An emerging strategy for the prevention of HPV infection and disease in males
Daron G. Ferris, MD
Department of Family Medicine
Department of Obstetrics and Gynecology
Medical College of Georgia
According to the Centers for Disease Control and Prevention, about 20 million people are infected with human papillomavirus (HPV) in the United States.1 HPV has the highest incidence of all sexually transmitted infections (STIs), and it is most common in young, sexually active populations.2 Approximately 25%, 45%, and 27% of females between the ages of 14 and 19, 20 and 24, and 25 and 29 years, respectively, are infected with HPV.3 HPV infection rates as high as 70% have been reported among men.4
HPV belongs to a large family of viruses, and thus far, more than 100 different types have been identified in humans. Approximately 40 of these small, nonenveloped, double-stranded DNA viruses can be transmitted from one person to another through sexual contact.1,5 HPVs infect stratified squamous epithelia, columnar epithelia, and mucous membranes, where they cause benign and premalignant lesions, some of which have the potential to progress to invasive cancer.5
HPV-associated disease burden in men and women
Genital human papillomaviruses are classified as high or low risk based on oncogenic potential.6 The 2 most prevalent high-risk HPV types are 16 and 18, which cause approximately 70% of cervical cancer cases.7,8 Additionally, approximately half of cancers of the vulva and vagina in women, as well as 85% of anal cancer, 36% of oropharyngeal cancers, and 24% of cancers of the larynx in men and women are attributable to HPV infection with high-risk strains.9,10 Although anal cancer is relatively rare, its incidence has been increasing over the past 50 years, especially among men who have sex with men.11 Moreover, approximately 50% of cancers of the penis are associated with HPV infection.11
Low-risk HPV types, the most common of which are HPV 6 and 11, are associated with the development of cervical intraepithelial neoplasia (CIN 1 and some CIN 2), Condylomata acuminata (genital warts), and recurrent respiratory papillomatosis—a rare but potentially fatal disease. HPV types 6 and 11 are responsible for approximately 90% of cases of genital warts. About 1% of sexually active Americans have genital warts at any given time,1 with the percentage higher in women (7.2%) than in men (4%).12
Prevention of HPV infection
Two L1 virus-like-particle HPV vaccines have been developed and have been demonstrated to be safe and efficacious in the prevention of HPV infection and its associated diseases in women.13-16 A quadrivalent vaccine has been approved by the US Food and Drug Administration (FDA) for the prevention of HPV types 6/11/16/18-associated cervical cancer, adenocarcinoma in situ, CIN grades 1 to 3, vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia grades 2/3, vaginal cancer, vulvar cancer, and genital warts in girls and women 9 to 26 years of age.17,18 The Advisory Committee on Immunization Practices has recommended the vaccine for 11- and 12-year-old girls and for females 13 to 26 years of age who have not yet been vaccinated or completed the vaccine series.19 A bivalent HPV vaccine that protects women against types 16 and 18 is currently under FDA review. Although it is thought that expanding HPV vaccination to include males would enhance herd immunity and thus reduce the overall incidence of HPV-related disease, neither HPV vaccine is currently approved for use in males in the United States.
HPV vaccination in males?
Great interest has been expressed in the vaccination of boys and men against HPV. Although the quadrivalent HPV vaccine has been shown to be highly immunogenic and provides durable immunity through a postvaccination period of 1 year in 9- to 15-year-old boys,20 until recently there has been no safety and efficacy data available for males. A randomized, double-blind, placebo-controlled phase 3 trial designed to determine the efficacy of the quadrivalent HPV vaccine in preventing HPV 6, 11, 16, or 18–related external genital lesions in males aged 16 to 26 years is ongoing.21,22 The quadrivalent HPV vaccine or placebo was administered to study participants (N=4065) at enrollment, month 2, and month 6, with 36 months of planned follow-up from day 1.21,22
In the study, preliminary analysis revealed that the quadrivalent HPV vaccine was 90.4% effective in reducing external genital lesions (95% confidence interval [CI], 69.2-98.1) in males; this is a composite end point that includes genital warts, penile/perineal/perianal intraepithelial neoplasia, and penile/perineal/perianal cancers. In comparison, a small number of cases of penile/perianal/perineal intraepithelial neoplasia occurred in the placebo group. The vaccine also prevented genital warts in men, with an efficacy of 89.4% (95% CI, 65.5-97.9).21 In addition, the quadrivalent vaccine was 85.6% effective in the reduction of persistent infection (defined as the detection of the same HPV type over 2 or more consecutive visits 6 months apart) (95% CI, 75.1-92.2).22 Persistence of oncogenic HPV infection is a major risk factor for the development of cancer. Data are pending concerning the efficacy of preventing intra-anal HPV infection and related diseases in men.
No serious adverse events were linked to the quadrivalent vaccine during the study. However, as expected, a slightly higher proportion of patients reported injection-site adverse events in the vaccine group compared with the placebo group.21
The quadrivalent vaccine already is approved for use in boys and men in several countries, including Australia, Mexico, and some European Union nations. However, there is no clinical evidence as of yet demonstrating that HPV vaccination prevents anal cancer or other HPV-associated cancers in men. There is also no evidence that vaccination prevents men from transmitting HPV to women. The bivalent vaccine is currently being studied in boys in Finland to examine whether vaccination will reduce the incidence of cervical cancer in women.23 Although neither the quadrivalent nor bivalent vaccine is currently approved by the FDA for administration in males, the results of a recent survey indicate that about one-third of 571 men expressed interest in receiving the HPV vaccine.24
Human papillomaviruses are one of the most common STIs, and HPV-related disease constitutes a significant health burden worldwide. Persistent infection with high-risk oncogenic HPV types is associated with anal, penile, and oropharyngeal cancers and precancers in men. Although about one-quarter of HPV-related cancers occur in men, HPV vaccines are currently approved for use only in girls and young women. Recent interim data demonstrate that the quadrivalent HPV vaccine is both safe and effective in reducing external genital lesions and persistent HPV infection in young men. These promising results suggest that HPV vaccination of males may be beneficial.
Dr Ferris has received grants and research support from, is a consultant to, and is on the speakers bureau of GlaxoSmithKline and Merck & Co., Inc.
This e-newsletter is sponsored by SciMed and supported by an educational grant from Merck & Co., Inc.