Determinants and Outcomes of Nicotine Metabolite Ratio in HIV + Smokers

项目摘要 艾滋病毒感染者（PLWH）的吸烟率超过40%，几乎是未感染者的3倍。心血管 包括心肌梗死（MI）在内的心血管疾病（CVD）在PLWH中很常见，部分原因是吸烟。尽管 由于缺乏戒烟药物治疗，艾滋病毒携带者和艾滋病患者的戒烟率仍然很低。框架 了解戒烟强调生物，心理和社会因素。然而， 在确定和解决与艾滋病毒携带者吸烟有关的生物因素方面仍然存在差距。在 一般人群中，尼古丁代谢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测量 (NMR)结果：尼古丁清除更快，每天吸烟更多，尼古丁依赖性更高， 更严重的戒断症状和减少停止。我们实验室最近的研究发现 HIV中较高的NMR表明对HIV的影响可能不同。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是由炎症诱导的， 这可能反映了HIV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减少炎症来减少NMR，通过抑制CYP2A6来减少NMR，或 通过CYP2A6诱导增加NMR。这些机制可能因ART药物而异。此外， 对吸烟和吸烟并发症的更高NMR（例如，目前尚不清楚。更高 NMR影响吸烟形貌（例如，更高的抽吸量），这与更大的暴露于 炎症和凝血的诱导剂。虽然较高的NMR会增加肺癌风险，但其对MI的影响是 未知我们建议：1）确定NMR是否在HIV感染后比感染前更快，2） 确定病毒抑制是否会降低NMR，以及ART药物的效果是否不同， 不改变CYP2A6活性，3）确定较低的NMR是否预示着较高的戒烟率， PLWH对ART与病毒抑制，以及4）确定NMR是否是PLWH中MI的风险因素。我们将 使用目的1和2的配对样本进行回顾性队列研究和巢式病例对照研究 目标3和4。数据和标本将从多中心艾滋病队列研究（MACS）中获得 /妇女机构内保健研究和CFAR网络综合临床系统 数据库和标本库。阐明艾滋病毒，ART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，例如增加药物， 降低CYP2A6活性或关闭诱导CYP2A6的ART药物。如果NMR是MI的预测因子， 帮助我们确定更迫切需要干预的艾滋病毒携带者亚群。携带艾滋病毒的吸烟者损失更多 吸烟与艾滋病毒感染的相关性比吸烟与艾滋病毒感染的相关性高，部分原因是吸烟相关的合并症（包括心血管疾病）增加。 因此，针对艾滋病毒阳性吸烟者的干预措施可能会大大降低全球死亡率。

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.