High cure rates and tolerability of artesunate-amodiaquine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Kibaha and Kigoma, Tanzania

Celine I Mandara, Filbert Francis, Mercy G Chiduo, Billy Ngasala, Renata Mandike, Sigsbert Mkude, Frank Chacky, Fabrizio Molteni, Ritha Njau, Ally Mohamed, Marian Warsame, Deus S Ishengoma, Celine I Mandara, Filbert Francis, Mercy G Chiduo, Billy Ngasala, Renata Mandike, Sigsbert Mkude, Frank Chacky, Fabrizio Molteni, Ritha Njau, Ally Mohamed, Marian Warsame, Deus S Ishengoma

Abstract

Background: The Tanzanian National Malaria Control Programme (NMCP) and its partners have been implementing regular therapeutic efficacy studies (TES) to monitor the performance of different drugs used or with potential use in Tanzania. However, most of the recent TES focused on artemether-lumefantrine, which is the first-line anti-malarial for the treatment of uncomplicated falciparum malaria. Data on the performance of other artemisinin-based combinations is urgently needed to support timely review and changes of treatment guidelines in case of drug resistance to the current regimen. This study was conducted at two NMCP sentinel sites (Kibaha, Pwani and Ujiji, Kigoma) to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP), which are the current alternative artemisinin-based combinations in Tanzania.

Methods: This was a single-arm prospective evaluation of the clinical and parasitological responses of ASAQ and DP for directly observed treatment of uncomplicated falciparum malaria. Children aged 6 months to 10 years and meeting the inclusion criteria were enrolled and treated with either ASAQ or DP. In each site, patients were enrolled sequentially; thus, enrolment of patients for the assessment of one artemisinin-based combination was completed before patients were recruited for assessment of the second drugs. Follow-up was done for 28 or 42 days for ASAQ and DP, respectively. The primary outcome was PCR corrected cure rates while the secondary outcome was occurrence of adverse events (AEs) or serious adverse events (SAEs).

Results: Of the 724 patients screened at both sites, 333 (46.0%) were enrolled and 326 (97.9%) either completed the 28/42 days of follow-up, or attained any of the treatment outcomes. PCR uncorrected adequate clinical and parasitological response (ACPR) for DP on day 42 was 98.8% and 75.9% at Kibaha and Ujiji, respectively. After PCR correction, DP's ACPR was 100% at both sites. For ASAQ, no parasite recurrence occurred giving 100% ACPR on day 28. Only one patient in the DP arm (1.1%) from Ujiji had parasites on day 3. Of the patients recruited (n = 333), 175 (52.6%) had AEs with 223 episodes (at both sites) in the two treatment groups. There was no SAE and the commonly reported AE episodes (with > 5%) included, cough, running nose, abdominal pain, diarrhoea and fever.

Conclusion: Both artemisinin-based combinations had high cure rates with PCR corrected ACPR of 100%. The two drugs had adequate safety with no SAE and all AEs were mild, and not associated with the anti-malarials. Continued TES is critical to monitor the performance of nationally recommended artemisinin-based combination therapy and supporting evidence-based review of malaria treatment policies. Trial registration This study is registered at ClinicalTrials.gov, No. NCT03431714.

Keywords: Artesunate–amodiaquine; Dihydroartemisinin–piperaquine; Efficacy; Plasmodium falciparum; Safety; Tanzania.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Map of Tanzania showing the two NMCP sentinel sites marked with red triangles
Fig. 2
Fig. 2
Trial profile for ASAQ showing the flow of patients during screening, enrolment and follow-up
Fig. 3
Fig. 3
Trial profile for DP showing the flow of patients during screening, enrolment and follow-up

References

    1. WHO . World Malaria Report 2016. Geneva: World Health Organization; 2016.
    1. Snow RW, Sartorius B, Kyalo D, Maina J, Amratia P, Mundia CW, et al. The prevalence of Plasmodium falciparum in sub-Saharan Africa since 1900. Nature. 2017;550:515–518. doi: 10.1038/nature24059.
    1. WHO . World Malaria Report 2018. Geneva: World Health Organization; 2018.
    1. Ministry of Health . Annual Health Statistics Abstract. Tanzania: Dar es Salaam; 2006.
    1. WHO . Guidelines for the treatment of malaria. Geneva: World Health Organization; 2006.
    1. WHO . Guidelines for treatment of malaria. Geneva: World Health Organization; 2015.
    1. Sagara I, Beavogui AH, Zongo I, Soulama I, Borghini-Fuhrer I, Fofana B, et al. Safety and efficacy of re-treatments with Pyronaridine–artesunate in African patients with malaria: a substudy of the WANECAM randomised trial. Lancet Infect Dis. 2016;16:189–198. doi: 10.1016/S1473-3099(15)00318-7.
    1. West African network for clinical trials of antimalarial drugs Pyronaridine–artesunate or dihydroartemisinin–piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet. 2018;391:1378–1390. doi: 10.1016/S0140-6736(18)30291-5.
    1. 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.
    1. WHO . World Malaria Report 2011. Geneva: World Health Organization; 2011.
    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, Canavati SE, Khim N, Vestergaard LS, Borghini-Fuhrer I, Kim S, et al. Efficacy and safety of Pyronaridine–artesunate for treatment of uncomplicated Plasmodium falciparum malaria in Western Cambodia. Antimicrob Agents Chemother. 2016;60:3884–3890. doi: 10.1128/AAC.00039-16.
    1. Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC, Dondorp AM, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis. 2015;211:670–679. doi: 10.1093/infdis/jiu491.
    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. Phuc BQ, Rasmussen C, Duong TT, Dong LT, Loi MA, Menard D, et al. Treatment failure of dihydroartemisinin/piperaquine for Plasmodium falciparum malaria, Vietnam. Emerg Infect Dis. 2017;23:715–717. doi: 10.3201/eid2304.161872.
    1. Thanh NV, Thuy-Nhien N, Tuyen NT, Tong NT, Nha-Ca NT, Dong LT, et al. Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin–piperaquine in the south of Vietnam. Malar J. 2017;16:27. doi: 10.1186/s12936-017-1680-8.
    1. Ministry of Health . National Guidelines for malaria diagnosis and treatment. Tanzania: Dar es Salaam; 2006.
    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. Mandara CI, Kavishe RA, Gesase S, Mghamba J, Ngadaya E, Mmbuji P, et al. High efficacy of artemether–lumefantrine and dihydroartemisinin–piperaquine for the treatment of uncomplicated falciparum malaria in Muheza and Kigoma Districts, Tanzania. Malar J. 2018;17:261. doi: 10.1186/s12936-018-2409-z.
    1. Kakolwa MA, Mahende MK, Ishengoma DS, Mandara CI, Ngasala B, Kamugisha E, et al. Efficacy and safety of artemisinin-based combination therapy, and molecular markers for artemisinin and piperaquine resistance in mainland Tanzania. Malar J. 2018;17:369. doi: 10.1186/s12936-018-2524-x.
    1. Mwaiswelo R, Ngasala B, Gil JP, Malmberg M, Jovel I, Xu W, et al. Sustained high cure rate of artemether–lumefantrine against uncomplicated Plasmodium falciparum malaria after 8 years of its wide-scale use in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2017;97:526–532. doi: 10.4269/ajtmh.16-0780.
    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. Menard D, Dondorp A. Antimalaria drug resistance: a threat to malaria elimination. In: Biology in the era of eradication. Wirth D, Alonso P, Eds. New York: Cold Spring Harb Perspect Med. 2017;7:255–78.
    1. WHO. Methods for surveillance of antimalarial drug efficacy. Geneva, World Health Organization, 2009.
    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 . National guidelines for malaria diagnosis and treatment. Tanzania: Dar es Salaam; 2000.
    1. Ministry of Health . National guidelines for diagnosis and treatment of malaria. Tanzania: Dar es Salaam; 2014.
    1. United Republic of Tanzania . Tanzania HIV and Malaria Indicator Survey. Tanzania: Dar es Salaam; 2017.
    1. Tanzania Demographic and Health Survey and Malaria Indicator Survey (TDHS-MIS) 2015–16. Dar es Salaam/Tanzania, 2016.
    1. United Republic of Tanzania . Tanzania HIV/AIDS and Malaria indicator survey 2007/2008. Tanzania: Dar es Salaam; 2008.
    1. United Republic of Tanzania, ICF International. Tanzania HIV/AIDS and Malaria Indicator Survey 2011–2012. Dar es Salaam, 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 and techniques for clinical trials on antimalarial drug efficacy: genotyping to identify parasite population. Amsterdam, Medicine for Malaria Venture, World Health Organization; 2007.
    1. WHO . Tools for monitoring antimalarial drug efficacy: WHO data entry and analysis tool. Geneva: World Health Organization; 2018.
    1. Kabanywanyi AM, Mwita A, Sumari D, Mandike R, Mugittu K, Abdulla S. Efficacy and safety of artemisinin-based antimalarial in the treatment of uncomplicated malaria in children in southern Tanzania. Malar J. 2007;6:146. doi: 10.1186/1475-2875-6-146.
    1. Mårtensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, et al. Efficacy of artesunate plus amodiaquine versus that of artemether–lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005;41:1079–1086. doi: 10.1086/444460.
    1. Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, Drakeley C, et al. Amodiaquine alone, amodiaquine + sulfadoxine-pyrimethamine, amodiaquine + artesunate, and artemether–lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet. 2005;365:1474–1480. doi: 10.1016/S0140-6736(05)66417-3.
    1. Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA. 2007;297:2210–2219. doi: 10.1001/jama.297.20.2210.
    1. Ndayiragije A, Niyungeko D, Karenzo J, Niyungeko E, Barutwanayo M, Ciza A, et al. Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi. Trop Med Int Health. 2004;9:673–679. doi: 10.1111/j.1365-3156.2004.01255.x.
    1. Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, Van Overmeir C, et al. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria. Trop Med Int Health. 2004;9:1091–1098. doi: 10.1111/j.1365-3156.2004.01316.x.
    1. Thwing JI, Odero CO, Odhiambo FO, Otieno KO, Kariuki S, Ord R, et al. In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya. Trop Med Int Health. 2009;14:294–300. doi: 10.1111/j.1365-3156.2009.02222.x.
    1. Yeka A, Lameyre V, Afizi K, Fredrick M, Lukwago R, Kamya MR, et al. Efficacy and safety of fixed-dose artesunate–amodiaquine vs. artemether–lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children. PLoS ONE. 2014;9:e113311. doi: 10.1371/journal.pone.0113311.
    1. Yeka A, Kigozi R, Conrad MD, Lugemwa M, Okui P, Katureebe C, et al. Artesunate/amodiaquine versus artemether/lumefantrine for the treatment of uncomplicated malaria in Uganda: a randomized trial. J Infect Dis. 2016;213:1134–1142. doi: 10.1093/infdis/jiv551.
    1. Ndiaye JL, Faye B, Diouf AM, Kuete T, Cisse M, Seck PA, et al. Randomized, comparative study of the efficacy and safety of artesunate plus amodiaquine, administered as a single daily intake versus two daily intakes in the treatment of uncomplicated falciparum malaria. Malar J. 2008;7:16. doi: 10.1186/1475-2875-7-16.
    1. Zwang J, Olliaro P, Barennes H, Bonnet M, Brasseur P, Bukirwa H, et al. Efficacy of artesunate–amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis. Malar J. 2009;8:203. doi: 10.1186/1475-2875-8-203.
    1. Lemnge M, Alifrangis M, Kafuye MY, Segeja MD, Gesase S, Minja D, et al. High reinfection rate and treatment failures in children treated with amodiaquine for falciparum malaria in Muheza villages, Northeastern Tanzania. Am J Trop Med Hyg. 2006;75:188–193. doi: 10.4269/ajtmh.2006.75.188.
    1. Lemnge MM, Ali AS, Malecela EK, Sambu E, Abdulla R, Juma MS, et al. Therapeutic efficacy of sulfadoxine-pyrimethamine and amodiaquine among children with uncomplicated Plasmodium falciparum malaria in Zanzibar, Tanzania. Am J Trop Med Hyg. 2005;73:681–685. doi: 10.4269/ajtmh.2005.73.681.
    1. Yeka A, Banek K, Bakyaita N, Staedke SG, Kamya MR, Talisuna A, et al. Artemisinin versus non-artemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda. PLoS Med. 2005;2:e190. doi: 10.1371/journal.pmed.0020190.
    1. WHO . Artemisinin resistance and artemisinin-based combination efficacy: status report. Geneva: World Health Organization; 2018.
    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. 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. 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. Agarwal A, McMorrow M, Onyango P, Otieno K, Odero C, Williamson J, et al. A randomized trial of artemether–lumefantrine and dihydroartemisinin–piperaquine in the treatment of uncomplicated malaria among children in western Kenya. Malar J. 2013;12:254. doi: 10.1186/1475-2875-12-254.
    1. Karema C, Fanello CI, Van Overmeir C, Van Geertruyden JP, Van Doren W, Ngamije D, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–1111. doi: 10.1016/j.trstmh.2006.01.001.
    1. Wanzira H, Kakuru A, Arinaitwe E, Bigira V, Muhindo MK, Conrad M, et al. Longitudinal outcomes in a cohort of Ugandan children randomized to artemether–lumefantrine versus dihydroartemisinin–piperaquine for the treatment of malaria. Clin Infect Dis. 2014;59:509–516. doi: 10.1093/cid/ciu353.
    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. 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.

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