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Complex dynamics and stability of resistance to antimalarial drugs

Published online by Cambridge University Press:  23 January 2006

I. M. HASTINGS
I. M. HASTINGS
Affiliation:
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA
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Abstract

A succession of antimalarial drugs has been deployed to treat human falciparum malaria but each has, in turn, been nullified by the spread of drug resistance. The consensus view has always been that, once present, resistance will inevitably rapidly increase to 100%. However, recent field evidence has shown this is not inevitable, and that drug resistance may initially spread and then stabilize at relatively low frequencies. It is proposed that intense competition between separate malaria clones co-infecting the same human can generate complex dynamics capable of explaining this observation. Standard population genetic analysis confirms this assertion. The dynamics underlying the evolution of antimalarial resistance may therefore be much more complex than previously realized, and can resolve the apparent paradox between field data and the underlying theory of the evolution of resistance. This explanation is novel and the results are equally applicable to other parasitic species where multiple infections of the same host are common.

Keywords

Plasmodium falciparumdrug resistancedynamicscompetitionfitness
Type
Research Article
Information
Parasitology , Volume 132 , Issue 5 , May 2006 , pp. 615 - 624
Copyright
2006 Cambridge University Press

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References

REFERENCES

Anderson, R. M. and May, R. M. ( 1992). Infectious Diseases of Humans. Oxford University Press, Oxford.
Anderson, T. J. C., Haubold, B., Williams, J. T., Estrada-Franco, J. G., Richardson, L., Mollinedo, R., Bockarie, M., Mokili, J., Mharakurwa, S., French, N., Whitworth, J., Velez, I. D., Brockman, A. H., Nosten, F., Ferreira, M. U. and Day, K. P. ( 2000). Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Molecular Biology and Evolution 17, 1467–1482.CrossRefGoogle Scholar
Anderson, T. J. C. and Roper, C. ( 2005). The origins and spread of antimalarial drug resistance: lessons for policy makers. Acta Tropica 94, 269–280.CrossRefGoogle Scholar
Ariey, F., Duchemin, J.-B. and Robert, V. ( 2003). Metapopulation concepts applied to falciparum malaria and their impacts on the emergence and spread of chloroquine resistance. Infection, Genetics and Evolution 2, 185–192.CrossRefGoogle Scholar
Arnot, D. E. ( 1998). Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 580–585.CrossRefGoogle Scholar
Awadzi, K., Boakye, D. A., Edwards, G., Opoku, N. O., Attah, S. K., Osei-Atweneboana, M. Y., Lazdins-Helds, J. K., Ardrey, A. E., Addy, E. T., Quartey, B. T., Ahmed, K., Boatin, B. A. and Soumbey-Alley, E. W. ( 2004). An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Annals of Tropical Medicine and Parasitology 98, 231–249.CrossRefGoogle 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
Coleman, P. G., Morel, C., Shillcutt, S., Goodman, C. and Mills, A. J. ( 2004). A threshold analysis of the cost-effectiveness of artemisinin-based combination therapies in sub-Saharan Africa. American Journal of Tropical Medicine and Hygiene 71 (Suppl. 2), 196–204.Google Scholar
Coles, G. C., Bruce, J. I., Kinoti, G. K., Mutahi, W. T., Dias, L. C. S., Rocha, R. S. and Katz, N. ( 1987). The Potential for Drug resistance in Schistosomiasis. Parasitology Today 3, 349–350.CrossRefGoogle Scholar
Cortese, J. F., Caraballo, A., Contreras, C. E. and Plowe, C. V. ( 2002). Origin and dissemination of Plasmodium falciparum drug-resistance mutations in South America. Journal of Infectious Diseases 186, 999–1006.CrossRefGoogle Scholar
Crofton, H. D. ( 1971). A quantitative approach to parasitism. Parasitology 62, 179–193.CrossRefGoogle Scholar
Cross, A. P. and Singer, B. ( 1991). Modelling the development of resistance of Plasmodium falciparum to anti-malarial drugs. Transactions of the Royal Society of Tropical Medicine and Hygiene 85, 349–354.CrossRefGoogle Scholar
Curtis, C. F. and Otoo, L. N. ( 1986). A simple model of the build-up of resistance to mixtures of anti-malarial drugs. Transactions of the Royal Society of Tropical Medicine and Hygiene 80, 889–892.CrossRefGoogle Scholar
Dadzie, Y., Neira, M. and Hopkins, D. ( 2003). Final report of the conference on the eradicability of onchocerciasis. Filaria Journal 2, 2.CrossRefGoogle Scholar
de Rood, J. C., Culleton, R., Bell, A. S. and Read, A. F. ( 2004). Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections. Malaria Journal 3, 33.Google Scholar
Doenhoff, M. J., Kusel, J. R., Coles, G. C. and Cioli, D. ( 2002). Resistance of Schistosoma mansoni to praziquantel: is there a problem? Transactions of the Royal Society of Tropical Medicine and Hygiene 96, 465–469.Google Scholar
Dye, C. and Williams, B. G. ( 1997). Multigenic drug resistance among inbred malaria parasites. Proceedings of the Royal Society of London 264, 61–67.CrossRefGoogle Scholar
Hagan, P., Appleton, C. C., Coles, G. C., Kusel, J. R. and Tchuem-Tchuente, L. A. ( 2004). Schistosomiasis control: keep taking the tablets. Trends in Parasitology 20, 92–97.CrossRefGoogle Scholar
Hastings, I. M. ( 1997). A model for the origins and spread of drug resistant malaria. Parasitology 115, 133–141.CrossRefGoogle Scholar
Hastings, I. M. ( 2003). Malaria control and the evolution of drug resistance: an intriguing link. Trends in Parasitology 19, 70–73.CrossRefGoogle Scholar
Hastings, I. M. ( 2004 a). Epidemiological models for the spread of anti-malarial resistance; note appended to ‘Epidemiological models for the spread of anti-malarial resistance’ by Koella and Antia. Malaria Journal 2, 3.Google Scholar
Hastings, I. M. ( 2004 b). The origins of antimalarial drug resistance. Trends in Parasitology 20, 512–518.Google Scholar
Hastings, I. M. and D'Alessandro, U. ( 2000). Modelling a predictable disaster: The rise and spread of drug-resistant malaria. Parasitology Today 16, 340–347.CrossRefGoogle Scholar
Hastings, I. M. and Donnelly, M. J. ( 2005). The impact of antimalarial drug resistance mutations on parasite fitness, and its implications for the evolution of resistance. Drug Resistance Updates 8, 43–50.CrossRefGoogle Scholar
Hastings, I. M. and Watkins, W. M. ( 2005). Intensity of malaria transmission and the evolution of drug resistance. Acta Tropica 94, 218–229.CrossRefGoogle Scholar
Hastings, I. M., Watkins, W. M. and White, N. J. ( 2002). The evolution of drug resistant malaria; the role of drug elimination half-life. Philosophical Transactions of the Royal Society 357, 505–519.CrossRefGoogle Scholar
Koella, J. C. ( 1998). Costs and benefits of resistance against antimalarial drugs. Parasitology Today 14, 360–364.CrossRefGoogle Scholar
Koella, J. C. and Antia, R. ( 2003). Epidemiological models for the spread of anti-malarial resistance. Malaria Journal 2, 3.CrossRefGoogle Scholar
Kublin, J. G., Cortese, J. F., Njuniu, E. M., Mukadam, R. A. G., Wirima, J. J., Kazembe, P. N., Djimde, A. A., Kouriba, B., Taylor, T. E. and Plowe, C. V. ( 2003). Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. Journal of Infectious Diseases 187, 1870–1875.CrossRefGoogle Scholar
Laxminarayan, R. ( 2004). Act now or later? Economics of malaria resistance. American Journal of Tropical Medicine and Hygiene 71 (Suppl. 2), 187–195.Google Scholar
McKenzie, F. E. ( 2000). Why model malaria? Parasitology Today 16, 511–516.Google Scholar
McKenzie, F. E. and Samba, E. M. ( 2004). The role of mathematical modeling in evidence-based malaria control. American Journal of Tropical Medicine and Hygiene 71 (Suppl. 2), 94–96.Google Scholar
Mita, T., Kaneko, A., Lum, J. K., Bwijo, B., Takechi, N., Zungu, I. L., Tsukahara, T., Tanabe, K., Kobayakawa, T. and Bjorkman, A. ( 2003). Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi. American Journal of Tropical Medicine and Hygiene 68, 413–415.Google Scholar
Nair, S., Williams, J. T., Brockman, A., Paiphun, L., Mayxay, M., Newton, P. N., Guthman, J.-P., Smithuis, F. M., Hien, T. T., White, N. J., Nosten, F. and Anderson, T. J. C. ( 2003). A selective sweep driven by pyrimethamine treatment in SE Asian malaria parasites. Molecular Biology and Evolution 20, 1526–1536.CrossRefGoogle Scholar
Paul, R. E. L., Packer, M. J., Walmsley, M., Lagog, M., Ranford-Cartwright, L. C., Paru, R. and Day, K. P. ( 1995). Mating patterns in malarial parasite populations of Papua New Guinea. Science 269, 1709–1711.CrossRefGoogle Scholar
Pearce, R. J., Drakeley, C., Chandramohan, D., Mosha, F. and Roper, C. ( 2003). Molecular determination of point mutation haplotypes in the dihydrofolate reductase and dihydropteroate synthase of Plasmodium falciparum in three districts of northern Tanzania. Antimicrobial Agents and Chemotherapy 47, 1347–1354.CrossRefGoogle Scholar
Plowe, C. V., Kublin, J. G., Dzinjalamala, F. K., Kamwendo, D. S., Mukadam, R. A. G., Chimpeni, P., Molyneux, M. E. and Taylor, T. E. ( 2004 a). Sulfadoxine-pyrimethamine for uncomplicated falciparum malaria – Treatment failure and resistance in Malawi remain subject for debate – Reply. British Medical Journal 328, 1260.Google Scholar
Plowe, C. V., Kublin, P. G., Dzinjalamala, F. K., Kamwendo, D. S., Mukadam, R. A. G., Chimpeni, P., Molyneux, M. E. and Taylor, T. E. ( 2004 b). Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Malawi after 10 years as first line treatment: five year prospective study. British Medical Journal 328, 545–548.Google Scholar
Price, R. N., Uhlemann, A. C., Brockman, A., McGready, R., Ashley, E., Phaipun, L., Patel, R., Laing, K., Looareesuwan, S., White, N. J., Nosten, F. and Krishna, S. ( 2004). Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364, 438–447.CrossRefGoogle Scholar
Ranford-Cartwright, L. C., Balfe, P., Carter, R. and Walliker, D. ( 1991). Genetic hybrids of Plasmodium falciparum identified by amplification of genomic DNA from single oocysts. Molecular and Biochemical Parasitology 49, 239–244.CrossRefGoogle Scholar
Ringwald, P. ( 2004). Sulfadoxine-pyrimethamine for uncomplicated falciparum malaria – Treatment failure and resistance in Malawi remain subject for debate. British Medical Journal 328, 1259–1260.CrossRefGoogle Scholar
Roper, C., Pearce, R., Bredenkamp, B., Gumede, J., Drakeley, C., Mosha, F., Chandramohan, D. and Sharp, B. ( 2003). Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361, 1174–1181.CrossRefGoogle Scholar
Roper, C., Pearce, R., Nair, S., Sharp, B., Nosten, F. and Anderson, T. ( 2004). Intercontinental spread of pyrimethamine-resistant malaria. Science 305, 1124.CrossRefGoogle Scholar
Sama, W., Owusu-Agyei, S., Felger, I., Vounatsou, P. and Smith, T. ( 2005). An immigration-death model to estimate the duration of malaria infection when detectability of the parasite is imperfect. Statistics in Medicine 24, 3269–3288.CrossRefGoogle Scholar
Sirawaraporn, W., Sathitkul, T., Sirawaraporn, R., Yuthavong, Y. and Santi, D. V. ( 1997). Antifolate-resistant mutants of Plasmodium falciparum dihydrofolate reductase. Proc. Natl. Acad. Sci. USA. 94, 1124–1129.CrossRefGoogle Scholar
Smith, T., Charlwood, J. D., Takken, W., Tanner, M. and Spiegelhalter, D. J. ( 1995). Mapping the densities of malaria vectors within a single village. Acta Tropica 59, 1–18.CrossRefGoogle Scholar
Snow, R. W., Eckert, E. and Teklehaimanot, A. ( 2003). Estimating the needs for artesunate-based combination therapy for malaria case-management in Africa. Trends in Parasitology 19, 363–369.CrossRefGoogle Scholar
Talisuna, A. O., Langi, P., Mutabingwa, T. K., Van Marck, E., Speybroeck, N., Egwang, T. G., Watkins, W. W., Hastings, I. M. and D'Alessandro, U. ( 2003). Intensity of transmission and spread of gene mutations linked to chloroquine and sulphadoxine-pyrimethamine resistance in falciparum malaria. International Journal for Parasitology 33, 1051–1058.CrossRefGoogle Scholar
Taylor-Robinson, A. W. ( 1995). Regulation of immunity to malaria: valuable lessons learned from murine models. Parasitology Today 11, 334–342.CrossRefGoogle Scholar
Trape, J. F., Pison, G., Preziosi, M. P., Enel, C., duLou, A. D., Delaunay, V., Samb, B., Lagarde, E., Molez, J. F. and Simondon, F. ( 1998). Impact of chloroquine resistance on malaria mortality. Comptes Rendus De L Academie Des Sciences Serie Iii-Sciences De La Vie-Life Sciences 321, 689–697.CrossRefGoogle Scholar
Walliker, D., Hunt, P. and Babiker, H. ( 2005). Fitness of drug-resistant malaria parasites. Acta Tropica 94, 251–259.CrossRefGoogle Scholar
Watkins, W. M., Sibley, C. H. and Hastings, I. M. ( 2005). The search for effective and sustainable treatments for falciparum malaria in Africa: a model of the selection of resistance by antifolate drugs and their combinations. American Journal of Tropical Medicine and Hygiene 72, 163–173.Google Scholar
White, N. ( 2004). Sulfadoxine-pyrimethamine for uncomplicated falciparum malaria – Sulfadoxine-pyrimethamine is not working in Malawi. British Medical Journal 328, 1259.CrossRefGoogle Scholar
Wolstenholme, A. J., Fairweather, I., Prichard, R., Von Samson-Himmelstjerna, G. and Sangster, N. C. ( 2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 467–476.CrossRefGoogle Scholar
Wootton, J. C., Feng, X. R., Ferdig, M. T., Cooper, R. A., Mu, J. B., Baruch, D. I., Magill, A. J. and Su, X. Z. ( 2002). Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature, London 418, 320–323.CrossRefGoogle Scholar
WORLD HEALTH ORGANIZATION ( 2001). Antimalarial drug combination therapy. Report of a technical consultation. WHO, Geneva.
WORLD HEALTH ORGANIZATION ( 2000). Overcoming antimicrobial resistance. World Health Organization Report on Infectious Diseases 2000. WHO, Geneva.
Yeung, S., Pongtavornpinyo, W., Hastings, I. M., Mills, A. J. and White, N. J. ( 2004). Antimalarial drug resistance, artemisinin based combination therapy (ACT) and the contribution of modelling to elucidating policy choices. American Journal of Tropical Medicine and Hygiene 71 (Suppl. 2), 179–186.Google Scholar