The incidence of anal cancer in the general population is higher among women than men, and has been rising steadily since the 1970s. Certain at-risk groups, including HIV-infected men and women are at especially high risk of anal cancer, and among HIV-infected men who have sex with men, the incidence of anal cancer may be as high as 131/100,000. Like cervical cancer, anal cancer is caused by HPV and is preceded by HPV-associated high-grade squamous intraepithelial lesions (HSIL). Like cervical cancer, anal cancer may be preventable through identification and treatment of anal HSIL.
Current methods of treatment for anal HSIL include various methods of physical removal (e.g., surgical excision, hyfrecation, infrared coagulation, laser) and use of topical creams (e.g., 5-fluorouracil, imiquimod). These are often painful and have limited efficacy. High rates of metachronous disease reflect persistence of an HPV reservoir capable of reactivation and producing new disease, and/or inability to completely clear existing lesions.
Improvements in understanding the biology of HPV infection and its role in pathogenesis of anal HSIL are leading to new approaches to treating anal HSIL. These include systemic approaches such as therapeutic vaccines targeting cells expressing HPV proteins such as E6 or E7. The anatomic location of anal HSIL also offers therapeutic opportunities for topical approaches, including the possibility of repeated application. These include drugs that interfere with expression of HPV oncogenes including siRNA and clustered regularly interspaced short palindromic repeats (CRISPR) approaches. Drugs that affect cellular pathways perturbed by HPV and which are important in pathogenesis of HSIL may include those that affect methylation status and microRNAs. Drugs that may stimulate cellular immune response to HPV are also being developed such as checkpoint inhibitors that block binding of programmed death ligand (PDL)-1 binding to the programmed cell death protein (PD-1).
Challenges to treatment include large lesions, multifocal disease and anatomic impediments that preclude complete treatment, such as hypertrophic papillae, crypts, hemorrhoids and folds. Treatments that target HPV gene products specifically or cellular pathways specifically altered by HPV infection, or treatments that augment cellular immune response to HPV proteins may provide an improved therapeutic index, particularly if they can be applied repeatedly with minimal inconvenience and toxicity to the patient.