Review Article

The Drug Resistance of Plasmodium falciparum and P. vivax in Iran: A Review Article


Background: One of the main obstacles to malaria control in the world has been the emergence of resistance in Plasmodium falciparum to chloroquine and other anti-malarial drugs. This study aimed to review studies in Iran on resistance in P. falciparum and P. vivax to drugs, and to reveal the mechanisms and molecular markers of resistance of these two species.

Methods: The databases of PubMed, Scopus, Google Scholar, Magiran, and reputable Iranian journals were searched to find published studies on the resistance in P. falciparum and P. vivax to antimalarial drugs in Iran.

Results: There is a significant relationship between resistance to chloroquine in P. falciparum and the emergence of K76T mutation in the P. falciparum chloroquine-resistance transporter gene in Iran. Resistance to sulfadoxine-pyrimethamine (SP) in P. falciparum is also significantly associated with the development of mutations in the dihydrofolate reductase and dihydropteroate synthase genes. Resistance to chloroquine in P. vivax has not been reported in Iran and it is used as a first-line treatment for P. vivax malaria.

Conclusion: P. falciparum has become resistant to chloroquine in different regions of Iran and is not currently used to treat malaria. Besides, cases have emerged of P. falciparum resistance to SP in different parts of southern Iran, and SP is not administered alone for treating P. falciparum.

1. Myers-Hansen JL, Abuaku B, Oyebola MK, et al. Assessment of antimalarial drug resistant markers in asymptomatic Plasmodium falciparum infections after 4 years of indoor residual spraying in Northern Ghana. PLoS One. 2020;15(12):e0233478.
2. Edrissian, GH. Malaria in Iran: Past and present situation. Iran J Parasitol. 2006; 1(1): 1-14.
3. Slater L, Betson M, Ashraf S, et al. Current meth-ods for the detection of antimalarial drug resistance in Plasmodium parasites infecting humans. Acta Trop. 2021;216:105828.
4. WHO. World malaria report 2020: 20 years of global progress and challenges. World Health Or-ganization. 2020.
5. Baird JK. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin Microbiol Rev. 2013;26(1):36-57.
6. Ehtesham R, Fazaeli A, Raeisi A, et al. Detection of mixed-species infections of Plasmodium falciparum and Plasmodium vivax by nested PCR and rapid diagnos-tic tests in southeastern Iran. Am J Trop Med Hyg. 2015;93(1):181-5.
7. Raeisi A, Gouya MM, Nadim A, et al. Determina-tion of malaria epidemiological status in Iran’s ma-larious areas as baseline information for implemen-tation of malaria elimination program in Iran. Iran J Public Health. 2013;42(3):326-333.
8. Vatandoost H, Raeisi A, Saghafipour A, et al. Mala-ria situation in Iran: 2002–2017. Malar J. 2019;18(1):200.
9. Heidari A, Keshavarz H, Rokni MB, et al. Genetic diversity in merozoite surface protein (MSP)-1 and MSP-2 genes of Plasmodium falciparum in a major en-demic region of Iran. Korean J Parasitol. 2007;45(1):59-63.
10. Miahipour A, Keshavarz H, Heidari A, et al. Genet-ic variation of MSP-1 gene in Plasmodium vivax isolat-ed from patients in hormozgan Province, Iran us-ing SSCP-PCR. Iran J Parasitol. 2012;7(4):1-7.
11. Mardani A, Keshavarz H, Heidari A, et al. Genetic diversity and natural selection at the domain I of ap-ical membrane antigen-1 (AMA-1) of Plasmodium fal-ciparum in isolates from Iran. Exp Parasitol. 2012;130(4):456-62.
12. Heidari A, Keshavarz H, Hajjaran H, et al. Genetic variation and selection of domain I of the Plasmodi-um vivax apical membrane antigen-1 (AMA-1) gene in clinical isolates from Iran. Iran J Parasitol. 2013;8(4):536-544.
13. Moin Vaziri V, Heidari A, Farokhi Z, et al. PCR-RFLP analysis of Plasmodium vivax reticulocyte bind-ing protein2c gene in field isolates of Iran. Trop Bi-omed. 2017;34(3):533-9.
14. Abolghazi A, Heidari A, Moin Vaziri V, et al. Ge-netic diversity in C-terminal of SERA5 gene in the blood stage of human isolates of Plasmodium vivax in Sistan and Baluchistan, Iran. Iran J Parasitol. 2018 ;13(3):440-447.
15. Gebreyohannes EA, Bhagavathula AS, Seid MA, et al. Anti-malarial treatment outcomes in Ethiopia: a systematic review and meta-analysis. Malar J. 2017;16(1):269.
16. Commons RJ, Simpson JA, Thriemer K, et al. The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a Worldwide Antimalar-ial Resistance Network systematic review and indi-vidual patient pooled meta-analysis. Lancet Infect Dis. 2018;18(9):1025-34.
17. Abdel Hameed AA. Antimalarial drug resistance in the Eastern Mediterranean Region. East Mediterr Health J. 2003;9(4):492-508.
18. Thu AM, Phyo AP, Landier J, et al. Combating multidrug‐resistant Plasmodium falciparum malaria. FEBS J. 2017;284(16):2569-78.
19. WHO. Guidelines for the treatment of malaria. World Health Organization; 2015.
20. WHO. Guide Lines for the treatment of malaria. World Health Organization;2006
21. Erah PO, Arienmughare G, Okhamafe AO. Plas-modium falciparum malaria resistance to chloroquine in five communities in Southern Nigeria. Afr J Bio-technol. 2003;2(10):384-9.
22. Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144.
23. Slater AF. Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum. Pharmac Ther. 1993;57(2-3):203-35.
24. Tse EG, Korsik M, Todd MH. The past, present and future of anti-malarial medicines. Malar J. 2019;18(1):93.
25. Lei ZN, Wu ZX, Dong S, et al. Chloroquine and Hydroxychloroquine in the Treatment of Malaria and Repurposing in Treating COVID-19. Phar-macol Ther. 2020;216:107672.
26. Mosawi SH, Dalimi A, Safi N, et al. An unlabelled probe based real time PCR and modified semi nested PCR as molecular tools for analysis of chlo-roquine resistant in Plasmodium vivax isolates from Afghanistan. Malar J. 2020; 19(1):253.
27. Wicht KJ, Mok S, Fidock DA. Molecular mecha-nisms of drug resistance in Plasmodium falciparum ma-laria. Annu Rev Microbiol. 2020;74:431-54.
28. Vander Jagt DL, Hunsaker LA, Campos NM. Characterization of a hemoglobin-degrading, low molecular weight protease from Plasmodium falciparum. Mol Biochem Parasitol. 1986;18(3):389-400.
29. Durand R, Jafari S, Vauzelle J, et al. Analysis of pfcrt point mutations and chloroquine susceptibility in isolates of Plasmodium falciparum. Mol Biochem Para-sitol. 2001;114(1):95-102.
30. Summers RL, Martin RE. Functional characteristics of the malaria parasite's" chloroquine resistance transporter": implications for chemotherapy. Viru-lence. 2010;1(4):304-8.
31. Rohrbach P, Sanchez CP, Hayton K, et al. Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. EMBO J. 2006;25(13):3000-11.
32. Picot S, Olliaro P, de Monbrison F, et al. A system-atic review and meta-analysis of evidence for corre-lation between molecular markers of parasite re-sistance and treatment outcome in falciparum ma-laria. Malar J. 2009;8:89.
33. Zaim M. Malaria control in Iran–present and future. J Am Mosq Control Assoc. 1987;3(3):392-6.
34. Manouchehri AV, Motabar M, Alemo-hammad A. Assessment of the response of Plasmodium falcipa-rum to chlorioquine in southern Iran. Iran J Public Health. 1973;2(2):97-102.
35. Suroso T, Hamidi AN, Manouchehri AV. The activity of chloroquine against Plasmodium falciparum in Bandar Abbas, Southern Iran, 1976. Bull Soc Pathol Exot Filiales. 1978;71(2):164-71.
36. Edrissian GH, Afshar A, Kanani A, et al. The re-sponse of Plasmodium falciparum to chloroquine and mefloquine in Bandar-Abbas and Minab areas, Hormozgan Province, southern Iran. J Trop Med Hyg. 1989;92(2):75-9.
37. Raeisi A, Ringwald P, Safa O, et al. Monitoring of the therapeutic efficacy of chloroquine for the treatment of uncomplicated, Plasmodium falciparum malaria in Iran. Ann Trop Med Parasitol. 2006;100(1):11-6
38. Jafari S, Le Bras J, Asmar M, et al. Molecular survey of Plasmodium falciparum resistance in south–eastern Iran. Ann Trop Med Parasitol. 2003;97(2):119-24.
39. Zakeri S, Afsharpad M, Kazemzadeh T, et al. As-sociation of pfcrt but not pfmdr1 alleles with chlo-roquine resistance in Iranian isolates of Plasmodium falciparum. Am J Trop Med Hyg. 2008;78(4):633-40.
40. Esmaeili RA, Nateghpour M, ASMAR M, et al. Detection of K76T mutation in pfcrt gene as an ap-plicable genetic marker for prediction of chloro-quine resistant falciparum malaria in isolates from an endemic district of Iran. Iran J Parasitol. 2008;3(2):48-56.
41. Zakeri S, Afsharpad M, Raeisi A, et al. Prevalence of mutations associated with antimalarial drugs in Plasmodium falciparum isolates prior to the introduction of sulphadoxine-pyrimethamine as first-line treat-ment in Iran. Malar J. 2007;6:148.
42. Jalousian F, Dalimi A, Samiee SM, et al. Mutation in Pfmdr1 gene in chloroquine-resistant Plasmodium falci-parum isolates, Southeast Iran. Int J Infect Dis. 2008;12(6):630-4.
43. Edrissian G, Afshar A, Sayedzadeh A, et al. As-sessment of the response in vivo and in vitro of Plasmodium falciparum to sulphadoxine-pyrimethamine in the malarious areas of Iran. J Trop Med Hyg. 1993;96(4):237-40.
44. Eskandarian AA, Keshavarz H, Basco LK, et al. Do mutations in Plasmodium falciparum dihydrop-teroate synthase and dihydrofolate reductase confer resistance to sulfadoxine-pyrimethamine in Iran?. Trans R Soc Trop Med Hyg. 2002;96(1):96-8.
45. Heidari A, Dittrich S, Jelinek T, et al. Genotypes and in vivo resistance of Plasmodium falciparum isolates in an endemic region of Iran. Parasitol Res. 2007;100(3):589-92.
46. Zakeri S, Gil JP. High prevalence of double Plasmo-dium falciparum dhfr mutation at codons 108 and 59 in the Sistan–Baluchistan province, Iran. J Infect Dis. 2003;187(11):1828–1829.
47. Sharifi-Sarasiabi K, Haghighi A, Kazemi B, et al. Molecular surveillance of Plasmodium vivax and Plas-modium falciparum DHFR mutations in isolates from southern Iran. Rev Inst Med Trop Sao Paulo. 2016;58:16.
48. Afsharpad M, Zakeri S, Pirahmadi S, et al. Molecu-lar monitoring of Plasmodium falciparum resistance to antimalarial drugs after adoption of sulfadoxine–pyrimethamine plus artesunate as the first line treatment in Iran. Acta trop. 2012;121(1):13-8.
49. Saebi E, Masoumi Asl H, Salehi M, et al. national malaria treatment guideline (Persian). Ministry of Health and Medical Education. 5th Edition 2020.
50. Suresh N, Haldar K. Mechanisms of artemisinin resistance in Plasmodium falciparum malaria. Curr Opin Pharmacol. 2018;42:46-54.
51. Noedl H, Se Y, Schaecher K, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359(24):2619-20.
52. Duru V, Witkowski B, Ménard D. Plasmodium falcipa-rum resistance to artemisinin derivatives and pipera-quine: a major challenge for malaria elimination in Cambodia. Am J Trop Med Hyg. 2016;95(6):1228-38.
53. Amato R, Pearson RD, Almagro-Garcia J, et al. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. Lancet Infect Dis. 2018;18(3):337-45.
54. Mbengue A, Bhattacharjee S, Pandharkar T, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015 ;520(7549):683-7.
55. Moghadm HA, Nateghpour M, Raeisi A, et al. Monitoring the Response of Plasmodium vivax to Chloroquine and Uncomplicated P. falciparum to Artesunate-fansidar Antimalarials in Southeastern Iran. Iran J Parasitol. 2018;13(1):31-38.
56. Battle KE, Lucas TC, Nguyen M, et al. Mapping the global endemicity and clinical burden of Plasmo-dium vivax, 2000–17: a spatial and temporal model-ling study. Lancet. 2019;394(10195):332-43.
57. Rieckmann KH, Davis DR, Hutton DC. Plasmodi-um vivax resistance to chloroquine? Lancet. 1989;2(8673):1183-4.
58. Heidari A, Keshavarz H, Shojaee S, et al. In vivo susceptibility of Plasmodium vivax to chloroquine in Southeastern Iran. Iran J Parasitol. 2012;7(2):8-14.
59. Nateghpour M, Sayedzadeh SA, Edrissian GhH, et al. Evaluation of sensitivity of Plasmodium vivax to chloroquine. Iran J Public Health. 2007;36(3):60-3.
60. Hamedi Y, Nateghpour M, Tan-Ariya P, et al. Plas-modium vivax malaria in Southeast Iran in 1999-2001: establishing the response to chloroquine in vtiro and in vivo. Southeast Asian J Trop Med Public Health. 2002;33(3):512-8.
61. Edrissian GhH, Nateghpour M, Afshar A, et al. Monitoring the response of Plasmodium falciparum and Plasmodium vivax to antimalarial drugs in the ma-larious areas in south-east Iran. Arch Irn Med. 1999; 2(2): 61-6.
62. Waheed AA, Ghanchi NK, Rehman KA, et al. Vivax malaria and chloroquine resistance: a neglect-ed disease as an emerging threat. Malar J. 2015;14:146.
63. Ferreira MU, de Sousa TN, Rangel GW, et al. Monitoring Plasmodium vivax resistance to antimalari-als: Persisting challenges and future directions. Int J Parasitol Drugs Drug Resist. 2021;15:9-24.
64. Maghsoodloorad S, Haghighi A, Sarasiabi KS. Genetic diversity of dihydropteroate synthetase gene (dhps) of Plasmodium vivax in Hormozgan province, Iran. Iran J parasitol. 2016;11(1):98-103.
65. Zaman J, Shahbazi A, Asgharzadeh M. Plasmodium vivax dhfr mutations among isolates from malarious areas of Iran. Korean J Parasitol. 2011;49(2):125-131.
66. Parsaei M, Raeisi A, Spotin A. Molecular evaluation of pvdhfr and pvmdr-1 mutants in Plasmodium vivax isolates after treatment with sulfadox-ine/pyrimethamine and chloroquine in Iran during 2001–2016. Infect Genet Evol. 2018;64:70-5.
67. Daher A, Aljayyoussi G, Pereira D, et al. Pharma-cokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with pri-maquine. Malar J. 2019;18(1):325.
68. Miahipour A, Keshavarz H, Heidari A, et al. As-sessment of the efficacy of 8 weeks of primaquine for the prevention of relapse in vivax malaria pa-tients using SSCP-PCR and sequencing in south and south-east Iran, 2008–2011. Trans R Soc Trop Med Hyg. 2013;107(7):420-6.
69. Heidari A, Sheikhi S, Fallah P, et al. Relapse of a Plasmodium vivax infection in an Iranian patient: A case report. Jundishapur J Nat Pharm Prod. 2017;12(4):e14499.
IssueVol 16 No 2 (2021) QRcode
SectionReview Article(s)
Malaria Plasmodium falciparum; Plasmodium vivax Drug resistance; Iran

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Heidari A, Keshavarz H. The Drug Resistance of Plasmodium falciparum and P. vivax in Iran: A Review Article. Iran J Parasitol. 16(2):173-185.