Bell, David J., Nyirongo, Suzgo K., Mukaka, Mavuto, Zijlstra, Ed E., Plowe, Christopher V., Molyneux, Malcolm E., Ward, Steve A. and Winstanley, Peter. (2008) Sulfadoxine-pyrimethamine–based combinations for malaria : a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi. PLoS ONE, Vol.3 (No.2). e1578. ISSN 1932-6203

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Abstract

Background: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ) since sulfadoxinepyrimethamine (SP) replaced CQ as first line treatment for uncomplicated malaria. When used for prophylaxis, Amodiaquine (AQ) was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa. Here we compare the efficacy, safety and selection of resistance using SP or CQ+SP or artesunate (ART)+SP or AQ+SP for the treatment of uncomplicated falciparum malaria. Methodology and Findings: 455 children aged 1–5 years were recruited into a double-blinded randomised trial comparing SP to the three combination therapies. Using intention to treat analysis with missing outcomes treated as successes, and without adjustment to distinguish recrudescence from new infections, the day 28 adequate clinical and parasitological response (ACPR) rate for SP was 25%, inferior to each of the three combination therapies (p,0.001). AQ+SP had an ACPR rate of 97%, higher than CQ+SP (81%) and ART+SP (70%), p,0.001. Nineteen children developed a neutropenia of #0.56103 cells/ml by day 14, more commonly after AQ+SP (p = 0.03). The mutation pfcrt 76T, associated with CQ resistance, was detected in none of the pre-treatment or post-treatment parasites. The prevalence of the pfmdr1 86Y mutation was higher after treatment with AQ+SP than after SP, p = 0.002. Conclusions: The combination AQ+SP was highly efficacious, despite the low efficacy of SP alone; however, we found evidence that AQ may exert selective pressure for resistance associated mutations many weeks after treatment. This study confirms the return of CQ sensitivity in Malawi and importantly, shows no evidence of the re-emergence of pfcrt 76T after treatment with CQ or AQ. Given the safety record of AQ when used as a prophylaxis, our observations of marked falls in neutrophil counts in the AQ+SP group requires further scrutiny.

Item Type:	Journal Article
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Plasmodium falciparum -- Treatment -- Malawi, Antimalarials
Journal or Publication Title:	PLoS ONE
Publisher:	Public Library of Science
ISSN:	1932-6203
Date:	13 February 2008
Volume:	Vol.3
Number:	No.2
Page Range:	e1578
Identification Number:	10.1371/journal.pone.0001578
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Wellcome Trust (London, England)
Grant number:	066681 (WT)
References:	1. Plowe CV, Kublin JG, Dzinjalamala FK, Kamwendo DS, Mukadam RA, et al. (2004) Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. BMJ 328: 545. 2. Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, et al. (2006) Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 355: 1959–1966. 3. World Health Organisation (2006) Guidelines for the treatment of malaria. . 4. Olumese P (2007) Antimalarial treatment policies for P.falciparum and P.vivax by country in WHO Africa region. http://www.who.int/malaria/amdp/amdp_ afro.htm. 5. Obonyo CO, Juma EA, Ogutu BR, Vulule JM, Lau J (2007) Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a metaanalysis. Trans R Soc Trop Med Hyg 101: 117–126. 6. Brasseur P, Guiguemde R, Diallo S, Guiyedi V, Kombila M, et al. (1999) Amodiaquine remains effective for treating uncomplicated malaria in west and central Africa. Trans R Soc Trop Med Hyg 93: 645–650. 7. Gasasira AF, Dorsey G, Nzarubara B, Staedke SG, Nassali A, et al. (2003) Comparative efficacy of aminoquinoline-antifolate combinations for the treatment of uncomplicated falciparum malaria in Kampala, Uganda. Am J Trop Med Hyg 68: 127–132. 8. Hatton CS, Peto TE, Bunch C, Pasvol G, Russell SJ, et al. (1986) Frequency of severe neutropenia associated with amodiaquine prophylaxis against malaria. Lancet 1: 411–414. 9. Neftel KA, Woodtly W, Schmid M, Frick PG, Fehr J (1986) Amodiaquine induced agranulocytosis and liver damage. Br Med J (Clin Res Ed) 292: 721–723. 10. Olliaro P, Mussano P (2003) Amodiaquine for treating malaria. Cochrane Database Syst Rev CD000016. 11. Djimde AA, Dolo A, Ouattara A, Diakite S, Plowe CV, et al. (2004) Molecular diagnosis of resistance to antimalarial drugs during epidemics and in war zones. J Infect Dis 190: 853–855. 12. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, et al. (2003) Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 187: 1870–1875. 13. Plowe CV, Cortese JF, Djimde A, Nwanyanwu OC, Watkins WM, et al. (1997) Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and resistance. J Infect Dis 176: 1590–1596. 14. World Health Organisation (2003) Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. http:// www.who.int/malaria/docs/ProtocolWHO.pdf. 15. Cattamanchi A, Kyabayinze D, Hubbard A, Rosenthal PJ, Dorsey G (2003) 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 68: 133–139. 16. Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, et al. (2002) Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis 185: 380–388. 17. Abuya TO, Mutemi W, Karisa B, Ochola SA, Fegan G, et al. (2007) Use of over-the-counter malaria medicines in children and adults in three districts in Kenya: implications for private medicine retailer interventions. Malar J 6: 57. 18. Hawley SR, Bray PG, Park BK, Ward SA (1996) Amodiaquine accumulation in Plasmodium falciparum as a possible explanation for its superior antimalarial activity over chloroquine. Mol Biochem Parasitol 80: 15–25. 19. Dorsey G, Njama D, Kamya MR, Cattamanchi A, Kyabayinze D, et al. (2002) Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 360: 2031–2038. 20. Rwagacondo CE, Niyitegeka F, Sarushi J, Karema C, Mugisha V, et al. (2003) Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate. Am J Trop Med Hyg 68: 743–747. 21. Watkins WM, Mosobo M (1993) 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 87: 75–78. 22. Happi CT, Gbotosho GO, Folarin OA, Bolaji OM, Sowunmi A, et al. (2006) Association between mutations in Plasmodium falciparum chloroquine resistance transporter and P. falciparum multidrug resistance 1 genes and in vivo amodiaquine resistance in P. falciparum malaria-infected children in Nigeria. Am J Trop Med Hyg 75: 155–161. 23. Humphreys GS, Merinopoulos I, Ahmed J, Whitty CJ, Mutabingwa TK, et al. (2007) Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrob Agents Chemother 51: 991–997. 24. Nsobya SL, Dokomajilar C, Joloba M, Dorsey G, Rosenthal PJ (2007) Resistance-Mediating Plasmodium falciparum pfcrt and pfmdr1 Alleles after Treatment with Artesunate-Amodiaquine in Uganda. Antimicrob Agents Chemother 51: 3023–3025. 25. Zongo I, Dorsey G, Rouamba N, Tinto H, Dokomajilar C, et al. (2007) Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised noninferiority trial. Lancet 369: 491–498. 26. Dokomajilar C, Nsobya SL, Greenhouse B, Rosenthal PJ, Dorsey G (2006) Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrob Agents Chemother 50: 1893–1895. 27. Sisowath C, Stromberg J, Martensson A, Msellem M, Obondo C, et al. (2005) In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). J Infect Dis 191: 1014–1017. 28. Duraisingh MT, Roper C, Walliker D, Warhurst DC (2000) Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Mol Microbiol 36: 955–961. 29. Alker AP, Mwapasa V, Purfield A, Rogerson SJ, Molyneux ME, et al. (2005) Mutations associated with sulfadoxine-pyrimethamine and chlorproguanil resistance in Plasmodium falciparum isolates from Blantyre, Malawi. Antimicrob Agents Chemother 49: 3919–3921. 30. Phillips-Howard PA, West LJ (1990) Serious adverse drug reactions to pyrimethamine-sulphadoxine, pyrimethamine-dapsone and to amodiaquine in Britain. J R Soc Med 83: 82–85. 31. Douer D, Schwartz E, Shaked N, Ramot B (1985) Amodiaquine-induced agranulocytosis: drug inhibition of myeloid colonies in the presence of patient’s serum. Isr J Med Sci 21: 331–334. 32. Carr R (1986) Neutropenia and prophylactic amodiaquine. Lancet 1: 556. 33. Rhodes EG, Ball J, Franklin IM (1986) Amodiaquine induced agranulocytosis: inhibition of colony growth in bone marrow by antimalarial agents. Br Med J (Clin Res Ed) 292: 717–718. 34. Ellis ME, Steed AJ, Addison GM (1987) Neutropenia associated with dual antimalarial chemoprophylaxis--use of bone-marrow culture as an aid in further drug management. J Infect 15: 147–152.
URI:	http://wrap.warwick.ac.uk/id/eprint/36678

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