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EUROGIN 2008 - 8th International Multidisciplinary Congress

Nice, France / November 12-15, 2008

After four years of follow-up, the FUTURE studies demonstrated that the quadrivalent L1 virus-like-particle human papillomavirus (HPV) vaccine was 100% effective in preventing vaginal, vulvar, perineal and perianal intraepithelial lesions or warts caused by HPV types contained in the vaccine based on the per protocol analysis. “The vaccine also provides quite extraordinary overall efficacies of 98% against cervical intraepithelial neoplasia [CIN] 2/3 lesions and adenocarcinoma in situ, 100% against CIN-2 and 97% against CIN-3, giving us a >98% protection against high-grade intraepithelial disease of the cervix, vulva and vagina, and genital warts,” confirmed Prof. Margaret Stanley, Deputy Head, Department of Pathology, University of Cambridge, UK.

As Prof. Stanley noted, it might be too early to predict how long the quadrivalent vaccine will remain protective against HPV infection. However, it is well accepted that if a vaccine provokes an anamnestic immune-memory response following re-exposure to previously encountered antigens—as the quadrivalent vaccine has been robustly shown to do—it is capable of inducing long-lasting immunity. “Researchers have demonstrated sustained efficacy over time and this efficacy is not going to disappear overnight,” Prof. Stanley concluded.

At 60 months, published data from a subset of protocol 007 indicated that the efficacy against vaccine-type-related CIN or external genital lesions was 100%.

HPV Vaccination and Adult Women

The incidence of HPV disease peaks within 10 years following sexual debut, as pointed out by Dr. Nubia Muñoz, former chief of Field and Intervention Studies, International Agency for Research on Cancer, Lyon, France. However, women remain susceptible to HPV infection and the burden of HPV-related disease throughout their lives. Furthermore, “Social changes in many countries, including delay in first marriage and increasing divorce rates, increase the risk of HPV infection among women in their late 20s, 30s and 40s,” Dr. Muñoz observed, “and such ‘mid-adult’ women may benefit from prophylactic HPV vaccination as well.”

Thus, researchers carried out an international efficacy trial of the quadrivalent HPV vaccine against CIN and external genital lesions involving 3819 24- to 45-year-old sexually active women who were naive to HPV 16 and 18 at baseline. As reported by Dr. Muñoz, interim data at 2.2 years of follow-up indicated that the quadrivalent vaccine was 92.4% effective in preventing HPV 6-, 11-, 16- and 18-related CIN and external genital lesions. Efficacy against HPV 16- and 18-related CIN and external genital lesions was 87.8% while efficacy against HPV 6- and 11-related CIN and external genital lesions was 100%. Overall, the quadrivalent HPV vaccine demonstrated an acceptable safety and tolerability profile in mid-adult women.

“These interim data demonstrate that the quadrivalent HPV vaccine is highly effective in preventing HPV 6-, 11-, 16/18-related CIN or external genital lesions in women aged 24 to 45,” Dr. Muñoz concluded, adding that 24- to 45-year-old women could definitely benefit from HPV vaccination.

HPV Vaccination in Males

Dr. Joel Palefsky, Department of Medicine, University of California, San Francisco, remarked, “When you add up the numbers of HPV-related cancer cases in men, it is similar to the number of cervical cancers in a screened population of women—and the incidence is increasing alarmingly.”

He added that these come from a wide variety of cancers of the pharynx, oral cavity, larynx, anus and penis. A Danish study found that 58% of anal cancers among heterosexual men and 100% among homosexual men were positive for high-risk HPV DNA. Anal cancer rates due to HPV in homosexual men has traditionally been at least twice as high in those infected with HIV and with the advent of antiretroviral therapy, the incidence of anal cancer has risen substantially, reaching 75 to 137 per 100,000.

In data presented for the first time here, findings from a pivotal study in 4000 men between the ages of 16 and 26 years—3400 heterosexual males and approximately 600 men who have sex with men—showed that the quadrivalent vaccine prevented 90% of external genital lesions caused by HPV 6, 11, 16 and 18. The three external lesions seen among vaccine recipients were cases of genital warts, suggesting that the quadrivalent vaccine is 89.4% effective in preventing genital warts in this patient cohort.

There were no cases of penile/perineal/perianal intraepithelial neoplasia (PIN) among vaccine recipients vs. three cases of PIN 1 or PIN 2/3 in the placebo group. No cases of penile, perineal or perianal cancer were seen in either the vaccine or control group. At the time of the analysis, the study had a mean duration of 29 months.

“In young men 16 to 26 years [of age], quadrivalent HPV vaccine was effective in reducing persistent anogenital HPV 6/11/16/18 infection and HPV 6/11/16/18 DNA detection in at least one visit,” he concluded. “But decisions on male vaccine implementation strategies will require further consideration by policymakers.”

HPV 6- and 11-related Diseases

“Even though cervical cancer is the second most common cause of cancer death among young women, it should not overshadow the importance of other HPV-related genital cancers and precancers,” stated Dr. Marc Steben, Institut national de santé publique du Québec, Montréal. “HPV can also cause vulvar and vaginal intraepithelial neoplasias and cancers, as well as genital warts.”

HPV 6 and 11 are common in the population and linked to the following main clinical presentations: CIN-1, low-grade vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), genital warts and recurrent respiratory papillomatosis. In fact, genital warts may be the most common condition attributable to HPV 6/11, accounting for around 90%. Given the substantial clinical/economic burden attributable to HPV 6/11, Dr. Steben evaluated the efficacy of the quadrivalent HPV vaccine in preventing HPV 6/11-related CIN and external genital lesions using four-year data from phase IIb/III clinical trials.

In the study, he reported 18,174 women aged 16 to 26 years were randomized to vaccine or placebo. Four per cent were PCR-positive and 8.2% were seropositive, so 12% of the women were already exposed to HPV 6 at baseline. Efficacy of the quadrivalent HPV vaccine against any external genital lesion was 80.5%. “There were two cases of condyloma in the per protocol vaccinated population analysis vs. 189 is the placebo cohort, giving an efficacy rate of 99%,” Dr. Steben reported. There was no VIN or VaIN grade 1 in the vaccinated population compared with 22 cases in the placebo group, for an efficacy rate of 100%.

Dr. Steben concluded that the HPV vaccine was highly effective in preventing 6- and 11-related CIN and external genital lesions both in the primary population of 6- and 11-naive participants and in the ITT population. He told delegates, “We were surprised to see a low baseline 6 and 11 positivity rate and relatively frequent occurrence of HPV 6/11-related lesions at 44 months. So protection against 6 and 11 is a substantial benefit of the quadrivalent vaccine and is expected to contribute to the early benefit of vaccination programs.”