Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA): A Trial Protocol

Abstract

Importance: Human papillomavirus (HPV), particularly HPV type 16, causes most anal and vulvar high-grade squamous intraepithelial lesions (HSIL), which are precursors to cancer. After initial treatment of HSIL, more than 30% of patients will have disease recurrence, with even higher recurrence among HIV-positive individuals and men who have sex with men. Recurrences can be debilitating and lead to significant morbidity and medical expense. Observational studies suggest a possible therapeutic benefit of the licensed HPV vaccines in reducing recurrent lesions in previously infected persons.

Objective: To test whether the licensed prophylactic HPV vaccine (Gardasil-9) can reduce the risk of HSIL recurrence by 50% in previously unvaccinated individuals recently treated for anal or vulvar HSIL.

Design, setting, and participants: This is a trial protocol for a randomized, double-blind, placebo-controlled, proof-of-concept clinical trial. Eligible participants are aged 27 to 69 at study start and have not received prior HPV vaccination, have had anal or vulvar HSIL diagnosed on or after January 1, 2014, and have no evidence of HSIL recurrence at screening. Persons infected with HIV are eligible for the study provided they are receiving antiretroviral therapy. Target enrollment is 345 individuals. The primary outcome is time to histopathologically confirmed recurrence of HSIL. Differences in the risk for recurrence of HSIL will be evaluated using Cox proportional hazard models. Additional analyses include (1) frequency of HSIL recurrence; (2) role of HPV antibodies in deterring recurrence; (3) role of HPV persistence in recurrence, as measured by HPV genotype or HPV-16 variant lineage determined using swab samples collected at months 0, 18, and 36; and (4) incidence of adverse events. The study will be conducted at the University of Washington Virology Research Clinic from 2017 through 2022. Participants will be followed up for up to 36 months in the clinic, and up to 42 months by telephone.

Discussion: Management of persistent or rapidly recurring anogenital HSIL remains challenging. Results from this study will provide evidence on whether incorporating the nonavalent HPV vaccine into routine care can decrease recurrence of anal and vulvar HSIL.

Trial registration: ClinicalTrials.gov identifier: NCT03051516.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Schouten reported grants from Fred Hutchinson Cancer Research Center during the conduct of the study. Dr Galloway reported personal fees from Merck outside the submitted work. Dr Wald reported grants from Vical and grants from Genocea outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram of the Vaccine to Interrupt Progression of Vulvar and Anal Neoplasia (VIVA) Trial

HSIL indicates high-grade squamous intraepithelial lesions; 9vHPV, nonavalent human papillomavirus vaccine.

Figure 2.. Allocation Algorithm for the Vaccine to Interrupt Progression of Vulvar and Anal Neoplasia Trial Using Dynamic Randomization

The procedure for randomizing a new participant is as follows. At the top level, within all those persons sharing the same anatomical site, HIV status, and category of time since diagnosis as the current participant to be enrolled, we check whether there are approximately equal numbers randomized to both groups. If strong imbalance exists (δ1 > 3, where δ is the difference between numbers enrolled to placebo and vaccine), then we force that participant into the group with fewer participants to improve the balance of characteristics between the vaccine and placebo groups. If no strong imbalance exists, we proceed to check the balance at the second level of hierarchy, and so on. We set δ1 = δ2 = δ3 = δ4 = 3. Dx indicates diagnosis; HSIL, high-grade squamous intraepithelial lesions.