Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda

Hasifa Bukirwa, Adoke Yeka, Moses R Kamya, Ambrose Talisuna, Kristin Banek, Nathan Bakyaita, John Bosco Rwakimari, Philip J Rosenthal, Fred Wabwire-Mangen, Grant Dorsey, Sarah G Staedke, Hasifa Bukirwa, Adoke Yeka, Moses R Kamya, Ambrose Talisuna, Kristin Banek, Nathan Bakyaita, John Bosco Rwakimari, Philip J Rosenthal, Fred Wabwire-Mangen, Grant Dorsey, Sarah G Staedke

Abstract

Objectives: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda.

Design: Randomized single-blind controlled trial.

Setting: Tororo, Uganda, an area of high-level malaria transmission.

Participants: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria.

Interventions: Amodiaquine + artesunate or artemether-lumefantrine.

Outcome measures: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections.

Results: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens.

Conclusions: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Trial Profile
Figure 1. Trial Profile
AQ + AS, amodiaquine + artesunate; AL, artemether–lumefantrine.
Figure 2. Day of Recurrent Malaria due…
Figure 2. Day of Recurrent Malaria due to New Infection Stratified by Treatment Group
Figure 3. Risk of Recurrent Parasitemia and…
Figure 3. Risk of Recurrent Parasitemia and Recurrent Malaria Stratified by Date of Enrollment
The peak in risks corresponds to the period following the rainy season. The p-values are for differences in risks across the different time periods for each regimen.

References

    1. White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, et al. Averting a malaria disaster. Lancet. 1999;353:1965–1967.
    1. Winstanley PA, Ward SA, Snow RW. Clinical status and implications of antimalarial drug resistance. Microbes Infect. 2002;4:157–164.
    1. Nosten F, van Vugt M, Price R, Luxemburger C, Thway K, et al. Effects of artesunate–mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: A prospective study. Lancet. 2000;356:297–302.
    1. Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, et al. Effects of artemisinin derivatives on malaria transmissibility. Lancet. 1996;347:1654–1658.
    1. Bloland PB, Kachur SP, Williams HA. Trends in antimalarial drug deployment in sub-Saharan Africa. J Exp Biol. 2003;206:3761–3769.
    1. Malenga G, Palmer A, Staedke S, Kazadi W, Mutabingwa T, et al. Antimalarial treatment with artemisinin combination therapy in Africa. BMJ. 2005;331:706–707.
    1. Kamya M, Bakyaita N, Talisuna A, Were W, Staedke SG. Increasing antimalarial drug resistance in Uganda and revision of the national drug policy. Trop Med Int Health. 2002;7:1031–1041.
    1. Bakyaita N, Dorsey G, Yeka A, Banek K, Staedke SG, et al. Sulfadoxine–pyrimethamine plus chloroquine or amodiaquine for uncomplicated falciparum malaria: A randomized, multisite trial to guide national policy in Uganda. Am J Trop Med Hyg. 2005;72:573–580.
    1. Staedke SG, Mpimbaza A, Kamya MR, Nzarubara BK, Dorsey G, et al. Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: Randomised clinical trial. Lancet. 2004;364:1950–1957.
    1. Yeka A, Banek K, Bakyaita N, Staedke SG, Kamya MR, et al. Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: Randomized clinical trials from four sites in Uganda. PLoS Med. 2005;2:e190. DOI: .
    1. Omari AA, Gamble C, Garner P. Artemether–lumefantrine for uncomplicated malaria: A systematic review. Trop Med Int Health. 2004;9:192–199.
    1. World Health Organization [WHO] Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: WHO; 2003. Available: . Accessed 17 April 2006.
    1. Cattamanchi A, Kyabayinze D, Hubbard A, Rosenthal PJ, Dorsey G. Distinguishing recrudescence from reinfection in a longitudinal antimalarial drug efficacy study: Comparison of results based on genotyping of msp-1, msp-2, and glurp. Am J Trop Med Hyg. 2003;68:133–139.
    1. Piola P, Fogg C, Bajunirwe F, Biraro S, Grandesso F, 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.
    1. Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, 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.
    1. Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, 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.
    1. 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;94:545–548.
    1. Lefevre G, Looareesuwan S, Treeprasertsuk S, Krudsood S, Silachamroon U, 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;64:247–256.
    1. Barnes KI, Durrheim DN, Little F, Jackson A, Mehta U, et al. Effect of artemether–lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa. PLoS Med. 2005;2:e330. DOI: .
    1. White NJ. Intermittent presumptive treatment for malaria. PLoS Med. 2005;2:e3. DOI: .
    1. Watkins WM, Mosobo M. Treatment of Plasmodium falciparum malaria with pyrimethamine–sulfadoxine: Selective pressure for resistance is a function of long elimination half-life. Trans R Soc Trop Med Hyg. 1993;87:75–78.
    1. Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, et al. In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether–lumefantrine (Coartem) J Infect Dis. 2005;191:1014–1017.
    1. Omari AA, Gamble C, Garner P. Artemether–lumefantrine (six-dose regimen) for treating uncomplicated falciparum malaria. Cochrane Database Syst Rev: CD005564; 2005.
    1. Ndayiragije A, Niyungeko D, Karenzo J, Niyungeko E, Barutwanayo M, 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.
    1. Sutherland CJ, Ord R, Dunyo S, Jawara M, Drakeley CJ, et al. Reduction of malaria transmission to anopheles mosquitoes with a six-dose regimen of co-artemether. PLoS Med. 2005;2:e92. DOI: .

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir