Epidemiology of Malaria

Conway

2007

Clin Microbiol Rev

103

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“…Use of atovaquone alone leads to high rates of treatment recrudescence (2), which is attributed to mutations in the cytochrome b gene (pfcytb) (3). Plasmodium falciparum atovaquone-resistant isolates have been described following atovaquone or AP treatment failures (4)(5)(6)(7)(8)(9)(10)(11) and in vitro drug susceptibility testing (5,8,10,12). In vitro and in vivo resistance to atovaquone has been associated with point mutations at codon 268 in pfcytb (5,9,10,13).…”

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confidence: 99%

Molecular Characterization of the Cytochrome b Gene and In Vitro Atovaquone Susceptibility of Plasmodium falciparum Isolates from Kenya

Ingasia

Akala

Imbuga

et al. 2015

Antimicrob Agents Chemother

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The prevalence of a genetic polymorphism(s) at codon 268 in the cytochrome b gene, which is associated with failure of atovaquone-proguanil treatment, was analyzed in 227 Plasmodium falciparum parasites from western Kenya. The prevalence of the wild-type allele was 63%, and that of the Y268S (denoting a Y-to-S change at position 268) mutant allele was 2%. There were no pure Y268C or Y268N mutant alleles, only mixtures of a mutant allele(s) with the wild type. There was a correlation between parasite 50% inhibitory concentration (IC 50 ) and parasite genetic polymorphism; mutant alleles had higher IC 50 s than the wild type.A tovaquone-proguanil (AP) is a fixed-dose combination antimalarial drug, mostly used for treatment and chemoprophylaxis of falciparum malaria for international travelers (1). Use of atovaquone alone leads to high rates of treatment recrudescence (2), which is attributed to mutations in the cytochrome b gene (pfcytb) (3). Plasmodium falciparum atovaquone-resistant isolates have been described following atovaquone or AP treatment failures (4-11) and in vitro drug susceptibility testing (5,8,10,12). In vitro and in vivo resistance to atovaquone has been associated with point mutations at codon 268 in pfcytb (5, 9, 10, 13). These mutations include Y268S (denoting the Y-to-S change at position 268), Y268N, and Y268C (5, 9, 11, 13, 14) and can induce a Ͼ1,000-fold increase in atovaquone 50% inhibitory concentration (IC 50 ) (13, 15). There are cases of AP treatment failure for travelers returning from Africa (4-6, 9-11, 16-19) and appearance of pfcytb mutations following AP treatment (4-6, 9-11, 14). However, treatment failure is not always associated with a known pfcytb mutation (17,18,20,21), indicating that other factors such as genetic polymorphisms in other genetic loci play a role in AP resistance.Kenya has a large number of international travelers and foreign residents who use AP for malaria prophylaxis. Additionally, AP is one of the second-line treatment options for uncomplicated malaria (22). In this study, a baseline epidemiological surveillance study was conducted to determine the prevalence of a genetic polymorphism(s) at codon 268 of pfcytb in Kenyan P. falciparum parasites. Field clinical isolates from an ongoing approved malaria epidemiological surveillance protocol (KEMRI SSC document 1330 and WRAIR document 1384), collected between 2008 and 2012 from three locations in Kenya (Kisumu, Kisii, and Kericho), were randomly selected for inclusion in the study. Kisumu is a lowland where malaria is endemic, with highly stable transmission, whereas Kisii and Kericho are highlands, with unstable transmission (23). Sample collection and preparation were performed as previously described (24). Genomic DNA from whole blood was extracted using a Qiagen DNA minikit (Qiagen, Valencia, CA) as recommended by the manufacturer. Clinical isolates were culture adapted before being subjected to the SYBR green I assay as previously described (25). A total of 227 (167 from Kisumu, 37 from Kisii, and 23 f...

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“…In recent years several reports have documented AP treatment failure with laboratory evidence of resistance. 9,10,20 To date, very few treatment failures had been documented with AL. [13][14][15] Some reported AL failures may have been due, as in our case, to incomplete drug administration rather than to parasite resistance.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 However, in recent years there have been reports of treatment failure with both clinical and laboratory resistance shown. 9,10 Artemisinin derivatives are considered to be the fastest and most potent current malaria treatment. 11 In 2006 the World Health Organization (WHO) declared artemisinin combination therapy (ACT) such as AL to be the regimen of choice for treating P. falciparum malaria in Africa, 12 because of its relatively low cost and high efficiency.…”

Section: Introductionmentioning

confidence: 99%

Artemether-Lumefantrine Compared to Atovaquone-Proguanil as a Treatment for Uncomplicated Plasmodium falciparum Malaria in Travelers

Grynberg¹,

Lachish²,

Kopel³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Atovaquone-proguanil (AP) and artemether-lumefantrine (AL) are both treatments for uncomplicated Plasmodium falciparum malaria, but comparative clinical trials are lacking. We performed a retrospective analysis, comparing treatment failure and fever clearance time in non-immune travelers with uncomplicated P. falciparum malaria, treated with AP or AL. Sixty-nine patients were included during 2001-2013: 44 in the AP group and 25 in the AL group. Treatment failure was observed in 6 of 44 (13.6%) and 1 of 25 (4.0%) patients in the AP and AL groups, respectively. Six treatment failures were observed in travelers from West Africa. Fever clearance time was 44 ± 23 h in AL group versus 77 ± 28 h in AP group, (P 0.001). Hospitalization time was significantly shorter in the AL group; 3.8 + 1.3 versus 5.1 + 2.8 days in the AP group (P = 0.04) In conclusion, travelers with uncomplicated P. falciparum malaria recover faster on AL than on AP. The AL should probably be the drug of choice for this population.

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Screening for Mutations Related to Atovaquone/Proguanil Resistance in Treatment Failures and Other Imported Isolates ofPlasmodium falciparumin Europe

Abstract: Tyr268Ser seems to be a sufficient, but not a necessary, cause for atovaquone/proguanil treatment failure. The prevalence of both codon-268 mutations is currently unlikely to be >1% in the European patient pool.

Cited by 61 publications

References 30 publications

Molecular Epidemiology of Malaria

Molecular Epidemiology of Malaria

Molecular Characterization of the Cytochrome b Gene and In Vitro Atovaquone Susceptibility of Plasmodium falciparum Isolates from Kenya

Artemether-Lumefantrine Compared to Atovaquone-Proguanil as a Treatment for Uncomplicated Plasmodium falciparum Malaria in Travelers

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