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.
More than 90% of high-grade anal and vulvar precancerous lesions are caused by HPV, and 30% of patients with these precancers will have a local recurrence or progression of their disease in the 5-years following initial surgery. Recurrences can be debilitating, and have been associated with disfiguring tissue removal and loss of function. We propose a clinical trial to test whether the licensed HPV vaccine (Gardasil 9) can reduce the rate of recurrence by 50% in previously unvaccinated individuals recently treated for anal and vulvar precancerous lesions