ANAL NEOPLASIA CHEMOPREVENTION IN HIV SEROPOSITIVE MEN

与艾滋病毒相关的肛门癌发病率似乎在增加 流行病。在旧金山和西雅图进行的关于患病率的平行研究， 肛门癌前驱病变的发展和自然病史 显示这些病变(肛门上皮内瘤变或AIN)非常 在男同性恋者中很常见，但在艾滋病毒血清阳性(HIV+)中尤为常见 男人。我们检测到了高级别的AIN(HGAIN)，被认为是 与随后的肛门癌发展关系最密切的是，6% HIV+男性；此外，HIV+男性患HGAIN的可能性比 是HIV血清阴性(HIV-)的男性。肛门癌和宫颈癌在 常见，其前驱病变(AIN和宫颈肿瘤(CIN))也是如此。 宫颈上皮内瘤变的治疗成功地降低了宫颈侵袭率 癌症，我们相信对AIN的有效治疗将有类似的 对浸润性肛门癌发病率的影响。一期消融治疗 被认为是AIN的标准治疗方法，尽管这还不是 系统评估。也有可能在HIV+的情况下进行消融治疗 受试者会导致肛门疾病的高复发率，这是基于 有限的男性数据和初步数据表明CIN复发率较高 HIV+妇女中的感染率。我们提议进行一项合作的I-II期试验 异维甲酸或异维甲酸和干扰素-α的组合物 (干扰素)作为一次消融治疗的辅助，将设在加州大学旧金山分校和 华盛顿大学。目标是：1)确定最大值 异维A酸加干扰素和不加干扰素的耐受量(MTD)(I期)，以及 2)评估单独一次消融或消融加消融的效果 辅助化疗预防AIN复发(II期)。 受试者将从正在进行的研究中登记的HIV+男性中招募 两个临床点的肛门肿瘤。每组最多21名受试者 网站将在第一阶段研究中注册；研究对象在西雅图注册 在旧金山注册的受试者的CD4计数将超过300 让CD4低于300。第二阶段的研究将招募39名患有 HGAIN患者将随机分为三组：初级消融组 单独治疗；一期消融加异维A酸；或一期治疗 消融治疗加异维甲酸和干扰素。每门课都要认真学习 监测药物毒性，并将跟踪一年以确定 人乳头瘤病毒的复发率及治疗效果 DNA水平。这些数据将对未来第三阶段的设计非常重要 试验，并最终将在开发中潜在地有用 预防HIV感染者发生鳞状细胞癌的策略 还有女人。

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.