Therapeutic Vaccination Against Human Papillomavirus Type 16 for the Treatment of Anal Intraepithelial Neoplasia in HIV+ Men

Rationale: Since the introduction of combination antiretroviral therapy (cART), human immunodeficiency virus (HIV)-related morbidity and mortality have considerably decreased. However, as a result of the significantly prolonged life span of HIV-positive patients, 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 cancer precursor lesions: anal intraepithelial neoplasia (AIN). Over 90% of HIV-positive MSM have persisting anal HPV infection, in 88% of patients high-risk HPV is present, and high-grade disease (AIN 2 or 3, HG AIN) is present in 25-52% of all HIV+ MSM. The majority of HG AIN is caused by HPV type 16. As in cervical intraepithelial neoplasia, early diagnosis and treatment of AIN have been advocated to prevent malignancy.

Several treatment options exist for AIN, but success rates are disappointingly low. An alternative strategy might be therapeutic HPV vaccination. In women with vulvar intraepithelial neoplasia (VIN), a condition with a comparable pathogenesis, therapeutic vaccination with a synthetic long-peptide vaccine SLP-HPV-01® , consisting of a mix of long peptides from the HPV-16 viral oncoproteins E6 and E7, was well tolerated, and proved to be effective in a high percentage of women, with a durable response, and induction of HPV-16-specific immunity.

Objective: The objective of the current proposal is to assess, in a phase 1/2 study, the safety and efficacy of this synthetic vaccine SLP-HPV-01® in HIV+ men with CD4 counts > 350 x 10E6/l and intra-anal high-grade, HPV16 positive AIN, who failed on previous treatment.

Study population: HIV-positive MSM with a CD4 count > 350 cells/ul with HPV16-induced intra-anal high-grade AIN (grade 2-3) that was resistant to, or recurred after conventional cauterization or other forms of local treatment.

During the past years the study group in the Academic Medical Center in Amsterdam has built a large cohort of well-characterized HIV-positive patients with histology-proven AIN. Material has been stored of these patients and their lesions. Those patients with AIN resistant to previous treatment will be identified. The causative HPV type will be determined in stored biopsies of these patients, using microdissection (LCM) and in-situ PCR. Only patients with HPV-16-induced lesions (the majority of patients) will be eligible for the current study.