Therapeutic use of HPV L1 Vaccine in Anogenital Neoplasia: VIVA Trial

项目摘要 肛门和外阴高度上皮内病变（AIN 3/VIN 3）在初次治疗后经常复发，30% 治疗后5年内局部复发或进展。复发的surgery可能会使人虚弱 并与生活质量受损有关。大多数AIN 3/VIN 3（>90%）与人类相关。 乳头瘤病毒（HPV），和新的数据表明，治疗使用许可的预防性HPV疫苗 可以降低复发的风险。许可试验表明，HPV疫苗可预防AIN 3/VIN 3， 接种时HPV阴性（未感染）的女性。我们提出一个随机双盲安慰剂- 对照试验，以测试9价HPV疫苗（Gardasil 9）是否会减少以前的复发 未接种疫苗的人接受AIN 3/VIN 3治疗。一项非随机研究表明， 通过HPV疫苗接种，AIN 2/3的手术治疗减少了50%。此外，我们的初步研究表明， HPV 16抗体阳性的女性在VIN 3后复发的可能性低于那些没有HPV 16抗体阳性的女性。 未接种疫苗的女性中HPV 16抗体应答（风险比（HR）0.4，95% CI 0.2-0.9）。基于 根据先前的研究和我们的初步数据，我们假设AIN 3/VIN 3的高复发负担可能是 通过接种疫苗减少了50%。在初次手术治疗后，我们将345例患者随机分为 AIN 3/VIN 3接受9价Gardasil或安慰剂。主要终点是疫苗的有效性， 活检证实复发。这项研究名为HPV疫苗，以阻止外阴和肛门的进展， 病变试验（VIVA试验）也将评估疫苗在研究人群中的安全性。VIVA试验 包括对初始和复发病灶进行集中病理学审查，并对复发进行积极监测 在研究访视期间超过3年。次要终点将探索病因学问题，以评估是否 HPV感染和HPV抗体的持续存在与复发有关;这些数据最终可能 重要的是选择个体患者进行更密切的监测或更积极的治疗。我们 科学团队在进行疫苗试验、进行HPV监测和 组织病理学和进行HPV实验室测定。指定的研究病理学家将评价所有研究 活检以评估复发状态。这将是该概念在美国的首次试验，如果成功， 可能导致实践的变化，因为许可的HPV疫苗的管理将是一种低成本的额外措施， AIN 3/VIN 3的治疗。

PROJECT SUMMARY Anal and vulvar high-grade intraepithelial lesions (AIN3/VIN3) often recur after primary treatment, with 30% local recurrence or progression in the 5-years following treatment. Surgeries for recurrence can be debilitating and associated with compromised quality of life. Most AIN3/VIN3 (>90%) are associated with human papillomavirus (HPV), and emerging data suggest a therapeutic use of the licensed prophylactic HPV vaccine may reduce risk of recurrence. The licensure trials showed that the HPV vaccine prevents AIN3/VIN3 among women who were HPV negative (uninfected) at vaccination. We propose a randomized, double-blind, placebo- controlled trial to test whether the 9-valent HPV vaccine (Gardasil 9) will reduce recurrence in previously unvaccinated persons treated for AIN3/VIN3. A non-randomized study suggested that recurrence following surgical treatment for AIN2/3 was reduced by 50% by HPV vaccination. In addition, our pilot study showed that recurrence after VIN3 was less likely among HPV16 antibody positive women compared to those without an HPV16 antibody response (hazard ratio (HR) 0.4, 95% CI 0.2-0.9) among unvaccinated women. Based on prior studies and our pilot data, we hypothesize that the high burden of recurrence of AIN3/VIN3 could be reduced 50% by vaccination. Following primary surgical treatment, we will randomize 345 patients with AIN3/VIN3 to receive 9-valent Gardasil or placebo. The primary endpoint is the efficacy of the vaccine against biopsy-documented recurrence. The study, called the HPV Vaccine to Interrupt Progression of Vulvar and Anal Lesions Trial (the VIVA Trial), will also evaluate the safety of the vaccine in the study population. The VIVA trial includes centralized pathology review of initial and recurrent lesions and active surveillance for recurrence during study visits over 3 years. Secondary endpoints will explore etiologic questions to assess whether persistence of HPV infection and HPV antibodies are associated with recurrence; these data could eventually add importantly to selection of individual patients for closer monitoring or more aggressive treatment. Our scientific team has extensive expertise in conducting vaccine trials, conducting HPV surveillance and histopathology, and performing HPV laboratory assays. The designated study pathologist will evaluate all study biopsies to assess recurrence status. This will be the first US-based trial of the concept and, if it is successful, could lead to changes in practice, as administration of the licensed HPV vaccine would be a low-cost additional treatment for AIN3/VIN3.