JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science
Incidence and Epidemiology of Anal Cancer in the Multicenter AIDS Cohort Study
D'Souza, Gypsyamber PhD*; Wiley, Dorothy J PhD†; Li, Xiuhong MAS*; Chmiel, Joan S PhD‡; Margolick, Joseph B MD, PhD§; Cranston, Ross D MD, FRCP‖; Jacobson, Lisa P PhD*
From the *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; †University of California at Los Angeles School of Nursing, Los Angeles, CA; ‡Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL; §Department of Molecular Microbiology and Immunology, John Hopkins Blamberg School of Public Health, Baltimore, MD; and ‖Department of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA.
Received for publication November 29, 2007; accepted April 3, 2008.
Correspondence to: Gypsyamber D'Souza, PhD, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe Street E7137, Baltimore, MD 21205 (e-mail: firstname.lastname@example.org).
Objective: To examine the incidence and risk factors for anal cancer in a multicenter cohort of human immunodeficiency virus (HIV) positive and HIV-negative men who have sex with men followed between 1984 and 2006 (Multicenter AIDS Cohort Study).
Methods: Prospective analysis using Poisson regression and Cox proportional hazard models and a nested case-control study using conditional logistic regression.
Results: There were 28 cases of anal cancer among the 6972 men who were evaluated. The incidence rate was significantly higher in HIV-positive men than in HIV-negative men (incidence rate = 69 vs 14 per 100,000 person-years). Among HIV-positive men, anal cancer incidence was higher in the highly active antiretroviral therapy (HAART) era than the pre-HAART era (incidence rate = 137 vs 30 per 100,000 person-years). In multivariate analysis restricted to the HAART era, anal cancer risk increased significantly with HIV infection (relative hazard = 4.7, 95% confidence interval = 1.3 to 17) and increasing number of unprotected receptive anal sex partners at the first 3 study visits (P trend = 0.03). Among HIV-positive men, current HAART use did not decrease anal cancer risk.
Conclusions: HIV-positive men had increased risk of anal cancer. Improved survival of HIV-positive individuals after HAART initiation may allow for sufficient time for human papillomavirus-associated anal dysplasias to develop into malignancies, thus explaining the increased incidence of anal cancer in the HAART era.
The incidence of anal cancer has increased in the past decade,1 particularly in certain population subgroups. Human immunodeficiency virus (HIV) positive men and men who have sex with men (MSM) are at increased risk of anal cancer compared with the general population.2-4 HIV-negative MSM have an estimated incidence rate (IR) of 35/100,000,5 which is comparable to the incidence of cervical cancer in the general female population before widespread cervical Pap screening was introduced (40-50 cases/100,000)6 and greater than the current incidence of cervical cancer (6-15/100,000).1,2 The incidence of anal cancer among HIV-positive MSM is thought to be even higher (~70-100 cases/100,000).7 As HIV-positive men are living longer after the introduction of highly active antiretroviral therapy (HAART), cancer poses a larger problem for this population.
Recent evidence suggests that anal infection with human papillomavirus (HPV) is strongly associated with the subsequent development of anal cancer.8-11 Anal HPV infection is believed to be sexually transmitted, and cross-sectional studies suggest that a higher number of sexual partners is associated with an increased odds of anal dysplasia12 and anal cancer.5,9,13 Sexual risk behaviors are believed to serve as a surrogate for anogenital HPV infection,14 likely explaining the association of these behaviors with cancer risk. Longitudinal analysis to establish a temporal relationship between high-risk sexual behaviors and subsequent risk of anal cancer has not been reported.
The cancer subsites in the anus and rectum most likely to have an HPV etiology have not been thoroughly evaluated. Studies of anal cancer have used varying inclusion criteria for cancer site based on differing surgical and histological definitions of the boundaries of the anal canal. Most studies included rectal2,9,15 and perianal skin9,15,16 cancers in their “anal cancer” case definitions which could attenuate results by including etiologically heterogeneous cancers. Although HPV is known to infect squamous cells and the majority of anal cancers are squamous cell carcinomas (SCCs), few studies17 have focused exclusively on the epidemiology of anal SCC. Results from rectal cancer studies have varied, with some suggesting low9 and others a high18,19 HPV prevalence in rectal adenocarcinomas. HPV has been recently shown to be an important cause of cervical adenocarcinomas,11,20 so it is possible that HPV may play a role in rectal adenocarcinomas as well.
The natural history of anal HPV infection and cofactors for persistence of anal HPV infection are not well understood. In addition, the effects of HIV-associated immunosuppression and HAART on anal cancer risk are not well described. Recent studies have suggested that the incidence of anal cancer in HIV-positive individuals is higher in the HAART era than the pre-HAART era3,17 and that anal HPV persistence and progression of HPV-associated precancers are not reduced in those on HAART.21,22
This manuscript describes the incidence of, and risk factors for, anal cancer using longitudinal data from HIV-positive and HIV-negative men in the Multicenter AIDS Cohort Study (MACS). This is one of the first studies to evaluate incidence or risk factors for anal cancer using exposure information collected before the cancer diagnosis.
The study included all men in the MACS, a cohort that has been described elsewhere.23-25 In brief, the MACS includes primarily HIV-positive and HIV-negative MSM and has study sites in Baltimore, Chicago, Los Angeles, and Pittsburgh. The study began in 1984 and a total of 6972 men have been enrolled over 3 separate enrollment periods (1984-1985, 1987-1991, and 2001-2003). Anal cancer cases included only men with T1 invasive anal or rectal disease.
Subject self-report of cancer was verified by histology report. Histology reports and medical records were collected, reviewed, and summarized by trained abstractors and centrally rereviewed for this paper. Tumor specimens were not available for histological review, testing, or adjudication for these analyses.
Incident anal (ICD-O = 154.2-154.8 or ICD-O3 = 21.0-21.8), perianal (ICD-O3 = 44.5 with record noting perianal location), and rectal (ICD-O = 154.0-154.1 or ICD-O3 = 19.9-20.9) ICD codes were classified together as anal cancer for these analyses. Cases were classified using documented pathology reports (n = 23) or physician narrative indicating diagnosis of anal cancer (n = 1). Where no medical documentation was available, self-report of anal cancer by study subject was accepted (n = 4). Subanalysis using only those cancers with anal tumor site and squamous cell morphology (ICD-O code 8052-8084 or ICD-03 = 8070.2-8078) was also performed, and these cancers are referred to as anal squamous cell carcinomas (ASCCs); only T1 invasive cancers confirmed by pathology report review were included in the ASCC subanalysis. Data gathered between 1984 and March 2007 were included in these analyses.
Detailed behavioral data were collected from participants every 6 months using interviewer-administered and/or audio computer-assisted self-interview format. Recent sexual behaviors assessed at each visit included the number of total, anal insertive, anal receptive, and unprotected anal receptive sexual partners in the past 6 months. The number of unprotected anal receptive partners “at baseline” was chosen for this analysis due to the long latency period between HPV infection and development of cancer and the expectation that more distant measures of sexual risk better represent current risk of malignancy. A summary measure of baseline sexual risk was created by adding the number of recent unprotected anal receptive partners reported at each of the 3 initial study visits. Recent tobacco use was also assessed at each visit as tobacco use has been associated with elevated anal HPV prevalence, viral load,26 and odds of anal cancer.15
Positive enzyme-linked immunosorbent assays with confirmatory Western blot tests were used to determine HIV seropositivity. Plasma HIV RNA levels were determined using the Roche Ultrasensitive RNA PCR assay (Hoffman-LaRoche, Nutley, NJ), with a detection limit of 50 copies/mL. T-lymphocyte subset levels were quantified by each MACS center using standardized flow cytometry.27
Self-reported use of antiretroviral medications at each visit was summarized to define whether participants were using HAART. The definition of HAART was guided by the Department of Health and Human Services/Kaiser Panel28 guidelines and defined as follows: (a) 2 or more nucleoside reverse transcriptase inhibitors (NRTIs) in combination with at least one protease inhibitor (PI) or 1 nonnucleoside reverse transcriptase inhibitor (NNRTI) (89% of observations classified as HAART); (b) 1 NRTI in combination with at least one PI and at least one NNRTI (5%); (c) a regimen containing ritonavir and saquinavir in combination with 1 NRTI and no NNRTIs (1%); and (d) an abacavir- or tenofovir-containing regimen of 3 or more NRTIs in the absence of both PIs and NNRTIs (5%), except for the 3 NRTI regimens consisting of abacavir, tenofovir and lamivudine OR didanosine, and tenofovir and lamivudine. Combinations of zidovudine and stavudine with either a PI or NNRTI were not considered HAART.
Semiannual visits also included standardized physical examinations, medical histories, and phlebotomy for laboratory measurements and storage of cells, serum, and plasma in centralized repositories. Medical records were sought and reviewed for confirmation of all reported acquired immunodeficiency syndrome (AIDS) defining illnesses, cancers, and other specified conditions. Passive and active methods were used to ascertain deaths, and information on causes of death was captured by death certificate review.
Poisson regression models were used to calculate anal cancer IRs. Given the very long follow-up involved in this study, reasons for right censoring (ie, time when follow-up ended) varied between the original and more recently recruited participants in the MACS. More than two thirds (69%) of men enrolled in 2001-2003 remained in active follow-up as of September 2006 compared with only 27% of those whose baseline visit was before 2001. At the time of analysis, death (64% vs 4%, respectively) was much more common among HIV-positive men enrolled before 2001 than among similar men who were more recently enrolled.
Cox proportional hazard models were used to calculate the relative hazard (RH) for risk factors of interest. Study entry (baseline) was used as the time origin, and men were at risk up to the date of anal cancer diagnosis, last date of contact, or March 30, 2007, whichever came first. Tobacco use, current HAART use, nadir CD4 cell count, and HIV viral load were evaluated as time-updated covariates in these models. Trends in risk were tested by modeling ordinal variables as single, continuous, independent variables.
Kaplan-Meier curves were generated using age as the timescale and assuming anal cancer-free time from study entry back to age 30 years. HIV-positive participants who contributed time before 1996 were included in a “HIV+, pre-HAART era” curve, with exit age at the date of anal cancer, last date of contact, or December 31, 1995, whichever came first. HIV-positive participants who contributed time after 1996 were included in a “HIV+, HAART era” curve, with entry age at January 1, 1996. Thus, HIV-positive men who were enrolled before 2001 and still enrolled and anal cancer free in 1996 contributed to both pre-HAART and HAART era curves.
Given the large proportion of men in the original MACS cohort who died before HAART became available, competing risks could affect interpretation of longitudinal analysis.
Many men early in the epidemic died before having the “opportunity” to develop cancer but still contributed time to the longitudinal analysis. To address this concern, we performed a nested case-control study.
Case-control analysis was performed using conditional logistic regression. Each anal cancer case was individually matched to 3 controls using the following matching criteria: age at diagnosis (±5 years), year of study enrollment, HIV serostatus, ever/never HAART use, and follow-up time (+2.5 years). Follow-up time was defined as the time from study entry until anal cancer diagnosis for HIV-negative and HIV-positive HAART-naive participants. HIV-positive cases who used HAART before their cancer diagnosis were matched to controls on the time of HAART initiation (±3 years) and time from first HAART use until diagnosis (±2.5 years). Cases who were HIV seropositive at study entry were also matched by CD4 cell count at study entry (±50 cells/μL) to account for duration of infection. Cases with incident HIV during the study were matched with HIV-prevalent participants with baseline CD4 counts >750 cells/μL due to unavailability of seroconverters as matched controls. All analyses were performed using SAS 9.1 (Cary, NC). Graphical illustrations were generated by S-plus 6.2 (Insightful Corporation, Seattle, WA).
Description of Cancers
Between 1984 and March 2007, 28 anal, perianal, or rectal (hereafter referred collectively as anal) cancers were observed among the 6972 men in the MACS cohort. This included 21 anal cancers of which 17 were SCC, 1 was neuroendocrine, and 3 had unconfirmed morphology. Of the 7 rectal cancers included, 5 were adenocarcinomas and 2 were SCCs. Six anal cancers were diagnosed among HIV-negative men, and 22 were diagnosed among HIV-positive men (Table 1). More than half (67%; 4 of 6) the anal cancers in HIV-negative men were rectal adenocarcinomas compared with only 14% (3 of 22) of anal cancers in HIV-positive men (P < 0.001). Anal cancers in HIV-positive men were twice as likely to have squamous morphology (68% vs 33%) as cancers in HIV-negative men (P = 0.034). The median age at cancer diagnosis was 47.4 years in HIV-positive and 57.8 years in HIV-negative men. The median follow-up time for men enrolled between 1984-1991 and 2001-2003 was 10.5 and 3.9 years, respectively. Participants enrolled earlier in the study were more likely to have died (34.2% vs 2.7%, P < 0.001) and equally likely to have been lost to follow-up (29.5% vs 28.4%, P = 0.19) than participants enrolled in 2001-2003.
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.
1. Saraiya M, Ahmed F, Krishnan S, et al. Cervical cancer incidence in a prevaccine era in the United States, 1998-2002. Obstet Gynecol
2. Chan PG, Sung HY, Sawaya GF. Changes in cervical cancer incidence after three decades of screening US women less than 30 years old. Obstet Gynecol
3. Hessol NA, Pipkin S, Schwarcz S, et al. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol
4. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet
5. Daling JR, Weiss NS, Hislop TG, et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med
6. Qualters JR, Lee NC, Smith RA, et al. Breast and cervical cancer surveillance, United States, 1973-1987. MMWR CDC Surveill Summ
7. Chin-Hong P, Palefsky J. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect Dis
8. Fox PA. Human papillomavirus and anal intraepithelial neoplasia. Curr Opin Infect Dis
9. Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med
10. Bjorge T, Engeland A, Luostarinen T, et al. Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer
11. Munoz N, Castellsague X, de Gonzalez AB, et al. Chapter 1: HPV in the etiology of human cancer. Vaccine
12. Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst
13. Wilkin TJ, Palmer S, Brudney KF, et al. Anal intraepithelial neoplasia in heterosexual and homosexual HIV-positive men with access to antiretroviral therapy. J Infect Dis
14. Ault KA. Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol
15. Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer
16. Tseng HF, Morgenstern H, Mack TM, et al. Risk factors for anal cancer: results of a population-based case-control study. Cancer Causes Control
17. Diamond C, Taylor TH, Aboumrad T, et al. Increased incidence of squamous cell anal cancer among men with AIDS in the era of highly active antiretroviral therapy. Sex Transm Dis
18. Perez LO, Abba MC, Laguens RM, et al. Analysis of adenocarcinoma of the colon and rectum: detection of human papillomavirus (HPV) DNA by polymerase chain reaction. Colorectal Dis
19. Bodaghi S, Yamanegi K, Xiao SY, et al. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res
20. Castellsague X, Diaz M, de Sanjose S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst
21. Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS
22. Palefsky JM, Holly EA, Ralston ML, et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr
23. Kaslow RA, Ostrow DG, Detels R, et al. The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol
24. Dudley J, Jin S, Hoover D, et al. The Multicenter AIDS Cohort Study: retention after 9 1/2 years. Am J Epidemiol
25. Silvestre AJ, Hylton JB, Johnson LM, et al. Recruiting minority men who have sex with men for HIV research: results from a 4-city campaign. Am J Public Health
26. Brockmeyer N, Kreuter A, Pfister H, et al. Smoking is associated with elevated anal HPV16-DNA loads in HIV-positive men with and without anal dysplasia. Conference on Retroviruses and Opportunistic Infections (CROI)
. Los Angeles, CA; February 25-27, 2007. http://www.retroconference.org/2007/Abstracts/28999.htm
27. Giorgi JV, Cheng HL, Margolick JB, et al. Quality control in the flow cytometric measurement of T-lymphocyte subsets: the multicenter AIDS cohort study experience. The Multicenter AIDS Cohort Study Group. Clin Immunol Immunopathol
28. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: Henry J Kaiser Family Foundation Panel on Clinical Practices for the Treatment of HIV Infection; October 2004 Revision
29. Melbye M, Cote TR, Kessler L, et al. High incidence of anal cancer among AIDS patients. The AIDS/Cancer Working Group. Lancet
30. Grulich AE, Li Y, McDonald A, et al. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS
31. Grulich AE, Wan X, Law MG, et al. Risk of cancer in people with AIDS. AIDS
32. Frisch M, Biggar RJ, Engels EA, et al. Association of cancer with AIDS-related immunosuppression in adults. JAMA
33. Koblin BA, Hessol NA, Zauber AG, et al. Increased incidence of cancer among homosexual men, New York City and San Francisco, 1978-1990. Am J Epidemiol
34. Rabkin CS, Yellin F. Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst
35. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet
36. Melbye M, Rabkin C, Frisch M, et al. Changing patterns of anal cancer incidence in the United States, 1940-1989. Am J Epidemiol
37. Bower M, Powles T, Newsom-Davis T, et al. HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr
38. Lyter DW, Bryant J, Thackeray R, et al. Incidence of human immunodeficiency virus-related and nonrelated malignancies in a large cohort of homosexual men. J Clin Oncol
39. Frisch M, Melbye M, Moller H. Trends in incidence of anal cancer in Denmark. BMJ
40. Maggard MA, Beanes SR, Ko CY. Anal canal cancer: a population-based reappraisal. Dis Colon Rectum
. 2003;46:1517-1523; discussion 1523-1523; author reply 1524.
41. Cress RD, Holly EA. Incidence of anal cancer in California: increased incidence among men in San Francisco, 1973-1999. Prev Med
42. Chiao EY, Krown SE, Stier EA, et al. A population-based analysis of temporal trends in the incidence of squamous anal canal cancer in relation to the HIV epidemic. J Acquir Immune Defic Syndr
43. Huang H, Chmiel JS, Detels R, et al. Factors associated with survival following secondary AIDS: 1988-1995. J Acquir Immune Defic Syndr Hum Retrovirol
44. Holly EA, Whittemore AS, Aston DA, et al. Anal cancer incidence: genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst
45. Daling JR, Sherman KJ, Hislop TG, et al. Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol
46. Frisch M, Glimelius B, Wohlfahrt J, et al. Tobacco smoking as a risk factor in anal carcinoma: an antiestrogenic mechanism? J Natl Cancer Inst
47. Yan AF, Chiu YW, Stoesen CA, et al. STD-/HIV-related sexual risk behaviors and substance use among U.S. rural adolescents. J Natl Med Assoc
48. Valois RF, Oeltmann JE, Waller J, et al. Relationship between number of sexual intercourse partners and selected health risk behaviors among public high school adolescents. J Adolesc Health
49. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med
50. Castellsague X, Munoz N. Chapter 3: cofactors in human papillomavirus carcinogenesis-role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr
51. Palefsky JM, Holly EA, Hogeboom CJ, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol
52. Holly EA, Ralston ML, Darragh TM, et al. Prevalence and risk factors for anal squamous intraepithelial lesions in women. J Natl Cancer Inst
53. International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst
54. Biggar RJ, Chaturvedi AK, Goedert JJ, et al. AIDS-related cancer and severity of immunosuppression in persons with AIDS. J Natl Cancer Inst
55. Palefsky JM. Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection. J Acquir Immune Defic Syndr
. 1999;21(Suppl 1):S42-S48.
56. Piketty C, Darragh TM, Heard I, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis
57. Anal cancer incidence rates increased in antiretroviral era. Rates increased for men and women. AIDS Alert
This article has been cited 34 time(s).
Clinical Infectious DiseasesEffects of Smoking on Non-AIDS-Related Morbidity in HIV-Infected PatientsClinical Infectious Diseases
Sexual HealthAnal cytological abnormalities are poor predictors of high-grade intraepithelial neoplasia amongst HIV-positive men who have sex with menSexual Health
International Journal of CancerAnal squamous intraepithelial lesions are frequent among young HIV-infected men who have sex with men followed up at the Spanish AIDS Research Network Cohort (CoRIS-HPV)International Journal of Cancer
British Journal of CancerThe interaction between smoking status and highly active antiretroviral therapy (HAART) use on the risk of Kaposi's sarcoma (KS) in a cohort of HIV-infected menBritish Journal of Cancer
Journal of Adolescent HealthHuman Papillomavirus-Related Disease in Men: Not Just a Women's IssueJournal of Adolescent Health
International Journal of CancerImmunosuppressive disorders and risk of anal squamous cell carcinoma: a nationwide cohort study in Denmark, 1978-2005International Journal of Cancer
Current HIV Research
The Changing Face of HIV/AIDS in Treated Patients
Current HIV Research, 7(4):
American Journal of Obstetrics and GynecologyAbnormal anal cytology in HIV-infected womenAmerican Journal of Obstetrics and Gynecology
American Journal of Public HealthGay and Bisexual Men's Willingness to Receive Anal Papanicolaou TestingAmerican Journal of Public Health
Archives of Otolaryngology-Head & Neck Surgery
Bidirectional Association of Anogenital and Oral Cavity/Pharyngeal Carcinomas in Men
Archives of Otolaryngology-Head & Neck Surgery, 135(4):
Surgical Clinics of North AmericaCondyloma and Other Infections Including Human Immunodeficiency VirusSurgical Clinics of North America
Future OncologyCancer risk in HIV-infected persons: influence of CD4(+) countFuture Oncology
Journal of Medical VirologyHuman Papillomavirus (HPV) Prevalence and Type Distribution, and HPV-Associated Cytological Abnormalities in Anal Specimens From Men Infected With HIV Who Have Sex with MenJournal of Medical Virology
Obstetrics and Gynecology Clinics of North AmericaThe Epidemiology of Anal Human Papillomavirus and Related NeoplasiaObstetrics and Gynecology Clinics of North America
Diagnostic CytopathologyAnal cytology as a predictor of anal intraepithelial neoplasia in HIV-positive men and womenDiagnostic Cytopathology
Medicina ClinicaCD4 lymphocytes as a protective factor against infection by oncogenic genotypes of human papillomavirus in the anal mucosa of men who have sex with human immunodeficiency virus positive menMedicina Clinica
Oncotargets and TherapyCurrent treatment options for management of anal intraepithelial neoplasiaOncotargets and Therapy
Sexually Transmitted InfectionsHPV vaccination to prevent anal cancer in men who have sex with menSexually Transmitted Infections
Ca-A Cancer Journal for CliniciansThe role of human papillomavirus in nongenital cancersCa-A Cancer Journal for Clinicians
Anal Cytology as a Screening Tool for Early Detection of Anal Dysplasia in HIV-infected Women
Anticancer Research, 30(5):
HIV Clinical TrialsHigh-Grade Anal Intraepithelial Neoplasia Among HIV-1-Infected Men Screening for a Multicenter Clinical Trial of a Human Papillomavirus VaccineHIV Clinical Trials
Clinical Infectious DiseasesIncidence and Timing of Cancer in HIV-Infected Individuals Following Initiation of Combination Antiretroviral TherapyClinical Infectious Diseases
Sexual HealthAnal cancers attributed to human papillomavirus are more common in areas in Victoria, Australia, with higher HIV notificationsSexual Health
VaccineReframing Cervical Cancer Prevention. Expanding the Field Towards Prevention of Human Papillomavirus Infections and Related DiseasesVaccine
VaccineModeling Preventative Strategies against Human Papillomavirus-Related Disease in Developed CountriesVaccine
American Journal of EpidemiologyRisk Factors for Anal Cancer in Persons Infected With HIV: A Nested Case-Control Study in the Swiss HIV Cohort StudyAmerican Journal of Epidemiology
Journal of Health PsychologyGay and bisexual men's human papillomavirus vaccine intentions: A theory-based structural equation analysisJournal of Health Psychology
Current Opinion in Infectious DiseasesAnal cytology screening in HIV-positive men who have sex with men: what's new and what's now?Current Opinion in Infectious Diseases
Current Opinion in Infectious DiseasesHuman papillomavirus-associated diseases in HIV-infected men who have sex with menCurrent Opinion in Infectious Diseases
Current Opinion in OncologyAnal cancer prevention in HIV-positive men and womenCurrent Opinion in Oncology
Diseases of the Colon & RectumDetection of Oncogenic Human Papillomavirus Impacts Anal Screening Guidelines in Men Who Have Sex With MenDiseases of the Colon & Rectum
anal; rectal; cancer; incidence; MACS; sexual risk; HAART
© 2008 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.