Tuberculosis has emerged as a major public health problem in Georgia and in many of the former Soviet Republics. High rates of tuberculosis (prevalence of 200 cases per 100,000 population in 1998) are being reported in Georgia. The U.S. (NIH)-Georgia Conference on HIV/AIDS, emerging infectious diseases and immunodeficiencies, held in Tbilisi in May 1998 concluded that “tuberculosis is the highest priority health threat to Georgia today and should be the first priority for public health and research efforts”. Preliminary data from collaborative studies from the Georgian National Tuberculosis Program (NTP) and Emory University and CDC (Atlanta) suggest the emergence in Georgia of multi-drug resistant (MDR)-TB (which is associated with extremely high morbidity and mortality). A 3-year project is proposed to study the molecular epidemiology of drug resistant TB in Georgia and to subsequently expand these investigations to include the entire Caucuses (i.e., Armenia and Azerbaijan) in the second half of the project. In addition to the research objectives proposed, this project will also provide substantial infrastructure development for the Georgian National Center for Disease Control (NCDC) and Georgian NTP and will facilitate the development of a TB reference laboratory in Tbilisi, given the ICRC construction of a new building at the NTP to house a TB laboratory. It will also expand the capabilities of the NCDC to perform molecular typing studies on M. tuberculosis. This project also contains a training component as a pocket sized booklet (TB Reference Guide) is planned, appropriate for Georgia (and other former Soviet Republics), which is based on World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommendations. This project is a Partnership Project with DHHS-BTEP-ITSC.
Specific aims of proposal include:
1) To further assess rates of and risk factors for drug resistant TB (including MDR-TB) in Georgia (and subsequently the Caucuses) and to confirm whether there is widespread drug resistance among M. tuberculosis isolates recovered from patients in Georgia. Rates of both primary (newly diagnosed patients) and secondary (patients with a prior history of treatment) drug resistance among M. tuberculosis isolates, recovered from patients in the Republic of Georgia, will be investigated. Surveillance will be conducted at sentinel sites in Tbilisi, in one city in western Georgia (Kutaisi) and in one city in Eastern Georgia. Patients with suspected pulmonary TB, who access care at these sentinel sites, will have sputum samples collected for AFB smear and culture studies, which will be performed at the NTP laboratory, equipped with the capability to perform such studies. Capabilities of the NTP laboratory will be upgraded to perform susceptibility testing to at least the first line antituberculosis drugs (isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin). M. tuberculosis isolates will be shipped to Atlanta for confirmatory susceptibility testing studies. Findings from the proposed studies are critical for implementing appropriate control strategies for TB in Georgia, especially given that the WHO directly observed therapy--short course (DOTs) strategy is not likely not to work in areas where there is a high degree of drug resistance, especially MDR-TB. In such cases alternative strategies such as "DOTs-PLUS" would need to be considered. In addition, a case control study will be conducted to determine risk factors for primary and secondary drug resistance.
2) To study the molecular epidemiology of drug resistant TB, including MDR-TB in Georgia and the Caucuses, employing IS-6110 restriction fragment length polymorphism (RFLP) analysis. Molecular typing studies will be performed at the NCDC in collaboration with NTP staff and US collaborators. The NCDC already has a molecular typing laboratory and capabilities will be expanded to include IS-6110 RFLP typing of M. tuberculosis. Investigations will include a comparison of isolates recovered from patients in the community and those with TB who are incarcerated in Georgian prisons. These studies will help determine the transmission dynamics of M. tuberculosis in Georgia, the degree of recent transmission of M. tuberculosis and whether drug resistant TB has emerged in a limited number of clones or in multiple strains. Since we will be using the internationally recognized standard method for performing RFLP [11], we would have the ability in future to compare RFLP patterns from M. tuberculosis isolates recovered from patients in the Republic of Georgia to those in other countries in the Caucuses (i.e., Armenia and Azerbaijan) as well as Russia and other former Soviet Republics, as part of efforts to study the molecular epidemiology of TB on a global basis.
3) To evaluate the proportion of patients with tuberculosis who are co-infected with the human immunodeficiency virus (HIV), a major risk factor for the development of tuberculosis following infection with M. tuberculosis. Only very limited surveys have been performed to date to assess the impact of HIV upon the tuberculosis epidemic in Georgia.
4) To develop a pocket-sized reference manual (TB Reference Guide), containing basic information for clinicians in Georgia and other former Soviet Republics on TB epidemiology, diagnostics, treatment and infection control issues appropriate for these countries. This booklet will be produced in the Georgian language and a Russian edition will be produced for other former Soviet Republics. The Guide will be based on World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommendations.
COLLABORATION AND TRAINING: A 4-year history of collaboration exists between U.S. investigators and those in the Republic of Georgia. Emory University (Henry M. Blumberg, MD) and the Georgian NCTLD-NTP (George Khechinashvili, MD, PhD) have had ongoing projects, funded by the Civilian Research and Development Foundation (CRDF) for the Independent States of the Former Soviet Union, and this has enabled preliminary drug susceptibility studies to be carried out. This collaboration has been productive; it has resulted in scientific presentations at national and international meetings and a peer-reviewed publication. Dr. Beverly Metchock, Chief, Diagnostic Mycobacteriology Section in the TB/Mycobacteriology Branch at CDC has served as a consultant on the CRDF project. The Georgian NCTLD-NTP laboratory has the capability to perform AFB cultures and to recover and identify M. tuberculosis. This has been validated by studies in Atlanta at Emory University and CDC. The proposed project would provide resources and the opportunity to expand investigations to achieve the specific aims as outlined above; the NCTLD-NTP laboratory capability would be upgraded to provide drug susceptibility testing and could become a tuberculosis reference laboratory for the Caucuses. NCDC has molecular typing capabilities and these would be expanded to include M. tuberculosis. To achieve these goals, Georgian collaborators would be trained at Emory and CDC laboratories in Atlanta at the beginning of the grant and a staff member from Emory would travel to Tbilisi to assist in the establishment of a TB Reference Laboratory at NCTLD-NTP and a TB Molecular Typing Laboratory at the NCDC.
