High efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Muheza and Kigoma Districts, Tanzania

Celine I Mandara, Reginald A Kavishe, Samuel Gesase, Janneth Mghamba, Esther Ngadaya, Peter Mmbuji, Sigsbert Mkude, Renata Mandike, Ritha Njau, Ally Mohamed, Martha M Lemnge, Marian Warsame, Deus S Ishengoma, Celine I Mandara, Reginald A Kavishe, Samuel Gesase, Janneth Mghamba, Esther Ngadaya, Peter Mmbuji, Sigsbert Mkude, Renata Mandike, Ritha Njau, Ally Mohamed, Martha M Lemnge, Marian Warsame, Deus S Ishengoma

Abstract

Background: Artemether-lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania. Recently, dihydroartemisinin-piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania. This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity.

Methods: This was an open-label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively. Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively. Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator. The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively.

Results: Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively. In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji. With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p = 0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p = 0.021). The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites. Parasite clearance rate constant was similar in the two groups and at both sites (< 0.28/h); the slope half-life was < 3.0 h and all but only one patient cleared parasites by 72 h.

Conclusion: These findings confirm high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Tanzania. The high parasite clearance rate suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance. Trial registration This trial is registered at ClinicalTrials.gov under registration number NCT02590627.

Keywords: Artemether–lumefantrine; Dihydroartemisinin–piperaquine; Efficacy; Parasite clearance; Plasmodium falciparum.

Figures

Fig. 1
Fig. 1
Trial profile showing screening, randomization and follow-up of children treated with either AL or DP at Muheza and Ujiji sites
Fig. 2
Fig. 2
Haemoglobin levels of children treated with AL or DP measured at enrolment on day 0 to day 42 (AL) and day 0 to ay 63 (DP) at Muheza and Ujiji sites

References

    1. WHO . World malaria report. Geneva: World Health Organization; 2017.
    1. WHO . Global report on antimalarial drug efficacy and drug resistance: 2000–2010. Geneva: World Health Organization; 2010.
    1. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411–423. doi: 10.1056/NEJMoa1314981.
    1. Leang R, Taylor WR, Bouth DM, Song L, Tarning J, Char MC, et al. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in Western Cambodia: dihydroartemisinin–piperaquine open-label multicenter clinical assessment. Antimicrob Agents Chemother. 2015;59:4719–4726. doi: 10.1128/AAC.00835-15.
    1. Tun KM, Imwong M, Lwin KM, Win AA, Hlaing TM, Hlaing T, et al. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. Lancet Infect Dis. 2015;15:415–421. doi: 10.1016/S1473-3099(15)70032-0.
    1. WHO . Guidelines for treatment of malaria. 3. Geneva: World Health Organization; 2015.
    1. WHO . World malaria report 2011. Geneva: World Health Organization; 2011.
    1. Ministry of Health. National guidelines for malaria diagnosis and treatment. Edited by A. Mwita and F. Molten. Dar es Salam, United Republic of Tanzania; 2006.
    1. Ministry of Health . National Guidelines for diagnosis and treatment of malaria. Dar es Salam: Ministry of Health and Social Welfare, United Republic of Tanzania; 2014.
    1. Shayo A, Buza J, Ishengoma DS. 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. Malar J. 2015;14:135. doi: 10.1186/s12936-015-0649-8.
    1. Mwaiswelo R, Ngasala BE, Jovel I, Gosling R, Premji Z, Poirot E, et al. Safety of a single low-dose of primaquine in addition to standard artemether–lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Malar J. 2016;15:316. doi: 10.1186/s12936-016-1341-3.
    1. Bassat Q, Mulenga M, Tinto H, Piola P, Borrmann S, Menendez C, et al. Dihydroartemisinin–piperaquine and artemether–lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PLoS ONE. 2009;4:e7871. doi: 10.1371/journal.pone.0007871.
    1. Kamya MR, Yeka A, Bukirwa H, Lugemwa M, Rwakimari JB, Staedke SG, et al. Artemether–lumefantrine versus dihydroartemisinin–piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials. 2007;2:e20. doi: 10.1371/journal.pctr.0020020.
    1. Ndiaye JL, Faye B, Gueye A, Tine R, Ndiaye D, Tchania C, et al. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial. Malar J. 2011;10:237. doi: 10.1186/1475-2875-10-237.
    1. Ogouyemi-Hounto A, Azandossessi C, Lawani S, Damien G, de Tove YS, Remoue F, et al. Therapeutic efficacy of artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Benin. Malar J. 2016;15:37. doi: 10.1186/s12936-016-1091-2.
    1. Ogutu BR, Onyango KO, Koskei N, Omondi EK, Ongecha JM, Otieno GA, et al. Efficacy and safety of artemether–lumefantrine and dihydroartemisinin–piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children aged less than five years: results of an open-label, randomized, single-centre study. Malar J. 2014;13:33. doi: 10.1186/1475-2875-13-33.
    1. Sow D, Ndiaye JL, Sylla K, Ba MS, Tine RC, Faye B, et al. Evaluation of the efficacy and safety of three 2-drug combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Senegal: artesunate–amodiaquine, dihydroartemisinin–piperaquine, and artemether–lumefantrine. Med Sante Trop. 2016;26:45–50.
    1. Ursing J, Rombo L, Rodrigues A, Kofoed PE. Artemether–lumefantrine versus dihydroartemisinin–piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in children aged less than 15 years in Guinea-Bissau—an open-label non-inferiority randomised clinical trial. PLoS ONE. 2016;11:e0161495. doi: 10.1371/journal.pone.0161495.
    1. Zwang J, Ashley EA, Karema C, D’Alessandro U, Smithuis F, Dorsey G, et al. Safety and efficacy of dihydroartemisinin–piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis. PLoS ONE. 2009;4:e6358. doi: 10.1371/journal.pone.0006358.
    1. WHO . Artemisinin and artemisinin-based combination resistance. Geneva: World Health Organization; 2017.
    1. Flegg JA, Guerin PJ, White NJ, Stepniewska K. Standardizing the measurement of parasite clearance in falciparum malaria: the parasite clearance estimator. Malar J. 2011;10:339. doi: 10.1186/1475-2875-10-339.
    1. Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, et al. In vivo parasitological measures of artemisinin susceptibility. J Infect Dis. 2010;201:570–579. doi: 10.1086/650301.
    1. Muhindo MK, Kakuru A, Jagannathan P, Talisuna A, Osilo E, Orukan F, et al. Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria. Malar J. 2014;13:32. doi: 10.1186/1475-2875-13-32.
    1. Maiga AW, Fofana B, Sagara I, Dembele D, Dara A, Traore OB, et al. No evidence of delayed parasite clearance after oral artesunate treatment of uncomplicated falciparum malaria in Mali. Am J Trop Med Hyg. 2012;87:23–28. doi: 10.4269/ajtmh.2012.12-0058.
    1. East African Network for Monitoring Antimalarial Treatment (EANMAT) Monitoring antimalarial drug resistance within National Malaria Control Programmes: the EANMAT experience. Trop Med Int Health. 2001;6:891–898. doi: 10.1046/j.1365-3156.2001.00799.x.
    1. East African Network for Monitoring Antimalarial Treatment (EANMAT) The efficacy of antimalarial monotherapies, sulphadoxine-pyrimethamine and amodiaquine in East Africa: implications for sub-regional policy. Trop Med Int Health. 2003;8:860–867. doi: 10.1046/j.1360-2276.2003.01114.x.
    1. Ministry of Health, Community Development, Gender, Elderly and Children, MoH/Zanzibar, National Bureau of Statistics, OCGS/Zanzibar, and ICF. Tanzania demographic and health survey and malaria indicator survey (TDHS-MIS), 2015–16. Dar es Salaam, Tanzania; 2016.
    1. TACAIDS, ZAC, NBS, OCGS, and Macro International Inc. Tanzania HIV/AIDS and malaria indicator survey 2007/2008. Dar es Salaam, United Republic of Tanzania; 2008.
    1. TACAIDS, ZAC, NBS, OCGS, and ICF International. Tanzania HIV/AIDS and malaria indicator survey 2011–2012. Dar es Salaam, United Republic of Tanzania; 2014.
    1. Ishengoma DS, Shayo A, Mandara CI, Baraka V, Madebe RA, Ngatunga D, et al. The role of malaria rapid diagnostic tests in screening of patients to be enrolled in clinical trials in low malaria transmission settings. Health Syst Policy Res. 2016;3:1–10.
    1. WHO . Methods for surveillance of antimalarial drug efficacy, 2009. Geneva: World Health Organization; 2015.
    1. WHO . Evidence review group on the cardiotoxicity of antimalarial medicines. Geneva: World Health Organization; 2017.
    1. WHO . Basic malaria microscopy: part I. Learner’s guide. 2. Geneva: World Health Organization; 2010.
    1. WHO. Methods and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite population. Edited by Informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World Health Organization. Amsterdam: Medicine for Malaria Venture and The World Health Organization; 2007.
    1. WHO. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization; 2003. . Accessed 8 Aug 2017.
    1. Plucinski MM, Dimbu PR, Macaia AP, Ferreira CM, Samutondo C, Quivinja J, et al. Efficacy of artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in Angola, 2015. Malar J. 2017;6:62. doi: 10.1186/s12936-017-1712-4.
    1. Plucinski MM, Talundzic E, Morton L, Dimbu PR, Macaia AP, Fortes F, et al. Efficacy of artemether–lumefantrine and dihydroartemisinin–piperaquine for treatment of uncomplicated malaria in children in Zaire and Uige Provinces, angola. Antimicrob Agents Chemother. 2015;59:437–443. doi: 10.1128/AAC.04181-14.
    1. 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.
    1. Zongo I, Dorsey G, Rouamba N, Dokomajilar C, Sere Y, Rosenthal PJ, 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. Clin Infect Dis. 2007;45:1453–1461. doi: 10.1086/522985.
    1. Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C, et al. Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016;6:357–365. doi: 10.1016/S1473-3099(15)00487-9.
    1. Kamau E, Campino S, Amenga-Etego L, Drury E, Ishengoma D, Johnson K, et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J Infect Dis. 2015;211:1352–1355.
    1. Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, et al. A worldwide map of Plasmodium falciparum K13-propeller polymorphisms. N Engl J Med. 2016;374:2453–2464. doi: 10.1056/NEJMoa1513137.
    1. Taylor SM, Parobek CM, DeConti DK, Kayentao K, Coulibaly SO, Greenwood BM, et al. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis. 2015;211:680–688. doi: 10.1093/infdis/jiu467.
    1. Sumari D, Mwingira F, Selemani M, Mugasa J, Mugittu K, Gwakisa P. Malaria prevalence in asymptomatic and symptomatic children in Kiwangwa, Bagamoyo district, Tanzania. Malar J. 2017;16:222. doi: 10.1186/s12936-017-1870-4.
    1. WWARN Gametocyte Study Group Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data. BMC Med. 2016;14:79. doi: 10.1186/s12916-016-0621-7.
    1. Stepniewska K, Price RN, Sutherland CJ, Drakeley CJ, von Seidlein L, Nosten F, et al. Plasmodium falciparum gametocyte dynamics in areas of different malaria endemicity. Malar J. 2008;7:249. doi: 10.1186/1475-2875-7-249.
    1. Bousema T, Okell L, Shekalaghe S, Griffin JT, Omar S, Sawa P, et al. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar J. 2010;9:136. doi: 10.1186/1475-2875-9-136.
    1. Goncalves BP, Kapulu MC, Sawa P, Guelbeogo WM, Tiono AB, Grignard L, et al. Examining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity. Nat Commun. 2017;8:1133. doi: 10.1038/s41467-017-01270-4.
    1. Ngui R, Lim YA, Chong KL, Sek CC, Jaffar S. Association between anaemia, iron deficiency anaemia, neglected parasitic infections and socioeconomic factors in rural children of West Malaysia. PLoS Negl Trop Dis. 2012;6:e1550. doi: 10.1371/journal.pntd.0001550.
    1. Koukounari A, Estambale BB, Njagi JK, Cundill B, Ajanga A, Crudder C, et al. Relationships between anaemia and parasitic infections in Kenyan schoolchildren: a Bayesian hierarchical modelling approach. Int J Parasitol. 2008;38:1663–1671. doi: 10.1016/j.ijpara.2008.05.013.
    1. Magalhaes RJ, Clements AC. Mapping the risk of anaemia in preschool-age children: the contribution of malnutrition, malaria, and helminth infections in West Africa. PLoS Med. 2011;8:e1000438. doi: 10.1371/journal.pmed.1000438.
    1. Sousa-Figueiredo JC, Gamboa D, Pedro JM, Fancony C, Langa AJ, Magalhaes RJ, et al. Epidemiology of malaria, schistosomiasis, geohelminths, anemia and malnutrition in the context of a demographic surveillance system in northern Angola. PLoS ONE. 2012;7:e33189. doi: 10.1371/journal.pone.0033189.
    1. Said K, Hella J, Knopp S, Nassoro T, Shija N, Aziz F, et al. Schistosoma, other helminth infections, and associated risk factors in preschool-aged children in urban Tanzania. PLoS Negl Trop Dis. 2017;11:e0006017. doi: 10.1371/journal.pntd.0006017.

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