Health officials consider HPV vaccination for males

With one human papillomavirus vaccine on the market and another on the way, the Advisory Committee on Immunization Practices and the FDA have several factors to consider in determining whether to extend the vaccine’s use to boys and men. The Advisory Committee on Immunization Practices (ACIP) is expected to discuss use of the vaccine in young men at its next regular meeting and the FDA could make a decision by the end of the year.

Merck officials said at the ACIP meeting in June that they hope that data on Gardasil, approved for use in women since 2006, will convince both the ACIP and the FDA that the vaccine is effective for the prevention of the malignancies that HPV can cause in men, such as penile and anal cancers, and cancers of the mouth and throat.

Cervarix (GSK), meanwhile, is under FDA consideration for approval in girls and women. Data from the 25th Annual Human Papillomavirus Conference indicate that Cervarix is protective against the most common and aggressive cancer-causing types, HPV-16 and HPV-18.

CDC data indicate that about 20 million Americans are currently infected with HPV, and another 6.2 million people become newly infected each year. Considering only new cases in men believed to be affiliated with HPV, the American Cancer Society expected almost 10,000 new cases of cancer in 2008.

“Efficacy and safety must be considered in the approval of this vaccine,” said Stan L. Block, MD, a practicing pediatrician and Infectious Diseases in Children Editorial Board member. “The FDA is looking at data in males aged 9 through 26. They must consider in males the efficacy for the disease itself, the efficacy for the precancers and cancers, for non-cancer related ailments such as genital warts and for the vaccine’s potential to protect against other HPV-associated cancers, such as head and neck tumors.”

David Kimberlin, MD, also an Infectious Diseases in Children Editorial Board member, said he believes that the safety and cost-effectiveness analyses will likely play a pivotal role in the committee’s decision.

Scientific data

While the vaccine’s efficacy in women has been well established — Merck officials presented data at the 25th Annual Human Papillomavirus Conference that showed 100% protection against HPV — studies of the vaccine’s use in men are just starting to appear. Data presented at the ACIP meeting in June indicated that the vaccine was generally well tolerated in 9- to 26-year-old males.

According to Anna R. Giuliano, PhD, of the H. Lee Moffitt Cancer Center, vaccinating both men and women would reduce the prevalence of the virus that can be transmitted with hopes that there will be a benefit not only to men themselves but also their partners.

Other data presented by Merck officials at the ACIP meeting:

• The vaccine prevented 90.4% of external genital lesions related to HPV types 6, 11, 16 and 18.
• The vaccine reduced persistent infection with vaccine HPV types 6, 11, 16 and 18 by 85.6%.

In terms of safety, the CDC and the FDA officials reported last month in The Journal of the American Medical Association that the rate of adverse events associated with the 23 million doses of Gardasil administered since 2006 is similar to the prelicensing rate in girls who tested it in clinical trials. The researchers noted there was an increased risk of fainting and developing blood clots more often than those receiving other vaccines, but this data — which focused on the vaccine’s use in girls — also noted most of the girls may have been more vulnerable to developing clots because they smoked or were overweight or on birth control pills.

Block, who has conducted research on the HPV vaccine for Merck, said there are no data to suggest the vaccine is any less safe or effective in boys than girls. In fact, antibody levels achieved in boys were higher than in girls in the age range from 10 to 15 years.

GSK, meanwhile, has reported that its vaccine protects against HPV types 16 and 18, which cause most of the HPV-related penile, anal and oropharyngeal cancers and precancers in men, as well as cervical, vaginal, and vulvar cancers and precancers in women. HPV types 6 and 11 cause laryngeal papillomas and more than 90% of sexually-transmitted genital warts.

Cervarix generated higher immune responses than Gardasil in a comparative trial between the two. The neutralizing antibody levels for Cervarix were more than two times higher than those for Gardasil for HPV type 16 and more than six times higher for HPV type 18. The GSK vaccine also produced three times more memory B cells for both HPV types 16 and 18 compared with Gardasil; both vaccines were well tolerated, according to GSK data presented at the annual 25th International Papillomavirus Conference,.

“The GSK data are interesting, but we don’t know right now if the higher antibody titers are clinically meaningful,” Kimberlin said.

Cost considerations

Vaccination cost is another factor health care officials must consider. The Merck product costs about $400 to $500 for the series. That amount, when coupled with average reimbursement for the vaccine, has made some physicians reluctant to administer the vaccine.

According to Block, the bigger question is whether insurance companies will cover the vaccine if it is recommended for routine use in males. If the vaccine is licensed by the FDA and the ACIP provides a broad recommendation, the coverage will be reliable; but if it is simply just permissive, there will be major coverage issues.

“Prevention of transmission from males to females is a major linchpin for this vaccine. It’s much more likely to be cost effective if transmission is preventable,” Block said. “The college-age male group is a great candidate group to focus on because of the effectiveness the vaccine has already shown in preventing genital warts.”

Male HPV vaccination programs generally have less effect and are less cost-effective as vaccine coverage for girls increases, according to Harrell Chesson, PhD, and health economist for the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention for the CDC.

Most studies focus on the prevention of cervical intra-epithelial neoplasia, cervical cancer and genital warts, but more recent cost models are incorporating additional HPV outcomes, including anal, oral cavity and oropharyngeal cancers; penile, vaginal and vulvar cancers and recurrent respiratory papillomatosis in both males and females.

Two cost-effectiveness models of HPV vaccination were presented at the June ACIP meeting.

One presentation by Jane Kim, PhD, and colleague Sue J. Goldie, MD, MPH, both professors of Health Decision Science in the Department of Health Policy and Management at Harvard, examined the effects of adding 12-year-old boys to already-existing vaccination programs for 12-year-old girls. A second model proposed by Merck examined a strategy of vaccinating both males and females aged 9 to 26.

According to Kim and Goldie, HPV vaccination of 12-year-old girls would cost about $43,600 per quality-adjusted life year (QALY) gained at a coverage level of 75% for the full three-dose series. That number falls below the $50,000 per QALY threshold that many researchers use as a measure of good value for money, although other researchers use a benchmark of $100,000 per QALY to gauge the cost-effectiveness of health interventions, Kim said at the ACIP meeting.

However, Kim and Goldie’s model projects $97,300 per QALY to vaccinate girls and women through age 18, $121,400 per QALY for women up to age 21, and as high as $152,700 for women up to age 26. Merck’s model, on the other hand, shows that vaccinating men and women up to age 24 is less than $50,000 per QALY, but greater than $100,000 per QALY when including only cervical, vaginal and vulvar cancers and genital warts in a scenario of 75% effective coverage in females. Differences in these two unpublished results were reduced but not eliminated when selected assumptions were aligned.

Giuliano stressed that there are no other measures to prevent these types of HPV-related cancers in men.

“We currently do not have screening guidelines for cancers caused by HPV in men. Therefore, we have no proven prevention methods for HPV cancers in men such as are available for women, for example, Pap screening to prevent cervical cancer,” Giuliano said. “HPV vaccination may fill this need by providing a method to prevent the HPV infections that cause related cancers in men.”

Other considerations

In addition to cost-effectiveness, there are other factors when considering recommendations for male vaccination against HPV.

According to Lauri Markowitz, MD, who conducts research on HPV at the CDC, HPV prevalence and incidence is high in sexually active men; some groups, such as men who have sex with men have higher rates of infection and some HPV-related cancers such as anal cancer.

The vaccine can provide strong protection for men who have sex with men, according to Block.

“Determining this group is difficult at or before high school age. Without knowledge of those at risk, it would become harder to vaccinate to prevent transmission unless the vaccine becomes recommended for all young males,” Block told Infectious Diseases in Children.

There are also epidemiologic data revealing the importance of persistent HPV infection in the development of cancers of the head and neck and anogenital regions.

Vaccinating both males and females may reduce rates of cancers of the head, neck and anogenital regions similarly to that of cervical cancer, according to Maurie Markman, MD, vice president for clinical research in the department of gynecologic medical oncology at The University of Texas MD Anderson Cancer Center.

“The data are not yet mature enough, but there is increasing evidence that certain types of HPV may cause cancers of the head and neck, which was thought to be smoking related,” said Markman. Data show that HPV-16 and HPV-18 are responsible for oropharyngeal cancers, and these types of cancers are on the rise. As the incidence of smoking goes down, HPV is believed to be playing a factor.

“Head and neck cancers are very morbid to treat and affect males just as much as females. It just simply follows the path of why HPV vaccination might be relevant to males,” Markman said.

What is less clear is how well-received this vaccine would be among boys and men. After the FDA approved the vaccine in 2006 for girls as young as age 9, medical authorities recommended that girls be given the vaccine at age 11 or 12 to protect them before they start having sex. This recommendation prompted a number of critics to charge that vaccination of girls at this age would encourage earlier age of sexual debut.

“There will still be the same small segment of people refusing the vaccine because it’s associated with sex, but the general population will hopefully see that HPV transmission is a real issue and that this vaccine can help prevent risks of exposure,” Block said.

He said in his experience during the clinical trials of the vaccine, families that had struggled first-hand with cancers were more prone to favor vaccination for their boys.

Giuliano said that she is hoping for a broad-based recommendation for the HPV vaccination in boys and men, but at the very least, a recommendation for adolescent boys would help build on the idea of a regular adolescent visit.

“A lot of adolescent boys have to go in for sports physicals anyway. There are a lot of adolescent medicine physicians who would like to see this be a regular well-child visit, so recommending this vaccine in that population would be a huge help,” Giuliano said. She concurred with Block that college-aged males would be another target group for this vaccine.– by Erin Hopkins

For more information:

• Dubin G. Bivalent HPV vaccine.
• Haupt R. Quadrivalent HPV vaccine.
• Kim J. Cost-effectiveness of male vaccination.
• Chesson H. Overview of cost-effectiveness models of male vaccination.
• Markowitz L. Issues and potential recommendation options: vaccination of males.
• All presented at: Advisory Committee on Immunization Practices Meeting. June 24-26, 2009; Atlanta.HPV Prevention: A new era in patient care. www.vindicomeded.com/cmelc/idc_monograph0309.asp.