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Revealing the artemisinin and piperaquine treatment failure: a systematic review

  • Farindira Vesti Rahmasari ,
  • Mallika Imwong ,
  • Irfanul Chakim ,
  • Winny Setyonugroho ,
  • Tri Wulandari Kesetyaningsih ,
  • Agus Gunadi ,
  • Desto Arisandi ,


Background: Artemisinin-based combination therapy (ACT) consists of a potent artemisinin component. Since the dihydroartemisinin performance effectiveness depends on piperaquine interaction still challenging, further research needs to establish the current status of artemisinin resistance relative to its geography and recognize any drug resistance interaction between dihydroartemisinin and piperaquine. 

Aim: This systematic review was aimed to find out the effect of dihydroartemisinin and piperaquine interaction concerning resistance, recurrence, parasitological failure, clinical failure, parasite clearance time, parasite reduction ratio, cure rate, which may affect treatment failure of patients with uncomplicated P. falciparum.

Method: The article was not limited to year and country. This study analyzed any effect of interaction. Pubmed and Scopus were used as electronic databases, and MeSH terms and keywords were used to find specific studies. A total of 2131 studies were initially identified; however, 20 were eligible for qualitative synthesis.

Result: The dihydroartemisinin piperaquine cure rate reported in Asia and Africa was above 98%. Eight RCTs, eleven prospective cohort studies, and one retrospective and prospective cohort study were included in this review. Design studies did not compare the same anti-malarial drug pattern, so it was difficult to do a pooled analysis. Even though this drug combination did not show a clear description of piperaquine resistance can affect artemisinin resistance, the adequate clinical and parasitological failure (ACPR) from this research reached above 93%, and for early treatment failure (ETF), late clinical failure (LCF), and late parasitological failure (LPF), were almost 0 %.

Conclusion: The dihydroartemisinin-piperaquine combination still has highly efficacious therapy to fight malaria in some areas based on these multiple factors and reviews.


  1. World Health Organization. Guidelines for the treatment of malaria: World Health Organization; 2015.
  2. Davis TME, Hung T-Y, Sim I-K, Karunajeewa HA, Ilett KF. Piperaquine: a resurgent antimalarial drug. Drugs. 2005/01/01 2005;65(1):75-87. doi:
  3. White NJJPM. Intermittent presumptive treatment for malaria. PloS Journal. 2005;2(1):e3. doi: 10.1371/journal.pmed.0020003
  4. Eastman RT, Fidock DAJAa. Artemisinin-based combination therapies: a vital tool in efforts to eliminate malaria. Nature Reviews Microbiology. 2009;7(12):864-874. doi: 10.1038/nrmicro2239
  5. Carneiro I, Smith L, Ross A, et al. Intermittent preventive treatment for malaria in infants: a decision-support tool for sub-Saharan Africa. Bulletin of the World Health Organization. 2010;88:807-814. doi: 10.2471/BLT.09.072397
  6. Fairhurst RMJCoiid. Understanding artemisinin-resistant malaria: what a difference a year makes. Current opinion in infectious diseases Journal. 2015;28(5):417. doi: 10.1097/QCO.0000000000000199
  7. Amaratunga C, Lim P, Suon S, et al. Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016;16(3):357-365. doi: 10.1016/S1473-3099(15)00487-9
  8. Thriemer K, Van Hong N, Rosanas-Urgell A, et al. Delayed parasite clearance after treatment with dihydroartemisinin- Piperaquine in plasmodium falciparum malaria patients in central vietnam. Antimicrob Agents Chemother. 2014;58(12):7049-7055. doi: 10.1128/AAC.02746-14
  9. Sundell K, Jagannathan P, Huang L, et al. Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children. Malaria Journal. 2015;14(1):1-8.doi: 10.1186/s12936-015-0908-8
  10. Wang Y, Yang Z, Yuan L, et al. Clinical efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated plasmodium falciparum malaria at the China-Myanmar Border. American Journal Tropical Medicine. 2015;93(3):577-583. doi: 10.4269/ajtmh.15-0029
  11. Liu H, Yang HL, Tang LH, et al. In vivo monitoring of dihydroartemisininpiperaquine sensitivity in Plasmodium falciparum along the China-Myanmar border of Yunnan Province, China from 2007 to 2013. Malaria Journal. 2015;14:47. doi: 10.1186/s12936-015-0584-8
  12. Duru V, Khim N, Leang R, et al. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: Retrospective and prospective investigations. BMC Medicine. 2015;13:305. doi: 10.1186/s12916-015-0539-5
  13. Nankabirwa JI, Conrad MD, Legac J, et al. Intermittent preventive treatment with dihydroartemisinin- piperaquine in ugandan schoolchildren selects for plasmodium falciparum transporter polymorphisms that modify drug sensitivity. Antimicrob Agents Chemother. 2016;60(10):5649-5654. doi: 10.1128/AAC.00920-16
  14. Mohamed AO, Abdel Hamid MM, Mohamed OS, et al. Efficacies of DHA-PPQ and AS/SP in patients with uncomplicated Plasmodium falciparum malaria in an area of an unstable seasonal transmission in Sudan. Malaria Journal. 2017;16(1):163. doi: 10.1186/s12936-017-1817-9
  15. Plucinski MM, Dimbu PR, Macaia AP, et al. Efficacy of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in Angola, 2015. Malaria Journal. 2017;16(1):62. doi: 10.1186/s12936-017-1712-4
  16. Witkowski B, Duru V, Khim N, et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study. The Lancet, Infectious disease. 2017;17(2):174-183. doi: 10.1016/S1473-3099(16)30415-7
  17. Thanh NV, Thuy-Nhien N, Tuyen NTK, et al. Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin-piperaquine in the south of Vietnam. Malaria Journal. 2017;16(1):27. doi: 10.1186/s12936-017-1680-8
  18. Ebenebe JC, Ntadom G, Ambe J, et al. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old nigerian children ten years following adoption as first-line anti-malarials. American Journal Tropical Medicine Hygiene. 2018;99(3):649-664. doi: 10.4269/ajtmh.18-0115
  19. Dama S, Niangaly H, Djimde M, et al. A randomized trial of dihydroartemisinin-piperaquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Malaria Journal. 2018;17(1):347. doi: 10.1186/s12936-018-2496-x
  20. von Seidlein L, Peto TJ, Landier J, et al. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: A cluster randomised trial. PLoS Med. Feb 2019;16(2):e1002745. doi: 10.1371/journal.pmed.1002745
  21. Pau MC, Pantaleo A, Tsamesidis I, et al. Clinical impact of the two ART resistance markers, K13 gene mutations and DPC3 in Vietnam. PLoS One. 2019;14(4):e0214667. doi: 10.1371/journal.pone.0214667
  22. Mwesigwa J, Achan J, Affara M, et al. Mass drug administration with dihydroartemisininpiperaquine and malaria transmission dynamics in the gambia: A prospective cohort study. Clinical Infectious Diseases. 2019;69(2):278-286. doi: 10.1016/S1473-3099(19)30391-3
  23. van der Pluijm RW, Imwong M, Chau NH, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. The Lancet Infectious Diseases. 2019;19(9):952-961. doi: 10.1016/S1473-3099(19)30391-3
  24. Rehman AM, Maiteki-Sebuguzi C, Gonahasa S, et al. Intermittent preventive treatment of malaria delivered to primary schoolchildren provided effective individual protection in Jinja, Uganda: secondary outcomes of a cluster-randomized trial (START-IPT). Malar J. Sep 18 2019;18(1):318. doi: 10.1186/s12936-019-2954-0
  25. Warsame M, Hassan AM, Hassan AH, et al. High therapeutic efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Somalia. Malar J. Jul 11 2019;18(1):231. doi: 10.1186/s12936-019-2864-1
  26. Mandara CI, Francis F, Chiduo MG, et al. High cure rates and tolerability of artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Kibaha and Kigoma, Tanzania. Malar J. Mar 25 2019;18(1):99. doi: 10.1186/s12936-019-2740-z
  27. Mandara CI, Kavishe RA, Gesase S, et al. High efficacy of artemether–lumefantrine and dihydroartemisinin–piperaquine for the treatment of uncomplicated falciparum malaria in Muheza and Kigoma Districts, Tanzania. Malaria Journal. 2018;17(1):261. doi: 10.1186/s12936-018-2409-z
  28. Kakolwa MA, Mahende MK, Ishengoma DS, et al. Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania. Malaria Journal. 2018;17(1):369. doi: 10.1186/s12936-018-2524-x
  29. Hien TT, Thuy-Nhien NT, Phu NH, et al. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malaria Journal. 2012;11(1):355. doi: 10.1186/1475-2875-11-355
  30. Arinaitwe E, Sandison TG, Wanzira H, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. J Clinical Infectious Diseases. 2009;49(11):1629-1637.doi: 10.1086/647946
  31. Ngasala BE, Malmberg M, Carlsson AM, et al. Efficacy and effectiveness of artemether-lumefantrine after initial and repeated treatment in children< 5 years of age with acute uncomplicated Plasmodium falciparum malaria in rural Tanzania: a randomized trial. J Clinical Infectious Diseases. 2011;52(7):873-882. doi: 10.1093/cid/cir066
  32. Bukirwa H, Yeka A, Kamya MR, et al. Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PloS Clinical Trial. 2006;1(1):e7. doi: 10.1371/journal.pctr.0010007
  33. Zongo I, Dorsey G, Rouamba N, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. J Clinical infectious diseases. 2007;45(11):1453-1461. doi: 10.1086/522985
  34. Shayo A, Buza J, Ishengoma DSJMj. Monitoring of efficacy and safety of artemisinin-based anti-malarials for treatment of uncomplicated malaria: a review of evidence of implementation of anti-malarial therapeutic efficacy trials in Tanzania. Malaria Journal. 2015;14(1):135. doi: 10.1186/s12936-015-0649-8
  35. World Health Organization. World Malaria Report 2018. Geneva; 2018.
  36. World Health Organization. Methods for surveillance of anti-malarial drug efficacy. Geneva; 2009.
  37. van der Pluijm RW, Imwong M, Chau NH, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. The Lancet Infectious Disease. 2019;19(9):952-961. doi:
  38. Hoglund RM, Workman L, Edstein MD, et al. Population pharmacokinetic properties of piperaquine in falciparum malaria: an individual participant data meta-analysis. PLoS Medicine. 2017;14(1):e1002212. doi: 10.1371/journal.pmed.1002212
  39. Bousema JT, Schneider P, Gouagna LC, et al. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. The Journal of infectious diseases. 2006;193(8):1151-1159. doi: 10.1086/503051
  40. Hastings IM, Kay K, Hodel EMJAa, chemotherapy. How robust are malaria parasite clearance rates as indicators of drug effectiveness and resistance? J Antimicrobial agents chemotherapy. 2015;59(10):6428-6436.
  41. Phuc BQ, Rasmussen C, Duong TT, et al. Treatment failure of dihydroartemisinin/piperaquine for Plasmodium falciparum malaria, Vietnam. J Emerging infectious diseases. 2017;23(4):715-717.doi: 10.3201/eid2304.161872
  42. Nosten F, White NJJTAjotm, hygiene. Artemisinin-based combination treatment of falciparum malaria. J The American journal of tropical medicine hygiene. 2007;77(6_Suppl):181-192. doi:
  43. Harrison NE, Olufunlayo TF, Agomo CO. Utilization of the current national anti-malarial treatment guidelines among doctors in army hospitals in Lagos, Nigeria. Open Journal of Preventive Medicine. 2012;3(2):390-393. doi: 10.4236/ojpm.2012.23056

How to Cite

Farindira Vesti Rahmasari, Imwong, M., Chakim, I., Setyonugroho, W. ., Tri Wulandari Kesetyaningsih, Gunadi, A. ., & Arisandi, D. (2023). Revealing the artemisinin and piperaquine treatment failure: a systematic review. Bali Medical Journal, 12(1), 360–368.




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Mallika Imwong
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Irfanul Chakim
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