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Plasmodium vivax dhfr and dhps mutations in isolates from Madagascar and therapeutic response to sulphadoxine-pyrimethamine

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Barnadas, Céline, Tichit, Magali, Bouchier, Christiane, Ratsimbasoa, Arsène, Randrianasolo, Laurence, Raherinjafy, Rogelin, Jahevitra, Martial, Picot, Stéphane, Ménard, Didier·2008·Malaria Journal
DOI 10.1186/1475-2875-7-35PMC PMC2268703
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Abstract

BACKGROUND: Four of five Plasmodium species infecting humans are present in Madagascar. Plasmodium vivax remains the second most prevalent species, but is understudied. No data is available on its susceptibility to sulphadoxine-pyrimethamine, the drug recommended for intermittent preventive treatment during pregnancy. In this study, the prevalence of P. vivax infection and the polymorphisms in the pvdhfr and pvdhps genes were investigated. The correlation between these polymorphisms and clinical and parasitological responses was also investigated in P. vivax-infected patients. METHODS: Plasmodium vivax clinical isolates were collected in eight sentinel sites from the four major epidemiological areas for malaria across Madagascar in 2006/2007. Pvdhfr and pvdhps genes were sequenced for polymorphism analysis. The therapeutic efficacy of SP in P. vivax infections was assessed in Tsiroanomandidy, in the foothill of the central highlands. An intention-to-treat analysis of treatment outcome was carried out. RESULTS: A total of 159 P. vivax samples were sequenced in the pvdhfr/pvdhps genes. Mutant-types in pvdhfr gene were found in 71% of samples, and in pvdhps gene in 16% of samples. Six non-synonymous mutations were identified in pvdhfr, including two novel mutations at codons 21 and 130. For pvdhps, beside the known mutation at codon 383, a new one was found at codon 422. For the two genes, different combinations were ranged from wild-type to quadruple mutant-type. Among the 16 patients enrolled in the sulphadoxine-pyrimethamine clinical trial (28 days of follow-up) and after adjustment by genotyping, 3 (19%, 95% CI: 5%-43%) of them were classified as treatment failure and were pvdhfr 58R/117N double mutant carriers with or without the pvdhps 383G mutation. CONCLUSION: This study highlights (i) that genotyping in the pvdhfr and pvdhps genes remains a useful tool to monitor the emergence and the spread of P. vivax sulphadoxine-pyrimethamine resistant in order to improve the national antimalarial drug policy, (ii) the issue of using sulphadoxine-pyrimethamine as a monotherapy for intermittent preventive treatment of pregnant women or children.

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  • Barnadas et al. (2007) found that sulfadoxine-pyrimethamine (SP) is effective as monotherapy for intermittent preventive treatment of pregnant women or children.

    “A study by Barnadas et al. (2007) found that sulfadoxine-pyrimethamine (SP) is effective as monotherapy, for intermittent preventive treatment of pregnant women or children [144] (Additional file 5:Table S5).”

    From Current update on malaria in pregnancy: a systematic review (2025) · cites this paper as [144]

    The Conclusion says SP will not be completely effective for intermittent preventive treatment during pregnancy in Madagascar and raises concern about using it as monotherapy for pregnant women or children. The Results report a 19% treatment-failure rate after adjustment by genotyping; the study does not find the claimed effectiveness for preventive treatment. (LLM, conf=0.92)

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  • Mefloquine is safe and effective for malaria prophylaxis in the second half of pregnancy.

    “Other studies have reported that mefloquine is safe and effective for malaria prophylaxis in the second half of pregnancy [143].”

    From Current update on malaria in pregnancy: a systematic review (2025) · cites this paper as [143]

    The Background and Conclusion discuss sulphadoxine-pyrimethamine for intermittent preventive treatment during pregnancy, not mefloquine. Searches for mefloquine prophylaxis and its safety and efficacy in pregnancy found no passage addressing the claim. No page numbers were available in our copy. (LLM, conf=0.76)

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Research works printed but not linked: 6

  1. Jeremiah M SA: Mortalité des enfants de moins de 5 ans à Madagascar. Enquête Démographique et de la Santé III à Madagascar. 2004, 191-201.
  2. UNICEF: Multiple Indicator Cluster Survey (MICS). Edited by: http://www.childinfo.org/MICS2/newreports/madagascar/madagascar.pdf . 2000
  3. Rabarijaona LP RT: Paludisme sur les hautes terres centrales de Madagascar: stratégies de lutte. Méd Trop. 2006, 66 (5): 504-512.
  4. Randrianarivelojosia M RL: Chimiorésistance de Plasmodium falciparum sur les régions cotières malgaches. Méd Trop. 2000, 60: 243-249.
  5. Randrianarivelojosia M RL: DHFR and Plasmodium falciparum resistance to antifolates: search for other mutations in the Indian Ocean region. Bull Soc Path Exot. 1999, 92: 282-
  6. WHO: WHO Expert Comittee on Malaria. 2000, Geneva, Switzerland , World Health Organization

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Authors
Barnadas, C., Tichit, M., Bouchier, C., Ratsimbasoa, A., Randrianasolo, L., Raherinjafy, R., Jahevitra, M., Picot, S., & Ménard, D.
Affiliations
  • Lyon 1 Université (FR)
  • Institut Pasteur (FR)
  • Institut Pasteur de Madagascar (MG)
Corresponding author
Barnadas, Céline
ORCID
Venue
Malaria Journal
Publisher
Springer Science and Business Media LLC
Published
2008-02-26
Volume
7
Issue
1
Pages
35-35
ISSN
1475-2875 (ISSN-L)
DOI
10.1186/1475-2875-7-35
PMC
PMC2268703
OpenAlex
W2038510509
Cited by
50
References
35
Citations by year
2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 3 · 2013: 5
FWCI
7.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Malaria Journal (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Global Fund to Fight AIDS, Tuberculosis and Malaria
  • Fondation de France
  • Hospices Civils de Lyon
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Immunology and Microbiology › Parasitology › Bird parasitology and diseases
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Phytochemical compounds biological activities
Keywords
Plasmodium vivax, dihydrofolate reductase, dihydrofolate reductase-thymidylate synthase, sulfadoxine-pyrimethamine resistance, antimalarial drug resistance, treatment failure, non-synonymous mutations, genotyping
MeSH terms
Adolescent, Adult, Animals, Antimalarials, Child, Child, Preschool, Dihydropteroate Synthase, Drug Combinations, Drug Resistance, Female, Humans, Infant, Madagascar, Male, Molecular Sequence Data, Mutation, Plasmodium vivax, Polymorphism, Genetic, Pyrimethamine, Sulfadoxine, Tetrahydrofolate Dehydrogenase, Protozoan Proteins, Polymerase Chain Reaction, Malaria, Vivax, Treatment Outcome, Sequence Analysis, DNA

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