Multidrug-resistant tuberculosis (MDR TB) has emerged as a significant global threat, with nearly 500,000 new cases annually. South Africa has the highest burden of HIV worldwide and also has a rapidly expanding MDR TB epidemic, raising concerns for a catastrophic convergence of these two diseases. In South Africa and in other regions, MDR TB/HIV co-infection has been associated with exceedingly high mortality-up to 80% at one year. Most mortality estimates, however, were derived prior to the availability of antiretroviral therapy (ART). Mortality rates for MDR TB/HIV co-infected persons treated with ART are currently unknown. ART has markedly improved survival in drug-susceptible TB/HIV co-infected persons. Though adding ART to MDR TB treatment is hoped to similarly improve survival in MDR TB/HIV co-infected persons, this benefit may be attenuated by microbial or host factors which may be more prevalent in MDR TB/HIV co-infection. HIV- infected persons may be more likely to develop MDR TB disease as a result of infection with more virulent TB strains, leading to higher mortality despite ART. Similarly, certain host factors, such as disseminated TB, immunosuppression, or low body mass index, which are more common in HIV, are independently associated with poor MDR TB outcomes and may worsen survival despite combined ART and MDR TB treatment. In addition to improving survival, combined ART and MDR TB treatment may result in complications (i.e., greater incidence of adverse reactions and immune reconstitution inflammatory syndrome [IRIS], or lower adherence) that compromise both MDR TB and HIV outcomes. Specifically, it may cause lower rates of MDR TB culture conversion and higher rates of MDR TB treatment failure, or HIV virologic failure. Identifying and understanding these potential complications will inform future intervention studies of MDR TB/HIV co-infection. In this application, we will assemble a cohort of MDR TB/HIV subjects and examine prospectively the impact of concurrent MDR TB treatment and ART on survival (Aim 1). The influence of host factors on survival will be examined. Additionally, we will genotype all MDR TB isolates to determine TB strain prevalence to determine whether this mediates differences in survival (Aim 2). We will further examine the effect of MDR TB and HIV co-treatment on outcomes for each disease, with rigorous measures of factors that may impact these outcomes, namely: adverse events, IRIS, and adherence (Aims 3 &4). The interactions between HIV and drug-resistant TB have been identified as a priority research area for the NIH/NIAID and the Federal TB Task Force, specifically epidemiologic research to improve understanding of HIV and drug-resistant TB, and clinical research to assess outcomes of patients afflicted with both diseases and undergoing concurrent treatment. This application will address these issues directly, and will take place at the epicenter of the convergent epidemics of TB, HIV, and drug-resistant TB in rural South Africa, where our international research group has been working to improve outcomes in TB/HIV co-infection since 2002. PUBLIC HEALTH RELEVANCE: While MDR TB/HIV co-infection was previously characterized by extremely high mortality, this was before life- saving antiretroviral therapy was available. Findings will help improve the health of individuals and communities affected by the MDR TB epidemic and will create an evidence-base to guide sound clinical practice and public health policy for MDR TB/HIV disease treatment throughout the developing world.