This is a proposal to the AIDS-Fogarty International Research Collaboration Award (AIDS- FIRCA) program requesting 3 years of support for a collaborative study on the role of tumor necrosis factor-alpha (TNF-alpha) in disease progression in HIV-1 positive tuberculosis patients in Thailand. The proposed investigation is an extension of ongoing studies carried out under a grant entitled """"""""Cell-mediated immunity in AIDS and tuberculosis,"""""""" grant number PO1-AI-24775A. The parent proposal has as one of its specific aims to determine whether thalidomide can inhibit the TNF-alpha mediated toxic manifestations of cell-mediated immunity in patients with tuberculosis and HIV-1 infection (specific aim number 4). In this AIDS-FIRCA proposal, the investigators plan to expand their observations made thus far in patients in New York City to include a foreign site for patient recruitment and evaluation. This will provide the investigators with a larger and more homogeneous pool of patients and accelerate their progress towards understanding of the role of TNF- alpha in HIV-1 and tuberculosis infection in humans. The pilot studies carried out by the investigators in New York City have demonstrated that thalidomide is safe and well-tolerated in patients with tuberculosis with or without HIV-1 infection. The drug improves general well-being, and leads to weight gain in association with a decrease in TNF-alpha levels in plasma and cells. What has not been resolved so far is the nature of thalidomide induced weight gain, and the effect of the drug on HIV-1 titers. Based upon the success of the pilot studies, the principal investigator and collaborators hope to perform a more comprehensive double-blind study of longer duration initiated with the funds requested in this proposal. This study will focus on evaluating the nature of the weight gain induced by the drug by including a metabolic work-up of the patients. The drug's effect on the HIV-1 titer will be evaluated by quantification of the viral load by the bDNA PCR technique and correlated with the immune status of the patients. AIDS and tuberculosis in Thailand are serious public health problems. Importantly, the two epidemics have overlapped extensively; most HIV-1 infected patients do not receive any anti-retroviral drugs or prophylactic medications because of financial constraints. The health care infrastructure, however, is highly functional and well-established, and the principal investigator has ongoing collaboration in Chiang Mai. These factors make northern Thailand an excellent location for new investigations into the epidemiology, clinical course, immunology and therapy of HIV-1 infection. In addition, the proposed studies will provide the patients with education concerning HIV-1 prevention, clinical evaluation and optimal treatment for AIDS and tuberculosis.
