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We sought to determine if the introduction of highly active antiretroviral therapy (HAART) corresponded with changes in anal squamous cell cancer rates among men with AIDSWe linked cancer registry data from 1988–2000 and AIDS registry data from 1981–July/2003 for San Diego County. We defined 1991–1995 and 1996–2000 as the pre- and post-HAART periods, respectively.The annual incidence of invasive anal cancer increased from zero per 100,000 men with AIDS aged 25 to 64 years (95% confidence interval [CI], 0–226) in 1991 to 224 per 100,000 (95% CI, 102–425) in the year 2000. Pre-HAART, the average annual incidence of invasive anal cancer was 49 per 100,000 men with AIDS aged 25 to 64 years (95% CI, 16–114) versus 144 per 100,000 (95% CI, 93–212) post-HAART. The relative risk of invasive anal cancer among men with AIDS compared with men without known HIV/AIDS was 98 (95% CI, 36–264) pre-HAART and 352 (95% CI, 186–669) post-HAART. The increased incidence of anal cancer among men with AIDS resulted in an increase in the overall rate of anal cancer among men in San Diego County.The rising incidence of anal cancer among men with AIDS may be related to increased longevity with HAART and the consequent increased time at risk for the development of malignancy and/or the result of greater use of cytologic screening.