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Rational deployment of antimalarial drugs in Africa: should first-line combination drugs be reserved for paediatric malaria cases?
- COLIN J. SUTHERLAND, HAMZA BABIKER, MARGARET J. MACKINNON, LISA RANFORD-CARTWRIGHT, BADRIA BABIKER EL SAYED
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- Journal:
- Parasitology / Volume 138 / Issue 12 / October 2011
- Published online by Cambridge University Press:
- 03 August 2011, pp. 1459-1468
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- Article
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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.
11 - The Evolution of Pathogen Virulence in Response to Animal and Public Health Interventions
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- By Andrew F. Read, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK, Sylvain Gandon, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK, Sean Nee, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK, Margaret J. Mackinnon, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, UK
- Edited by Krishna R. Dronamraju, Foundation for Genetic Research, Houston, Texas
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- Book:
- Infectious Disease and Host-Pathogen Evolution
- Published online:
- 10 August 2009
- Print publication:
- 05 April 2004, pp 265-292
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Summary
INTRODUCTION
Pathogen evolution poses the critical challenge for infectious disease management in the twenty-first century. As is already painfully obvious in many parts of the world, the spread of drug-resistant and vaccine-escape (epitope) mutants can impair and even debilitate public and animal health programs. But there may also be another way in which pathogen evolution can erode the effectiveness of medical and veterinary interventions. Virulence- and transmission-related traits are intimately linked to pathogen fitness and are almost always genetically variable in pathogen populations. They can therefore evolve. Moreover, virulence and infectiousness are the target of medical and veterinary interventions. Here, we focus on vaccination and ask whether large-scale immunization programs might impose selection that results in the evolution of more-virulent pathogens.
The word virulence is used in a variety of ways in different disciplines. We take a parasite-centric view as follows. We use “disease severity” (morbidity and/or mortality) to mean the harm to the host following infection. Disease severity is thus a phenotype measured at the whole-organism (host) level that is determined by host genes, parasite genes, environmental effects, and the interaction between those factors. One component of this is virulence, a phenotypic trait of the pathogen whose expression depends on the host. Thus, virulence is the component of disease severity that is due to pathogen genes, and it can be measured only on a given host. We assume no specificity in the interaction between host and pathogen (more-virulent strains are always more virulent, whatever host they infect).
12 - Kin-selection Models as Evolutionary Explanations of Malaria
- Edited by Ulf Dieckmann, International Institute for Applied Systems Analysis, Austria, Johan A. J. Metz, Universiteit Leiden, Maurice W. Sabelis, Universiteit van Amsterdam, Karl Sigmund, Universität Wien, Austria
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- Book:
- Adaptive Dynamics of Infectious Diseases
- Published online:
- 15 January 2010
- Print publication:
- 11 April 2002, pp 165-178
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Summary
Introduction
Malaria, a disease caused by protozoan parasites of the genus Plasmodium, can substantially reduce host fitness in wild animals (Atkinson and Van Riper 1991; Schall 1996). In humans, the major disease syndromes – severe anemia, coma, and organ failure, as well as general pathology such as respiratory distress, aches, and nausea – cause considerable mortality and morbidity (Marsh and Snow 1997).
Biomedical research attributes malaria to red cell destruction, infected cell sequestration in vital organs, and the parasite-induced release of cytokines (Marsh and Snow 1997). But mechanistic explanations are just one type of explanation for any biological phenomenon, and, in recent years, evolutionary biologists have become interested in offering evolutionary explanations of infectious disease virulence. This is entirely appropriate (Read 1994). In the context of malaria, for example, the clinical outcome of infection has an important impact on parasite and host fitness and is – at least in part – determined by heritable variation in host and parasite factors (Greenwood et al. 1991). Yet in the recent rush to provide evolutionary explanations of disease, there has been, in our view, too little interaction between the models built by evolutionary biologists and reality. There is unlikely to be a simple, general model of virulence: the causes of disease and the fitness consequences for host and parasite are too variable. Instead, different models, and even different frameworks, will be relevant in different contexts.