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Oral human papillomavirus (HPV) infection is the principal cause of a distinct form of oropharyngeal cancer (OPCA) that has been rising in incidence in the United States since 1973, particularly among young men. The possible contribution of the HIV-epidemic to this increase is unclear.Incidence rates for HPV-related OPCA increased with age and were strongly influenced by year of birth in the United States (cohort effect). Persons with HIV/AIDS are at increased risk (∼two to six-fold) for OPCA relative to the general population. However, this excess risk may be attributable to tobacco smoking rather than the three-fold higher prevalence of oral HPV infection in this population. Consistent with a viral attribution, however, is the apparent increase in risk of OPCA with severity of AIDS-related immunosuppression. Analogous to other HPV-related cancers (e.g. cervical and anal cancer), trends over time do not appear to be influenced by highly active antiretroviral (HAART) therapy.Healthcare providers may encounter HPV-related OPCA more frequently among individuals with HIV/AIDS as this population ages and due to the strong birth cohort effects observed in the general population. However, there is no evidence in support of different incidence trends over time among persons with and without HIV/AIDS.