Tuberculosis Epidemiologic Studies Consortium (TBESC)

Study 1: Evaluating tests for LTBI

No definitive diagnostic reference standard (gold standard) exists for LTBI. Three LTBI tests currently are on the market: the tuberculin skin test (TST), developed in 1908; and two recently developed interferon-gamma release assay (IGRA) blood tests-- the QuantiFERON^®-TB Gold In-Tube (QFT-GIT), and T-SPOT^®.TB test (T-SPOT), approved by the Food and  Drug Administration after 2000.  All three are indirect tests that measure the body’s immune responsiveness to Mycobacterium tuberculosis proteins. The three tests have varying sensitivities and specificities, and may perform differently in different populations.

This first TBESC-II study is a head-to-head comparison of the three tests in populations at high risk of LTBI and/or progression to TB disease:

• Persons born in or frequent visitors to countries with high rates of TB;
• Close contacts to persons with TB disease; and
• Persons with HIV infection.

When recruitment ends in mid-2017, approximately 21,400 enrollees will have received all three tests; all enrollees are actively followed for two years to identify those who develop TB disease.  This study, the largest of its kind to date, will provide more accurate estimates of the sensitivity and specificity of each test and its appropriate use in high-risk populations.

The study is supported by a web-based data management system. The system operates on one platform with modules to oversee enrollment, testing, treatment, and follow-up.

 Sub studies

• Repeatability and reproducibility of QFT and T-SPOT
• Feasibility and cost of testing for prediabetes and diabetes in high-risk persons tested for LTBI
• Cost-effectiveness of LTBI testing in high-risk populations

Study 2: The TB Prevention Cascade to Cure

A key barrier to TB elimination in the United States is incomplete knowledge of the burden of M. tuberculosis infection and inadequate preventive services for persons with LTBI.  The National Health and Nutrition Examination Survey (NHANES) periodically estimates the prevalence of LTBI among U.S. populations. The most recent estimates from 2012 range from 1.8% of U.S.-born persons to 18.7% of foreign-born persons. However, no programs on a national or local level conduct the type of ongoing and intensive data collection and evaluation of LTBI that is characteristic of the nation’s approach to TB disease.

Such LTBI surveillance programs should include:

• Population-based calculation of LTBI prevalence overall and in high-risk subpopulations;
• Evaluation of changes over time; and
• Identifying where patients are lost to care in the process from LTBI diagnosis to treatment completion.

These program activities comprise the TB Prevention Cascade to Cure, modeled after similar programs that focus intervention efforts for HIV and Hepatitis C.  The bar graph below (Figure 4) is a hypothetical example of the TB Prevention Cascade to Cure, with treatment of LTBI as the prevention.

Figure 4: TB Prevention Cascade to Cure: treatment as prevention*

The main goal of the TB Prevention Cascade to Cure study is to develop local estimates of LTBI prevalence in high-risk populations, and the proportions of those with LTBI who are identified, offered treatment, accept treatment, and complete treatment. Once methodologies are developed to calculate these estimates, they will be made available to other interested groups, including TB programs, federally qualified health centers (FQHCs), clinic groups, and clinicians who treat high-risk populations. Identification of these gaps is a first step in developing interventions to successfully close the gaps. 

To assist with these efforts, TBESC-II is developing an LTBI surveillance and case management system for TB programs. The Surveillance and TB Elimination Management System (STEMS) will contain modules for patient registration, testing, treatment, follow-up, and contact investigations.  TBESC II will use the first versions of this tool to construct the Prevention Cascade to Cure at local sites.

Sub studies

• Develop algorithms to estimate LTBI prevalence at any county or state level.
• Develop tools for local TB programs to identify local clinicians who treat high-risk underserved populations, so they can partner with these groups to increase LTBI treatment.
• Use insurance billing codes to estimate the extent and magnitude of LTBI testing and treatment in commercial and community health sectors.

Study 3: Development and assessment of interventions to close gaps in the Cascade to Cure

Study 3 will focus on the gaps identified in the Cascade to Cure, and the development and testing of interventions to close those gaps. For example, one gap might be that populations at high risk for LTBI are unaware of their risk, and therefore do not seek testing.  Possible interventions may include media campaigns; posters and/or flyers in social service offices and medical facilities that see large numbers of high-risk persons; and training of community members and service professionals who interact with high-risk populations.  

Study 4: Clinical trial to assess a shorter regimen for LTBI treatment

Although six to nine months of isoniazid (INH) therapy is highly effective (60-90%) in preventing progression of LTBI to TB disease, the long duration of therapy hinders treatment completion.  Recent trials have shown a 12-week regimen of INH and rifapentine (3HP) has equivalent effectiveness with higher completion rates (above 80%).  Study 4, a collaboration with the DTBE-sponsored Tuberculosis Trials Consortium and the British Medical Research Council, will compare short course rifampin-based regimens such as 3HP with an even shorter regimen: six weeks of daily rifapentine.  Researchers hope the results of this study will expand the LTBI treatment tools available to clinicians.