Patrick Cudahy, MD

patrickcudahyGHES US Fellow 2016-2017

Fellowship Site: Tugela Ferry, South Africa
U.S. Institution: Yale University

Project Title: Biomarkers of early response to multi-drug resistant tuberculosis and composition of multi-drug resistant mycobacterium tuberculosis strains during treatment

Individuals with HIV who are co-infected with multi drug-resistant tuberculosis (MDR-TB) in South Africa suffer early mortality of more than 50%. Mortality remains high after initiating treatment. Earlier identification of individuals failing to respond to standardized MDR-TB treatment might allow for modification of treatment regimens, avert morbidity and mortality and prevent further spread ofMDR-TB. Biologic markers of disease progression or non-response to therapy could help accomplish these goals but are limited and have not been tested prospectively.

For this project, our first aim is to evaluate trends in inflammatory proteins (CRP, d-dimer and fibrinogen) among individuals co-infected with MDR-TB and HIV to determine whether they can be used as early biomarkers of MDR-TB treatment response. We hypothesize that larger decreases in inflammatory markers during treatment, compared to baseline, will be associated with increased culture conversion, and decreased mortality.

The second aim is to obtain sputum samples during the course of treatment to perform whole genome sequencing of M. tuberculosis (Mtb). We seek to understand how diverse mycobacterial populations within a host respond to the selective pressure of treatment and affect treatment outcomes. Previous studies have been limited by the strain typing techniques employed, such as restriction fragment length polymorphism (RFLP) and spoligotyping. These are only able to resolve strains that make up roughly 1-10% of recovered bacilli. By performing whole genome sequencing, we may be able to increase our sensitivity for detecting mixed strain infections as well as track the selection of mycobacterial populations. We hypothesize that there is an association between within-host strain diversity and persistent culture positivity as well as final outcome of MDR-TB therapy.