Adverse drug events frequently complicate the course of anti-tubercular therapy in HIV-infected patients, particularly in patients with advanced HIV disease, raising the possibility that immunodeficiency itself contributes to increased drug toxicity through undefined pathways. A globally important example of this relationship is the increased risk of liver injury in HIV-infected patients taking the first line anti-tubercular drug isoniazid (INH). For example, in a large recent randomized clinical trial comparing different durations of INH prophylaxis to prevent tuberculosis (TB) in patients infected with HIV, a CD4 cell count <200 cells/mm3 increased the risk of INH-associated hepatotoxicity over 4 fold. INH is associated with elevated liver enzymes in up to 20% of patients being treated for TB, and overt hepatotoxicity occurs in up to 1% of those taking the drug. Furthermore, INH toxicity is likely to be increasingly common as INH prophylaxis was recently recommended by the World Health Organization for the millions of HIV-infected patients living in high-TB burden settings. The overarching hypothesis of this proposal is that systemic immune activation in HIV-infected individuals is associated with INH clearance (CL). Immune activation and inflammatory cytokines are known to regulate the expression and activity of xenobiotic metabolic enzymes and drug transporters, and patients with high levels of immune activation, such as those with sepsis, have been shown to have impaired ability to clear drugs. Chronic immune activation, characterized by increased co-expression of CD38 and HLA-DR on CD8+ T cells, is strongly associated with HIV infection. Furthermore, as the rate of HIV disease progression associates with the level of immune activation, the degree of immune activation is higher in patients with more advanced HIV disease. Thus, it is possible that patients with HIV, particularly those high levels of immune activation, have delayed INH CL and an increased risk for INH-associated hepatotoxicity. Furthermore, our preliminary data from Botswana indicate that circulating levels of cytokines involved in immune activation can increase dramatically in the initial weeks of antiretroviral therapy (ART) in patients with HIV/TB. In this proposal we will conduct cross-sectional and longitudinal INH pharmacokinetics studies to test the hypotheses that 1) levels of systemic immune activation prior to ART initiation and 2) changes in levels of systemic immune activation after ART initiation are associated with changes in INH CL in HIV-infected patients being treated for HIV/TB. An innovative aspect of this proposal is that both aims will take into account variability in the N- acetyltransferase 2 (NAT2) allele, which is a major determinant of INH CL.
In aim 1, we expect to observe a relationship where patients who have "slow" NAT2 genotypes and very high levels of immune activation will have severely impaired INH CL.
In aim 2, we expect to document acute severe impairments of INH CL in a sub-set of patients who have rapid increases in immune activation shortly after ART initiation. The significance of this project is underscored by the fact that up to 70% of individuals living in regions of the world where HIV/TB is common have slow NAT2 genotypes. This project will therefore test two highly innovative hypotheses with implications for public health and patient care, and will open new lines of research into the interplay between the immune system as it relates to drug exposure in HIV.
Adverse drug events frequently complicate the course of anti-tubercular therapy in HIV-infected patients, particularly in patients with advanced HIV disease, raising the possibility that immunodeficiency itself contributes to increased drug toxicity through undefined pathways. In this project we will test the hypothesis that increased immune activation in HIV is associated with decreased INH clearance in patients with HIV and pulmonary tuberculosis. This project will provide valuable information on the pharmacokinetic parameters of INH in patients with HIV while testing a highly innovative hypothesis with broad implications for patient care and public health.