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44th Annual Meeting of the Infectious Diseases Society of America

Toronto, Ontario / October 12-15, 2006

Curable sexually transmitted infections (STIs) have been undergoing a steady decline throughout the world in those areas where STI control programs have been implemented. This is not the case for sexually transmitted viral infections. As noted by Dr. King Holmes, Professor of Medicine, University of Washington, Seattle, “Now that we have vaccines against two of the four major viral STIs, they are going to help us control these infections if they are effectively applied.”

Because of its ubiquitous nature, the most important of the sexually transmitted viral infections is human papillomavirus (HPV). In one study of sexually naive female university students, for example, there was a 75% cumulative incidence of HPV infection at the end of four years of college.

HPV infection is also associated with a substantial disease burden. The two most prevalent oncogenic HPV types, 16 and 18, account for approximately 70% of all cervical cancer worldwide, while non-oncogenic types 6 and 11 account for approximately 90% of all genital warts, a significant amount of low-grade cervical dysplasia and essentially all laryngeal papillomatosis.

As discussed by Dr. Anna R. Giuliano, Professor of Medicine, Epidemiology and Biostatistics, Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, the disease burden associated with HPV infection in heterosexual, HIV-negative men is substantial. It causes penile and anal cancer, as well as cancers of the oral cavity, the oropharynx and possibly head-and-neck cancer as well. “All of these cancers are primarily attributable to HPV 16,” Dr. Giuliano confirmed. Indeed, a conservatively estimated 10,000 cancers are diagnosed in US men each year that are attributable to HPV, again primarily to HPV 16. State-of-the-art detection methods applied to a cohort of men living in the US, Mexico and Brazil also showed that approximately 60% of the cohort had been infected with HPV. In the US alone, this translates into approximately 500,000 cases of genital warts in men each year.

While rare, recurrent respiratory papillomatosis, a particularly unpleasant manifestation of HPV infection, occurs among affected children, giving rise to warty tumours in the larynx that can cause airway obstruction and which have the potential for malignant transformation. In the US, pediatricians see approximately 1500 to 2500 new cases of recurrent respiratory papillomatosis each year. Once diagnosed at between two and four years of age, children typically require about four surgeries per year until their airways are large enough to prevent airway obstruction, Dr. Giuliano told the audience.

Not only is HPV infection associated with a significant disease burden in men, but it influences disease risk in women as well. Case-control studies indicate, for example, that wives of men with penile cancer are at increased risk of cervical cancer, as are the second wives of men whose previous wife died of cervical cancer and wives of men with a larger number of sexual partners and prostitute contacts.

HPV Quadrivalent Vaccine

Clinical trials of the new HPV quadrivalent vaccine have so far been conducted in young women, but there is preliminary evidence that the vaccine could also be effective in young men. In a study carried out in boys aged nine to 15, antibody titres in response to the vaccine were two- to threefold higher in adolescent boys than in young women. The antibody response observed in these young boys was also higher than that seen in girls of the same age, added Dr. Giuliano: “There is a very profound, robust response to the vaccine in boys.” Consequently, a vaccination strategy that included both genders could potentially optimize protection against HPV infection, resulting in a more rapid and profound reduction in the burden of HPV disease in women, as has been shown by a mathematical model carried out by Dr. Giuliano and colleagues.

The same model also demonstrated that male vaccination would reduce disease burden substantially, particularly the incidence of genital warts. In the seminal phase III study of the quadrivalent vaccine containing HPV types 6, 11, 16 and 18, results showed that the vaccine was highly effective against all end points. As discussed by Dr. Darron Brown, Professor of Medicine, Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, the quadrivalent vaccine proved to be 97% effective against the development of cervical intraepithelial neoplasia (CIN) grades 1 or worse and 95% effective against both genital warts and vulvar or vaginal neoplasia at an average follow-up of 24 months. The vaccine also proved to be 97% effective against CIN grades 2 to 3 as well as cervical adenocarcinoma in situ.

At five years’ follow-up, the quadrivalent vaccine continued to provide 100% protection against all vaccine type-related CIN lesions and genital warts, and was 96% effective against HPV vaccine type-related persistent infection or disease.

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) recommend the vaccine for girls 11 to 12 years of age, as well as girls and women 13 to 26 years of age who have not yet been vaccinated. Any girl as young as 9 whom physicians believe would benefit from HPV protection may be considered for vaccination as well, according to ACIP recommendations. “There is no evidence that this vaccine has any therapeutic effect,” Dr. Brown commented, “but it can still be given to sexually-active women or those who have had cervical dysplasia, because we know that women who are infected with a vaccine type are still protected against other vaccine types by this vaccine.” Since only about 50% of women mount an antibody response to natural HPV infection, half of those women who have been infected with HPV remain at risk for a recurrence if re-infected with the same vaccine type. Thus, if immunity could be boosted through the use of the quadrivalent vaccine, it could provide significant protection against future episodes as well.

Extending the Spectrum of Protection

If approximately 70% of all cervical cancer is associated with HPV types 16 and 18, 30% is related to other oncogenic HPV types. Investigators now need to determine whether vaccination with the quadrivalent vaccine protects patients from HPV-related disease not caused by 6, 11, 16 and 18. Although it is still too early to confirm, Dr. Brown expressed confidence.

There are approximately 15 high-risk oncogenic types, including 31, 33, 35, 39, 45, 51, 52, 56 and 66. Types 16 and 31 are very closely related, as are 18 and 45. “Thus, there is reason to believe that immunization with VLP 16 might protect against 31 and immunization with VLP 18 might protect against 45,” he said.

Ongoing long-term clinical trials with the quadrivalent vaccine will likely provide a definitive answer to this question. In the meantime, consistent condom use does reduce the risk of HPV transmission, although it still cannot reliably prevent all HPV infection. Male circumcision also significantly reduces HPV transmission as well as HIV transmission. (In Israel, for example, there have been no cases of reported penile cancer over the past 10 years.)

A strategy that does not appear to yield success, as Dr. Brown related, is taking the pledge of abstinence. In one study in which women had taken the “virginity pledge,” the prevalence of HPV infection was 26.5%. For those who reported they had pledged at times but not always, HPV prevalence was 28.5%.