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HIV感染患者的抗结核治疗过程复杂化，特别是在晚期HIV疾病患者中，这增加了免疫缺陷本身通过未定义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）的艾滋病毒感染者肝损伤风险增加。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INH预防HIV感染患者的结核病（TB）， CD4细胞计数<200细胞/mm3使INH相关肝毒性的风险增加了4倍以上。在多达20%接受结核病治疗的患者中，INH与肝酶升高有关，在服用该药的患者中，出现明显肝毒性的患者高达1%。此外，INH毒性可能越来越普遍，因为最近世界卫生组织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INH预防。该建议的总体假设是，hiv感染者的全身免疫激活与INH清除（CL）有关。已知免疫激活和炎症细胞因子调节异种代谢酶和药物转运体的表达和活性，免疫激活水平高的患者，如败血症患者，已被证明清除药物的能力受损。以CD38和HLA-DR在CD8+ T细胞上的共表达增加为特征的慢性免疫激活与HIV感染密切相关。此外，由于HIV疾病进展的速度与免疫激活水平相关，在HIV疾病晚期患者中，免疫激活程度更高。因此，HIV患者，特别是那些免疫激活水平高的患者，可能会延迟INH CL，并增加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，参与免疫激活的细胞因子的循环水平可以在艾滋病毒/结核病患者抗逆转录病毒治疗（ART）的最初几周显著增加。在本提案中，我们将进行横断面和纵向INH药代动力学研究，以验证以下假设：1)抗逆转录病毒治疗开始前的全身免疫激活水平和2)抗逆转录病毒治疗开始后全身免疫激活水平的变化与接受HIV/TB治疗的HIV感染患者的INH CL变化相关。该提议的一个创新之处在于，这两个目标都将考虑到N-乙酰转移酶2 （NAT2）等位基因的可变性，这是INH CL的主要决定因素。在目标1中，我们期望观察到具有“缓慢”NAT2基因型和非常高水平免疫激活的患者将严重损害INH CL的关系。在目标2中，我们期望在开始抗逆转录病毒治疗后不久免疫激活迅速增加的一组患者中记录急性严重的INH CL损伤。生活在世界上艾滋病毒/结核病常见地区的个人中，高达70%的人患有缓慢的NAT2基因型，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重要意义的高度创新的假设，并将开辟新的研究路线，研究免疫系统与艾滋病毒药物暴露之间的相互作用。

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.