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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 HIV 和结核病 (TB) 的联合治疗因药物间相互作用和高发生率而变得复杂药物毒性和停药。结核病治疗的最佳持续时间的特点是结核病发病率低治疗失败和复发。治疗两个月后剩余痰培养呈阳性是传统的治疗方法随后结核病复发风险的标志。标准结核病治疗是基于异烟肼和利福平的为期 6 个月的治疗养生法；基于依非韦伦的抗逆转录病毒疗法通常用于治疗艾滋病毒，特别是在低度和中度艾滋病毒患者中。收入国家。这些治疗方案分别具有肝毒性和神经毒性。单核苷酸影响这些药物代谢的基因多态性 (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（慢速与高速）异烟肼的快速乙酰化）、CYP2B6（依非韦伦的慢代谢与快速代谢）、CYP2A6（两者的代谢）依非韦伦和异烟肼）、UGT2B7（依非韦伦的代谢）、SLCO1B1（利福平）和 UTG1A1（度鲁特韦）。 SNP、药物水平和毒性、两个月痰培养等结果之间的关系阳性和结核病治疗失败/复发尚不清楚，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。在在该提案中，我们寻求利用新成立的区域前瞻性观察研究结核病 (RePORT) - 巴西队列将招募并跟踪 800 名参与者（其中约 40% 将感染 HIV）并在结核病治疗后两年内患有经培养确认的药物敏感肺结核引发。我们还将利用范德比尔特最先进的质谱能力来确定血浆美国和巴西的结核病和艾滋病毒药物浓度以及药物基因组学专业知识考虑血统和其他因素后确定 SNP 与治疗结果之间的关系潜在的混杂变量，包括宿主免疫因素和结核分枝杆菌病原体特征。该项目的总体目标是在大范围内优化艾滋病毒相关结核病的治疗。巴西的遗传多样性队列。我们将描述人类遗传 SNP 与 TB 之间的关系和 HIV 药物水平，以及三个关键的结核病治疗结果：因毒性而停药（目标 1）、二- 月痰培养阳性，以及结核病治疗失败和复发（目标 2）。这些结果将奠定为改善艾滋病毒相关患者的结果和治疗效果的药物剂量和治疗方案奠定基础结核病。