How could preventive therapy affect the prevalence of drug resistance? Causes and consequences

Abstract

Various forms of preventive and prophylactic antimicrobial therapies have been proposed to combat HIV (e.g. pre-exposure prophylaxis), tuberculosis (e.g. isoniazid preventive therapy) and malaria (e.g. intermittent preventive treatment). However, the potential population-level effects of preventative therapy (PT) on the prevalence of drug resistance are not well understood. PT can directly affect the rate at which resistance is acquired among those receiving PT. It can also indirectly affect resistance by altering the rate at which resistance is acquired through treatment for active disease and by modifying the level of competition between transmission of drug-resistant and drug-sensitive pathogens. We propose a general mathematical model to explore the ways in which PT can affect the long-term prevalence of drug resistance. Depending on the relative contributions of these three mechanisms, we find that increasing the level of coverage of PT may result in increases, decreases or non-monotonic changes in the overall prevalence of drug resistance. These results demonstrate the complexity of the relationship between PT and drug resistance in the population. Care should be taken when predicting population-level changes in drug resistance from small pilot studies of PT or estimates based solely on its direct effects.

Benefits of continuous isoniazid preventive therapy may outweigh resistance risks in a declining tuberculosis/HIV coepidemic

“…If we allow for greater future transmission, however, the initial incidence and mortality benefits of longer IPT durations may subsequently be eroded by substantial increases in the incidence of isoniazid resistant TB. This finding likely reflects an increased importance of the selective pressure imposed by IPT relative to other resistance mechanisms when transmission is high [17], and is consistent with the results of previous models constructed at an earlier phase of the HIV epidemic when TB incidence was increasing [16, 18]. …”

“…Furthermore, the included studies were not powered to assess risks of resistance [1, 14]. This analysis also did not consider the potential competitive advantage that community-wide IPT could confer to isoniazid resistant TB strains at the population level [15–17]. …”

Why does drug resistance readily evolve but vaccine resistance does not?

“…Nevertheless, prophylactic use can sometimes facilitate the evolution of drug resistance [56]. This is because prophylaxis can favour the spread of resistance once it has emerged in a population [57]. When contemplating the evolutionary risks of prophylactic drug use, it is thus crucial to understand whether resistance is already present within a population (or within a coexisting population that can donate genetic material).…”

Preface

“…The difficulties in national surveillance, despite the availability of new scientific tools, are discussed by Johnson [9], while the complex world of drug resistance of bacterial populations in the human gut, and genetic transfer within this very large bacterial population, are examined by van Schaik [10]. Epidemiological and population genetic perspectives, based on the study of preventive therapy in hospital settings, are examined in a paper by Kunkel et al [11], while Mitchell et al [12] examine the important issue of how antibiotic treatment of pneumococcal carriage populations effects the evolution of vaccine escape mutants. The final two papers present views on research, development and commercialization in the pharmaceutical industry [13], and the task of government in policy formulation to both encourage innovation and reduce the spread of resistance [14].…”