Volume 97, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



is the most prevalent parasite worldwide, escalating by spread of drug resistance. Currently, in Qatar, chloroquine (CQ) plus primaquine are recommended for the treatment of malaria. The present study examined the prevalence of mutations in dihydrofolate reductase (), dihydropteroate synthase () genes and CQ resistance transporter () genes, associated with sulphadoxine-pyrimethamine (SP) and chloroquine resistance, among imported cases in Qatar. Blood samples were collected from patients positive for and seeking medical treatment at Hamad General Hospital, Doha, during 2013–2016. The Sanger sequencing method was performed to examine the single nucleotide polymorphisms in , , and genes. Of 314 examined isolates, 247 (78.7%), 294 (93.6%) and 261 (83.1%) were successfully amplified and sequenced for , , and , respectively. Overall, 53.8% ( = 133) carried mutant alleles (58R/117N) in , whereas 77.2% ( = 227) and 90% ( = 235) isolates possessed wild type allele in and genes, respectively. In addition, a total of eleven distinct haplotypes were detected in / genes. Interestingly, K10 insertion in the gene was observed only in patients originating from the Indian subcontinent. The results suggested that CQ remains an acceptable treatment regimen but further clinical data are required to assess the effectiveness of CQ and SP in Qatar to support the current national treatment guidelines. In addition, limited distribution of genetic polymorphisms associated with CQ and SP resistance observed in imported infections, necessitates regular monitoring of drug resistant malaria in Qatar.


Article metrics loading...

The graphs shown below represent data from March 2017
Loading full text...

Full text loading...



  1. World Health Organization, 2016. World Malaria Report. Available at: http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/. Accessed February 2, 2017.
  2. Behrens RH, 2010. The incidence of malaria in travellers to south-east Asia: is local malaria transmission a useful risk indicator? Malar J 9: 266. [Google Scholar]
  3. Naha K, Dasari S, Prabhu M, , 2012. Spectrum of complications associated with Plasmodium vivax infection in a tertiary hospital in south-western India. Asian Pac J Trop Med 5: 7982. [Google Scholar]
  4. Zubairi AB, Nizami S, Raza A, Mehraj V, Rasheed AF, Ghanchi NK, Khaled ZN, Beg MA, , 2013. Severe Plasmodium vivax malaria in Pakistan. Emerg Infect Dis 19: 18511854. [Google Scholar]
  5. Beljaev AE, , 2000. The malaria situation in the WHO eastern Mediterranean region. Med Parazitol (Mosk) 2: 1215. [Google Scholar]
  6. Al-Kuwari MG, , 2009. Epidemiology of imported malaria in Qatar. J Travel Med 16: 119122. [Google Scholar]
  7. Khan FY, Lutof AK, Yassin MA, Khattab MA, Saleh M, Rezeq HY, Almaslamani M, , 2009. Imported malaria in Qatar: a one year hospital-based study in 2005. Travel Med Infect Dis 7: 111117. [Google Scholar]
  8. Verlinden BK, Louw A, Birkholtz LM, , 2016. Resisting resistance: is there a solution for malaria? Expert Opin Drug Discov 11: 395406. [Google Scholar]
  9. Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ, , 2014. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis 14: 982991. [Google Scholar]
  10. Ferreira MU, Castro MC, , 2016. Challenges for malaria elimination in Brazil. Malar J 15: 284. [Google Scholar]
  11. Ghanchi NK, Shakoor S, Thaver AM, Khan MS, Janjua A, Beg MA, , 2016. Current situation and challenges in implementing Malaria control strategies in Pakistan. Crit Rev Microbiol 42: 588593. [Google Scholar]
  12. WHO, 2004. Drug Resistance in Malaria. Available at: http://www.who.int/csr/resources/publications/drugresist/malaria.pdf. Accessed March 7, 2017.
  13. Imwong M, Pukrittakayamee S, Looareesuwan S, Pasvol G, Poirreiz J, White NJ, Snounou G, , 2001. Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates. Antimicrob Agents Chemother 45: 31223127. [Google Scholar]
  14. Imwong M, Pukrittayakamee S, Rénia L, Letourneur F, Charlieu JP, Leartsakulpanich U, Looareesuwan S, White NJ, Snounou G, , 2003. Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure. Antimicrob Agents Chemother 47: 15141521. [Google Scholar]
  15. Hastings MD, Porter KM, Maguire JD, Susanti I, Kania W, Bangs MJ, Sibley CH, Baird JK, , 2004. Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine. J Infect Dis 189: 744750. [Google Scholar]
  16. Alam MT, 2007. Similar trends of pyrimethamine resistance-associated mutations in Plasmodium vivax and P. falciparum. Antimicrob Agents Chemother 51: 857863. [Google Scholar]
  17. Hawkins VN, 2008. Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase. Malar J 7: 72. [Google Scholar]
  18. Saralamba N, Nakeesathit S, Mayxay M, Newton PN, Osorio L, Kim JR, White NJ, Day NP, Dondorp AM, Imwong M, , 2016. Geographic distribution of amino acid mutations in DHFR and DHPS in Plasmodium vivax isolates from Lao PDR, India and Colombia. Malar J 15: 484. [Google Scholar]
  19. Imwong M, Sudimack D, Pukrittayakamee S, Osorio L, Carlton JM, Day NP, White NJ, Anderson TJ, , 2006. Microsatellite variation, repeat array length, and population history of Plasmodium vivax. Mol Biol Evol 23: 10161018. [Google Scholar]
  20. Triglia T, Cowman AF, , 1994. Primary structure and expression of the dihydropteroate synthetase gene of Plasmodium falciparum. Proc Natl Acad Sci USA 91: 71497153. [Google Scholar]
  21. Hawkins VN, Suzuki SM, Rungsihirunrat K, Hapuarachchi HC, Maestre A, Na-Bangchang K, Sibley CH, , 2009. Assessment of the origins and spread of putative resistance-conferring mutations in Plasmodium vivax dihydropteroate synthase. Am J Trop Med Hyg 81: 348355. [Google Scholar]
  22. Hawkins VN, Joshi H, Rungsihirunrat K, Na-Bangchang K, Sibley CH, , 2007. Antifolates can have a role in the treatment of Plasmodium vivax. Trends Parasitol 23: 213222. [Google Scholar]
  23. Korsinczky M, Fischer K, Chen N, Baker J, Rieckmann K, Cheng Q, , 2004. Sulfadoxine resistance in Plasmodium vivax is associated with a specific amino acid in dihydropteroate synthase at the putative sulfadoxine-binding site. Antimicrob Agents Chemother 48: 22142222. [Google Scholar]
  24. Suwanarusk R, 2007. Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms. PLoS One 2: e1089. [Google Scholar]
  25. Nyunt MH, Han JH, Wang B, Aye KM, Aye KH, Lee SK, Htut Y, Kyaw MP, Han KT, Han ET, , 2017. Clinical and molecular surveillance of drug resistant vivax malaria in Myanmar (2009–2016). Malar J 16: 117. [Google Scholar]
  26. Meleigy M, , 2007. The quest to be free of malaria. Bull World Health Organ 85: 507508. [Google Scholar]
  27. Singh B, Bobogare A, Cox-Singh J, Snounou G, Abdullah MS, Rahman HA, , 1999. A genus- and species-specific nested polymerase chain reaction malaria detection assay for epidemiologic studies. Am J Trop Med Hyg 60: 687692. [Google Scholar]
  28. Imwong M, Pukrittayakamee S, Cheng Q, Moore C, Looareesuwan S, Snounou G, White NJ, Day NP, , 2005. Limited polymorphism in the dihydropteroate synthetase gene (dhps) of Plasmodium vivax isolates from Thailand. Antimicrob Agents Chemother 49: 43934395. [Google Scholar]
  29. Marfurt J, 2008. Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1. J Infect Dis 198: 409417. [Google Scholar]
  30. JM, Nomura T, Neves Jd, Baird JK, Wellems TE, del Portillo HA, , 2005. Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains. Exp Parasitol 109: 256259. [Google Scholar]
  31. Hastings MD, Maguire JD, Bangs MJ, Zimmerman PA, Reeder JC, Baird JK, Sibley CH, , 2005. Novel Plasmodium vivax dhfr alleles from the Indonesian archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system. Antimicrob Agents Chemother 49: 733740. [Google Scholar]
  32. Rungsihirunrat K, Na-Bangchang K, Hawkins VN, Mungthin M, Sibley CH, , 2007. Sensitivity to antifolates and genetic analysis of Plasmodium vivax isolates from Thailand. Am J Trop Med Hyg 76: 10571065. [Google Scholar]
  33. Zakeri S, Motmaen SR, Afsharpad M, Djadid ND, , 2009. Molecular characterization of antifolates resistance-associated genes, (dhfr and dhps) in Plasmodium vivax isolates from the Middle East. Malar J 8: 20. [Google Scholar]
  34. Kaur S, Prajapati SK, Kalyanaraman K, Mohmmed A, Joshi H, Chauhan VS, , 2006. Plasmodium vivax dihydrofolate reductase point mutations from the Indian subcontinent. Acta Trop 97: 174180. [Google Scholar]
  35. Valecha N, Joshi H, Eapen A, Ravinderan J, Kumar A, Prajapati SK, Ringwald P, , 2006. Therapeutic efficacy of chloroquine in Plasmodium vivax from areas with different epidemiological patterns in India and their Pvdhfr gene mutation pattern. Trans R Soc Trop Med Hyg 100: 831837. [Google Scholar]
  36. Prajapati SK, Joshi H, Dev V, Dua VK, , 2011. Molecular epidemiology of Plasmodium vivax anti-folate resistance in India. Malar J 10: 102. [Google Scholar]
  37. Khatoon L, Baliraine FN, Bonizzoni M, Malik SA, Yan G, , 2009. Prevalence of antimalarial drug resistance mutations in Plasmodium vivax and P. falciparum from a malaria-endemic area of Pakistan. Am J Trop Med Hyg 81: 525528. [Google Scholar]
  38. Schmider N, Peyerl-Hoffmann G, Restrepo M, Jelinek T, , 2003. Short communication: point mutations in the dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Colombia. Trop Med Int Health 8: 129132. [Google Scholar]
  39. Khattak AA, Venkatesan M, Khatoon L, Ouattara A, Kenefic LJ, Nadeem MF, Nighat F, Malik SA, Plowe CV, , 2013. Prevalence and patterns of antifolate and chloroquine drug resistance markers in Plasmodium vivax across Pakistan. Malar J 12: 310. [Google Scholar]
  40. Ranjitkar S, Schousboe ML, Thomsen TT, Adhikari M, Kapel CM, Bygbjerg IC, Alifrangis M, , 2011. Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal. Malar J 10: 75. [Google Scholar]
  41. Pirahmadi S, Talha BA, Nour BY, Zakeri S, , 2014. Prevalence of mutations in the antifolates resistance-associated genes (dhfr and dhps) in Plasmodium vivax parasites from Eastern and Central Sudan. Infect Genet Evol 26: 153159. [Google Scholar]
  42. Mishra N, 2016. Monitoring the efficacy of antimalarial medicines in India via sentinel sites: outcomes and risk factors for treatment failure. J Vector Borne Dis 53: 168178. [Google Scholar]
  43. Lu F, 2010. Mutations in the antifolate-resistance-associated genes dihydrofolate reductase and dihydropteroate synthase in Plasmodium vivax isolates from malaria-endemic countries. Am J Trop Med Hyg 83: 474479. [Google Scholar]
  44. Tjitra E, Baker J, Suprianto S, Cheng Q, Anstey NM, , 2002. Therapeutic efficacies of artesunate-sulfadoxine-pyrimethamine and chloroquine-sulfadoxine-pyrimethamine in vivax malaria pilot studies: relationship to Plasmodium vivax dhfr mutations. Antimicrob Agents Chemother 46: 39473953. [Google Scholar]
  45. Zakeri S, Afsharpad M, Ghasemi F, Raeisi A, Safi N, Butt W, Atta H, Djadid ND, , 2010. Molecular surveillance of Plasmodium vivax dhfr and dhps mutations in isolates from Afghanistan. Malar J 9: 75. [Google Scholar]
  46. Srivastava HC, Yadav RS, Joshi H, Valecha N, Mallick PK, Prajapati SK, Dash AP, , 2008. Therapeutic responses of Plasmodium vivax and P. falciparum to chloroquine, in an area of western India where P. vivax predominates. Ann Trop Med Parasitol 102: 471480. [Google Scholar]
  47. Singh RK, , 2000. Emergence of chloroquine-resistant vivax malaria in south Bihar (India). Trans R Soc Trop Med Hyg 94: 327. [Google Scholar]
  48. Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y, , 2005. Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance. Proc Natl Acad Sci USA 102: 1304613051. [Google Scholar]
  49. Mokmak W, Chunsrivirot S, Hannongbua S, Yuthavong Y, Tongsima S, Kamchonwongpaisan S, , 2014. Molecular dynamics of interactions between rigid and flexible antifolates and dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium falciparum. Chem Biol Drug Des 84: 450461. [Google Scholar]
  50. Khan FY, Elshafie SS, Almaslamani M, Abu-Khattab M, El Hiday AH, Errayes M, Almaslamani E, , 2010. Epidemiology of bacteraemia in Hamad general hospital, Qatar: a one year hospital-based study. Travel Med Infect Dis 8: 377387. [Google Scholar]
  51. Battle KE, 2014. Geographical variation in Plasmodium vivax relapse. Malar J 13: 144. [Google Scholar]

Data & Media loading...

  • Received : 05 Jun 2017
  • Accepted : 23 Jul 2017
  • Published online : 02 Oct 2017

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error