The recent report of an extensively drug resistant (XDR) tuberculosis (TB) outbreak in Kwazulu-Natal, South Africa has alerted health authorities to the worsening global TB epidemic. TB control is increasingly compromised by the rise in drug resistant, multidrug resistant (MDR) and XDR-TB strains, reported in most countries surveyed. The goal of this research proposal is to explore host and pathogen factors that contribute to the failure of treatment of MDR-TB, ultimately leading to the emergence of XDR-TB strains. These studies will be done in South Africa, a country with some of the highest rates of TB worldwide. We will carry out two cross-sectional population-based studies of newly diagnosed MDR-TB patients from Gauteng Province, South Africa to characterize the nature and extent of the M/XDR-TB epidemic, to examine the diversity of MTB strains and drug resistance mutations represented in this population and to evaluate trends in the epidemic over the 5-year project period. We will also investigate the association between resistance to drugs in addition to INH and RIF and time to sputum culture clearance in patients undergoing treatment for MDR-TB. For these studies, two patient cohorts will be defined: Fast Responders (sputum culture clearance by the median time) and Slow Responders (failure to achieve sputum culture clearance by the median time). We will separately evaluate the impact of drug resistance (phenotypic/genotypic) that is pre- existing in the infecting bacillary population and drug resistance that is acquired de novo during treatment. Finally, we will explore selected nutritional and immunologic characteristics associated with poor response to treatment in the same patients undergoing treatment for MDR-TB. We will examine whether the time to sputum culture clearance and/or mortality observed among MDR-TB patients are associated with specific nutritional and/or immunologic profiles. The information gained from the cross-sectional studies can help to evaluate the extent to which XDR-TB may be attributed to primary transmission or acquired resistance and whether any M/XDR-TB strains are emerging in the region. The results of our clinical studies will help to elucidate factors that can contribute to poor response to treatment in MDR-TB patients, thereby fueling the increased incidence of XDR-TB. These data can inform current and future TB control strategies. As every additional M/XDR-TB patient is a public health hazard and a burden to the TB control program, our ability to identify factors that drive the epidemic will allow preemptive and targeted interventions. These may include improved treatment regimens, better approaches for monitoring patients during treatment, more intensive follow-up and other control strategies aimed at reducing the emergence of XDR-TB.

Public Health Relevance

Multidrug resistant (MDR) and extensively drug resistant (XDR)-TB have been found in most countries surveyed. MDR- and XDR-TB are associated with high morbidity and mortality, prolonged treatment to cure, and increased risk of spread in the community. These studies will evaluate trends in incidence of M/XDR-TB in a region of South Africa and will additionally investigate various factors contributing to poor response to treatment in MDR-TB patients. Results of these studies can contribute to improved TB control strategies aimed at reducing the emergence of XDR-TB and the development of new therapeutic approaches for combating this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080737-02
Application #
7912852
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Parker, Tina M
Project Start
2009-08-10
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$585,448
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Ferrian, Selena; Manca, Claudia; Lubbe, Sugnet et al. (2017) A combination of baseline plasma immune markers can predict therapeutic response in multidrug resistant tuberculosis. PLoS One 12:e0176660
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Middelkoop, Keren; Bekker, Linda-Gail; Mathema, Barun et al. (2014) Factors affecting tuberculosis strain success over 10 years in a high TB- and HIV-burdened community. Int J Epidemiol 43:1114-22
Riou, Catherine; Gray, Clive M; Lugongolo, Masixole et al. (2014) A subset of circulating blood mycobacteria-specific CD4 T cells can predict the time to Mycobacterium tuberculosis sputum culture conversion. PLoS One 9:e102178
Danaviah, S; Sacks, J A; Kumar, K P S et al. (2013) Immunohistological characterization of spinal TB granulomas from HIV-negative and -positive patients. Tuberculosis (Edinb) 93:432-41
Gray, Clive M; Hong, Heather A; Young, Katherine et al. (2013) Plasma interferon-gamma-inducible protein 10 can be used to predict viral load in HIV-1-infected individuals. J Acquir Immune Defic Syndr 63:e115-6

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