Numerous clinical trials, epidemiologic and observational studies have been completed as well as smaller developmental projects all focused on addressing important questions, issues, and controversies in the human response to M. tuberculosis exposure, infection, and disease. Our findings have largely been reported in the literature although a number of follow-up activities and completion studies have carried over or extended into current studies.
Major Scientific Insights that Impact New Approaches to TB Treatment and Prevention
- Adjuvant immune therapy during TB treatment for drug sensitive TB: it is difficult to demonstrate a benefit (M. vaccae, rIL-2 trials) when 2 month culture conversion on solid media is the endpoint.
- EBA studies evaluated the following existing antibiotics: moxifloxacin, high dose levofloxacin, gatifloxacin, linezolid and found them to be effective TB drugs.
- EBA studies are much improved when combined with PK/PD studies; TBRU was one of the first to use them systematically with EBA studies and this has become the new standard for EBA studies worldwide.
- BCG vaccination of HIV exposed (but not infected) infants induces effective immune responses and has resulted in a new WHO recommendation to not vaccinate infants with BCG when they are known to be HIV infected.
- The combination of rapid sterilization of sputum (negative 2 mo. sputum culture) and absence of cavities on CXR fail to identify persons who can be treated with a shortened course (4 vs 6 months) with current anti-TB drugs. Thus better biomarkers than combining the two most commonly used to assess severity of TB disease are needed to identify persons who could benefit from shortened TB treatment with current or new anti-TB drugs.
- Differences in growth of M. tuberculosis in human mononuclear phagocytes correlates with epidemiological data suggesting differences in M. tuberculosis strain virulence (i.e. households with minimal infection/disease vs. those with more infection/disease).
- Sputum cytokines (IFN-gamma, TNF-alpha) can be detected in TB patients and correlate with changes in sputum CFU over time, and thus may represent a promising host biomarker of response to treatment.
- CD8+ T cell responses to M. tuberculosis proteins are characterized by marked diversity in range of antigens recognized and differ from those of CD4+ T cells, indicating an urgent need for further characterize the human CD4 and CD8 T cell repertoire to M. tuberculosis protein antigens to identify optimal and dominant antigens for vaccine and diagnostic development.
- Human genetics influence not only progression of M. tuberculosis infection from LTBI to TB, but also whether one becomes infected and risk for progression when HIV co-infected.
- TNF-alpha and IFN-gamma responses to M. tuberculosis proteins are in part determined by host genetics.
- Baseline immune responses in household contacts can be used to predict those who will become M. tuberculosis infected (i.e. become a TST converter) and thus at higher risk for progression from infection to disease.
- mRNA of M. tuberculosis genes can be detected in sputum and thus a possible microbial biomarker of response to TB treatment.
- Inhibiting immune activation with corticosteroids during TB treatment in HIV-infected persons does not provide long-term benefit in terms of HIV progression or improved responses to TB treatment.
- HIV-infection and active TB are synergistic, resulting in each disease worsening the other.
- Studies of the human response to M. tuberculosis require a multidisciplinary approach given the complexities of the host-pathogen interaction, clinical research in resource-limited settings and the long-term human and financial resources required for clinical TB research.
- Specimen collection and well-designed and focused sub-studies increase the cost up front but greatly enhance the value of expensive clinical trials and observational/epidemiologic studies of M. tuberculosis infection and disease (in particular when the primary endpoints of the clinical trial are negative).
- Collaboration across institutions and investigators from TB endemic and non-endemic areas is essential for TB clinical research.
- TB differs from region to region in terms of relative importance of HIV infection, drug resistance (MDR/XDR), role of private vs. public TB care, use of preventive treatment for latent M. tuberculosis infection, access to anti-retroviral therapy, and BCG vaccination; these issues affect the clinical research questions that one can address, issues one needs to confront in study design and barriers to the successful implementation of a research study.
- Excellent baseline clinical phenotypes and follow-up are essential for clinical TB research.
- Solid epidemiological study design provides an optimal framework for genetic and immunologic studies of M. tuberculosis natural history and disease.
- The time to complete clinical trials of new anti-TB drugs using current endpoints and paradigms is a major obstacle to improving treatment. Validated biomarkers of clinical endpoints are needed. These can be initially evaluated in small cohorts but ultimately must be validated in large clinical trials based on failure/recurrence endpoints.