Impact of HIV and Diabetes Mellitus on TB Drug Resistance and Recurrence

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Tuberculosis (TB) is the leading cause of mortality globally. With increasing burden of HIV and diabetes mellitus (DM), there is a critical need to understand the microbial response and ensuing disease dynamics of TB in the HIV-infected and diabetic host to optimally control TB globally. Among several contributing factors, Mtb microevolution (acquisitions of mutations over time) is likely a key driver of adverse TB treatment outcomes. HIV-infection increases the risk of TB drug resistance by 5-fold and evidence for the association between DM and TB drug resistance is mounting.
We hypothesize that Mtb strains from patients with HIV and patients with DM will demonstrate a higher frequency of microevolution events and development of drug-resistance conferring mutations, than strains from TB patients without HIV or DM. HIV and DM increases the risk of TB recurrence. While most TB recurrence is due to exogenous reinfection among HIV-infected patients, limited data on type of recurrence are available for patients with DM.
We hypothesize that, similar to HIV, TB recurrence in patients with DM will be primarily due to exogenous re-infection, rather than endogenous reactivation specifically in India, a high TB prevalence setting. Our study will systematically evaluate the role of HIV and DM on TB strain microevolution and type TB recurrence, utilizing whole genome sequencing.
Our specific aims are: 
  1. To characterize and quantify the Mtb strain microevolution events among patients with HIV and patients with DM, as compared to patients with TB alone during the first course of ATT; and
  2. To investigate the relative frequency of exogenous re-infection and endogenous reactivation as type of TB recurrence among patients with DM, as compared to HIV-uninfected and HIV-infected TB patients.
To address one of the stated objectives of RePORT India consortium—assessing the microbial factors and host interactions with TB treatment outcomes—we will leverage existing successful RePORT India consortium collaborations between Johns Hopkins University, BJ Government Medical College, Prof. M. Vishwanathan Diabetes Research Center, University of Massachusetts Medical School and National Institute of Research in Tuberculosis and engage the TB molecular epidemiology expertise at the New Jersey Medical School Rutgers.
  • Prof. M. Vishwanathan Diabetes Research Center
  • University of Massachusetts Medical School
  • New Jersey Medical School Rutgers