Predictors of treatment toxicity, failure, and relapse in HIV-related tuberculosis

HIV 相关结核病治疗毒性、失败和复发的预测因素

• 批准号: 9199006
• 负责人: Valeria Cavalcanti Rolla
• 金额: $ 65.57万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-12 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9199006
• 关键词: Accounting; Acetylation; Address; Adherence; Adverse effects; Adverse event; Adverse reactions; Affect; Alcohols; Biological Assay; Body mass index; Brazil; CYP2B6 gene; CYP2E1 gene; Cessation of life; Characteristics; Clinical; Confounding Factors (Epidemiology); Data; Dermatologic; Disease; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug toxicity; Enrollment; Ensure; Ethambutol; Failure; GSTM1 gene; Genes; Genetic; Genotype; Goals; Guidelines; HIV; HIV Infections; HIV therapy; HIV-1; Health; Hepatic; Hospitalization; Human; Human Genetics; Immune; Immune response; Infection; Integrase Inhibitors; Lamivudine; Mass Spectrum Analysis; Measures; Metabolism; Mycobacterium tuberculosis; NAT2 gene; Neuraxis; Observational Study; Outcome; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Plasma; Predisposition; Pulmonary Tuberculosis; Pyrazinamide; Regimen; Relapse; Research Infrastructure; Resources; Rifampin; Risk; Single Nucleotide Polymorphism; Specimen; Sputum; Tenofovir; Testing; Time; Toxic effect; Treatment Effectiveness; Treatment Failure; Treatment Protocols; Treatment outcome; Tuberculosis; UGT1A1 gene; UGT2B7 UDP-glucuronosyltransferase; United States; United States National Institutes of Health; Variant; Viral hepatitis; antiretroviral therapy; base; burden of illness; co-infection; cohort; drug metabolism; efavirenz; ethnic diversity; exome sequencing; genetic variant; improved outcome; isoniazid; liver injury; low and middle-income countries; neurotoxic; non-genetic; novel; pathogen; personalized approach; prospective; relapse risk; repository; response; screening; success; tuberculosis drugs; tuberculosis treatment

Project Summary Concomitant treatment of HIV and tuberculosis (TB) is complicated by drug-drug interactions and high rates of drug toxicity and discontinuation. The optimal duration of TB treatment is characterized by low rates of TB treatment failure and relapse. Remaining sputum culture-positive after two months of treatment is a traditional marker of subsequent TB relapse risk. Standard TB treatment is a 6-month isoniazid and rifampin-based regimen; efavirenz-based antiretroviral therapy is routinely used to treat HIV, particularly in low- and middle- income countries. These treatment regimens are hepatotoxic and neurotoxic, respectively. Single nucleotide polymorphisms (SNPs) in genes that affect metabolism of these drugs may affect pharmacokinetics and susceptibility to drug toxicity, as well as other treatment outcomes. This includes variants of NAT2 (slow vs. rapid acetylation of isoniazid), CYP2B6 (slow vs. rapid metabolism of efavirenz), CYP2A6 (metabolism of both efavirenz and isoniazid), UGT2B7 (metabolism of efavirenz), SLCO1B1 (rifampin), and UTG1A1 (dolutegravir). The relationships between SNP, drug level, and outcomes such as toxicity, two-month sputum culture- positivity, and TB treatment failure/relapse are not well-understood, particularly given drug interactions of TB and HIV drugs. Differences in human ancestry may also influence the effect of SNPs on drug metabolism. In this proposal we seek to utilize the newly-established Regional Prospective Observational Research on Tuberculosis (RePORT)-Brazil cohort that will enroll and follow 800 participants (approximately 40% of whom will be HIV-infected) with culture-confirmed drug-susceptible pulmonary TB for two years after TB treatment initiation. We will also utilize state-of-the-art mass spectrometry capacity at Vanderbilt to determine plasma concentrations of TB and HIV drugs, and pharmacogenomics expertise in the United States and Brazil to determine the relationships between SNP and treatment outcome after accounting for ancestry and other potentially confounding variables, including host immune factors and M. tuberculosis pathogen characteristics. The over-arching goal of this project is to optimize the treatment of HIV-related tuberculosis in a large, genetically diverse cohort in Brazil. We will characterize the relationship between human genetic SNPs, TB and HIV drug levels, and three key TB treatment outcomes: drug discontinuation due to toxicity (Aim 1), two- month sputum culture-positivity, as well as TB treatment failure and reIapse (Aim 2). These results will lay the groundwork for drug dosing and regimens that improve outcomes and treatment effectiveness of HIV-related TB.

项目摘要 艾滋病毒和结核病（TB）的伴随治疗因药物相互作用而复杂 药物毒性和中断。结核病治疗的最佳持续时间的特征是结核病的速率较低 治疗失败和复发。两个月后，持续的痰培养阳性是传统的 随后的结核病复发风险标记。标准结核病治疗是基于6个月的ISONIAZID和利福平 方案；基于efavirenz的抗逆转录病毒疗法通常用于治疗HIV，特别是在低和中间 收入国家。这些治疗方案分别为肝毒性和神经毒性。单核苷酸 影响这些药物代谢的基因中的多态性（SNP）可能会影响药代动力学和 对药物毒性的敏感性以及其他治疗结果。这包括Nat2的变体（慢速VS。 Isoniazid的快速乙酰化），CYP2B6（Efavirenz的快速代谢），CYP2A6（两者的代谢 Efavirenz和Isoniazid），UGT2B7（Efavirenz的代谢），SLCO1B1（Rifampin）和UTG1A1（Dolutegravir）。 SNP，药物水平和毒性等结果之间的关系，两个月的痰培养 - 阳性和结核病治疗失败/复发没有得到充分理解，特别是考虑到结核病的药物相互作用 和艾滋病毒药物。人类血统的差异也可能影响SNP对药物代谢的影响。在 我们试图利用新建立的区域前瞻性观察研究的这一建议 结核病（报告） - 巴西队列将参加并关注800名参与者（其中约40％ TB处理后两年 引发。我们还将利用范德比尔特的最先进的质谱能力来确定等离子体 美国和巴西的结核病和艾滋病毒药物的浓度以及药物基因组学专业知识 确定SNP和治疗结果之间的关系，并在祖先和其他 可能混淆变量，包括宿主免疫因子和结核分枝杆菌病原体特征。 该项目的整个目标是优化大型，大型的HIV相关结核病的处理 巴西的遗传多样性队列。我们将表征人类遗传SNP，TB之间的关系 HIV药物水平以及三个关键结核病治疗结果：由于毒性而导致的药物停用（AIM 1），两种 月痰培养物阳性，以及结核病治疗失败和REIAPSE（AIM 2）。这些结果将是 药物剂量和方案的基础，可改善与HIV相关的结果和治疗有效性 TB。