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
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
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
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
: 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
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
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
Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
anal; rectal; cancer; incidence; MACS; sexual risk; HAART