Abstract SY32-01: Human papillomavirus vaccines in females and males
Authors: Palefsky Joel 
Published: June 2012

Abstract
Like cervical cancer, a high proportion of anal cancers are associated with human papillomavirus (HPV) infection, particularly HPV 16. Anal cancer is more common in women than men in the general population. While it is an uncommon cancer, the incidence of anal cancer in the general population is increasing by 2% per year among both men and women. Certain risk groups, such as men who have sex with men (MSM) and individuals immunocompromised by HIV infection or other causes, are at substantially higher risk of anal cancer than the general population, with reported incidences exceeding 100/100,000 in some studies.
The incidence of cervical cancer in the developed world has declined substantially in the last few decades with the advent of routine cervical cytology screening to identify women with the cervical cancer precursor lesion, high-grade cervical intraepithelial neoplasia (CIN), followed by removal of the CIN lesions prior to progression to cancer. The natural history of anal cancer appears to be similar to that of cervical cancer, with high-grade anal intraepithelial neoplasia (HGAIN) being the precursor lesion to anal cancer. Unlike screening and treatment of high-grade CIN, however, there is no routine screening for and treatment of HGAIN in high-risk populations to prevent anal cancer. Consequently, there are few options currently available to prevent anal cancer.
In addition to screening for and treatment of HGAIN, one such option would be to prevent anal HPV infection and HPV-associated anal diseases through prophylactic HPV vaccination. Since 2006, two highly effective HPV vaccines (bivalent, protecting against HPV 16 and 18) and quadrivalent (protecting against HPV 6, 11, 16 and 18) have been available to women to prevent infection with vaccine types and CIN/cervical cancer due to these types. To determine the safety and efficacy of HPV vaccination in males, and to determine its efficacy to prevent anogenital infection and HPV-associated disease of the anus and external genital region (penis, scrotum, perianal region), a randomized, placebo-controlled, double-blind trial of the quadrivalent vaccine (the Merck 020 protocol) was performed. The protocol included 3,463 heterosexual men and 602 MSM aged 16-26 years enrolled from 18 countries. Participants were eligible if they had at least one but no more than 5 lifetime sexual partners. MSM were excluded from participation if they were HIV-positive at baseline, but continued to participate in the study if they acquired HIV after vaccination.
Efficacy against HPV 6/11/16/18-associated external genital lesions (EGL) in the in the per protocol efficacy (PPE) population was 90.4% [95% CI: 69.2, 98.1]. Efficacy against HPV 6/11/16/18-related EGL in the intent to treat (ITT) population was 65.5% (95% CI: 45.8, 78.6). Almost all of the EGL were condyloma acuminatum. Efficacy against HPV 6/11/16/18-related persistent infection was 85.6% (97.5% CI: 73.4, 92.9) in the PPE population and 47.8% (95% CI: 36.0, 57.6) in the ITT population. Overall the vaccine was well tolerated, with no vaccine-related serious adverse events. Injection-site pain occurred significantly more frequently among those receiving the quadrivalent vaccine vs placebo (57% vs. 51%; p&lt;0.001).
To determine the efficacy of the quadrivalent vaccine against anal HPV infection and anal HPV-associated disease including HGAIN, the 602 MSM included in the study of EGL prevention were also studied for AIN prevention. In addition to the study procedures performed as part of the EGL study, the MSM underwent testing for anal HPV infection using anal swabs and AIN using high-resolution anoscopy-guided biopsies of lesions in the anal canal.
Among these MSM, the observed efficacy against HPV 6/11/16/18-related AIN (all grades combined including anal condyloma) in the PPE and ITT populations was 77.5% (95% CI: 39.6, 93.3) and 50.3% (95% CI: 25.7, 67.2), respectively. HGAIN specifically was reduced by 74.9% (95% CI: 8.8, 95.4) and 54.2% (95% CI: 18.0, 75.3) in the PPE and ITT populations. Persistent anal HPV 6/11/16/18 infection was reduced by 94.9% (95% CI: 80.4, 99.4) and 59.4% (95% CI: 43.0, 71.4) in the PPE and ITT populations, respectively.
Based on EGL data from the Merck 020 protocol, the quadrivalent vaccine was approved by the U.S. Food and Drug Administration (FDA) in 2009 for use in boys and men aged 9-26 years for prevention of genital warts. The Advisory Committee on Immunization Practices (ACIP) issued a permissive recommendation for the use of vaccine in males, with coverage under the Vaccines for Children program for eligible males up to the age of 18 years. The anal data were not available at the time of the FDA and ACIP review, but were reviewed by the FDA in December, 2010, which then approved the quadrivalent vaccine for prevention of AIN and anal cancer in both men and women.
Since HIV-seropositive individuals are at especially high risk of HPV-associated anogenital cancers, several studies have been done to determine safety and immunogenicity prior to studying vaccine efficacy. Currently HPV vaccination is not contraindicated in HIV-seropositive individuals, but efficacy may be limited among those with a high degree of prior exposure to vaccine HPV types due to extensive pre-vaccination sexual activity. A study of HIV-seropositive children (PACTG 1047) and older HIV-seropositive adult MSM (AIDS Malignancy Consortium) 052) both showed that the vaccine was safe and did not perturb CD4+ levels or HIV viral loads. Among individuals naïve to a given vaccine HPV type, almost all seroconverted. Efficacy studies are expected to being shortly among HIV-seropositive MSM.
In summary, anal cancer is a growing problem in the general population and especially among certain risk groups such as MSM and HIV-seropositive individuals, even among those who are well controlled on antiretroviral therapy. In the absence of routine screening programs to identify and treat HGAIN to reduce the risk of anal cancer, vaccination against HPV offers a promising long-term approach to reduction of anal cancer, as well as other male HPV-related lesions such as external genital and anal condyloma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY32-01. doi:10.1158/1538-7445.AM2011-SY32-01