Recent observations from retrospective cohort studies indicate that HIV-associated TB is associated with reduced survival and increased rate of opportunistic infections compared to CD4-matched controls. Mounting evidence from immunologic and virologic studies, in fact, supports the concept of co-pathogenesis in which cytokines such as tumor necrosis factor alpha (TNF) are over-expressed during the course of TB and stimulate viral replication in latently infected cells, possibly leading to greater viral load. The results of recent Phase I/II trials in HIV/TB of selective cytokine inhibitors, such as thalidomide and pentoxifylline, indicate short-term clinical benefit and reduced viral load, despite the only partial inhibition of TNF achieved by either agent. Because TB is associated with increased expression of multiple cytokines, a less selective agent than thalidomide and a more potent agent than pentoxifylline may be more effective. Attractive alternatives to the more selective inhibitors are the glucocorticoids because they are potent inhibitors of cytokines, including TNF, and because clinicians have extensive experiences with their use in HIV infection. Although corticosteroid use in HIV infection has a record of safety, the safety and bioavailability of corticosteroids in HIV/TB has not been established. The Investigator, therefore, proposes two interrelated studies with the following specific objectives: (1) to determine the dose of oral prednisolone that provides optimal therapeutic activity, as measured by reduction in induced TNF ex vivo, and is safe as adjuvant therapy for smear-positive pulmonary TB in HIV -infected Ugandan adults; (2) to evaluate the biologic activity, as the change in viral load and CD4 count, of oral prednisolone in this population. To address these objectives, the Investigator and his associates will perform a Phase I, pharmokinetic study to identify the optimal dose of oral prednisolone and a Phase II study to confirm the safety of prednisolone and evaluate its biologic activity. The proposed trial will be conducted in a developing country setting because prednisolone is an affordable and available intervention which, if found safe and effective, could have substantial impact on the morbidity of HIV-associated TB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032414-06
Application #
2667725
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Project Start
1992-07-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Mupere, Ezekiel; Malone, LaShaunda; Zalwango, Sarah et al. (2014) Wasting among Uganda men with pulmonary tuberculosis is associated with linear regain in lean tissue mass during and after treatment in contrast to women with wasting who regain fat tissue mass: prospective cohort study. BMC Infect Dis 14:24
Jaganath, Devan; Zalwango, Sarah; Okware, Brenda et al. (2013) Contact investigation for active tuberculosis among child contacts in Uganda. Clin Infect Dis 57:1685-92
Mupere, Ezekiel; Malone, Lashaunda; Zalwango, Sarah et al. (2012) Lean tissue mass wasting is associated with increased risk of mortality among women with pulmonary tuberculosis in urban Uganda. Ann Epidemiol 22:466-73
Mupere, Ezekiel; Zalwango, Sarah; Chiunda, Allan et al. (2010) Body composition among HIV-seropositive and HIV-seronegative adult patients with pulmonary tuberculosis in Uganda. Ann Epidemiol 20:210-6
Srikantiah, P; Lin, R; Walusimbi, M et al. (2007) Elevated HIV seroprevalence and risk behavior among Ugandan TB suspects: implications for HIV testing and prevention. Int J Tuberc Lung Dis 11:168-74
Jones-Lopez, Edward C; Okwera, Alphonse; Mayanja-Kizza, Harriet et al. (2006) Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in Uganda: should anergy be a criterion to start antiretroviral therapy in low-income countries? Am J Trop Med Hyg 74:154-61
Mayanja-Kizza, Harriet; Jones-Lopez, Edward; Okwera, Alphonse et al. (2005) Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda. J Infect Dis 191:856-65
Van Lettow, M; Kumwenda, J J; Harries, A D et al. (2004) Malnutrition and the severity of lung disease in adults with pulmonary tuberculosis in Malawi. Int J Tuberc Lung Dis 8:211-7
Shah, S; Whalen, C; Kotler, D P et al. (2001) Severity of human immunodeficiency virus infection is associated with decreased phase angle, fat mass and body cell mass in adults with pulmonary tuberculosis infection in Uganda. J Nutr 131:2843-7
Whalen, C C; Nsubuga, P; Okwera, A et al. (2000) Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 14:1219-28

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