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

项目总结 肛门和外阴高度上皮内病变(AIN3/VIN3)通常在初次治疗后复发，30% 治疗后5年内局部复发或进展。针对复发的手术可能会使人虚弱 并与生活质量受损有关。大多数AIN3/VIN3(&gt；90%)与人类有关 乳头瘤病毒(HPV)，以及新出现的数据表明，已获许可的预防性HPV疫苗可用于治疗 可能会降低复发的风险。许可试验表明，HPV疫苗可以预防AIN3/VIN3 接种时HPV阴性(未感染)的妇女。我们提出一种随机、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 未接种AIN3/VIN3疫苗的人接受治疗。一项非随机研究表明，以下是复发 通过接种HPV疫苗，AIN2/3的外科治疗减少了50%。此外，我们的初步研究表明， 与未感染HPV16抗体的妇女相比，HPV16抗体阳性妇女在VIN3感染后复发的可能性较小 未接种疫苗妇女的HPV16抗体应答(危险比(HR)0.4，95%可信区间0.2~0.9)。基于 以前的研究和我们的试点数据，我们假设AIN3/VIN3复发的高负担可能是 通过接种疫苗减少了50%。在初次手术治疗后，我们将随机选择345名 AIN3/VIN3接受9价Gardasil或安慰剂。主要的终点是疫苗的效力。 活组织检查显示复发。这项名为HPV疫苗的研究中断了外阴和肛门的进展 皮损试验(Viva试验)，还将在研究人群中评估疫苗的安全性。万岁审判 包括对初始和复发病变进行集中的病理检查，并积极监测复发情况 在3年以上的学习访问期间。次要终端将探索病因学问题，以评估 HPV感染的持续性和HPV抗体与复发有关；这些数据最终可能 重要的是选择个别患者进行更密切的监测或更积极的治疗。我们的 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实验室检测。指定的研究病理学家将对所有研究进行评估 活组织检查以评估复发情况。这将是这一概念在美国的首次试验，如果成功， 可能会导致实践上的变化，因为获得许可的HPV疫苗的管理将是一项低成本的额外 AIN3/VIN3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.