Cidofovir for Perianal Dysplasia in HIV Patients

西多福韦治疗 HIV 患者肛周发育不良

• 批准号: 6997638
• 负责人: ELIZABETH A. Stier
• 金额: $ 31.83万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997638
• 关键词: AIDS; HIV infections; biopsy; cervix neoplasms; cidofovir; clinical research; clinical trial phase II; gene expression; human papillomavirus; human subject; human therapy evaluation; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; nucleic acid methylation; opportunistic infections; patient oriented research; polymerase chain reaction; rectum neoplasms; squamous cell carcinoma; topical drug application; virus DNA; virus classification; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): High-grade perianal dysplasia (PAIN 2-3) occurs with increased frequency in HIV-infected patients. These anogenital skin lesions are frequently diffuse, treatment is associated with significant morbidity, recurrence rates after treatment are high, and invasive cancers may develop. For these reasons, there is a need for better-tolerated and effective therapy. Cidofovir has been reported to have activity against human papillomaviruses (HPV) and to induce regression of HPV-associated lesions when used topically. The primary aims of this clinical trial are to evaluate the efficacy and safety of topical cidofovir 1% for the treatment of PAIN 2-3 in HIV-infected patients. The study will also increase our knowledge of the biology of PAIN 2-3 in HIV-infected patients through exploratory studies evaluating the following aims: 1) To determine the HPV DNA types and HPV strain variants present in PAIN 2-3 and normal perianal tissue and determine if clinical regression is associated with clearance of HPV DNA; 2) To identify the HPV DNA types present in the anal canal and cervix and compare them with the HPV DNA of the perianus to determine if the HPV types associated with the perianal lesions are the same as those infecting the anal canal and cervix; 3) To determine if there are abnormally methylated genes in PAIN 2-3 compared with normal tissue and if these genes are the same or different from those that have been previously identified in anal and cervical dysplasia. Also, to investigate whether methylated genes are changed after treatment with cidofovir; 4) To characterize differences in gene expression in PAIN 2-3 compared with normal perianal tissue, and to examine changes in gene expression in PAIN after exposure to cidofovir with RNA microarray analysis and confirm results with real-time PCR. 5) To evaluate whether pretreatment CD4 count, HIV viral load, lesion size, methylation pattern, and/or HPV type/strain are correlated with the clinical efficacy of topical cidofovir. New anti-retroviral medications have increased the life expectancy of HIV-infected patients, but have not changed the incidence of dysplasias or cancers of the anogenital epithelium. Novel treatments, such as topical cidofovir, may prevent pre-cancerous lesions from developing into cancer in HIV-infected patients.

描述（由申请人提供）： HIV 感染者中，重度肛周发育不良 (PAIN 2-3) 的发生频率增加。这些肛门生殖器皮肤病变通常是弥漫性的，治疗与显着的发病率相关，治疗后的复发率很高，并且可能发展为浸润性癌症。由于这些原因，需要更好的耐受性和有效的治疗。据报道，西多福韦具有抗人乳头瘤病毒 (HPV) 的活性，并且局部使用时可诱导 HPV 相关病变消退。该临床试验的主要目的是评估外用 1% 西多福韦治疗 HIV 感染患者的 PAIN 2-3 的有效性和安全性。该研究还将通过评估以下目标的探索性研究来增加我们对 HIV 感染患者中 PAIN 2-3 生物学的了解： 1) 确定 PAIN 2-3 和正常肛周组织中存在的 HPV DNA 类型和 HPV 毒株变异，并确定临床消退是否与 HPV DNA 的清除相关； 2）鉴定肛管和宫颈中存在的HPV DNA类型，并将其与肛周HPV DNA进行比较，以确定与肛周病变相关的HPV类型是否与感染肛管和宫颈的HPV类型相同； 3) 确定PAIN 2-3中与正常组织相比是否存在异常甲基化基因，以及这些基因与先前在肛门和宫颈发育不良中鉴定的基因是否相同或不同。此外，研究西多福韦治疗后甲基化基因是否发生改变； 4) 与正常肛周组织相比，表征 PAIN 2-3 中基因表达的差异，并通过 RNA 微阵列分析检查暴露于西多福韦后 PAIN 中基因表达的变化，并通过实时 PCR 确认结果。 5) 评估治疗前CD4计数、HIV病毒载量、病变大小、甲基化模式和/或HPV类型/毒株是否与外用西多福韦的临床疗效相关。 新的抗逆转录病毒药物延长了艾滋病毒感染者的预期寿命，但并没有改变肛门生殖器上皮发育不良或癌症的发生率。新的治疗方法，例如外用西多福韦，可以防止艾滋病毒感染患者的癌前病变发展为癌症。