Risk Factors for Anal HPV Infection and Anal Precancer in HIV-Infected Men Who Have Sex With Men

MAJOR ARTICLE Risk Factors for Anal HPV Infection and Anal Precancer in HIV-Infected Men Who Have Sex With Men Lauren M. Schwartz,1 Philip E. Castle,2 Stephen Follansbee,3 Sylvia Borgonovo,3 Barbara Fetterman,4 Diane Tokugawa,4 Thomas S. Lorey,4 Vikrant V. Sahasrabuddhe,1 Patricia Luhn,1 Julia C. Gage,1 Teresa M. Darragh,5 and Nicolas Wentzensen1 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, and 2Global Cancer Initiative, Inc., Chestertown, Maryland; 3Kaiser Permanente Medical Center, San Francisco; 4Kaiser Permanente TPMG Regional Laboratory, Berkeley; and 5University of California, San Francisco Keywords. anal cancer; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); anal intraepithelial neoplasia (AIN). Anal cancer is relatively uncommon in the United States, with an expected 6000 new cases in 2012 and an overall annual incidence rate of 2/100 000 [1, 2]. Most anal cancers are caused by human papillomavirus (HPV) infection [3]. Certain populations, such as human immunodeficiency virus (HIV)–infected and other immunosuppressed individuals, appear to have an increased risk of both HPV infection and anal Received 26 March 2013; accepted 10 May 2013; electronically published 1 August 2013. Correspondence: Nicolas Wentzensen, MD, PhD, MS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Room 5024, Rockville, MD 20852-7234 (). The Journal of Infectious Diseases 2013;208:1768–75 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jit374 1768 • JID 2013:208 (1 December) • Schwartz et al cancer. A recent worldwide metaanalysis showed that HIV-infected men who have sex with men (MSM) have an estimated 46/100 000 incident anal cancer cases per year compared with HIV-negative MSM who have 5/ 100 000 incident cases per year [4]. Since the advent of highly active antiretroviral therapy (HAART), the life expectancy for HIV-infected individuals has significantly increased. This may have allowed time for progression of carcinogenic HPV infections to anal cancer and possibly explains an increase in anal cancer incidence in the United States [5–8]. Anal cancer natural history presumably follows the same steps as cervical cancer natural history: HPV acquisition, HPV persistence, progression of persistent HPV infections to high-grade anal intraepithelial neoplasia (AIN), and invasion to anal cancer [5]. Studies have identified risk factors for each stage in the Background. Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. Methods. Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. Results. Low CD4 count (<350 cells/mm3) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28–10.40 and OR, 4.24; 95% CI, 1.16–15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43–5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. Conclusions. We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression. progression from cervical HPV infection to cervical cancer [9– 11], and we are beginning to find similar risk factors in anal cancer natural history. Risk factors for anal HPV infection are related to sexual behavior, such as lifetime number of sexual partners, as well as low CD4 count in HIV-infected populations [12–15]. Smoking history has been shown to be associated with anal HPV persistence [16, 17] and anal cancer [18, 19], but it is unclear at what stage smoking influences the natural history. To add to our understanding of risk factors that influence the natural history of HPV and anal cancer, we conducted a study of lifestyle characteristics and clinical parameters for HIVinfected MSM undergoing routine anal cancer screening at Kaiser Permanente Northern California (KPNC) Health Maintenance Organization. METHODS The study was based at the San Francisco KPNC Anal Cancer Screening Clinic. Using the Kaiser HIV registry, we identified men aged ≥18 years who were not diagnosed with anal cancer prior to enrollment and provided informed consent as eligible for the study. The study was reviewed and approved by the KPNC and National Cancer Institute institutional review boards. In total, 363 men were enrolled between August 2009 and June 2010. To collect risk factor information, participants completed a self-administered questionnaire. Additional information on HIV status and medication, sexually transmitted diseases, and histopathology results were abstracted from the KPNC clinical database. Of those enrolled, 271 had no highgrade AIN detected at the enrollment visit; however, we were able to obtain follow-up information from 86 of these subjects from additional clinic visits up to December 2011. This followup information was included in the analysis to improve ascertainment of prevalent disease, as anoscopy has less-thanperfect sensitivity. We excluded 54 participants who had no questionnaire data and 4 who had invalid HPV DNA, resulting in a final population of 305 men. Cytology, Anoscopy, Histology, and HPV Detection The clinical procedures used in this study have been described previously [20–23]. In brief, during the clinical examination, 2 cytology specimens were collected by inserting a wetted swab into the anal canal up to the distal rectal vault and withdrawing with rotation and lateral pressure. A third anal specimen was collected for routine Chlamydia trachomatis and Neisseria gonorrhea testing using nucleic acid amplification testing (GenProbe). After specimen collection, participants received a digital anorectal exam followed by high-resolution anoscopy (HRA). At most, 2 suspicious-appearing lesions identified during HRA were biopsied and sent for routine histopathological evaluation. From the first specimen, a ThinPrep slide was Statistical Analysis The following risk factor associations at different stages of anal carcinogenesis were estimated using combined endpoints (...truncated)