Efficacy of artesunate-amodiaquine, dihydroartemisinin-piperaquine and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Maradi, Niger

Francesco Grandesso, Ousmane Guindo, Lynda Woi Messe, Rockyath Makarimi, Aliou Traore, Souleymane Dama, Ibrahim Maman Laminou, Jean Rigal, Martin de Smet, Odile Ouwe Missi Oukem-Boyer, Ogobara K Doumbo, Abdoulaye Djimdé, Jean-François Etard, Francesco Grandesso, Ousmane Guindo, Lynda Woi Messe, Rockyath Makarimi, Aliou Traore, Souleymane Dama, Ibrahim Maman Laminou, Jean Rigal, Martin de Smet, Odile Ouwe Missi Oukem-Boyer, Ogobara K Doumbo, Abdoulaye Djimdé, Jean-François Etard

Abstract

Background: Malaria endemic countries need to assess efficacy of anti-malarial treatments on a regular basis. Moreover, resistance to artemisinin that is established across mainland South-East Asia represents today a major threat to global health. Monitoring the efficacy of artemisinin-based combination therapies is of paramount importance to detect as early as possible the emergence of resistance in African countries that toll the highest burden of malaria morbidity and mortality.

Methods: A WHO standard protocol was used to assess efficacy of the combinations artesunate-amodiaquine (AS-AQ Winthrop®), dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) and artemether-lumefantrine (AM-LM, Coartem®) taken under supervision and respecting pharmaceutical recommendations. The study enrolled for each treatment arm 212 children aged 6-59 months living in Maradi (Niger) and suffering with uncomplicated falciparum malaria. The Kaplan-Meier 42-day PCR-adjusted cure rate was the primary outcome. A standardized parasite clearance estimator was used to assess delayed parasite clearance as surrogate maker of suspected artemisinin resistance.

Results: No early treatment failures were found in any of the study treatment arms. The day-42 PCR-adjusted cure rate estimates were 99.5, 98.4 and 99.0% in the AS-AQ, DHA-PPQ and AM-LM arms, respectively. The reinfection rate (expressed also as Kaplan-Meier estimates) was higher in the AM-LM arm (32.4%) than in the AS-AQ (13.8%) and the DHA-PPQ arm (24.9%). The parasite clearance rate constant was 0.27, 0.26 and 0.25 per hour for AS-AQ, DHA-PPQ and AM-LM, respectively.

Conclusions: All the three treatments evaluated largely meet WHO criteria (at least 95% efficacy). AS-AQ and AL-LM may continue to be used and DHA-PPQ may be also recommended as first-line treatment for uncomplicated falciparum malaria in Maradi. The parasite clearance rate were consistent with reference values indicating no suspected artemisinin resistance. Nevertheless, the monitoring of anti-malarial drug efficacy should continue. Trial registration details Registry number at ClinicalTrial.gov: NCT01755559.

Keywords: Antimalarial; Artemisinin; Efficacy; Malaria; Niger; Parasite clearance; Resistance.

Figures

Fig. 1
Fig. 1
Study flowchart
Fig. 2
Fig. 2
Kaplan–Meier PCR-corrected efficacy estimates or the three study treatments
Fig. 3
Fig. 3
Reinfection rate expressed as a Kaplan–Meier probability of having a reinfection

References

    1. WHO . World malaria report 2016. Geneva: World Health Organization; 2016.
    1. Direction de la lutte contre la maladie et les endémies—Division des maladies transmissibles. Politique Nationale de Lutte contre le Paludisme. Niamey; 2008 (in French).
    1. Salissou A, Halima BM, Abani M, Adehossi E, Daou M, Boureima S, et al. Efficacité et tolérance de l’association artéméther luméfantrine dans le traitement du paludisme simple à Plasmodium falciparum au Niger. Journal de la Recherche Scientifique de l’Université de Lomé. 2012;14:79–84.
    1. Laminou IM, Fatouma S, Maman D, Boubacar H, Maazou A, Zamanka H, et al. Comparison of the efficacy and safety of artemether–lumefantrine with artesunate–amodiaquine in Niger. Mali Med. 2016;31:1–7.
    1. Denis MB, Tsuyuoka R, Poravuth Y, Narann TS, Seila S, Lim C, et al. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006;11:1360–1366. doi: 10.1111/j.1365-3156.2006.01690.x.
    1. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960–1966. doi: 10.1016/S0140-6736(12)60484-X.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467. doi: 10.1056/NEJMoa0808859.
    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. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM, et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359:2619–2620. doi: 10.1056/NEJMc0805011.
    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. Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A-C, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50–55. doi: 10.1038/nature12876.
    1. Laminou IM, Lamine MM, Mahamadou B, Ascofaré OM, Dieye A. Polymorphism of pfk13-propeller in Niger: detection of novel mutations. Journal of Advances in Medicine and Medical Research. 2017;22:1–5. doi: 10.9734/JAMMR/2017/34192.
    1. Bassat Q, Mulenga M, Tinto H, Piola P, Borrmann S, Menéndez 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. Arinaitwe E, Sandison TG, Wanzira H, Kakuru A, Homsy J, Kalamya J, et al. Artemether–lumefantrine versus dihydroartemisinin–piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. Clin Infect Dis. 2009;49:1629–1637. doi: 10.1086/647946.
    1. Cisse B, Cairns M, Faye E, NDiaye O, Faye B, Cames C, et al. Randomized trial of piperaquine with sulfadoxine–pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. PLoS ONE. 2009;4:e7164. doi: 10.1371/journal.pone.0007164.
    1. European Medicines Agency. Eurartesim. 2011. . Accessed 6 Dec 2011.
    1. WHO. Antimalarial treatment policy. In: Guidelines for the treatment of malaria. 2nd ed. Geneva: World Health Organization; 2010. p. 8–9.
    1. WHO . Methods for surveillance of antimalarial drug efficacy. Geneva: World Health Organization; 2009.
    1. Sagara I, Fofana B, Gaudart J, Sidibe B, Togo A, Toure S, et al. Repeated artemisinin-based combination therapies in a malaria hyperendemic area of Mali: efficacy, safety, and public health impact. Am J Trop Med Hyg. 2012;87:50–56. doi: 10.4269/ajtmh.2012.11-0649.
    1. Stepniewska K, White NJ. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J. 2006;5:127. doi: 10.1186/1475-2875-5-127.
    1. WorldWide Antimalarial Resistance Network (WWARN). Methodology for the WWARN Parasite Clearance Estimator. 2012. . Accessed 20 May 2015.
    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. Piola P, Fogg C, Bajunirwe F, Biraro S, Grandesso F, Ruzagira E, et al. Supervised versus unsupervised intake of six-dose artemether–lumefantrine for treatment of acute, uncomplicated Plasmodium falciparum malaria in Mbarara, Uganda: a randomised trial. Lancet. 2005;365:1467–1473. doi: 10.1016/S0140-6736(05)66416-1.
    1. ICH Expert Working Group. ICH harmonised tripartite guideline: guideline for good clinical practice E6(R1). 1996. .
    1. ICH Expert Working Group. ICH Harmonised Tripartite Guideline. Structure and Content of Clinical Study Reports E3. 1995. .
    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. Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, et al. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–935. doi: 10.4269/ajtmh.13-0248.
    1. Siribié M, Diarra A, Tiono AB, Soulama I, Sirima SB. Efficacy of artemether–lumefantrine in the treatment of uncomplicated malaria in children living in a rural area of Burkina Faso in 2009. Bull Soc Pathol Exot. 2012;105:202–207. doi: 10.1007/s13149-012-0209-6.
    1. Checchi F, Piola P, Fogg C, Bajunirwe F, Biraro S, Grandesso F, et al. Supervised versus unsupervised antimalarial treatment with six-dose artemether–lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda. Malar J. 2006;5:59. doi: 10.1186/1475-2875-5-59.
    1. Katrak S, Gasasira A, Arinaitwe E, Kakuru A, Wanzira H, Bigira V, et al. Safety and tolerability of artemether–lumefantrine versus dihydroartemisinin–piperaquine for malaria in young HIV-infected and uninfected children. Malar J. 2009;8:272. doi: 10.1186/1475-2875-8-272.
    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. Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother. 2000;44:697–704. doi: 10.1128/AAC.44.3.697-704.2000.
    1. Orrell C, Little F, Smith P, Folb P, Taylor W, Olliaro P, et al. Pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers. Eur J Clin Pharmacol. 2008;64:683–690. doi: 10.1007/s00228-007-0452-8.
    1. Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NPJ, et al. Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin–piperaquine in patients with Plasmodium falciparum malaria in Thailand. Antimicrob Agents Chemother. 2008;52:1052–1061. doi: 10.1128/AAC.00955-07.
    1. Smithuis F, Kyaw MK, Phe O, Win T, Aung PP, Oo APP, et al. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infect Dis. 2010;10:673–681. doi: 10.1016/S1473-3099(10)70187-0.
    1. Dama S, Niangaly H, Ouattara A, Sagara I, Sissoko S, Traore OB, et al. Reduced ex vivo susceptibility of Plasmodium falciparum after oral artemether–lumefantrine treatment in Mali. Malar J. 2017;16:59. doi: 10.1186/s12936-017-1700-8.
    1. Karunakara U. Data sharing in a humanitarian organization: the experience of Médecins Sans Frontières. PLoS Med. 2013;10(12):e1001562. doi: 10.1371/journal.pmed.1001562.

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