Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis

Autoři: Cho Naing aff001;  Maxine A. Whittaker aff002;  Norah Htet Htet aff001;  Saint Nway Aye aff001;  Joon Wah Mak aff001
Působiště autorů: International Medical University, Kuala Lumpur, Malaysia aff001;  Faculty of Tropical Heath and Medicine, James Cook University, Queensland, Australia aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225882



The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region.


Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach.


Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08–5.8). There is low certainty evidence due to limited number of studies and small trials.

Discussion/ Conclusions

The findings suggest the superiority of DHP (3–day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.

Klíčová slova:

Antimalarials – Antimicrobial resistance – Drug therapy – Malaria – Malarial parasites – Network analysis – Plasmodium


1. WHO. World malaria report 2018. Geneva: World Health Organization; 2018.

2. WHO. Global technical strategy for malaria 2016–2030. Available at https://www.who.int/malaria/areas/global_technical_strategy/en/

3. WHO. Antimalarial drug efficacy and drug resistance. 2018. Available at https://www.who.int/malaria/areas/treatment/drug_efficacy/en/

4. WHO. Guidelines For The Treatment of Malaria - 3rd edition. 2015. Available at https://apps.who.int/iris/bitstream/handle/10665/162441/9789241549127_eng.pdf?sequence=1

5. Satimai W, Sudathip P, Vijaykadga S, Khamsiriwatchara A, Sawang S, Potithavoranan T, et al. Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia. Malar 2012;11:300.

6. Bukirwa H, Unnikrishnan B, Kramer CV, Sinclair D, Nair S, Tharyan P. Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2014;(3):CD006404. doi: 10.1002/14651858.CD006404.pub2 24596021

7. Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2014;(1):CD010927. doi: 10.1002/14651858.CD010927 24443033

8. Naing C, Racloz V, Whittaker MA, Aung K, Reid SA, Mak JW, et al. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium vivax malaria in endemic countries: meta-analysis of randomized controlled studies. PLoS One. 2013;8(12):e78819. doi: 10.1371/journal.pone.0078819 24312446

9. WWARN Parasite Clearance Study Group. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis. Malar J. 2015; 14:359. doi: 10.1186/s12936-015-0874-1 26390866

10. Lu G. and Ades A.E. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004; 23: 3105–24. doi: 10.1002/sim.1875 15449338

11. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods. 2012;3:80–97. doi: 10.1002/jrsm.1037 26062083

12. Cornell JE. The PRISMA extension for network meta-analysis: bringing clarity and guidance to the reporting of systematic reviews incorporating network meta-analyses. Ann Intern Med. 2015; 162:797–8. doi: 10.7326/M15-0930 26030637

13. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org.

14. Rachmawati R, Rampengan N, Tatura S, Rampengan T. Comparison of the efficacy of artemether-lumefantrine vs. artesunate plus sulfadoxine-pyrimethamine in children with uncomplicated falciparum malaria. PI.2010;50(2):113 Available at https://paediatricaindonesiana.org/index.php/paediatrica-indonesiana/article/view/1216

15. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. doi: 10.1136/bmj.39489.470347.AD 18436948

16. Salanti G, Ades AE, Ioannidis JPA. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64:163–71. doi: 10.1016/j.jclinepi.2010.03.016 20688472

17. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6. doi: 10.1016/j.jclinepi.2010.07.015 21208779

18. Shim S, Yoon B-H, Shin I-S, Bae J-M. Network meta-analysis: application and practice using Stata. Epidemiol Health. 2017;39:e2017047. doi: 10.4178/epih.e2017047 29092392

19. White IR, Barrett JK, Jackson D, Higgins JPT. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods 2012;3(2):111–25. doi: 10.1002/jrsm.1045 26062085

20. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med 2010;29(7–8):932–44. doi: 10.1002/sim.3767 20213715

21. Brignardello-Petersen R, Bonner A, Alexander PE, Siemieniuk RA, Furukawa TA, Rochwerg B, et al. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol 2018;93:36–44. doi: 10.1016/j.jclinepi.2017.10.005 29051107

22. Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JPT. Evaluating the quality of evidence from a network meta-analysis. PLoS One 2014;9(7):e99682. doi: 10.1371/journal.pone.0099682 24992266

23. Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, Leowattana W et al. Randomized controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis 2004; 190:1773–82. doi: 10.1086/425015 15499533

24. Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, Proux S, et al. A Randomized controlled study of a simple once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 2005;41(4):425–32. doi: 10.1086/432011 16028147

25. Kshirsagar NA, Gogtay NJ, Moorthy NS, Garg MR, Dalvi SS, Chogle AR, et al. A randomized, double blind, parallel group, comparative safety, and efficacy trial of co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India. Am J Trop Med Hyg. 2000;62:402–8. doi: 10.4269/ajtmh.2000.62.402 11037786

26. Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann et al. A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg, 2001; 64:247–56

27. Houng NM, Davis TM, Cox-Singh J, Hewitt S, Tran QT, Tran BK, et al. Treatment of uncomplicated falciparum malaria in southern Vietnam: can chloroquine or sulfadoxine-pyrimethamine be reintroduced in combination with artesunate? Clin Infect Dis 2003;37(11):1461–6. doi: 10.1086/379323 14614668

28. Silachamroon U, Krudsood S, Thanachartwet W et al. An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health 2005; 36: 591–6. 16124422

29. Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet 2006;367(9528):2075–85. doi: 10.1016/S0140-6736(06)68931-9 16798391

30. Song J, Socheat D, Tan B, Seila S, Xu Y, Ou F, et al. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. Malar J 2011;10(1):231.

31. Thanh NX, Trung TN, Phong NC, Thien NX, Dai B, Shanks GD, et al. Open label randomized comparison of dihydroartemisinin-piperaquine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam. Trop Med Int Health. 2009;14(5):504–11. doi: 10.1111/j.1365-3156.2009.02269.x 19320869

32. Thanh NX, Trung TN, Phong NC, Quang HH, Dai B, Shanks GD, et al. The efficacy and tolerability of artemisinin-piperaquine (Artequick®) versus artesunate-amodiaquine (Coarsucam™) for the treatment of uncomplicated Plasmodium falciparum malaria in south-central Vietnam. Malar J 2012;11:217. doi: 10.1186/1475-2875-11-217 22741618

33. Thapa S, Hollander J, Linehan M, Cox-Singh J, Bista MB, Thakur GD, et al. Comparison of artemether-lumefantrine with sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in eastern Nepal. Am J Trop Med Hyg. 2007;77(3):423–30. 17827354

34. Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg. 2001;65(4):309–17. doi: 10.4269/ajtmh.2001.65.309 11693875

35. Trung TN, Tan B, Van Phuc D, Song JP. A randomized, controlled trial of artemisinin-piperaquine vs dihydroartemisinin-piperaquine phosphate in treatment of falciparum malaria. Chin J Integr Med. 2009;15(3):189–92. doi: 10.1007/s11655-009-0189-6 19568711

36. Valecha N, Srivastava P, Mohanty SS, Mittra P, Sharma SK, Tyagi PK, et al. Therapeutic efficacy of artemether-lumefantrine in uncomplicated falciparum malaria in India. Malar J. 2009;8(1):107.

37. van Vugt M, Looareesuwan S, Wilairatana P, McGready R, Villegas L, et al. Artemether-lumefantrine for the treatment of multidrug resistant falciparum malaria. Trans R Soc Trop Med Hyg 2000; 94: 545–8. doi: 10.1016/s0035-9203(00)90082-8 11132386

38. Wijeyaratne PM, Chand PB, Valech N, Shahi B, Adak T, Ansari MA, et al. 2005. Therapeutic efficacy of antimalarial drugs along the eastern Indo-Nepal border: a cross-border collaborative study. Trans R Soc Trop Med Hyg 99: 423–9. doi: 10.1016/j.trstmh.2004.09.011 15837354

39. Chaimani A, Higgins JPT, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS ONE 2013; 8(10): e76654. doi: 10.1371/journal.pone.0076654 24098547

40. Naing C, Poovorawan Y, Tong KS. Comparative effectiveness of anti-viral drugs with dual activity for treating hepatitis B and HIV co-infected patients: a network meta-analysis. BMC Infect Dis. 2018;18(1):564. doi: 10.1186/s12879-018-3506-x 30428847

41. Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, et al. Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 2003;47(3):901–4. doi: 10.1128/AAC.47.3.901-904.2003 12604519

42. Leang R, Barrette A, Bouth DM, Menard D, Abdur R, Duong S, et al. Efficacy of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in Cambodia, 2008 to 2010. Antimicrob Agents Chemother 2013;57(2):818–26. doi: 10.1128/AAC.00686-12 23208711

43. Carrara VI, Lwin KM, Phyo AP, Ashley E, Wiladphaingern J, Sriprawat K, et al. Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai–Myanmar border, 1999–2011: An observational study. PLoS Med 2013; 10(3):e1001398. doi: 10.1371/journal.pmed.1001398 23472056

44. Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347(6220):428–31. doi: 10.1126/science.1260867 25502314

45. Hay SI, Okiro EA, Gething PW, Patil AP, Tatem AJ, Guerra CA, et al. Estimating the global clinical burden of Plasmodium falciparum malaria in 2007. PLoS Med 2010;7(6):e1000290. doi: 10.1371/journal.pmed.1000290 20563310

46. Youdom SW, Tahar R, Basco LK. Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis. Malar. J. 2017;16: 311. doi: 10.1186/s12936-017-1963-0 28774303

47. WHO. Antimalarial drug combination therapy: report of a WHO technical consultation. 2001.

48. Tjitra E, Hasugian AR, Siswantoro H, Prasetyorini B, Ekowatiningsih R, Yusnita EA, et al. Efficacy and safety of artemisinin-naphthoquine versus dihydroartemisinin-piperaquine in adult patients with uncomplicated malaria: a multi-centre study in Indonesia. Malar J 2012;11(1):153.

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