HPV vaccination after treatment of anal intraepithelial neoplasia

Since the introduction of combination antiretroviral therapy (cART), HIV-related morbidity and mortality have considerably decreased. However, as a result of the significantly prolonged life span, new causes of morbidity and mortality have become evident. In particular, anal cancer incidence has increased dramatically in HIV-positive men. Like cervical cancer, anal cancer is causally linked to infections with high-risk papillomaviruses (HPV), and is preceded by precursor lesions: anal intraepithelial neoplasia (AIN). Over 90% of HIV-positive MSM have persisting anal HPV infection, and high-grade (HG) AIN is present in 30% of all HIV+ MSM, i.e. 3000-6000 MSM with HG AIN in the Netherlands. As in cervical intraepithelial neoplasia, early diagnosis and treatment of AIN have been advocated to prevent malignancy. Electrocoagulation/cauterization is standard of care for intra-anal AIN, but after treatment, recurrence of lesions occurs in approx. 30-40% of cases. This is a major problem in an effective screening program for AIN. In a nonconcurrent cohort study qHPV vaccination significantly (HR 0.50) reduced HG AIN recurrence among MSM successfully treated for AIN. This is in accordance with findings in women treated for cervical intraepithelial neoplasia. Previous vaccination with quadrivalent HPV vaccine among women who had surgical treatment for HPV related disease significantly reduced the incidence of subsequent HPV related disease, including high grade disease. Therefore, a strategy that is worth investigating is vaccination with the qHPV vaccine to prevent recurrences in HIV+ MSM who were successfully treated for HG AIN. The OBJECTIVE of the current study is to assess the efficacy and safety of qHPV vaccination in HIV+ MSM with CD4 counts > 350 x 10E6/l who were successfully treated for high-grade AIN. DESIGN: multicentre, double-blind RCT Main INCLUSION CRITERIA are: HIV+ MSM, CD4 count > 350/ul, with biopsy-proven intra-anal high-grade AIN which was successfully treated with cauterization, cryotherapy, Efudix or imiquimod. INTERVENTION: Patients will be vaccinated 3 times with the qHPV vaccine (Gardasil) or matching placebo, at months 0,2 and 6. ASSESSMENTS - Safety Monitoring for spontaneous adverse events and injection-site reactions, clinical assessments, and laboratory tests will be performed after each vaccination and thereafter every 6 months for a total of 12 months of follow-up. - Efficacy: screening for AIN will be performed by high-resolution anoscopy (HRA), at inclusion (first vaccination) and at last vaccination (6 months), and repeated at 6 and 12 months after the last vaccination. The transformation zone will be photographed at each visit. Detailed photos plus biopsies of suspected lesions will be obtained. All histologic results will be evaluated in a blinded fashion with respect to clinical outcome. PRIMARY END POINTS will be recurrence of HG AIN at 6 and 12 months after the last vaccination, as assessed by HRA, with biopsies taken in case of remaining lesions. SECONDARY outcome measures are toxicity/safety, recurrence of Low Grade (LG)AIN at 6 and 12 months, and causative HPV type in recurrent AIN lesions, as assessed by LCM/PCR. STATISTICAL ANALYSIS The main analysis will focus on the primary outcome in a comparison between the trial treatment groups. The statistical analysis will include the use of Kaplan-Meier analysis and Cox proportional hazards analysis. REQUIRED SAMPLE SIZE is 190 patients. TIME SCHEDULE: months 1-4: preparation of the study and obtaining ethical approval Month 5-28: enrolment of patients Month 34: last vaccination in last enrolled patient Month 46: last follow-up visit of last enrolled patient Month 46-48: analysis of results