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Healio
Issue: July 2010
July 01, 2010
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HPV disease in males and vaccination: Implications and opportunities for pediatricians

Issue: July 2010
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One of the greatest advances in cancer research in the last 2 decades has been the demonstration that infection with certain types of human papillomavirus is a necessary cause of cervical cancer.

HPVs are double-stranded DNA viruses that are transmitted through sexual contact. As many as 50% of sexually active individuals acquire HPV during their lifetime, although it results in disease in only a minority of them. Nearly 120 HPV types have been identified and 70% to 80% have been sequenced and classified.

Although most health care providers are aware of the morbidity and mortality of HPV infection in women, there is less knowledge regarding the burden of HPV-related disease in men. Recent supplements published in Infectious Disease in Children, the Journal of Adolescent Heath and Gynecologic Oncology raise awareness for both health care providers and the public regarding the prevalence of HPV infection and disease in males. The articles also draw attention to the sexual health needs of adolescent males. A review of studies in which multiple anatomic sites or specimens were evaluated showed that up to 72.9% of men are infected with HPV. In the developed world, the number of HPV-related cancers in men is similar to that of cervical cancer in women. In the United States, when the estimated numbers of HPV-related cancers (oral/oropharyngeal, laryngeal, anal/rectal, and penile) are added, the sum is 10,968 cases (2008 estimates) and equals the 11,000 cases of cervical cancers that occur each year in women. Additionally, HPV infection in men may lead to genital warts, with an estimated 500,000 new cases diagnosed in the United States each year.

Recent data have also shown that the incidence of HPV-related cancers in men is increasing.

For example, in the United States, the incidence of oropharyngeal squamous cell carcinoma increased by 22% between 1999 and 2006, after showing no change between 1975 and 1999. The United Kingdom saw a 51% increase in oral and oropharyngeal squamous cell carcinoma in men between 1989 and 2006. The increase seems to be accounted for by a rise in HPV-related oropharyngeal carcinoma. HPV-related oropharyngeal carcinoma has been reported in 60% to 80% of recent oropharyngeal biopsy samples in studies conducted in the United States compared with 40% in the previous decade.

Similarly, the incidence of HPV-related anal cancers is also increasing. In the United States, the incidence increased from 0.5 per 100,000 in 1974 to 1.3 per 100,000 in 2004 and was the most commonly diagnosed anogenital HPV-associated cancer in men in 2007. Among men who have sex with men, the incidence of anal cancer is estimated to be as high as that of cervical cancer in the general population of women in the United States before the introduction of cervical cytology screening. HPV infection in men may also increase the risk of acquiring HIV infection.

HPV types

As in women, most HPV-related cancers among men are associated with the high-oncogenic risk HPV types 16 and 18. The low oncogenic risk types 6 and 11 cause 90% of genital wart cases and are also associated with recurrent respiratory papillomatosis (RRP). In 2006, the FDA approved a quadrivalent vaccine (Gardasil, Merck), which targets these four HPV types. It was first approved for use in girls and women aged 9 to 26 years for the prevention of cervical, vulvar, and vaginal cancers, their respective pre-cancerous lesions, and genital warts. In October, a bivalent vaccine (Cervarix, GlaxoSmithKline) was approved for prevention of HPV16 and HPV18 infections and for prevention of cervical intraepithelial neoplasia grade 1, 2 and 3 in females aged 10 to 25 years.

In the United States, both have been recommended by the CDC’s Advisory Committee on Immunization Practice and incorporated into the Vaccines for Children Fund. Both vaccines have received WHO pre-qualification, which means they are eligible for procurement by the United Nations Children’s Fund and other United Nations agencies (including the Pan American Health Organization) for use in national immunization programs.

In October, the FDA approved Gardasil for use in boys and men aged 9 to 26 years for the prevention of genital warts caused by HPV types 6 and 11. Data from the ongoing clinical trial in males have also shown the vaccine prevents the precursor lesions to HPV16/18- related anal cancer; however, there is no expansion of the indication to cancer in males at this time.

Currently, the ACIP supports the permissive use of Gardasil in males and voted to recommend funding be provided for use of Gardasil in males through the VFC. A permissive recommendation means providers may offer the vaccine but immunizers are not expected to offer the vaccine proactively, as they are with the routine recommendation for females (see table).

The permissive recommendation carries specific consequences with respect to patient and provider reimbursement. Most insurance plans currently cover Gardasil for females aged 9 to 26 years according to the prescribing information. It is typically covered as a medical benefit and coverage is usually the same across all plan types. For males, many managed care organizations have decided to provide coverage, including WellPoint, Aetna, CIGNA and Kaiser. Qualifying males without private health insurance may receive Gardasil through the Merck Patient Assistance Program (www.merck.com/merckhelps/ patientassistance/home.html). This program is available to adults older than the age of 18 who reside in the United States and have special circumstances of financial and medical hardship.

It is not known what effect the permissive recommendation will have with respect to vaccine uptake.

Although the participation of some managed care organizations is encouraging and provides some opportunity for privately insured males to be vaccinated, there are challenges with a permissive recommendation for obtaining private insurance coverage that mostly stem from the misunderstanding that receiving a permissive recommendation translates as not being ACIP- recommended. Due in part to this lack of clarity of recommendation, at the time of this article, private insurance provided coverage for only about 65% of all male lives in commercial plans.

Indications and ACIP Recommendations for Use of Gardasil In Males Aged 9 to 26 years

Even with a routine recommendation, there are challenges with respect to vaccine uptake. For example, though the ACIP gave a routine recommendation for females, uptake in the United States has been low. Data from the CDC’s National Immunization Study indicate that, in 2008, only 37.2% of adolescent females had initiated the HPV vaccination series (one dose), and only 18% received all three doses. Possible reasons for suboptimal immunization rates include a perception of vaccine safety concerns. In response to those concerns, a CDC-FDA report analyzing adverse events following Gardasil administration from June 2006 through December 2008 found that, “The findings were generally not that different from what is seen in the safety reviews of other vaccines recommended for a similar age group, 9 to 26 years old (meningitis and TDaP). Based on the review of available information by FDA and CDC, the HPV vaccine continues to be safe and effective, and its benefits continue to outweigh its risks.” Despite these conclusions by the FDA and CDC, some in the lay press, as well as many immunization critics have continued to question the vaccine’s safety. Some parents are also reluctant to vaccinate their children because they are not sexually active and some critics feel is it a license to engage in premarital sex.

In addition to providing protection against genital warts, anogenital cancers, and in theory, HPV-related cancers of the head and neck, there are other compelling reasons for the routine vaccination of adolescent boys and men.

The vaccine is highly effective against HPV 6, 11, 16, and 18-related persistent infection in both genders. With the low uptake among females, immunizing males against HPV could conceivably reduce the risk of male-to-female transmission. In Australia, where there is a nationwide school-based program for female vaccination, the coverage rate for the three-dose regimen approaches 80%. Although vaccination was recently initiated in 2007, there are already published data that show the rates of genital warts among heterosexual males has decreased, which is in line with reduced heterosexual transmission resulting from female vaccination. Though not proven, it is expected that vaccination of males will similarly reduce transmission of HPV to females. Gender neutral vaccination is the quickest way to achieve herd immunity, and vaccinating males is a more equitable public health policy and recognizes that both genders contribute to the transmission of HPV. Furthermore, risk-based and gender-based vaccination policies have been less effective and more confusing to the public.

Opportunities for pediatricians

HPV vaccination of adolescent males also provides unique opportunities for pediatricians. First, it provides them with a means to initiate discussion of male sexual health, an area that has historically lacked attention. Second, the inclusion of Gardasil in the adolescent vaccination schedule provides an opportunity for physicians to co-administer other recommended vaccines. Two other vaccines have been approved and recommended by the ACIP for administration to adolescents: 1) a single dose of meningococcal polysaccharide conjugate vaccine for prevention of meningococcal disease caused by serogroups A, C, Y, and W-135, types that account for the majority of disease in this age group; and 2) a single dose of an acellular pertussis vaccine to protect against diphtheria and tetanus and, particularly, pertussis, which has had a resurgence in recent years as a result of waning immunity in adolescents and young adults. The concomitant administration of these vaccines should improve vaccine uptake, and several clinical trails that have measured the immune response following concomitant administration suggest the same level of protection will be obtained as when the vaccines are administered separately.

In summary, HPV-associated genital lesions are a significant burden in males, as well as females. Although the ACIP has given Gardasil a permissive recommendation for males, private insurance currently provides coverage for about 65% of all male lives. In addition to preventing HPV-related cancers and other malignancies, there are other reasons for administering the HPV vaccine to males that merit consideration. With the low uptake among females, immunizing males against HPV could conceivably reduce the risk of male-to-female transmission. In addition, it provides pediatricians with an opportunity to discuss male sexual health. Finally, the inclusion of Gardasil in the adolescent vaccination schedule provides an opportunity for physicians to co-administer other recommended vaccines, with the ultimate goal of increased compliance, enhanced implementation, and disease prevention.

Acknowledgements

The authors are employees of Merck, the maker of Gardasil. We thank Heather L. Sings (Merck) for writing assistance.

Richard M. Haupt, MD, MPH, is executive director of clinical research at Merck and Co, Inc, in West Point, Pennsylvania.

Gregg C. Sylvester MD, MPH, is senior medical director for the policy, public health & medical affairs within Merck Vaccine Division in Philadelphia.

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