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11 The Evolution of Drug Resistance and the Curious Orthodoxy of Aggressive Chemotherapy--ANDREW F. READ, TROY DAY, and SILVIE HUIJBEN
Pages 237-252

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From page 237...
... Yet "radical pathogen cure" maximizes the evolutionary advantage of any resistant pathogens that are present. It could promote the very evolution it is intended to retard.
From page 238...
... We hereafter refer to this practice as "radical pathogen cure." For a wide variety of infectious diseases, recommended drug doses, interdose intervals, and treatment durations (which together constitute "patient treatment regimens") are designed to achieve com plete pathogen elimination as fast as possible.
From page 239...
... In our view, the current scientific challenge is to identify, among patient treatment regimens that are similarly effective at restoring health and preventing transmission, those regimens that best effect resistance management. The aim of resistance management is to prevent clinical failures caused by high-level resistance.
From page 240...
... Because both mutational and selection processes together determine the useful life span of a drug, resistance evolution can be retarded by managing mutations, selection, or, ideally, both. Our view is that conventional wisdom focuses too much on managing mutational events (genetic origins)
From page 241...
... The strength of selection on resistance is primarily determined by the fate of resistant parasites in treated and untreated hosts. Resistant strains gain an advantage in treated hosts but often pay a cost in untreated hosts.
From page 242...
... Consequently, the coexistence of drug-sensitive and drugresistant parasites is common, and indeed may even be the rule (Day et al., 1992; Arnot, 1998; Babiker et al., 1999; Smith et al., 1999; Bruce et al., 2000; Jafari et al., 2004; Juliano et al., 2007, 2010; McCollum et al., 2008; Zhong et al., 2008; Owusu-Agyei et al., 2009)
From page 243...
... Benefits of Resistance The flip side of this ecology is that the fitness advantages resistant parasites experience in treated hosts are greatly magnified in mixed-clone infections. Consider the consequences of radical pathogen cure where competition is occurring.
From page 244...
... , some of which are represented at frequencies significantly less than 1%. Were those rare clones drug-resistant, aggressive chemotherapy could increase transmission success of resistant parasites >100-fold.
From page 245...
... Drug treatment rapidly suppresses sensitive parasites, allowing resistant parasites to dominate post-treatment populations; the expansion following competitive release is especially marked when the re sistant clone is rare. In untreated mice, resistant parasite densities are markedly lower than sensitive parasite densities throughout the infections, particularly when they were rare initially (compare with Fig.
From page 246...
... . Partially resistant parasites only have an evolutionary advantage at lower drug concentrations; thus, from a resistance management perspective, it is important to minimize the probability that such parasites encounter those lower concentrations.
From page 247...
... This is because aggressive treatment regimens increase the probability that any high-level resistance that has arisen de novo will avoid stochastic loss and reach transmissible frequencies. It is extremely challenging for a very rare resistant mutant to replicate to transmissible densities in a host [e.g., Mackinnon (2005)
From page 248...
... EVIDENCE-BASED RESISTANCE MANAGEMENT The foregoing suggests to us that radical parasite cure is not a priori the best way to manage resistance and that it could even promote the very evolution it is intended to retard. The scientific challenge is to determine how the contrasting evolutionary consequences of aggressive chemotherapy determine the rate of resistance evolution and whether, among the vast array of possible regimens, there are other ways of treating patients that would better delay resistance.
From page 249...
... None of the putative resistance management strategies slowed the spread of phenotypic resistance. Empirical assessments of evolutionary outcomes are problem atic for a drug against which resistance has yet to arise, but once high-level resistance has arisen, there is an ethical imperative to do such studies.
From page 250...
... HOW TO TREAT PATIENTS? A corollary of our observation that radical pathogen cure can very seriously promote the evolution of resistance is that less aggressive drug treatment could prolong the useful life span of a drug.
From page 251...
... It might also be that patient treatment regimens need to be modified as resistance evolution proceeds. Perhaps, for instance, aggressive chemotherapy can reduce the probability that mutations to high-level resistance will occur.
From page 252...
... There, the argument has recently been made that less aggressive chemotherapy might sustain life better than overwhelming drug treatment, which sim ply removes the competitively more able susceptible cell lineages, allow ing drug-resistant lineages to kill the host (Gatenby, 2009; Gatenby et al., 2009)


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