1. Risk Factors for Development of Anal Cancer in HIV-Infected Men Phillip Cole, M.D. 1, Wendy Leyden, M.P.H. 2, Michael Silverberg, Ph.D., M.P.H. 2 1 UC Davis Health System, Division of Infectious Diseases, Sacramento, CA, 2 Kaiser Permanente Northern California, Division of Research, Oakland, CA. 1. ABSTRACT Background: The incidence of anal cancer has increased in the last 20 years and is especially high in HIV-infected men who have sex with men (MSM). Conflicting data are reported on correlation between duration of infection or degree of immunosuppression and risk of anal cancer. The goal of this study was to compare the average duration of infection, CD4 count and viral load among HIV-infected men with and without anal cancer at a community-based hospital. Methods: Cases included all HIV-positive men at Kaiser Permanente Oakland Medical Center (KPOAK) diagnosed with anal cancer between 1/1/96 and 12/31/05. For each case, 3 age- and calendar-month matched HIV-positive men without anal cancer were randomly selected. The index date for controls was the date assigned as receiving care at KPOAK. For inclusion, patients were required to have at least one CD4 and HIV RNA test in the 12 months prior to the index date. Multivariate conditional logistic regression adjusted for age, CD4 count, viral load, and duration of infection. Results: A total of 15 HIV-infected anal cancer cases and 45 matched controls were identified. Mean CD4 count was 224.4/mm3 (standard deviation [sd] 139.9/mm3) for cases and 409/mm3 (sd 201.6/mm3) for controls (P=0.001). Mean viral load was 8718.5 (sd 20223.1 copies/mL) for cases and 9677.2 (sd 22763.4 copies/mL) for controls. (P=0.44). Duration of HIV infection at the time of cancer diagnosis for cases was 8.0 (sd 3.8) years and for controls 7.5 (sd 5.34) years (P=0.54). The crude odds ratio for CD4 count < 200/mm3 was 9.1 (CI 1.9-45.4). Other factors were not significant in univariate analyses. In multivariate analysis, the adjusted odds ratio for CD4 count < 200/mm3 was 21.9 (CI 2.0-235). Conclusions: These data suggest that degree of immunosuppression is an important risk factor for anal cancer in HIV-infected men. There have been general recommendations to screen all patients with HIV infection with CD4 counts < 500/mm3. This study lends further credence to this recommendation. 2. BACKGROUND  Anal cancer is increasing in prevalence and is especially high in HIV- infected men and women and men who have sex with men (MSM). 1,2,3  HIV-positive MSM have at least twice the risk of developing anal cancer as HIV-negative MSM. 4  Anal cancer prevalence in the HIV-infected has increased in the HAART era (post-1996) with a decrease in death secondary to opportunistic infections and HIV-associated malignancies. 5  It has been hypothesized that ongoing immune deficiency, even in the presence of HAART, has led to increased life-expectancy but has allowed for progression of HPV-mediated dysplasia to carcinoma. 6  The relationship of CD4 count, HIV-1 RNA viral load and duration of infection with risk of development of anal cancer is not entirely clear. 4. RESULTS H-2338 CONTACT INFORMATION Phillip A. Cole, M.D. Clinical Fellow UC Davis Health System Division of Infectious Diseases 2315 Stockton Boulevard Sacramento, CA 95817 phone: (916) 734-3815 fax: (916) 734-7766 phillip.cole@ucdmc.ucdavis.edu 3. METHODS Study Design  Retrospective case control study, data from 1/1/1996 to 12/31/2005. Study population  All HIV+ Kaiser Permanente Oakland Medical Center (KPOAK) male patients with anal cancer diagnosis by biopsy or resection.  Inclusions: a)≥ 18 years of age; b) male sex; c) anal cancer diagnosed after earliest evidence of HIV diagnosis (index date); d) enrolled to receive care at KPOAK in the month of cancer diagnosis; e) ≥1 CD4 count and ≥1 HIV-1 RNA viral load test in the 12 months prior to cancer diagnosis. Anal Cancer definition  SEER code that combines histology with primary site: 21060 Outcome variables  CD4 count closest prior to the index date  HIV-1 RNA viral load closest prior to the index date  Duration of infection defined as time from earliest diagnostic evidence of HIV disease (HIV+ antibody test, detectable HIV-1 RNA viral load, or clinical diagnosis with AIDS) Predictor variables  HIV-infected with anal cancer vs. HIV-infected without anal cancer  Race (White, non-Hispanic, African-American, Hispanic, Asian, unknown)  Route of HIV exposure (with hierarchy of Intravenous Drug Use (IVDU), MSM, Heterosexual contact, unknown)  AIDS at time of anal cancer diagnosis (yes or no)  Antiretroviral therapy use (HAART or no HAART) Statistical analysis  Two-sided, unpaired t-test performed for CD4 count, HIV-1 RNA viral load, and duration of infection.  Conditional logistic regression for multivariate analysis adjusted for age, CD4 count, HIV-1 RNA viral load, and duration of infection. PATIENT CHARACTERISTICS 5. DISCUSSION  The degree of immunosuppression as measured by CD4 count was an important risk factor for anal cancer in HIV- infected men.  All anal cancer cases in this study had a diagnosis of AIDS vs. 2/3 of the controls, providing further evidence of an association of immunosuppression and anal cancer risk.  Consistent with previous reports 4, MSM appears to be an additional risk factor for anal cancer.  Patients with HIV infection with low CD4 counts, particularly MSM, should be screened for anal cancer.  The exact threshold for screening (e.g. 200 vs. 500 cells/µL) remains to be established. CaseControlP N1545 Mean Age (yrs)46 n/a Mean Duration of HIV infection (yrs)7.997.480.539 Duration of HIV infection <10 yrs)10 (67%)30 (67%)1.0 Race0.587 White, non-Hispanic10 (67%)23 (51%) African American5 (33%)15 (33%) Hispanic03 (7%) Asian01 (2%) Unknown03 (7%) Attributed mode of infection0.020 MSM11 (73%)29 (64%) IVDU2 (13%)5 (11%) Heterosexual011 (24%) Unknown2 (13%)0 AIDS0.007 No016 (36%) Yes15 (100%)29 (64%) HAART0.294 No10 (67%)23 (51%) Yes5 (33%)22 (49%) Mean CD4 count (cells/µL)2244090.001 CD4 count ≤200 cells/µL8 (53%)5 (11%)0.001 Mean HIV-1 RNA viral load (copies/mL) 871896770.438 HIV-1 RNA <500 copies/mL10 (67%)23 (51%)0.294 UNIVARIATE ANALYSIS MULTIVARIATE ANALYSIS* OR95% CIP CD4 count <200 cells/µL9.141.94-43.01<0.001 HIV-1 RNA viral load <500 copies/mL 1.910.55-6.640.298 Duration of infection <10 yrs1.000.29-3.491.0 White, Non-Hispanic1.910.55-6.640.298 MSM1.520.41-5.640.531 HAART0.520.15-1.810.298 OR95% CIP CD4 count <200 cells/µL21.92.0-235<0.05 6. REFERENCES  1. Johnson LG, Madeleine MM, Newcomer LM, et al. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973-2000. Cancer 2004; 101:281-8.  2. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med 2008; 148:728-736.  3. Piketty C, Selinger-Luneman H, Grabar S, et al. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 2008; 22:1203-11.  4. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998; 351:1833-9.  5. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998; 338:850- 860.  6. Palefsky JM. Human papillomavirus virus infection in HIV-infected persons. Top HIV Medicine 2007; 15:130-3. Low grade squamous intraepithelial lesion with mildly dysplastic cells. High grade squamous intraepithelial lesion with severely dysplastic cells. Reproduced from Arain S, Walts AE, Thomas E, and Bose S. CytoJournal 2005; 2:4. * adjusted for age, CD4 count, HIV-1 RNA viral load, and duration of infection