Prospective evaluation of artemether-lumefantrine for the treatment of non-falciparum and mixed-species malaria in Gabon

Ghyslain Mombo-Ngoma, Christian Kleine, Arti Basra, Heike Würbel, Daisy A Diop, Mesküre Capan, Ayola A Adegnika, Florian Kurth, Benjamin Mordmüller, Fanny Joanny, Peter G Kremsner, Michael Ramharter, Sabine Bélard, Ghyslain Mombo-Ngoma, Christian Kleine, Arti Basra, Heike Würbel, Daisy A Diop, Mesküre Capan, Ayola A Adegnika, Florian Kurth, Benjamin Mordmüller, Fanny Joanny, Peter G Kremsner, Michael Ramharter, Sabine Bélard

Abstract

Background: The recommendation of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated falciparum malaria is supported by a plethora of high quality clinical trials. However, their recommendation for the treatment of mixed-species malaria and the large-scale use for the treatment of non-falciparum malaria in endemic regions is based on anecdotal rather than systematic clinical evidence.

Methods: This study prospectively observed the efficacy of artemether-lumefantrine for the treatment of uncomplicated non-falciparum or mixed-species malaria in two routine district hospitals in the Central African country of Gabon.

Results: Forty patients suffering from uncomplicated Plasmodium malariae, Plasmodium ovale or mixed-species malaria (including Plasmodium falciparum) presenting at the hospital received artemether-lumefantrine treatment and were followed up. All evaluable patients (n=38) showed an adequate clinical and parasitological response on Day 28 after oral treatment with artemether-lumefantrine (95% confidence interval: 0.91,1). All adverse events were of mild to moderate intensity and completely resolved by the end of study.

Conclusions: This first systematic assessment of artemether-lumefantrine treatment for P. malariae, P. ovale and mixed-species malaria demonstrated a high cure rate of 100% and a favourable tolerability profile, and thus lends support to the practice of treating non-falciparum or mixed-species malaria, or all cases of malaria without definite species differentiation, with artemether-lumefantrine in Gabon.

Trial registration: ClinicalTrials.gov Identifier: NCT00725777.

References

    1. Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev. 2009. p. CD007483.
    1. Kurth F, Belard S, Adegnika AA, Gaye O, Kremsner PG, Ramharter M. Do paediatric drug formulations of artemisinin combination therapies improve the treatment of children with malaria? A systematic review and meta-analysis. Lancet Infect Dis. 2010;10:125–132. doi: 10.1016/S1473-3099(09)70327-5.
    1. WHO. Guidelines for the treatment of malaria. Second. World Health Organization, Geneva; 2010.
    1. Pubmed. Accessed on September 29th 2011. For 2001–2011.
    1. Borrmann S, Szlezak N, Binder RK, Missinou MA, Lell B, Kremsner PG. Evidence for the efficacy of artesunate in asymptomatic Plasmodium malariae infections. J Antimicrob Chemother. 2002;50:751–754. doi: 10.1093/jac/dkf200.
    1. May J, Mockenhaupt FP, Ademowo OG, Falusi AG, Olumese PE, Bienzle U, Meyer CG. High rate of mixed and subpatent malarial infections in southwest Nigeria. AmJTrop Med Hyg. 1999;61:339–343.
    1. Walker-Abbey A, Djokam RR, Eno A, Leke RF, Titanji VP, Fogako J, Sama G, Thuita LH, Beardslee E, Snounou G, Zhou A, Taylor DW. Malaria in pregnant Cameroonian women: the effect of age and gravidity on submicroscopic and mixed-species infections and multiple parasite genotypes. AmJTrop Med Hyg. 2005;72:229–235.
    1. WHO. Access Date June 18th 2011.
    1. Ramharter M, Adegnika AA, Agnandji ST, Matsiegui PB, Grobusch MP, Winkler S, Graninger W, Krishna S, Yazdanbakhsh M, Mordmuller B, Lell B, Missinou MA, Mavoungou E, Issifou S, Kremsner PG. History and perspectives of medical research at the Albert Schweitzer Hospital in Lambarene, Gabon. Wien Klin Wochenschr. 2007;119(19–20 Suppl 3):8–12.
    1. Sylla EH, Kun JF, Kremsner PG. Mosquito distribution and entomological inoculation rates in three malaria-endemic areas in Gabon. Trans R Soc Trop Med Hyg. 2000;94:652–656. doi: 10.1016/S0035-9203(00)90219-0.
    1. Kurth F, Belard S, Mombo-Ngoma G, Schuster K, Adegnika AA, Bouyou-Akotet MK, Kremsner PG, Ramharter M. Adolescence as risk factor for adverse pregnancy outcome in Central Africa–a cross-sectional study. PLoS One. 2010;5:e14367. doi: 10.1371/journal.pone.0014367.
    1. Ramharter M, Schuster K, Bouyou-Akotet MK, Adegnika AA, Schmits K, Mombo-Ngoma G, Agnandji ST, Nemeth J, Afene SN, Issifou S, Onnas IN, Kombila M, Kremsner PG. Malaria in pregnancy before and after the implementation of a national IPTp program in Gabon. AmJTrop Med Hyg. 2007;77:418–422.
    1. Adegnika AA, Ramharter M, Agnandji ST, Ateba Ngoa U, Issifou S, Yazdanbahksh M, Kremsner PG. Epidemiology of parasitic co-infections during pregnancy in Lambarene, Gabon. Trop Med Int Health. 2010;15:1204–1209. doi: 10.1111/j.1365-3156.2010.02598.x.
    1. Ramharter M, Noedl H, Winkler H, Graninger W, Wernsdorfer WH, Kremsner PG, Winkler S. In vitro activity and interaction of clindamycin combined with dihydroartemisinin against Plasmodium falciparum. Antimicrob Agents Chemother. 2003;47:3494–3499. doi: 10.1128/AAC.47.11.3494-3499.2003.
    1. Binder RK, Borrmann S, Adegnika AA, Missinou MA, Kremsner PG, Kun JF. Polymorphisms in the parasite genes for pfcrt and pfmdr-1 as molecular markers for chloroquine resistance in Plasmodium falciparum in Lambarene, Gabon. Parasitol Res. 2002;88:475–476. doi: 10.1007/s00436-001-0546-7.
    1. Mombo-Ngoma G, Oyakhirome S, Ord R, Gabor JJ, Greutelaers KC, Profanter K, Greutelaers B, Kurth F, Lell B, Kun JF, Issifou S, Roper C, Kremsner PG, Grobusch MP. High prevalence of dhfr triple mutant and correlation with high rates of sulphadoxine-pyrimethamine treatment failures in vivo in Gabonese children. Malar J. 2011;10:123. doi: 10.1186/1475-2875-10-123.
    1. Ramharter M, Kurth FM, Belard S, Bouyou-Akotet MK, Mamfoumbi MM, Agnandji ST, Missinou MA, Adegnika AA, Issifou S, Cambon N, Heidecker JL, Kombila M, Kremsner PG. Pharmacokinetics of two paediatric artesunate mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon. J Antimicrob Chemother. 2007;60:1091–1096. doi: 10.1093/jac/dkm355.
    1. Calderaro A, Piccolo G, Perandin F, Gorrini C, Peruzzi S, Zuelli C, Ricci L, Manca N, Dettori G, Chezzi C, Snounou G. Genetic polymorphisms influence Plasmodium ovale PCR detection accuracy. J Clin Microbiol. 2007;45:1624–1627. doi: 10.1128/JCM.02316-06.
    1. Oyedeji SI, Awobode HO, Monday GC, Kendjo E, Kremsner PG, Kun JF. Comparison of PCR-based detection of Plasmodium falciparum infections based on single and multicopy genes. Malar J. 2007;6:112. doi: 10.1186/1475-2875-6-112.
    1. Singh B, Bobogare A, Cox-Singh J, Snounou G, Abdullah MS, Rahman HA. A genus- and species-specific nested polymerase chain reaction malaria detection assay for epidemiologic studies. AmJTrop Med Hyg. 1999;60:687–692.
    1. Snounou G, Viriyakosol S, Zhu XP, Jarra W, Pinheiro L, Do Rosario VE, Thaithong S, Brown KN. High sensitivity of detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol. 1993;61:315–320. doi: 10.1016/0166-6851(93)90077-B.
    1. Liu W, Li Y, Learn GH, Rudicell RS, Robertson JD, Keele BF, Ndjango JB, Sanz CM, Morgan DB, Locatelli S, Gonder MK, Kranzusch PJ, Walsh PD, Delaporte E, Mpoudi-Ngole E, Georgiev AV, Muller MN, Shaw GM, Peeters M, Sharp PM, Rayner JC, Hahn BH. Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature. 2010;467:420–425. doi: 10.1038/nature09442.
    1. Siswantoro H, Russell B, Ratcliff A, Prasetyorini B, Chalfein F, Marfurt J, Kenangalem E, Wuwung M, Piera KA, Ebsworth EP, Anstey NM, Tjitra E, Price RN. In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia. Antimicrob Agents Chemother. 2010;55:197–202.
    1. Bassat Q. The use of artemether-lumefantrine for the treatment of uncomplicated Plasmodium vivax malaria. PLoS Negl Trop Dis. 2011;5:e1325. doi: 10.1371/journal.pntd.0001325.
    1. Douglas NM, Anstey NM, Angus BJ, Nosten F, Price RN. Artemisinin combination therapy for vivax malaria. Lancet Infect Dis. 2010;10:405–416. doi: 10.1016/S1473-3099(10)70079-7.
    1. Gatti S, Gramegna M, Bisoffi Z, Raglio A, Gulletta M, Klersy C, Bruno A, Maserati R, Madama S, Scaglia M. A comparison of three diagnostic techniques for malaria: a rapid diagnostic test (NOW Malaria), PCR and microscopy. Ann Trop Med Parasitol. 2007;101:195–204. doi: 10.1179/136485907X156997.
    1. Kreidenweiss A, Kremsner PG, Dietz K, Mordmuller B. In vitro activity of ferroquine (SAR97193) is independent of chloroquine resistance in Plasmodium falciparum. AmJTrop Med Hyg. 2006;75:1178–1181.
    1. Smith A, Denholm J, Shortt J, Spelman D. Plasmodium species co-infection as a cause of treatment failure. Travel Med Infect Dis. 2011;9:306–309. doi: 10.1016/j.tmaid.2011.09.006.
    1. Franken G, Muller-Stover I, Holtfreter MC, Walter S, Mehlhorn H, Labisch A, Haussinger D, Richter J. Why doPlasmodium malariaeinfections sometimes occur in spite of previous antimalarial medication? Parasitol Res. 2012. Feb 18 Epub ahead of print.
    1. Poravuth Y, Socheat D, Rueangweerayut R, Uthaisin C, Pyae Phyo A, Valecha N, Rao BH, Tjitra E, Purnama A, Borghini-Fuhrer I, Duparc S, Shin CS, Fleckenstein L. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One. 2011;6:e14501. doi: 10.1371/journal.pone.0014501.

Source: PubMed

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