Factors Associated with Acquisition and Clearance of Human Papillomavirus Infection in a Cohort of US Men: A Prospective Study

MAJOR ARTICLE Factors Associated with Acquisition and Clearance of Human Papillomavirus Infection in a Cohort of US Men: A Prospective Study Beibei Lu,1,2 Yougui Wu,2 Carrie M. Nielson,3 Roberto Flores,1 Martha Abrahamsen,1 Mary Papenfuss,1 Robin B. Harris,4 and Anna R. Giuliano1,2 Background. Our understanding of factors associated with acquisition and clearance of human papillomavirus (HPV) in men has been limited. This study sought to determine factors associated with those aspects of HPV infection in a cohort of US men. Methods. A total of 285 men aged 18 – 44 years were monitored every 6 months for ⬃18 months. Risk-factor information was obtained at each visit by use of a self-administered questionnaire. A continuous-time 2-state Markov model was applied. Results. Lifetime number of sex partners reported at enrollment was the most significant risk factor for acquisition of all types of HPV. Men reporting ⬎16 lifetime sex partners were at significantly elevated risk of any HPV infection (adjusted hazard ratio [AHR], 2.8 [95% confidence interval {CI}, 1.1–7.1]), oncogenic HPV infection (AHR, 9.6 [95% CI, 2.4 –37.8]), and nononcogenic HPV infection (AHR, 3.6 [95% CI, 1.3–9.9]), compared with those reporting 0 – 4 partners. Circumcised men were 3 and 6 times more likely to clear infection with any and oncogenic HPV types, respectively. In addition, having had ⬎16 lifetime sex partners was associated with greater likelihood of clearance of oncogenic HPV infection (AHR, 4.9 [95% CI, 1.2–19.8]). Conclusion. The key factor associated with acquisition of HPV was lifetime number of sex partners, whereas circumcision was the most significant determinant for clearance of any HPV infection and oncogenic HPV infection. Human papillomavirus (HPV) infection in men contributes significantly to infection and subsequent cervical disease in women [1– 4]. Studies of HPV infection in heterosexual couples have shown that males’ sexual behavior and HPV infection status are significantly associated with their female partners’ risk of precancerous le- Received 18 June 2008; accepted 25 August 2008; electronically published 10 January 2009. Presented in part: 24th International Papillomavirus Conference and Clinical Workshop, 3–9 November 2007, Beijing, China (abstract 295). Financial support: Arizona Disease Control Research Commission (contract 7016). A.R.G. receives support from Merck and Co., the manufacturer of HPV vaccine, for the Phase III Quadrivalent HPV Vaccine Trial among Men (Tampa, Florida, site). She is also a member of the Merck Young Women’s Advisory Board and on the speaker’s bureau for Merck. Reprints or correspondence: Dr. Anna Giuliano, Chair, Dept. of Cancer Epidemiology and Genetics, Program Leader, Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr. MRC-CANCONT, Tampa, FL 33612–9416 (). The Journal of Infectious Diseases 2009; 199:362–71 © 2009 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2009/19903-0011$15.00 DOI: 10.1086/596050 362 ● JID 2009:199 (1 February) ● Lu et al. sion and cervical cancer [1–7]. High prevalence and high incidence of genital HPV infection in men are also associated with anal and penile lesions [8 –10] and with cancer of the anal canal and penis [11–15], especially in immunocompromised men [16, 17]. Prevalence and incidence of HPV appear to be high in men. In a report by Dunne et al., in which HPV prevalence in men was systematically reviewed, prevalences of HPV were 1.8%–72.9% [18]. Several recent prevalence studies that evaluated a full spectrum of HPV types in a variety of male populations, including steady sex partners of HPV-positive women [19], patients at sexually transmitted infection (STI) clinics [20], male university students [21], and community residents [22, 23], observed prevalences of 16.5%–51.5%, depending on the anatomic sites evaluated for the presence of HPV infection. In 2 recently published prospective studies of US men, 62.4% of 18 –20-year-old male university students who had no detectable HPV infection at enrollment acquired HPV at least once during a 24-month period, and 1 H. Lee Moffitt Cancer Center and Research Institute, 2Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa; 3Oregon Health and Science University, Portland; 4Arizona Cancer Center and Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson SUBJECTS AND METHODS Study design and population. Between September 2003 and December 2005, the HPV Infection in Men study, a prospective study sponsored by the Arizona Disease Control Research Commission, was conducted in Tucson. Details of the study design have been described elsewhere [25]. In brief, participants were recruited via targeted community mailings and flyers placed on university and college campuses, face-to-face recruitment in classrooms and county health clinics, publicity at mass events, and radio and newspaper advertisements from September 2003 through May 2005. Men were eligible to participate if they (1) were 18 – 44 years old; (2) were residents of southern Arizona; (3) reported no prior diagnosis of penile or anal cancer; (4) reported no prior diagnosis of genital warts; (5) reported no current diagnosis or treatment of STI, including genital warts, genital herpes, chlamydia, gonorrhea, syphilis, nongonococcal urethritis, hepatitis B virus, hepatitis C virus, and HIV; (6) were willing to commit to 4 visits scheduled 6 months apart; and (7) had no plans to relocate during the subsequent 2 years. Participants were invited to return every 6 months and were monitored for ⬃18 months. At each visit, participants completed a selfadministered risk-factor questionnaire and had penile and scrotal skin samples taken for HPV DNA testing. Of 377 men present at the screening visit who were eligible for the study, 337 were willing to participate and were enrolled. Of these 337 men, 35 failed to return for follow-up visits, 12 did not provide samples adequate for detection of HPV DNA, and 5 did not provide complete information on the questionnaire, leaving 285 men who completed at least 2 study visits and for whom complete HPV DNA results and risk-factor information were available for analysis. HPV sampling and testing. To avoid interspecimen contamination, warts or lesions found on the genitals were sampled by swabbing the wart or lesion with a saline-prewetted Dacron swab before normal genital skin was sampled. Three Dacron swabs prewetted with sterile normal saline were used to sample genital skin, as described and validated elsewhere [22]. The first swab was used to sweep 360° around the coronal sulcus and then 360° around the glans penis; a second swab was used to sample the entire skin surface of each of the quadrants of the shaft of the penis; a third swab was used to sample scrotal skin. The 3 swabs were (...truncated)