Immune Activation and Isoniazid Metabolism in HIV/TB

描述（由申请方提供）：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，增加了免疫缺陷本身通过未定义的途径导致药物毒性增加的可能性。这种关系的一个全球性重要例子是，服用一线抗结核药物异烟肼（INH）的艾滋病毒感染者肝损伤的风险增加。例如，在最近的一项大型随机临床试验中，在感染HIV的患者中比较了不同持续时间的INH预防以预防结核病（TB），CD 4细胞计数<200个细胞/mm 3使INH相关肝毒性的风险增加4倍以上。INH与高达20%的结核病治疗患者的肝酶升高有关，并且高达1%的服用药物的患者发生明显的肝毒性。此外，由于世界卫生组织最近建议数百万生活在高结核病负担环境中的艾滋病毒感染者预防使用异烟肼，因此异烟肼毒性可能越来越普遍。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）相关。已知免疫活化和炎性细胞因子调节异生物质代谢酶和药物转运蛋白的表达和活性，并且具有高水平免疫活化的患者，例如脓毒症患者，已显示清除药物的能力受损。慢性免疫激活，其特征在于CD 8 + T细胞上CD 38和HLA-DR的共表达增加，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，因此在更晚期的HIV疾病患者中，免疫激活的程度更高。因此，HIV患者，特别是那些高水平免疫激活的患者，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，在艾滋病毒/结核病患者抗逆转录病毒治疗（ART）的最初几周，参与免疫激活的细胞因子的循环水平可能会急剧增加。在本提案中，我们将进行横断面和纵向INH药代动力学研究，以检验以下假设：1）ART开始前的全身免疫激活水平和2）ART开始后全身免疫激活水平的变化与接受HIV/TB治疗的HIV感染患者中INH CL的变化相关。该提议的一个创新方面是，两个目标都将考虑N-乙酰转移酶2（NAT 2）等位基因的变异性，这是INH CL的主要决定因素。在目标1中，我们期望观察具有“慢”NAT 2基因型和非常高水平的免疫激活的患者将具有严重受损的INH CL的关系。在目标2中，我们期望在ART开始后不久免疫激活迅速增加的患者亚组中记录INH CL的急性严重损伤。这个项目的重要性是由以下事实强调的：生活在世界上艾滋病毒/结核病常见地区的高达70%的人具有缓慢的NAT 2基因型。因此，该项目将测试两个高度创新的假设，对公共卫生和病人护理的影响，并将开辟新的研究路线，以了解免疫系统之间的相互作用，因为它涉及艾滋病毒的药物暴露。

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.