An international randomized clinical trial has shown that the vaccine Gardasil, which arms the immune system against four strains of the human papillomavirus (HPV), can reduce the incidence of anogenital HPV infections in young men 16 to 26 years of age at the time of vaccination. The results were published in the New England Journal of Medicine on February 3, 2011.
Gardasil was first approved by the FDA in 2006 for females 9 to 26 years of age to prevent cervical, vulvar, and vaginal cancers, as well as genital warts. Two of the four strains targeted by the vaccine—HPV-6 and HPV-11—cause most cases of genital warts, and the other two strains—HPV-16 and HPV-18—cause about 70 percent of all cervical cancers. In addition, HPV-16 and HPV-18 have been linked to cancers of the anus, penis, and oropharynx. In 2009, the FDA extended approval of the vaccine for the prevention of genital warts in young men based on the results of the current trial.
The trial, designed by Merck Pharmaceuticals, enrolled 4,065 young men from 18 countries; 2,032 of the participants were randomly assigned to receive the three-dose vaccine over a 6-month period, and 2,033 received a series of placebo injections over the same period of time. Anna R. Giuliano, Ph.D., of the H. Lee Moffitt Cancer Center and Research Institute and her colleagues measured HPV infection status at the time participants joined the study and again periodically for up to 3 years after enrollment. The men also underwent regular physical examinations to identify genital skin lesions associated with HPV.
The researchers performed analyses in two overlapping groups of men. The intention-to-treat cohort included men who all received at least one dose of vaccine or placebo, regardless of HPV status at enrollment. The per-protocol cohort included only men who received all three doses and tested negative for all four HPV types targeted by the vaccine throughout the vaccination phase of the study, and thus excluded men who developed infections before the vaccination was complete. Gardasil is designed to prevent HPV infections and does not appear to increase the rate of clearance of established infections; thus, the estimates of effectiveness will be higher in the per-protocol cohort than in the intention-to-treat cohort.
In the intention-to-treat cohort, the vaccine prevented 65.5 percent of skin lesions, mostly genital warts, associated with two of the four targeted HPV types; in the per-protocol population containing men with no evidence of previous exposure to the viruses, the vaccine prevented 83.8 percent of lesions.
The rate of persistent HPV infection with any of the four types anywhere in the body that lasted at least 6 months was reduced by 47.8 percent in the intention-to-treat cohort and by 85.6 percent in the per-protocol cohort. For HPV types 16 and 18—the two that can eventually cause cancer in a small proportion of infected individuals—persistent infection was reduced by 79 percent and 96 percent, respectively, in the per-protocol cohort, though these data are based on very small numbers of people. Much longer follow up and additional studies will be needed to determine whether the vaccine prevents the development of HPV-related cancers in men, explained the authors.
On December 22, 2010, the FDA approved Gardasil for both men and women ages 9 through 26 to prevent anal cancer and associated precancerous lesions. This approval was based on results in the subset of men in the current trial who have sex with other men. Dr. Giuliano and her colleagues found a 78 percent reduction in anal intraepithelial neoplasiagrades 1, 2, and 3 related to HPV-16 and HPV-18 infection. Approximately 90 percent of anal cancers have been linked to HPV infection.