BRIGHAM AND WOMEN'S HOSPITAL, INC., THE
Tuberculosis (TB) is an infectious disease of global importance; in 2006, there were more than 9 million incident cases and 1.7 million deaths attributable to TB. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB and the convergence of the HIV and TB epidemics are threats to effective TB control. Furthermore, evidence exists that previous M. tuberculosis infection confers limited immunity to re-infection, that an individual can simultaneously harbor more than one distinct strain of M. tuberculosis, that distinct lineages of M. tuberculosis differ in their virulence characteristics, and that M. tuberculosis diversifies within a host. Each of these factors contributes to the within-host complexity of M. tuberculosis infection and presents complications for the treatment of individuals and the control of disease in populations. I propose an observational study among individuals starting treatment for TB in Lima, Peru, and Pietermaritzburg, South Africa, to evaluate the prevalence, risk factors, and consequences of complex M. tuberculosis infection. I will: 1) estimate the site-specific prevalence of multiple-strain M. tuberculosis infection and clonal heterogeneity among individuals at the time of initial diagnosis, 2) determine the host- and strain-related risk factors for multiple-strain infection and clonal heterogeneity, 3) evaluate the effect of multiple-strain infection and clonal heterogeneity on early response to standard first-line treatment regimens, and 4) develop mathematical models to examine the individual- and population-level effects of multiple-strain infection and clonal heterogeneity.