RISK OF ANAL CARCINOMA IN-SITU IN RELATION TO HUMAN-PAPILLOMAVIRUS TYPE-16 VARIANTS

Infection with human papillomavirus (HPV), especially HPV16, is centra l to the development of squamous anogenital cancers and their precurso r lesions, termed ''squamous intraepithelial neoplasias.'' Men who hav e sex with men, particularly those who are infected with HN, are at a high risk for anal infection with HPV16 and for low-grade anal neoplas ia; however, only a subset of these men develop anal invasive cancer o r its immediate precursor lesion, anal carcinoma in situ (CIS). To exa mine the hypothesis that certain variants of HPV16 are most strongly a ssociated with development of anal CIS, we followed 589 men who have s ex with men whose initial anal cytological smears did not show anal CI S. Anoscopy, anal cytology, and PCR-based assays for detection and cla ssification of HPV types were performed every 4-6 months, with HPV16 f urther classified by single-stranded conformation polymorphism analysi s as being a prototype-like (PL) or non-prototype-like (NPL) variant. Anal CIS was histologically confirmed in 6 of 384 (1.6%) consistently HPV16-negative men, in 12 of 183 (6.6%) men with HPV16 PL variants, an d in 4 of 22 (18.2%) men with HPV16 NPL variants. After adjustment for anal cytological diagnoses at study entry, HIV status and CD4 count, and detection of HPV types other than type 16, men with HPV16 NPL vari ants were 3.2 times (95% confidence interval, 1.0-10.3) more likely to develop anal CIS than were those with PL variants. Neither detection of HPV16 DNA at high levels nor detection of HPV16 DNA for a prolonged period, factors that we previously demonstrated to be associated with risk of high-grade anal squamous intraepithelial neoplasia, was signi ficantly associated with HPV16 NPL variants. The biological mechanism relating to this excess risk remains undetermined.