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.