This is a competitive renewal to complete our ongoing study of disseminated tuberculosis (dTB) in HIV infection. Tuberculosis is the most common cause of death from HIV infection in the developing world and dTB represents a substantial proportion of these deaths. Our hypotheses are (1) that most cases of dTB occur in advanced AIDS and represent reactivation or re-infection in persons with waning cellular immunity to mycobacteria, and (2) that if BCG-primed subjects are boosted with an inactivated mycobacterial vaccine in earlyiHIV infection, their subsequent risk of both dTB and pulmonary tuberculosis (pTB) will be reduced by 50%. Heat-inactivated M. vaccae (MV) is a vaccine that protects against tuberculosis in an animal model, is safe and immunogenic in subjects with HIV infection and CD4 counts>200, and boosts mycobacterial immune responses primed by BCG.
Our specific aims are: (1) To define risk factors for HIV-associated dTB and to assess the relative contributions of primary infection, re-infection, and reactivation in its pathogenesis, and (2) To assess the safety and efficacy of a prime-boost immunization strategy for the prevention of HIVassociated dTB and pTB. Patient enrollment was delayed one year by the regulatory review process (initial monthly enrollment limits were reduced from 100 to 33) and the need to identify a new study site. We established laboratories and clinical facilities in Dar es Salaam, Tanzania, trained study personnel and developed referral relationships with 22 HIV testing centers. In 3 years we have screened 3228 subjects, enrolled 1303 (57%) of the targeted 2274 BCG-positive subjects, and administered 4695 doses of vaccine. GCP study standards have been met, and multiple reviews by the DSMB based on pre-approved safety criteria have all been satisfactory. We have documented the highest reported rate of previously undiagnosed active tuberculosis in ambulatory patients with HIV (15%), identified a new syndrome of subclinical tuberculosis and shown that 85% of subjects have detectable baseline immune responses to mycobacteria and are primed for booster immunization. A three year renewal is requested to complete enrollment and follow-up. Vaccine efficacy against dTB and pTB will be determined, and in vitro immunologic responses will be used to identify surrogate markers of efficacy. This study has important implications for the reduction of mortality from HIV-associated tuberculosis and for design of new vaccine trials against tuberculosis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI045407-07
Application #
7125088
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Germuga, Donna E
Project Start
2000-08-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
7
Fiscal Year
2006
Total Cost
$1,317,869
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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Lahey, Timothy; Czechura, Tom; Crabtree, Scott et al. (2013) Greater preexisting interferon ? responses to mycobacterial antigens and lower bacillary load during HIV-associated tuberculosis. J Infect Dis 208:1629-33
Kabali, Conrad; Mtei, Lillian; Brooks, Daniel R et al. (2013) Increased mortality associated with treated active tuberculosis in HIV-infected adults in Tanzania. Tuberculosis (Edinb) 93:461-6
Adams, Lisa V; Kreiswirth, Barry N; Arbeit, Robert D et al. (2012) Molecular epidemiology of HIV-associated tuberculosis in Dar es Salaam, Tanzania: strain predominance, clustering, and polyclonal disease. J Clin Microbiol 50:2645-50
von Reyn, C F; Bakari, M; Arbeit, R D et al. (2012) New vaccines for the prevention of tuberculosis in human immunodeficiency virus infection. Int J Tuberc Lung Dis 16:718-23
Lahey, Timothy; Mitchell, Brian K; Arbeit, Robert D et al. (2011) Polyantigenic interferon-? responses are associated with protection from TB among HIV-infected adults with childhood BCG immunization. PLoS One 6:e22074
von Reyn, C F; Kimambo, S; Mtei, L et al. (2011) Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality. Int J Tuberc Lung Dis 15:1087-92
Kabali, C; von Reyn, C F; Brooks, D R et al. (2011) Completion of isoniazid preventive therapy and survival in HIV-infected, TST-positive adults in Tanzania. Int J Tuberc Lung Dis 15:1515-21, i
Lahey, Timothy; Sheth, Siddharth; Matee, Mecky et al. (2010) Interferon ? responses to mycobacterial antigens protect against subsequent HIV-associated tuberculosis. J Infect Dis 202:1265-72
Maro, I; Lahey, T; MacKenzie, T et al. (2010) Low BMI and falling BMI predict HIV-associated tuberculosis: a prospective study in Tanzania. Int J Tuberc Lung Dis 14:1447-53

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