Cases occurred throughout the 22-year follow-up period, including 9 cases in the pre-HAART (1984-1995) and 19 in the HAART (1996-2006) era. Age, HIV viral load, and CD4 cell count at diagnosis varied considerably (Table 1). HIV-positive anal cases included both men with suppressed HIV viral RNA and high CD4 cell count and severely immunocompromised men. Among HIV-positive cases, half were diagnosed with an AIDS-defining condition at time of their anal cancer diagnosis (Table 1). This proportion was higher among HIV-positive cases in the pre-HAART (4 of 5) than the HAART era (7 of 17). When diagnosed with anal cancer, 27% of the HIV-positive cases were HAART naive. However, this included men who developed cancer in the pre-HAART era. Of the 16 cases which occurred in the HAART era, 15 (94%) started HAART before their cancer diagnosis.
The overall incidence of anal cancer was 37 per 100,000 person-years [95% confidence interval (CI) = 25 to 53] and that of confirmed ASCC cases was 22 per 100,000 person-years (95% CI = 14 to 36). Anal cancer incidence was 5-fold higher among HIV-positive men (IR = 69 per 100,000 person-years, 95% CI = 46 to 105) than among HIV-negative men (IR = 14 per 100,000 person-years, 95% CI = 6 to 30). Among HIV-positive men, the incidence of anal cancer was more than 4-fold higher in the HAART era (1996-2006; 137 per 100,000 person-years, 95% CI = 84 to 224) than in the pre-HAART era (1984-1995; IR = 30 per 100,000 person-years, 95% CI = 13 to 66).
Risk factors for anal cancer were explored using time-to-event analysis. In univariate analysis, risk of anal cancer increased nonsignificantly with increasing age (P trend = 0.15). Men with 7 or more unprotected anal receptive sexual partners at the first 3 study visits had significantly higher risk of anal cancer (RH = 2.7, 95% CI = 1.08 to 6.5) compared with men with no unprotected receptive anal sex partners. Additionally, a dose-response trend was suggested by significantly increasing risk with increasing number of unprotected receptive anal sex partners (P trend = 0.03, Table 2). Consistent with this finding, the median number of unprotected receptive anal sex partners reported in the initial 3 study visits was significantly higher in anal cancer cases than in other study participants (P = 0.018, Fig. 1). Results were similar when the sexual risk behavior analyzed was number of unprotected receptive anal sex partners reported in the 6 months before baseline (P trend = 0.06) or lifetime number of sexual partners reported at baseline (P trend = 0.07). In analysis limited to confirmed ASCC, history of more than 100 lifetime sexual partners was similarly associated with increased cancer risk (hazard ratio = 5.5, 95% CI = 0.67 to 44) but did not reach statistical significance due to the smaller number of cases.
HIV-positive men had a significantly higher risk of anal cancer (RH = 5.1, 95% CI = 2.1 to 12.6) or confirmed ASCC (RH = 10.4, 95% CI = 2.1 to 50) than HIV-negative men. Among HIV-positive men, anal cancer risk was significantly elevated in men with nadir CD4 cell count <200 cells/μL (RH = 3.3, 95% CI = 1.4 to 7.9) but was not associated with HIV viral load (Table 2). Risk of anal cancer was also significantly higher in ever-smokers than never-smokers (RH = 3.9, 95% CI = 1.2 to 12.8), but there was no evidence of increasing risk with current dose of tobacco used (Table 2).
To evaluate whether HAART therapy had an effect on anal cancer risk, we considered both ever and current HAART use. In analysis restricted to data during the HAART era, risk of anal cancer was elevated but was not significantly different in HIV-positive current HAART users and nonusers (RH = 1.8, 95% CI = 0.5 to 6.4) or HIV-positive ever and never HAART users (RH = 1.7, 95% CI = 0.23 to 13). In contrast, risk of rectal adenocarcinomas was more than 4-fold lower among ever than never HAART users (RH = 0.22, 95% CI = 0.02 to 3.13), suggesting a possible decrease in risk of these cancers with HAART use.
As age is an important risk factor for anal cancer, we further evaluated the difference in anal cancer risk in the HAART and pre-HAART eras using a Kaplan-Meier curve to examine risk in each era by participants' age (Fig. 2). These data suggest greater cancer risk (ie, shorter time to anal cancer) among HIV-positive than HIV-negative men (P < 0.001). These differences were more pronounced in the HAART than the pre-HAART era. Among HIV-positive men, anal cancer risk for younger men (younger than 50 years) was similar in the HAART and pre-HAART eras. However, as age increased above 50 years of age, HIV-positive men in the HAART era seem to have more risk of anal cancer than HIV-positive men in the pre-HAART era (P = 0.16, Fig. 2). Evaluation of the difference in cancer risk among HIV-positive men at older ages is limited by the smaller number of men available for analysis in the older age categories. Considerably fewer HIV-positive men from the pre-HAART enrollment lived to contribute data at ages above 60 years (n = 36 men) compared with men alive in the HAART era (n = 115 men).
Due to the high mortality in the pre-HAART era and the difference in anal cancer risk in the HAART and pre-HAART eras and to better evaluate anal cancer risk factors, we restricted multivariable analysis to time and events contributed by participants in the HAART era (1996 onward). In the multivariate analyses of all men in the HAART era, risk of anal cancer was elevated in participants with HIV infection (RH = 4.7, 95% CI = 1.3 to 17) and men with more unprotected anal receptive sex partners at the first 3 study visits (P trend = 0.03). As HIV infection was an important risk factor, the effect of other risk factors was then evaluated in analysis limited to HIV-positive participants. Number of unprotected anal receptive sexual partners at the initial 3 study visits (P trend = 0.014; Table 3) remained strongly associated with increased anal cancer risk in this analysis. Nadir CD4 cell count and ever tobacco use were associated with elevated but not statistically significant increased cancer risk (Table 3). As only one HAART era anal cancer case was HAART naive at time of anal cancer diagnosis, the effect of “ever” HAART use could not be evaluated in this model. Current HAART use, race, and age were not associated with increased cancer risk. Results were similar when restricted to ASCC (data not shown).
Risk factors identified in univariate case-control analysis were consistent with those observed in longitudinal analysis (Table 2). The effect of HIV, HAART, and age could not be evaluated because these factors were used for matching cases and controls. However, after controlling for these factors through matching, number of unprotected anal receptive sex partners at the first 3 study visits (P trend = 0.027) was associated with significantly increased odds of anal cancer. Nadir CD4 <200 cells/μL [odds ratio (OR) = 1.6, 95% CI = 0.54 to 4.5] and ever tobacco use (OR = 3.6, 95% CI = 0.78 to 16.9) were associated with elevated but not statistically significant increased odds of anal cancer.
In multivariate analyses of all subjects, the odds of anal cancer were elevated in those with 7 or more anal receptive sex partners reported at the first 3 study visits (P trend = 0.05), ever-smokers (OR = 4.5, 95% CI = 0.89 to 23), and HIV-positive men with nadir CD4 <200 cells/μL (OR = 2.1, 95% CI = 0.65 to 6.6). Results were similar when restricted to HIV-positive men (Table 3) or to ASCC (data not shown).
Registry data suggest higher anal cancer incidence among HIV-positive than among HIV-negative individuals (relative risk = 10-352)17,29-35 and increasing anal cancer rates in the past few decades1,17,36; however, few longitudinal studies have evaluated anal cancer incidence.37,38 The cohort study presented here utilized 22 years of longitudinal data from a well-characterized multicenter cohort study population with high participant retention. MACS data have an additional strength, compared with registry data, in that the exposure information analyzed was collected before cancer diagnosis. This study demonstrates significantly higher incidence of anal cancer in HIV-positive than in HIV-negative MSM. Consistent with the temporal trend of increasing anal cancer incidence suggested in several studies,1,36,39-42 this study found significantly higher anal cancer incidence in the HAART era (1996-2006) than the pre-HAART era (1984-1995). This trend is likely related to premature mortality witnessed in the pre-HAART period among HIV-positive men. In the MACS, the median age for diagnosis of AIDS before 1995 was 39 years,43 whereas the median age for anal cancer is above 50 years.44 Other explanations for the increase in anal cancer incidence could include a direct toxic effect of HAART or incomplete adjustment for the aging of the study cohort. Improved diagnosis or reporting of these cancers is less likely but cannot be excluded. Thus, anal cancer incidence may continue to increase in this population as HAART improves survival, thus allowing HIV-positive MSM to survive long enough to develop anal cancer.
Observed IRs among HIV-positive men in this study were comparable to those reported in other studies of HIV-positive persons in the HAART era (92-144 per 100,000 person-years) and pre-HAART era (12-69 per 100,000 person-years).17,36,37 Discrepancies between estimates may be partially explained by heterogeneity in definitions of which cancer subsites and morphologies are included as anal cancers and inclusion or exclusion of in situ cancers. Incidence of anal cancer among the high-risk HIV-negative men in this study was higher than IRs reported in some population-based samples during the same time period (0.4-0.8 and 1.0 per 100,000 person-years in pre-HAART and HAART eras, respectively36,39-42) but similar to estimates in 2 other studies during a similar time period.36,41
Sexual risk behaviors at study entry were strongly associated with risk of subsequently developing anal cancer in this study, supporting an HPV etiology to these cancers. This is consistent with the results of anal cancer case-control studies, which have shown increased odds of anal cancer in those with higher number of sexual partners,5,9,15 ever receptive anal sex partners,5,13,15 and number of receptive anal sex partners.16 Associations with sexual risk are likely attenuated in this study as most MACS participants were older than 30 years at study entry, and it is highly likely that many of the men were exposed to HPV before study entry. It takes many years from HPV infection to development of cancer, and as some of the anal cancer cases in this study occurred only a few years after study entry, the baseline sexual behaviors in these men may not be representative of their sexual risk when initially infected with HPV. Sexual risk behavior was similarly associated with anal cancer risk when rectal cases were included and when limited to only ASCC, suggesting that some rectal cancers may have an HPV-associated etiology.
As suggested in this study, tobacco use has been associated with increased odds of anal cancer (OR = 1.9-7.7) in most case-control studies of anal cancer.15,16,45,46 This study may have been underpowered to detect the effect of tobacco and did not have a measure of lifetime tobacco use. Sexual behavior is strongly associated with tobacco use,47,48 so residual confounding by sexual behavior could explain the observed moderate associations between tobacco and anal cancer risk. However, increased risk of other HPV-associated malignancies has also been observed in tobacco users,45,49,50 suggesting a possible effect of tobacco on HPV persistence or progression of HPV-associated dysplasias to cancer. The effect of tobacco may be small in relation to the effect of HIV and may therefore be harder to observe in a population of HIV-positive individuals.
Although cervical cancer is considered an AIDS-defining illness, anal cancer currently is not. However, studies suggest that individuals with HIV infection are at increased risk of anal high-grade squamous intraepithelial lesions7,51,52 and, as shown in this and other studies, at increased risk of anal cancer.2,29,35 Although HAART has reduced the risk of many HIV-associated morbidities,53 initial studies suggest that HAART does not decrease risk of HPV-associated anal, genital, and oropharyngeal cancers.2,21,53,54 Longitudinal analysis of the effect of HAART on anal HPV progression is limited but shows no apparent effect of HAART on anal HPV natural history,22,55 and cross-sectional analysis demonstrates a high prevalence of anal HPV infection in HIV-positive men despite HAART-related immune restoration.22,56 In this study, anal cancer cases that occurred during the HAART era were primarily in men currently on HAART. Many of these men had low HIV viral load and CD4 cell counts above 200 cells/μL, suggesting HAART-related immune restoration may not be effective (or may have a modest effect) against progression of anal HPV-associated cellular abnormality. As HAART leads to improved survival for HIV-positive individuals, it may thus allow sufficient time for development of invasive anal disease. Anal cancer incidence in individuals on HAART may therefore continue to rise.
This study was limited by the lack of tumor tissue for HPV DNA testing. Central pathology review of all cancers was also not possible although detailed review of existing pathology reports was performed to reduce misclassification. Longitudinal data were included from men enrolled into the MACS cohort in 3 different waves with variable characteristics and follow-up time. Additionally, baseline measures of sexual risk behaviors were used in this study, and as these may be after the peak time of sexual risk taking in some men, these measures may not accurately represent the behaviors when the men were most as risk at HPV infection.
Anal cancer incidence has increased significantly in the past 10 years and is currently estimated to be ~2.0 per 100,000 in the general US population.1 MSM and HIV-positive individuals have substantially higher rates of anal cancer.57 Anal cancer may be preventable, but the benefits of screening for and treating anal cancers have not yet been well evaluated. Further research is needed to determine the benefits and costs of risk reduction interventions, screening, and treating anal cancer precursors in high-risk populations such as HIV-positive individuals.
The Multicenter AIDS Cohort Study includes the following: Baltimore: The Johns Hopkins University Bloomberg School of Public Health: J.B.M. (Principal Investigator), Haroutune Armenian, Barbara Crain, Adrian Dobs, Homayoon Farzadegan, Joel Gallant, John Hylton, Lisette Johnson, Shenghan Lai, Ned Sacktor, Ola Selnes, James Shepard, and Chloe Thio. Chicago: Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: John P. Phair (Principal Investigator), J.S.C. (Co-Principal Investigator), Sheila Badri, Bruce Cohen, Craig Conover, Maurice O'Gorman, David Ostrow, Frank Palella, Daina Variakojis, and Steven M. Wolinsky. Los Angeles: University of California, UCLA Schools of Public Health and Medicine: Roger Detels (Principal Investigator), Barbara R. Visscher (Co-Principal Investigator), Aaron Aronow, Robert Bolan, Elizabeth Breen, Anthony Butch, Thomas Coates, Rita Effros, John Fahey, Beth Jamieson, Otoniel Martínez-Maza, Eric N. Miller, John Oishi, Paul Satz, Harry Vinters, D.W., Mallory Witt, Otto Yang, Stephen Young, and Zuo Feng Zhang. Pittsburgh: University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (Principal Investigator), Lawrence Kingsley (Co-Principal Investigator), James T. Becker, Robert L. Cook, Robert W. Evans, John Mellors, Sharon Riddler, and Anthony Silvestre. Data Coordinating Center: The Johns Hopkins University Bloomberg School of Public Health: L.P.J. (Principal Investigator), Alvaro Muñoz (Co-Principal Investigator), Stephen R. Cole, Christopher Cox, G.D.'S., Stephen J. Gange, Janet Schollenberger, Eric C. Seaberg, and Sol Su. NIH: National Institute of Allergy and Infectious Diseases: Robin E. Huebner; National Cancer Institute: Geraldina Dominguez; and National Heart Lung and Blood Institute: Cheryl McDonald. UO1-AI-35042, 5-MO1-RR-00722 (General Clinical Research Center), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041. Website located at http://www.statepi.jhsph.edu/macs/macs.html.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
anal; rectal; cancer; incidence; MACS; sexual risk; HAART