Immune Activation and Isoniazid Metabolism in HIV/TB

描述(由申请人提供)：药物不良事件经常使艾滋病毒感染患者，特别是晚期艾滋病毒患者的抗结核治疗过程复杂化，增加了免疫缺陷本身通过不明途径增加药物毒性的可能性。这种关系的一个全球重要例子是，服用一线抗结核药物异烟肼(INH)的艾滋病毒感染患者肝脏损伤的风险增加。例如，在最近的一项大型随机临床试验中，比较了不同持续时间的异烟肼预防艾滋病毒感染患者的结核病(TB)，发现CD4细胞计数为200个/mm3时，异烟肼相关肝毒性的风险增加了4倍以上。异烟肼与高达20%的接受结核病治疗的患者的肝酶升高有关，而在服用该药物的患者中，高达1%的患者发生了明显的肝毒性。此外，异烟肼的毒性可能会越来越普遍，因为世界卫生组织最近建议对生活在高结核病负担环境中的数百万艾滋病毒感染患者进行异烟肼预防。这一建议的主要假设是，HIV感染者的系统免疫激活与异烟肼清除(CL)有关。已知免疫激活和炎性细胞因子调节异物代谢酶和药物转运蛋白的表达和活性，免疫激活水平高的患者，如脓毒症患者，已被证明清除药物的能力受损。慢性免疫激活以CD8+T细胞表面CD38和HLA-DR共表达增加为特征，与HIV感染密切相关。此外，由于HIV疾病的进展速度与免疫激活水平有关，因此HIV疾病越严重的患者免疫激活程度越高。因此，HIV患者，特别是那些免疫激活水平高的患者，有可能延迟了INH CL，并增加了INH相关肝毒性的风险。此外，我们来自博茨瓦纳的初步数据表明，在HIV/TB患者接受抗逆转录病毒治疗(ART)的最初几周，参与免疫激活的细胞因子的循环水平可以显著增加。在这项建议中，我们将进行横向和纵向的异烟肼药代动力学研究，以检验以下假设：1)在抗逆转录病毒治疗前的系统免疫激活水平和2)在抗逆转录病毒治疗后的系统免疫激活水平的变化与正在接受艾滋病毒/结核病治疗的艾滋病毒感染患者的异烟肼CL的变化有关。这一建议的一个创新方面是，这两个目标都将考虑N-乙酰转移酶2(NAT2)等位基因的可变性，该等位基因是异烟肼CL的主要决定因素。在目标1中，我们希望观察到一种关系，在这种关系中，具有“慢”的Nat2基因类型和非常高水平的免疫激活的患者将严重损害INH CL。在目标2中，我们希望在ART开始后不久免疫活性迅速增加的患者亚组中记录INH CL的急性严重损害。生活在世界艾滋病毒/结核病流行地区的高达70%的人具有缓慢的Nat2基因类型，这一事实突显了该项目的重要性。因此，该项目将测试两个对公共卫生和患者护理具有影响的高度创新的假设，并将开辟新的研究路线，研究免疫系统之间的相互作用，因为它与艾滋病毒药物暴露有关。

DESCRIPTION (provided by applicant): 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.