ANAL NEOPLASIA CHEMOPREVENTION IN HIV SEROPOSITIVE MEN

肛门癌的发病率似乎与艾滋病毒有关 疫情在旧金山弗朗西斯科和西雅图进行的关于患病率的平行研究， 肛门癌前病变的发展和自然史 显示这些病变（肛门上皮内瘤变或AIN）非常 常见于男同性恋者，尤其是HIV阳性者（HIV+） 男人我们已经检测到高级别AIN（HGAIN），病变被认为是 与随后的肛门癌的发展密切相关，占6% HIV+男性;此外，HIV+男性比HIV+男性更容易发展HGAIN。 是HIV血清阴性（HIV-）男性。肛门癌和宫颈癌的发病率 常见，其前驱病变（AIN和宫颈瘤样病变（CIN））也是如此。 CIN的治疗成功地降低了浸润性宫颈癌的发生率， 癌症，我们相信有效的治疗AIN将有类似的 对浸润性肛门癌发病率的影响。初次消融治疗 被认为是AIN的标准治疗，尽管这还没有被 系统评价。在HIV+患者中进行消融治疗也可能 受试者导致肛门疾病的高复发率， 男性数据有限，初步数据表明CIN复发率较高 艾滋病毒阳性妇女的感染率。我们提议进行一项合作的I-II期试验 或异维A酸和干扰素-α的组合 (IFN)作为主要消融治疗的辅助治疗，将在加州大学旧金山分校进行， 华盛顿大学。目的是：1）确定最大 异维A酸联合和不联合IFN的耐受剂量（MTD）（I期），以及 2)评价单纯初次消融或消融加 持续化疗预防AIN复发（II期）。 将从入组正在进行的研究的HIV阳性男性中招募受试者 肛门肿瘤在两个临床部位。每次最多21名受试者 研究中心将入组I期研究;受试者在西雅图入组 CD 4计数高于300，在San弗朗西斯科入组的受试者将 CD 4细胞低于300 II期研究将招募39名男性， HGAIN患者将被随机分为三组之一： 单独治疗;原发性消融治疗加异维甲酸;或原发性 消融治疗加异维甲酸和IFN。每一个主题都将被仔细地 监测药物毒性，并将随访一年，以确定 AIN复发率和治疗对人乳头瘤病毒的影响 DNA水平。这些数据对未来第三阶段的设计很重要 试验，最终，将是潜在的有用的发展， 预防HIV感染男性鳞状细胞癌的策略 和妇女

Anal cancer incidence appears to be increasing in association with the HIV epidemic. Parallel studies in San Francisco and Seattle of the prevalence, development and natural history of anal cancer precursor lesions have shown that these lesions (anal intraepithelial neoplasia or AIN) are very common among homosexual men but particularly among HIV seropositive (HIV+) men. We have detected high grade AIN (HGAIN), the lesion thought to be most closely associated with development of subsequent anal cancer, in 6% of HIV+ men; furthermore, HIV+ men are more likely to develop HGAIN than are HIV seronegative (HIV-) men. Anal and cervical cancer share much in common, as do their precursor lesions (AIN and cervical neoplasia (CIN)). Treatment of CIN has successfully reduced the rates of invasive cervical cancer, and we believe that effective therapy for AIN will have a similar effect on the incidence of invasive anal cancer. Primary ablative therapy is considered the standard treatment for AIN, although this has not been systematically evaluated. It is also likely that ablative therapy in HIV+ subjects results in high recurrence rates of anal disease, based on very limited data in men and preliminary data indicating high CIN recurrence rates among HIV+ women. We are proposing a collaborative phase I-II trial of isotretinoin or a combination of isotretinoin and interferon-alpha (IFN) as an adjunct to primary ablative therapy, to be based at UCSF and the University of Washington. The aims are to: 1) determine the maximum tolerated dose (MTD) of isotretinoin with and without IFN (Phase I), and 2) evaluate the efficacy of primary ablation alone, or ablation plus adjunctive chemotherapy in preventing recurrence of AIN (Phase II). Subjects will be recruited from among HIV+ men enrolled in ongoing studies of anal neoplasia at the two clinical sites. Up to 21 subjects at each site will be enrolled in the phase I study; subjects enrolled in Seattle will have CD4 counts above 300, subjects enrolled at San Francisco will have CD4 counts below 300. The phase II study will enroll 39 men with HGAIN who will be randomized into one of three groups: primary ablative therapy alone; primary ablative therapy plus isotretinoin; or primary ablative therapy plus isotretinoin and IFN. Each subject will be carefully monitored for drug toxicity and will be followed for one year to determine AIN recurrence rates and the effect of treatment on human papillomavirus DNA levels. This data will be important for the design of future Phase III trials, and ultimately, will be potentially useful in developing strategies for preventing squamous cell carcinoma among HIV infected men and women.