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Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?

Published online by Cambridge University Press:  03 August 2011

COLIN J. SUTHERLAND ,
HAMZA BABIKER ,
MARGARET J. MACKINNON ,
LISA RANFORD-CARTWRIGHT  and
BADRIA BABIKER EL SAYED
COLIN J. SUTHERLAND*
Affiliation:
Department of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK
HAMZA BABIKER
Affiliation:
Biochemistry Department, Faculty of Medicine, Sultan Qaboos University, Oman School of Biological Sciences, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JZ, Edinburgh, Scotland, UK
MARGARET J. MACKINNON
Affiliation:
KEMRI-Wellcome Trust Research Programme, PO Box 230, Kilifi, Kenya and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, CCVTM, Oxford OX3 7LJ, UK
LISA RANFORD-CARTWRIGHT
Affiliation:
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary & Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA
BADRIA BABIKER EL SAYED
Affiliation:
Department of Epidemiology, Tropical Medicine Research Institute, National Centre for Research, Khartoum, Sudan
*
Corresponding author: Dr CJ Sutherland, Department of Immunology & Infection, Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel St, London, WC1E 7HT, UK. Tel: +44 (0)20 7927 2338; E-mail: [email protected]
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Summary

Artemisinin-based combination therapy is exerting novel selective pressure upon populations of Plasmodium falciparum across Africa. Levels of resistance to non-artemisinin partner drugs differ among parasite populations, and so the artemisinins are not uniformly protected from developing resistance, already present in South East Asia. Here, we consider strategies for prolonging the period of high level efficacy of combination therapy for two particular endemicities common in Africa. Under high intensity transmission, two alternating first-line combinations, ideally with antagonistic selective effects on the parasite genome, are advocated for paediatric malaria cases. This leaves second-line and other therapies for adult cases, and for intermittent preventive therapy. The drug portfolio would be selected to protect the ‘premier’ combination regimen from selection for resistance, while maximising impact on severe disease and mortality in children. In endemic areas subject to low, seasonal transmission of Plasmodium falciparum, such a strategy may deliver little benefit, as children represent a minority of cases. Nevertheless, the deployment of other drug-based interventions in low transmission and highly seasonal areas, such as mass drug administration aimed to interrupt malaria transmission, or intermittent preventive therapy, does provide an opportunity to diversify drug pressure. We thus propose an integrated approach to drug deployment, which minimises direct selective pressure on parasite populations from any one drug component. This approach is suitable for qualitatively and quantitatively different burdens of malaria, and should be supported by a programme of routine surveillance for emerging resistance.

Keywords

Malariadrug resistancerational therapeutics
Type
Research Article
Information
Parasitology , Volume 138 , Special Issue 12: Symposia of the British Society for Parasitology Volume 47 , October 2011 , pp. 1459 - 1468
Copyright
Copyright © Cambridge University Press 2011

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References

REFERENCES

Abdel-Muhsin, A. M., Mackinnon, M. J., Ali, E., Nassir, el-K. A., Suleiman, S., Ahmed, S., Walliker, D. and Babiker, H. A. (2004). Evolution of drug-resistance genes in Plasmodium falciparum in an area of seasonal malaria transmission in Eastern Sudan. Journal of Infectious Diseases 189, 1239–1244.Google Scholar
Adam, I., Osman, M. E., Elghzali, G., Ahmed, G. I., Gustafssons, L. L. and Elbashir, M. I. (2004). Efficacies of chloroquine, sulfadoxine-pyrimethamine and quinine in the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. Annals of Tropical Medicine and Parasitology 98, 661–666.CrossRefGoogle ScholarPubMed
Al-Saai, S., Kheir, A., Abdel-Muhsin, A. M., Al-Ghazali, A., Nwakanma, D., Swedberg, G. and Babiker, H. A. (2009). Distinct haplotypes of dhfr and dhps among Plasmodium falciparum isolates in an area of high level of sulfadoxine-pyrimethamine (SP) resistance in eastern Sudan. Infection, Genetics and Evolution 9, 778–783.CrossRefGoogle Scholar
Babiker, H. A., Pringle, S., Abdel-Muhsin, A., Mackinnon, M., Hunt, P. and Walliker, D. (2001). High level chloroquine resistance in Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene Pfcrt and the multi-drug resistance gene Pfmdr1. Journal of Infectious Diseases 183, 1535–1538.Google Scholar
Babiker, H. A., Satti, G., Ferguson, H., Bayoumi, R. and Walliker, D. (2005). Drug resistant Plasmodium falciparum in an area of seasonal transmission. Acta Tropica 94, 260–268.CrossRefGoogle Scholar
Bayoumi, R. A., Babiker, H. A., Ibrahim, S. M., Ghalib, H. W., Saeed, B. O., Khider, S., Elwasila, M. and Karim, E. A. (1989). Chloroquine-resistant Plasmodium falciparum in eastern Sudan. Acta Tropica 46, 157–165.CrossRefGoogle ScholarPubMed
Bayoumi, R. A., Creasey, A. M., Babiker, H. A., Carlton, J. M., Sultan, A. A., Satti, G., Sohal, A. K., Walliker, D., Jensen, J. B. and Arnot, D. E. (1993). Drug response and genetic characterization of Plasmodium falciparum clones recently isolated from a Sudanese village. Transactions of the Royal Society of Tropical Medicine and Hygiene 87, 454–458.Google Scholar
Beshir, K., Hallett, R. L., Eziefula, A. C., Bailey, R., Watson, J., Wright, S. G., Chiodini, P. L., Polley, S. D. and Sutherland, C. J. (2010 a). Measuring the efficacy of anti-malarial drugs in vivo: quantitative PCR measurement of parasite clearance. Malaria Journal 9, 312.CrossRefGoogle ScholarPubMed
Beshir, K., Sutherland, C. J., Merinopoulos, I., Durrani, N., Leslie, T., Rowland, M. and Hallett, R. L. (2010 b). Amodiaquine resistance in Plasmodium falciparum malaria in Afghanistan is associated with the pfcrt SVMNT allele at codons 72 to 76. Antimicrobial Agents and Chemotherapy 54, 3714–3716.Google Scholar
Bojang, K., Akor, F., Bittaye, O., Conway, D., Bottomley, C., Milligan, P. and Greenwood, B. M. (2010). A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children. PLoS One. 5, e11225.Google Scholar
Bouchaud, O., Imbert, P., Touze, J. E., Dodoo, A. N., Danis, M. and Legros, F. (2009). Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Malaria Journal 8, 289.Google Scholar
Bousema, J. T., Schneider, P., Gouagna, L. C., Drakeley, C. J., Tostmann, A., Houben, R., Githure, J. I., Ord, R., Sutherland, C. J., Omar, S. A. and Sauerwein, R. W. (2006). Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. Journal of Infectious Diseases 193, 1151–1159.Google Scholar
Carrara, V. I., Zwang, J., Ashley, E. A., Price, R. N., Stepniewska, K., Barends, M., Brockman, A., Anderson, T., McGready, R., Phaiphun, L., Proux, S., van Vugt, M., Hutagalung, R., Lwin, K. M., Phyo, A. P., Preechapornkul, P., Imwong, M., Pukrittayakamee, S., Singhasivanon, P., White, N. J. and Nosten, F. (2009). Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 4, e4551.CrossRefGoogle ScholarPubMed
Cisse, B., Cairns, M., Faye, E., NDiaye, O., Faye, B., Cames, C., Cheng, Y., NDiaye, M., Lô, A. C., Simondon., K., Trape, J. F., Faye, O., NDiaye, J. L., Gaye, O., Greenwood, B. and Milligan, P. (2009). Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. PLoS One 4, e7164.CrossRefGoogle ScholarPubMed
Diallo, D., Sutherland, C., Nebié, I., Konaté, A., Ord, R., Pota, H., Roper, C., Ilboudo-Sanogo, E., Greenwood, B. and Cousens, S. (2007). Children in Burkina Faso protected by insecticide treated materials are able to clear drug resistant parasites better than unprotected children. Journal of Infectious Diseases 196, 138–144.Google Scholar
Dokomajilar, C., Nsobya, S. L., Greenhouse, B., Rosenthal, P. J. and Dorsey, G. (2006). Selection of Plasmodium falciparum pfmdr1 alleles following therapy with artemether-lumefantrine in an area of Uganda where malaria is highly endemic. Antimicrobial Agents and Chemotheapy, 50, 1893–1895.CrossRefGoogle Scholar
Dondorp, A. M., Fanello, C. I., Hendriksen, I. C., Gomes, E., Seni, A., Chhaganlal, K. D., Bojang, K., Olaosebikan, R., Anunobi, N., Maitland, K., Kivaya, E., Agbenyega, T., Nguah, S. B., Evans, J., Gesase, S., Kahabuka, C., Mtove, G., Nadjm, B., Deen, J., Mwanga-Amumpaire, J., Nansumba, M., Karema, C., Umulisa, N., Uwimana, A., Mokuolu, O. A., Adedoyin, O. T., Johnson, W. B., Tshefu, A. K., Onyamboko, M. A., Sakulthaew, T., Ngum, W. P., Silamut, K., Stepniewska, K., Woodrow, C. J., Bethell, D., Wills, B., Oneko, M., Peto, T. E., von Seidlein, L., Day, NP. and White, N. J. (2010). AQUAMAT group. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376, 1647–1657.CrossRefGoogle ScholarPubMed
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P., Lindegardh, N., Socheat, D. and White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 361, 455–467.CrossRefGoogle ScholarPubMed
Dunyo, S., Milligan, P., Edwards, T., Sutherland, C., Targett, G. and Pinder, M. (2006). Gametocytaemia after drug treatment of asymptomatic Plasmodium falciparum. PLoS Clinical Trials 1, e20.CrossRefGoogle ScholarPubMed
Duraisingh, M. T., Drakeley, C. J., Muller, O., Bailey, R., Snounou, G., Targett, G. A. T., Greenwood, B. M., and Warhurst, D. C. (1997). Evidence for selection for the tyrosine-86 allele of the pfmdr 1 gene of Plasmodium falciparum by chloroquine and amodiaquine. Parasitology 114, 205–211.CrossRefGoogle ScholarPubMed
Duraisingh, M. T., Jones, P., Sambou, I., von Seidlein, L., Pinder, M., and Warhurst, D. C. (2000). The tyrosine-86 allele of pfmdr1 gene of the Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Molecular and Biochemical Parasitology 108, 13–23.Google Scholar
El-Sayed, B., El-Zaki, S. E., Babiker, H., Gadalla, N., Ageep, T., Mansour, F., Baraka, O., Milligan, P. and Babiker, A. (2007). A randomized open-label trial of artesunate-sulfadoxine-pyrimethamine with or without primaquine for elimination of sub-microscopic P. falciparum parasitaemia and gametocyte carriage in eastern Sudan. PLoS One 2, e1311.Google Scholar
Elamin, S. B., Awad, A. I., Eltayeb, I. B., Elmardi, K. A., Hassan, A. H., Mohamed, A. O., Malik, E. M. and Mohamad, T. A. (2010). Descriptive study on the efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Sudan. European Journal of Clinical Pharmacology 66, 231–237.CrossRefGoogle Scholar
Gadalla, N. B., Elzaki, S. E., Mukhtar, E., Warhurst, D. C., El-Sayed, B. and Sutherland, C. J. (2010). Dynamics of Pfcrt alleles CVMNK and CVIET in chloroquine-treated Sudanese patients infected with Plasmodium falciparum. Malaria Journal 9, 74.Google Scholar
Gosling, R. D., Drakeley, C. J., Mwita, A. and Chandramohan, D. (2008). Presumptive treatment of fever cases as malaria: help or hindrance for malaria control? Malaria Journal 7, 132.Google Scholar
Hallett, R. L., Dunyo, S., Ord, R., Jawara, M., Pinder, M., Randall, A., Alloueche, A., Walraven, G., Targett, G. A. T., Alexander, N. and Sutherland, C. J. (2006). Treatment of malaria in Gambian children with chloroquine plus sulphadoxine-pyrimethamine favours survival and transmission to mosquitoes of multi-drug-resistant Plasmodium falciparum. PLoS Clinical Trials 1, e15.CrossRefGoogle Scholar
Holmgren, G., Hamrin, J., Svard, J., Martensson, A., Gil, J. P. and Bjorkman, A. (2007). Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infection, Genetics and Evolution 7, 562–569.Google Scholar
Humphreys, G. S., Merinopoulos, I., Ahmed, J., Whitty, C. J., Mutabingwa, T. K., Sutherland, C. J. and Hallett, R. L. (2007). Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrobial Agents and Chemotherapy 51, 991–997.Google Scholar
Méndez, F., Herrera, S., Murrain, B., Gutiérrez, A., Moreno, L. A., Manzano, M., Muñoz, A. and Plowe, C. V. (2007). Selection of antifolate-resistant Plasmodium falciparum by sulfadoxine-pyrimethamine treatment and infectivity to Anopheles mosquitoes. American Journal of Tropical Medicine and Hygiene 77, 438–443.Google Scholar
Muangnoicharoen, S., Johnson, D. J., Looareesuwan, S., Krudsood, S., Ward, S. A. (2009). Role of known molecular markers of resistance in the antimalarial potency of piperaquine and dihydroartemisinin in vitro. Antimicrobial Agents and Chemotherapy 53, 1362–1366.CrossRefGoogle ScholarPubMed
Nassir, E., Abdel-Muhsin, A. M., Suliaman, S., Kenyon, F., Kheir, A., Geha, H., Ferguson, H. M., Walliker, D. and Babiker, H. A. (2005). Impact of genetic complexity on longevity and gametocytogenesis of Plasmodium falciparum during the dry and transmission-free season of eastern Sudan. International Journal for Parasitology 35, 49–55.Google Scholar
Noedl, H., Se, Y., Schaecher, K., Smith, B. L., Socheat, D., Fukuda, M. M. and Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. New England Journal of Medicine 359, 2619–2620.CrossRefGoogle ScholarPubMed
Ord, R., Alexander, N., Dunyo, S., Hallett, R. L., Jawara, M., Targett, G. A. T., Drakeley, C. J. and Sutherland, C. J. (2007). Seasonal carriage of pfcrt and pfmdr1 alleles in Gambian Plasmodium falciparum implies reduced fitness of chloroquine-resistant parasites. Journal of Infectious Diseases 196, 1613–1619.Google Scholar
Polley, S. D., Chokejindachai, W. and Conway, D. J. (2003). Allele frequency-based analyses robustly map sequence sites under balancing selection in a malaria vaccine candidate antigen. Genetics 165, 555–561.CrossRefGoogle Scholar
Reyburn, H., Mbatia, R., Drakeley, C., Carneiro, I., Mwakasungula, E., Mwerinde, O., Saganda, K., Shao, J., Kitua, A., Olomi, R., Greenwood, B. M. and Whitty, C. J. (2004). Overdiagnosis of malaria in patients with severe febrile illness in Tanzania: A prospective study. British Medical Journal 329, 1212.CrossRefGoogle ScholarPubMed
Sa, J. M. and Twu, O. (2010). Protecting the malaria drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type. Malaria Journal 9, 374.CrossRefGoogle ScholarPubMed
Sá, J. M., Twu, O., Hayton, K., Reyes, S., Fay, M. P., Ringwald, P. and Wellems, T. E. (2009). Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proceedings of the National Academy of Sciences, USA. 106, 18883–18889.CrossRefGoogle ScholarPubMed
Shekalaghe, S. A., ter Braak, R., Daou, M., Kavishe, R., van den Bijllaardt, W., van den Bosch, S., Koenderink, J. B., Luty, A. J., Whitty, C. J., Drakeley, C., Sauerwein, R. W. and Bousema, T. (2010). In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals. Antimicrobial Agents and Chemotherapy 54, 1762–1768.CrossRefGoogle Scholar
Sirima, S. B., Tiono, A. B., Gansané, A., Diarra, A., Ouédraogo, A., Konaté, A. T., Kiechel, J. R., Morgan, C. C., Olliaro, P. L. and Taylor, W. R. (2009). The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum. Malaria Journal 8, 48.Google Scholar
Sisowath, C., Ferreira, P. E., Bustamante, L. Y., Dahlstrom, S., Martensson, A., Bjorkman, A., Krishna, S. and Gil, J. P. (2007). The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Tropical Medicine and International Health 12, 736–742.Google Scholar
Sisowath, C., Petersen, I., Veiga, M. I., Martensson, A., Premji, Z., Bjorkman, A., Fidock, D. A. and Gil, J. P. (2009). In vivo selection of Plasmodium falciparum parasites carrying the chloroquine susceptible Pfcrt K76 allele after treatment with artemether-lumefantrine in Africa. Journal of Infectious Diseases 199, 750–757.Google Scholar
Smithuis, F., Kyaw, M. K., Phe, O., Win, T., Aung, P. P., Oo, A. P., Naing, A. L., Nyo, M. Y., Myint, N. Z., Imwong, M., Ashley, E., Lee, S. J. and White, N. J. (2010). Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Lancet Infectious Diseases 10, 673–681.Google Scholar
Sutherland, C. J., Drakeley, C. J. and Schellenberg, D. (2007). How is childhood development of immunity to Plasmodium falciparum enhanced by certain antimalarial interventions? Malaria Journal 6, 161.Google Scholar
Sutherland, C. J., Ord, R., Dunyo, S., Jawara, M., Drakeley, C. J., Alexander, N., Coleman, R., Pinder, M., Walraven, G. and Targett, G. A. T. (2005). Reduction of malaria transmission to Anopheles mosquitoes with a six-dose regimen of co-artemether. PLoS Medicine 2, e92.Google Scholar
Sutherland, C. J. and Polley, S. D. (2011). Genomic insights into the past, current and future evolution of human parasites of the genus Plasmodium. In Genetics and Evolution of Infectious Diseases (Ed. Tibayrenc, M.). Elsevier, London, 2011. ISBN: 978-0-12-384890-1.Google Scholar
Ursing, J., Kofoed, P. E., Rodrigues, A., Rombo, L. and Gil, J. P. (2007). Plasmodium falciparum genotypes associated with chloroquine and amodiaquine resistance in Guinea-Bissau. American Journal of Tropical Medicine and Hygiene. 76, 844–848.Google Scholar
Ursing, J., Kofoed, P. E., Rodrigues, A., Blessborn, D., Thoft-Nielsen, R., Björkman, A. and Rombo, L. (2011). Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau: a randomized trial. Journal of Infectious Diseases 203, 109–116.CrossRefGoogle ScholarPubMed
von Seidlein., L., Walraven, G., Milligan, P. J., Alexander, N., Manneh, F., Deen, J. L., Coleman, R., Jawara, M., Lindsay, S. W., Drakeley, C., De Martin, S., Olliaro, P., Bennett, S., Schim van der Loeff, M., Okunoye, K., Targett, G. A., McAdam, K. P., Doherty, J. F., Greenwood, B. M. and Pinder, M. (2003). The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia. Transactions of the Royal Society for Tropical Medicine and Hygiene. 97, 217–225.CrossRefGoogle ScholarPubMed
Weedall, G. D., Preston, B. M. J., Thomas, A. W., Sutherland, C. J. and Conway, D. J. (2007). Differential evidence of natural selection on two leading sporozoite stage malaria vaccine candidate antigens. International Journal for Parasitology 37, 77–85.Google Scholar
Wong, R. P., Karunajeewa, H., Mueller, I., Siba, P., Zimmerman, P. A. and Davis, T. M. (2011). Molecular assessment of Plasmodium falciparum resistance to antimalarial drugs in Papua New Guinea using an extended ligase detection reaction fluorescent microsphere assay. Antimicrobial Agents and Chemotherapy 55, 798–805.CrossRefGoogle ScholarPubMed
Zwang, J., Olliaro, P., Barennes, H., Bonnet, M., Brasseur, P., Bukirwa, H., Cohuet, S., D'Alessandro, U., Djimdé, A., Karema, C., Guthmann, J. P., Hamour, S., Ndiaye, J. L., Mårtensson, A., Rwagacondo, C., Sagara, I., Same-Ekobo, A., Sirima, S. B., van den Broek, I., Yeka, A., Taylor, W. R., Dorsey, G. and Randrianarivelojosia, M. (2009). Efficacy of artesunate-amodiaquine for treating uncomplicated falciparum malaria in sub-Saharan Africa: a multi-centre analysis. Malaria Journal 8, 203.CrossRefGoogle ScholarPubMed