Determinants and Outcomes of Nicotine Metabolite Ratio in HIV + Smokers

HIV 吸烟者尼古丁代谢比率的决定因素和结果

• 批准号: 10330407
• 负责人: Rebecca Ashare
• 金额: $ 41.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330407
• 关键词: AIDS/HIV problem; Address; Affect; Biological Factors; Biological Markers; Biological Specimen Banks; Blood; CYP2B6 gene; Cardiovascular Diseases; Cardiovascular system; Clinical; Coagulation Process; Cohort Studies; Complex; Cotinine; Country; Data; Database Management Systems; Development; Enzymes; Exposure to; Future; General Population; HIV; HIV Infections; HIV antiretroviral; Health; Heart; Hepatic; Income; Individual; Infection; Inflammation; Intervention; Lead; Life; Life Expectancy; Lipopolysaccharides; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Metabolism; Morbidity - disease rate; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nested Case-Control Study; Nicotine; Nicotine Dependence; Outcome; Persons; Pharmaceutical Preparations; Pharmacotherapy; Prognosis; Psychological Factors; Randomized; Research; Retrospective cohort study; Risk; Risk Factors; Severities; Sleep; Smoke; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; Specimen; The Multicenter AIDS Cohort Study; Time; Tobacco use; Viral; Withdrawal Symptom; Woman; Work; antiretroviral therapy; behavioral response; cancer risk; cardiovascular risk factor; cigarette smoke; comorbidity; efavirenz; enzyme activity; health disparity; hydroxycotinine; inhibitor; innovation; interest; isoniazid; low and middle-income countries; mortality; novel marker; randomized trial; smoking cessation; smoking prevalence; social factors; treatment response

PROJECT SUMMARY Smoking rates in people living with HIV (PLWH) exceed 40%, nearly 3x uninfected individuals. Cardiovascular disease (CVD), including myocardial infarction (MI), is common in PLWH, in part due to smoking. Despite availability of smoking cessation pharmacotherapy, cessation rates among PLWH remain low. Frameworks for understanding smoking cessation emphasize biological, psychological, and social factors. However, critical gaps in identifying and addressing biological factors related to tobacco use among PLWH remain. In the general population, the rate at which nicotine is metabolized is an important biomarker of smoking behavior and treatment response. Greater CYP2A6 enzyme activity, as measured by higher nicotine metabolite ratios (NMR), results in: faster nicotine clearance, more cigarettes smoked per day, higher nicotine dependence, greater severity of withdrawal symptoms and reduced cessation. Recent work from our lab found significantly higher NMRs in HIV suggesting effects in HIV may differ. Differences in NMR may be affected by HIV infection and/or antiretroviral therapy (ART). HIV itself may increase NMR as CYP2A6 is induced by inflammation, which may mirror dysregulation caused by HIV infection. ART drugs may alter NMR via other mechanisms: they may reduce NMR by reducing inflammation via viral suppression, reduce NMR via CYP2A6 inhibition, or increase NMR via CYP2A6 induction. And these mechanisms may differ by ART drug. Moreover, the impact of higher NMR on smoking and complications of smoking (e.g., MI) among PLWH are currently unknown. Higher NMR influences smoking topography (e.g., higher puff volume), which is associated with greater exposure to inducers of inflammation and coagulation. While higher NMR increases lung cancer risk, its effect on MI is unknown. We propose to: 1) determine whether NMR is faster after HIV infection, relative to before, 2) determine whether viral suppression decreases NMR and whether the effect differs by ART drugs which do and do not alter CYP2A6 activity, 3) determine whether lower NMR predicts higher smoking cessation rates in PLWH on ART with viral suppression, and 4) determine whether NMR is a risk factor for MI in PLWH. We will conduct retrospective cohort studies with paired specimens for Aims 1 and 2 and nested case-control studies for Aims 3 and 4. Data and specimens will be obtained from the Multicenter AIDS Cohort Study (MACS) /Women's Intra-agency Health Study (WIHS) and the CFAR Network Integrated Clinical Systems (CNICS) databases and specimen repositories. Elucidating the relationship between HIV, ART, and smoking, may lead to the development of targeted interventions for smokers with HIV infection such as adding drugs that decrease CYP2A6 activity or switching off ART drugs that induce CYP2A6. If NMR is a predictor of MI, it will help us identify a subpopulation of PLWH in more urgent need of interventions. Smokers with HIV lose more life years to tobacco use than to HIV, partly due to increases in smoking-related comorbidities including CVD. Thus, interventions targeting HIV+ smokers may substantially reduce mortality globally.

项目摘要 艾滋病毒（PLWH）患者的吸烟率超过40％，近3倍未感染的人。心血管 疾病（CVD），包括心肌梗塞（MI），在PLWH中很常见，部分原因是吸烟。尽管 戒烟药物治疗的可用性，PLWH中的戒烟率仍然很低。框架 了解戒烟强调生物学，心理和社会因素。但是，批评 识别和解决与PLWH中烟草使用相关的生物学因素的差距仍然存在。在 普通人群，尼古丁代谢的速度是吸烟行为的重要生物标志物 和治疗反应。较高的CYP2A6酶活性，如较高的尼古丁代谢物比例测量 （NMR），结果：更快的尼古丁清除率，每天吸烟更多的香烟，较高的尼古丁依赖性， 戒断症状的严重程度更大，停止减少。我们实验室的最新工作发现 艾滋病毒中较高的NMR提示在HIV中的影响可能有所不同。 NMR的差异可能受HIV感染的影响 和/或抗逆转录病毒疗法（ART）。 HIV本身可能会增加NMR，因为CYP2A6是由炎症引起的， 这可能会反映由HIV感染引起的失调。艺术药物可能会通过其他机制改变NMR： 它们可能通过通过病毒抑制减少炎症来减少NMR，通过CYP2A6抑制减少NMR或 通过CYP2A6诱导增加NMR。这些机制可能因艺术药物而有所不同。而且， 目前尚不清楚吸烟和吸烟并发症（例如MI）的NMR较高。更高 NMR影响吸烟地形（例如，粉扑量更高），这与更大的暴露有关 炎症和凝结的诱导者。虽然较高的NMR增加了肺癌的风险，但其对MI的影响是 未知。我们建议：1）确定HIV感染后NMR是否相对于之前的2） 确定病毒抑制是否会降低NMR，以及该作用是否因ART药物而不同 并且不要改变CYP2A6活性，3）确定较低的NMR是否预测了较高的戒烟率 plwh on Art on Art具有病毒抑制作用，4）确定NMR是否是PLWH中MI的危险因素。我们将 用配对标本的目标1和2进行回顾性队列研究，并进行嵌套的病例对照研究 对于目标3和4。数据和标本将从多中心艾滋病队列研究（MAC）中获得 /妇女妇女内部健康研究（WIHS）和CFAR网络综合临床系统（CNICS） 数据库和标本存储库。阐明艾滋病毒，艺术和吸烟之间的关系可能会导致 为艾滋病毒感染的吸烟者开发有针对性的干预措施，例如添加药物 降低CYP2A6活性或关闭诱导CYP2A6的ART药物。如果NMR是MI的预测指标，它将 帮助我们确定PLWH的亚群，以更迫切需要干预。艾滋病毒的吸烟者损失更多 烟草使用比艾滋病毒的生命年，部分原因是包括CVD在内的与吸烟有关的合并症的增加。 因此，针对HIV+吸烟者的干预措施可能会大大降低全球死亡率。