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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 HIV 感染者 (PLWH) 的吸烟率超过 40%，几乎是未感染者的 3 倍。心血管包括心肌梗塞 (MI) 在内的疾病 (CVD) 在 PLWH 中很常见，部分原因是吸烟。尽管由于戒烟药物治疗的可用性，艾滋病病毒感染者的戒烟率仍然很低。框架理解戒烟强调生物、心理和社会因素。然而，关键在确定和解决与艾滋病病毒感染者中烟草使用相关的生物因素方面仍然存在差距。在一般人群中，尼古丁的代谢速率是吸烟行为的重要生物标志物和治疗反应。更高的 CYP2A6 酶活性（通过更高的尼古丁代谢物比率来衡量）（NMR），结果是：尼古丁清除速度更快，每天吸更多的香烟，尼古丁依赖性更高，戒断症状更严重，戒烟次数减少。我们实验室最近的工作发现显着 HIV 中较高的 NMR 表明对 HIV 的影响可能有所不同。 NMR 的差异可能会受到 HIV 感染的影响和/或抗逆转录病毒治疗（ART）。 HIV 本身可能会增加 NMR，因为 CYP2A6 是由炎症诱导的，这可能反映了艾滋病毒感染引起的失调。 ART 药物可能通过其他机制改变 NMR：它们可以通过抑制病毒来减少炎症来减少 NMR，通过抑制 CYP2A6 来减少 NMR，或者通过 CYP2A6 诱导增加 NMR。这些机制可能因 ART 药物而异。此外，影响目前尚不清楚 PLWH 中吸烟和吸烟并发症（例如 MI）的较高 NMR。更高 NMR 会影响吸烟形态（例如，较高的抽吸量），这与接触更多的烟雾有关炎症和凝血的诱导剂。虽然较高的 NMR 会增加患肺癌的风险，但它对 MI 的影响是未知。我们建议：1) 确定 NMR 在 HIV 感染后是否比之前更快，2) 确定病毒抑制是否会降低 NMR，以及不同 ART 药物的效果是否不同并且不改变 CYP2A6 活性，3) 确定较低的 NMR 是否预示较高的戒烟率 PLWH 接受 ART 病毒抑制治疗，4) 确定 NMR 是否是 PLWH 中 MI 的危险因素。我们将对目标 1 和 2 的配对样本进行回顾性队列研究以及巢式病例对照研究目标 3 和 4。数据和样本将从多中心艾滋病队列研究 (MACS) 中获取 /妇女机构内健康研究 (WIHS) 和 CFAR 网络综合临床系统 (CNICS) 数据库和样本库。阐明艾滋病毒、抗逆转录病毒治疗和吸烟之间的关系可能会导致为感染艾滋病毒的吸烟者制定有针对性的干预措施，例如添加以下药物：降低 CYP2A6 活性或关闭诱导 CYP2A6 的 ART 药物。如果 NMR 可以预测 MI，那么它会帮助我们确定更迫切需要干预的感染者亚群。感染艾滋病毒的吸烟者损失更多吸烟导致的生命年数高于艾滋病毒，部分原因是包括心血管疾病在内的吸烟相关合并症的增加。因此，针对艾滋病毒+吸烟者的干预措施可能会大大降低全球死亡率。