SCIENTIFIC, TECHNICAL AND OTHER PROFESSIONAL SUPPORT SERVICES (STOPS)

意义和背景 对于美国的一般人群，烟草使用障碍（TUD）被公认为是主要的可预防的死亡原因1，2。没有得到充分认识的是，在艾滋病毒感染者（PWH）中，烟草使用的流行率是普通人群的三倍，相应的发病率和死亡率增加：TUD对PWH有重大影响3，4。虽然有适当的强调复杂的方法，以提高质量和生存期的PWH使用更有效的抗逆转录病毒药物，免疫调节剂，抗炎药，有效治疗TUD在这一人群中可能至少有相当的好处，这些策略。应更广泛地实施更有效地使用目前可用的TUD治疗方式，然而，目前任何方法的不良性能表明，需要新的和更有效的干预措施。 我们小组进行的一项系统回顾显示，在过去20年中，PWH的CVD发生率增加了两倍，与普通人群相比，CVD的风险增加了2倍5，TUD放大了这种风险6，7。尽管患病率和死亡率不成比例，但与普通人群相比，PWH戒烟的可能性较低7 -9。关于PWH有效戒烟策略的研究很少10，11，因为这些人被排除在评估药物戒烟策略疗效的研究之外7，12。为数不多的关于威尔斯亲王医院和戒烟的随机对照试验之一13表明，与安慰剂相比，使用伐尼克兰是安全的，并且在威尔斯亲王医院中的戒烟率更高，然而，18%的持续戒烟率显著低于伐尼克兰III期临床试验（招募非艾滋病毒感染者）中高达70%的戒烟率14。由于缺乏循证有效的戒烟策略，以及PWH的戒烟率较低，因此需要针对TUD制定新的治疗策略，以降低所有人群（包括PWH）的烟草相关发病率和死亡率。 与美国其他地区相比，DC的TUD不成比例地高。根据DC队列数据（作为DC PFAP一部分的前瞻性队列，N=7160），42.3%为当前吸烟者15，而美国的估计患病率为17.1% 16，17。2016年，在6，329名DC队列参与者中，230名（3.6%）患有COPD。此外，2011年至2017年期间，DC队列中非艾滋病定义癌症的发病率高于艾滋病定义癌症18。最常见的癌症是乳腺癌、前列腺癌、皮肤癌、肛门癌、头颈癌和肺癌18，所有这些癌症都与吸烟有关19 -28。 在美国，超过65%的吸烟者想要戒烟29，然而，超过50%的试图戒烟的人在一年内复发并开始再次吸烟30。复发的预测因素包括渴望31;在长期使用期间，渴望是由多巴胺的持续释放和杏仁核、前扣带回、眶额皮质和背外侧前额叶皮质的募集介导的32。虽然这种多巴胺激增是成瘾的核心部分，包括尼古丁成瘾33，但现有FDA批准的药理学治疗机制并未解决与成瘾和复发相关的多巴胺激增和随后的渴望，因此容易导致失败的戒烟尝试。因此，调节中枢神经系统多巴胺反应以减少烟草渴求是治疗TUD的一种未探索但重要的策略。 该提案旨在评估一种使用ANS-6637管理烟草渴望的新方法，ANS-6637是一种一流的醛脱氢酶2（ALDH-2）抑制剂，可防止多巴胺激增，抑制渴望，并减少动物模型中的尼古丁使用。虽然该药物目前处于阿片类药物使用障碍和酒精潜在的早期开发阶段，但重要的是要认识到所有物质使用障碍可能对一种药物干预的反应不同，并且所有患者组也不相同（例如PWH和非HIV感染），因此需要进行单独的研究。人们可能会认为，这是一个明显的目标，校内资金，但勤奋的努力与所有逻辑研究所表明缺乏兴趣，在TUD和艾滋病毒，虽然OAR认为这种发病率是一个优先事项。我们与杏仁核神经科学在其发展计划方面保持密切联系，我们有一个现成的患者群体，关于马里兰州和哥伦比亚特区TUD的良好数据，与生物相关的翻译问题的密切联系，与该小组工作人员现有诊所的适当患者群体的密切联系，以及快速方案实施和完成的跟踪记录。我们在巴尔的摩和华盛顿特区的诊所几乎只为低收入的非洲裔美国人患者提供服务，鉴于其TUD和CVD的发病率，这一人群尤其可以从成功的治疗策略中获益。这项研究是NIH-CC CCMD、NIH CC PET、马里兰州传染病大学、哥伦比亚特区艾滋病进展合作伙伴和马里兰州大学精神病学系的合作。

Significance and Background For the general population of the United States, tobacco use disorder (TUD) is well-recognized to be the leading preventable cause of death1,2. What is not as well appreciated is that in people with HIV (PWH), the prevalence of tobacco use is three times higher compared to the general population, and there is corresponding enhanced morbidity and mortality: TUD has substantial consequences in PWH3,4. While there is appropriate emphasis on sophisticated approaches to enhancing the quality and duration of survival for PWH by using more potent antiretrovirals, immunomodulators, and anti-inflammatory agents, effective treatment of TUD in this population would likely have at least comparable benefit to any of these strategies. More effective use of currently available therapeutic modalities for TUD should be implemented more widely, however, the poor performance of any current approach suggests that new and more effective interventions are needed. A systematic review conducted by our group shows the rates of CVD have tripled in PWH in the last 2 decades, conferring a 2-fold risk for CVD compared to the general population5, and TUD magnifies this risk6,7. Despite the disproportionate morbidity and mortality, PWH are less likely to quit smoking compared to the general population7-9. There is a scarcity of research on effective smoking cessation strategies for PWH10,11, since these individuals were excluded from studies evaluating the efficacy of pharmacologic smoking cessation strategies7,12. One of the few randomized control trials available on PWH and smoking cessation13 demonstrated that the use of varenicline was safe and had a higher rate of smoking cessation in PWH compared to placebo, however, the continued abstinence rate of 18% was significantly lower than the rate of up to 70% in phase III clinical trials of varenicline(which enrolled non-HIV infected individuals)14. The lack of evidence-based, effective smoking cessation strategies and the low smoking cessation rates among PWH highlight the need for novel therapeutic strategies for TUD in order to reduce tobacco-related morbidity and mortality in all populations, including PWH. TUD in DC is disproportionately high compared to other areas in the U.S. According to DC Cohort data (a prospective cohort that is a part of DC PFAP, N=7160), 42.3% are current smokers15, compared to an estimated prevalence of 17.1% in the United States16,17. In 2016, of 6,329 DC cohort participants, 230 (3.6%) had an incident diagnosis of COPD. In addition, the incidence of non-AIDS defining cancers was higher than AIDS-defining cancers in the DC Cohort between 2011 and 201718. The most common cancers were breast, prostate, skin, anal, head/neck, and lung cancer18, all of which are associated with tobacco use19-28. More than 65% of current smokers in the U.S. want to quit smoking29, however, over 50% of those who attempt to quit relapse and begin smoking again within a year30. Predictors of relapse include craving31; during chronic use, craving is mediated by the persistent release of dopamine and recruitment of the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex32. Though this dopamine surge is a central part of addictions, including addiction to nicotine33, the mechanisms of the available FDA- approved pharmacologic therapies do not address the dopamine surge and subsequent craving that is associated with addiction and relapse, thus predisposing to failed quit attempts. Therefore, modulating the CNS dopamine response in order to reduce tobacco craving is an unexplored but important strategy to treat TUD. This proposal aims to assess a novel approach to managing craving for tobacco using ANS-6637, a first-in-class aldehyde dehydrogenase 2 (ALDH-2) inhibitor, which prevents dopamine surge, inhibits craving, and decreases nicotine use in animal models. While this drug is currently in early stage development for opioid use disorder and potentially for alcohol, it is important to recognize that all substance use disorders may not respond identically to one pharmacologic intervention and all patient groups are not identical (e.g. PWH and non-HIV infected), therefore, separate investigations are warranted. It might be thought that this was an obvious target for intramural funding but assiduous efforts with all logical institutes have indicated lack of interest in TUD and HIV, although OAR considers such morbidities to be a priority. We are in close contact with Amygdala Neurosciences in terms of its development plans, and we have a ready population of patients, good data about TUD in Maryland and the District of Columbia, strong links to translational issues with biologic correlates, close ties to the appropriate populations of patients in existing clinics which this group staffs, and a track record of rapid protocol implementation and completion. Our clinics in Baltimore and DC serve low-income African American patients almost exclusively, and this population in particular could derive benefit from a successful treatment strategy, given its rates of TUD and CVD. This study is a collaboration between NIH-CC CCMD, NIH CC PET, University of Maryland Infectious Diseases, District of Columbia Partnership for AIDS Progress, and the University of Maryland Department of Psychiatry.