Determinants and Outcomes of Nicotine Metabolite Ratio in HIV + Smokers

项目总结 艾滋病病毒携带者(PLWH)的吸烟率超过40%，几乎是非感染者的3倍。心血管病 疾病(CVD)，包括心肌梗死(MI)，在PLWH中很常见，部分原因是吸烟。尽管 戒烟药物治疗的可获得性，PLWH中的戒烟率仍然很低。框架，适用于 了解戒烟强调生物、心理和社会因素。然而，关键是 在确定和解决与烟草使用有关的生物学因素方面，公共卫生部门仍然存在差距。在 在普通人群中，尼古丁的新陈代谢速度是吸烟行为的重要生物标志物 和治疗反应。通过更高的尼古丁代谢物比率来衡量更高的CYP2A6酶活性 (核磁共振)，结果是：尼古丁清除更快，每天吸烟更多，尼古丁依赖程度更高， 戒断症状更严重，戒断更少。我们实验室最近的研究发现， HIV中较高的NMRS表明对HIV的影响可能不同。核磁共振的差异可能受HIV感染的影响 和/或抗逆转录病毒疗法(ART)。HIV本身可能会增加核磁共振，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调节失调。抗逆转录病毒药物可能通过其他机制改变核磁共振： 它们可以通过抑制病毒减少炎症来降低核磁共振，通过抑制CYP2A6来降低核磁共振，或者 通过诱导CYP2A6提高核磁共振率。这些机制可能因抗逆转录病毒药物的不同而不同。此外， PLWH中关于吸烟和吸烟并发症(例如MI)的更高核磁共振目前尚不清楚。更高 核磁共振影响吸烟地形(例如，更高的烟雾量)，这与更多的暴露于 炎症和凝血的诱导物。虽然核磁共振较高会增加肺癌风险，但其对心肌梗死的影响是 未知。我们建议：1)确定感染HIV后核磁共振是否比感染前更快，2) 确定病毒抑制是否降低核磁共振，以及抗逆转录病毒药物是否有不同的作用 并且不改变CYP2A6的活性，3)确定较低的核磁共振是否预示着较高的戒烟率 4)确定核磁共振是否是PLWH中MI的危险因素。我们会 用AIMS 1和AIMS 2的配对样本进行回顾性队列研究和嵌套病例对照研究 对于目标3和4。数据和样本将从多中心艾滋病队列研究(MACS)获得 /妇女机构内健康研究(WIHS)和CFAR网络综合临床系统(CNICs) 数据库和标本储存库。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，如增加 降低细胞色素P450 2 A6活性或停用可诱导细胞色素P450 2 A6的抗逆转录病毒药物。如果核磁共振是MI的预测因子，它将 帮助我们确定更迫切需要干预的PLWH亚群。携带艾滋病毒的吸烟者损失更多 烟草使用的寿命比艾滋病毒少，部分原因是与吸烟有关的并发症增加，包括心血管疾病。 因此，针对艾滋病毒+吸烟者的干预措施可能会在全球范围内大幅降低死亡率。

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.