SCIENTIFIC, TECHNICAL AND OTHER PROFESSIONAL SUPPORT SERVICES (STOPS)

意义和背景 对于美国普通人群来说，烟草使用障碍(TUD)被公认为是导致死亡的主要可预防原因1，2。没有被很好地认识到的是，在HIV感染者(PWH)中，烟草使用的流行率是普通人群的三倍，并且相应地增加了发病率和死亡率：TUD在PWH3，4有重大后果。虽然适当地强调通过使用更有效的抗逆转录病毒药物、免疫调节剂和消炎剂来提高PWH的生存质量和持续时间的复杂方法，但在这一人群中有效地治疗TUD可能至少与这些策略中的任何一种具有同等的益处。更有效地利用目前可用的治疗方法治疗TUD应该得到更广泛的实施，然而，任何现有方法的糟糕表现表明，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，威斯康星医院的心血管疾病发病率增加了两倍，与普通人群相比，患心血管疾病的风险增加了2倍5，而TUD放大了这种风险6，7。尽管发病率和死亡率不成比例，但与普通人群相比，威斯汀医院戒烟的可能性较小。关于PWH10，11的有效戒烟策略的研究很少，因为这些人被排除在评估药物戒烟策略有效性的研究7，12。关于PWH和戒烟13的为数不多的随机对照试验之一表明，与安慰剂相比，在PWH中使用varenicline是安全的，并且有更高的戒烟率，然而，18%的持续戒烟率显著低于varenicline(纳入非HIV感染者)III期临床试验中高达70%的戒烟率14。威尔斯亲王有效的戒烟策略和较低的戒烟率突显了治疗TUD的新治疗策略的必要性，以减少包括威尔斯亲王在内的所有人群中与烟草相关的发病率和死亡率。 与美国其他地区相比，DC的TUD高得不成比例。根据DC Cohort的数据(DC PFAP的一个预期队列，N=7160)，42.3%的人目前吸烟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人(3.6%)被诊断为慢性阻塞性肺病。此外，在2011年至201718年间，DC队列中非艾滋病定义的癌症的发病率高于定义艾滋病的癌症的发病率。最常见的癌症是乳腺癌、前列腺癌、皮肤癌、肛门癌、头颈部癌和肺癌18，所有这些癌症都与吸烟有关。 在美国，超过65%的当前吸烟者想要戒烟29，然而，在那些试图戒烟并在一年内重新开始吸烟的人中，超过50%的人30。复发的预测因素包括渴望31；在长期使用期间，渴望是由持续释放的多巴胺和杏仁核、前扣带回、眶前皮质和背外侧前额叶皮质的招募所调节的32。虽然这种多巴胺激增是包括尼古丁成瘾在内的成瘾的核心部分，但FDA批准的现有药物疗法的机制并不能解决与成瘾和复发相关的多巴胺激增和随后的渴望，从而容易失败的戒烟尝试。因此，调节中枢神经系统的多巴胺反应以减少烟草欲望是治疗TUD的一种尚未探索但重要的策略。 这项建议旨在评估一种使用ANS-6637来控制对烟草的渴望的新方法，ANS-6637是一种一流的乙醛脱氢酶2(ALDH-2)抑制剂，在动物模型中可以防止多巴胺激增，抑制对烟草的渴望，并减少尼古丁的使用。虽然该药物目前正处于治疗阿片类药物使用障碍和潜在的酒精使用障碍的早期开发阶段，但重要的是要认识到，所有物质使用障碍对一种药物干预的反应可能并不相同，所有患者组也不是相同的(例如，PWH和未感染艾滋病毒的患者)，因此，有必要进行单独的研究。人们可能认为这是内部筹资的一个明显目标，但与所有合乎逻辑的机构的辛勤努力表明，人们对TUD和艾滋病毒缺乏兴趣，尽管OAR认为这种疾病是优先事项。我们在杏仁核神经科学的发展计划方面与其密切联系，我们拥有现成的患者群体，关于马里兰州和哥伦比亚特区的TUD的良好数据，与生物相关性翻译问题的紧密联系，与该组织工作的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裔美国人患者服务，考虑到他们的TUD和CVD比率，这一人群尤其可以从成功的治疗策略中受益。这项研究是由NIH-CC CCMD、NIH CC PET、马里兰大学传染病大学、哥伦比亚特区艾滋病进展伙伴关系和马里兰大学精神病学系合作完成的。

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.