The global burden of tuberculosis (TB) has increased over the past two decades despite widespread implementation of control measures, suggesting that many of these strategies could be improved. Contact patterns of an index case and the susceptibility of the exposed individual are critical determinants of TB transmission. Contact patterns are significantly influenced by the existence of networks within a population. At the same time, HIV-infection has been the most important factor in the resurgence of TB worldwide by increasing the susceptibility of the exposed individual. However, no studies have carefully looked into the effect of transmission networks and HIV-infection in the dynamics of TB epidemics in the community. Most of the current infection control strategies are based on the concept that TB acquisition requires prolonged and close contact with an infectious case. However, recent TB outbreak investigations, affecting primarily HIV-infected patients, have failed to identify any link or evidence of close contact among cases infected with the same strain of M. tuberculosis, challenging this widely spread concept. Contrary to the establish paradigm, we believe that casual encounters, occurring within unrecognized transmission networks, are important drivers of TB epidemics in dynamic populations with high prevalence of HIV infection. Botswana offers unique opportunities to determine the role of HIV, the degree of contact to an index case and unrecognized social networks in TB epidemics. Over the last 6 years, we have developed a nationwide TB surveillance program in Botswana. We have seen that new TB cases without clear exposure to an index case are more frequently seen in the Southern areas of the country and are more frequently HIV- associated. Consistent with this observation, molecular genotyping of M. tuberculosis from sputum samples from HIV-infected patients from this area show that, despite the absence of known contact with an index case, most of them are infected with the same strain, suggesting recent infection from a common source. In contrast, TB in the Western region, which has one of the highest rates of TB in the world, is more HIV-independent, and close contact with an index case is often evident. Thus, we believe that there are distinct epidemics within the larger TB epidemic in Botswana that are fueled by different mechanisms of transmission and acquisition, probably related to the population dynamics (close vs. casual exposures) and prevalence of HIV infection. In this proposal, we aim to determine the relative role of these factors (HIV, the degree of contact to an index case and unrecognized social networks) as drivers of the TB epidemics in these 2 populations by combining classical epidemiologic methods and molecular epidemiology. We expect this study will show that casual encounters, primarily occurring in unrecognized transmission networks, are the main drivers of TB epidemics in populations with high prevalence of HIV, which would represent a change in current paradigms.

Public Health Relevance

The demonstration that casual encounters, occurring primarily in nosocomial settings, are in fact the main drivers of TB epidemics in populations with high prevalence of HIV, will represent a major change in current paradigms leading to changes in public health and infection control interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097045-03
Application #
8522150
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Huebner, Robin E
Project Start
2011-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$551,578
Indirect Cost
$113,818
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shin, Sanghyuk S; Modongo, Chawangwa; Zetola, Nicola M (2016) The impact of mixed infections on the interpretation of molecular epidemiology studies of tuberculosis. Int J Tuberc Lung Dis 20:423-4
Zetola, N M; Modongo, C; Moonan, P K et al. (2016) Protocol for a population-based molecular epidemiology study of tuberculosis transmission in a high HIV-burden setting: the Botswana Kopanyo study. BMJ Open 6:e010046
Bisson, Gregory P; Zetola, Nicola; Collman, Ronald G (2015) Persistent high mortality in advanced HIV/TB despite appropriate antiretroviral and antitubercular therapy: an emerging challenge. Curr HIV/AIDS Rep 12:107-16
Modongo, Chawangwa; Pasipanodya, Jotam G; Zetola, Nicola M et al. (2015) Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients. Antimicrob Agents Chemother 59:6337-43
Shin, Sanghyuk S; Modongo, Chawangwa; Ncube, Ronald et al. (2015) Advanced immune suppression is associated with increased prevalence of mixed-strain Mycobacterium tuberculosis infections among persons at high risk for drug-resistant tuberculosis in Botswana. J Infect Dis 211:347-51
Zetola, Nicola M; Shin, Sanghyuk S; Tumedi, Kefentse A et al. (2014) Mixed Mycobacterium tuberculosis complex infections and false-negative results for rifampin resistance by GeneXpert MTB/RIF are associated with poor clinical outcomes. J Clin Microbiol 52:2422-9
Zetola, Nicola M; Modongo, Chawangwa; Olabiyi, Bisayo et al. (2014) Examining the relationship between alcohol use and high-risk sex practices in a population of women with high HIV incidence despite high levels of HIV-related knowledge. Sex Transm Infect 90:216-22
Modongo, Chawangwa; Sobota, Rafal S; Kesenogile, Boikobo et al. (2014) Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. BMC Infect Dis 14:542
Zetola, Nicola M; Modongo, Chawangwa; Moonan, Patrick K et al. (2014) Clinical outcomes among persons with pulmonary tuberculosis caused by Mycobacterium tuberculosis isolates with phenotypic heterogeneity in results of drug-susceptibility tests. J Infect Dis 209:1754-63
Zetola, Nicola M; Macesic, Nenad; Shin, Sanghyuk S et al. (2014) Longer hospital stay is associated with higher rates of tuberculosis-related morbidity and mortality within 12 months after discharge in a referral hospital in Sub-Saharan Africa. BMC Infect Dis 14:409

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