Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - EUROGIN 2010 9th International Multidisciplinary Congress

Monte Carlo, Monaco / February 17-20, 2010

The first substantial evidence that vaccination against human papillomavirus (HPV) reduces the burden of HPV-related disease was reported here by Australian investigators, who have already observed about a 50% reduction among young women in the incidence of genital warts after widespread uptake of the quadrivalent vaccine where HPV types 6 and 11 were included.

Irrespective of vaccination status, Dr. Suzanne Garland, The Royal Women’s Hospital, Victoria, Australia, and colleagues documented a significant decrease in the incidence of genital warts among women <28 years presenting with their first episode to sexual health clinics in Australia from the start of the quadrivalent vaccine campaign in July 2007 to the end of 2009 (Figure 1). “This is an extraordinary observation and it shows the benefit of the high uptake rate of the HPV program in Australia,” Dr. Garland observed. As of June 2009, approximately 80% of females in Australia aged 12 to 26 years had received the quadrivalent vaccine.

The incidence of genital warts was also reduced by 13% to 20% among heterosexual men attending the same sexual health clinics—the result of herd immunity, Dr. Garland noted, since there was no comparable reduction in the incidence of genital warts over the same interval among men who have sex with men (MSM).

Figure 1.

Broad Protective Benefits

Equally compelling evidence demonstrating long-lasting immunity following vaccination with the quadrivalent vaccine was also presented by Dr. Garland. The vaccine remained 98% effective against 16- and 18-related cervical intraepithelial neoplasia (CIN) grade 2 and 3 and 100% effective against 16- and 18-related adenocarcinoma in situ in the same study group. At 9.5 years of follow-up, the original monovalent HPV 16 vaccine has continued to be 100% protective against clinical disease (CIN of all grades). The quadrivalent vaccine also demonstrated 100% efficacy against all grades of vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) in the per-protocol population (PPP). Three to four years after vaccination in the FUTURE (Females United to Unilaterally Reduce Endo/Ectocervical Disease) studies cohorts, the vaccine was still 99% effective against HPV 6-, 11-, 16- and 18-related external genital lesions and 99% effective against genital warts.

Several speakers here noted that virus-like particle vaccines such as the quadrivalent vaccine are extraordinarily immunogenic and expectations are that vaccination in adolescence will continue to provide long-term immunity. Yet the protective benefits of the quadrivalent vaccine are not limited to young, HPV-naive females. Dr. Daron Ferris, Medical College of Georgia, Augusta, presented data demonstrating that at 2.2 years of follow-up, the vaccine was 92.7% effective against persistent infection, CIN and external genital lesions in the PPP and 30.9% effective in the full analysis set (intent-to-treat [ITT] cohort) in women between the ages of 24 and 45, approximately one-third of who were seropositive to HPV on enrolment. With a further 3.8 years of follow-up, efficacy increased to 47% in the ITT cohort, “Indicating that efficacy of the vaccine increases over time as previous infection is exhausted and incident infection in placebo patients continues to occur,” explained Dr. Ferris.

Evidence also indicates that efficacy is not age-dependent, nor does the adverse event profile differ in older vs. younger women. Even more clinically relevant were efficacy results in women with either a history of cervical, vulvar or vaginal precancerous lesions or genital warts or who had undergone definitive therapy for cervical, vulvar, vaginal disease or genital warts. Dr. Elmar Joura, Medical University of Vienna, Austria, noted that women who have been treated for HPV-related disease (CIN, VIN, VaIN, genital warts) are at high risk for “new” cervical disease. He showed that the quadrivalent vaccine reduced any CIN1+ by 47%, any CIN2+ by 65%, HPV vaccine type-related CIN1+ by 74% and HPV vaccine type-related CIN2+ by 61% at a mean follow-up of 1.6 years’ post-treatment. Following definitive cervical therapy, the vaccine also reduced the incidence of VIN, VaIN and genital warts by 46% and HPV 6-, 11-, 16- and 18-related disease by 82%. Following treatment for vulvar disease, the vaccine reduced vaccine-type CIN1+ by 67% and vaccine-type CIN2+ by 48%, while the incidence of new vulvar disease from both vaccine and non-vaccine types was also significantly reduced. Dr. Ole Erik Iversen, University Hospital, Bergen, Norway, noted that among the FUTURE cohorts, only about half of participants were negative to all tested HPV types while the other half had either been exposed to some HPV type (mixed) or had an abnormal Pap smear (exposed). In the HPV-naive vaccinated cohort, a significant 20% reduction in colposcopy vs. placebo was seen regardless of HPV causal type, as was a 22% reduction in cervical biopsy and a 42% reduction in definitive therapy. At the end of the study, there was also a 43% reduction in CIN3 or adenocarcinoma in situ. Importantly, investigators observed similar reductions in the same end points regardless of whether patients had been exposed to an HPV type or not at baseline—“suggesting that whether we offer the vaccine to women who are HPV-naive, a mixed population or a population of previously exposed women, we can expect to have the same public health impact in terms of disease reduction immediately following vaccination,” Dr. Iversen concluded.

Preventing HPV-related Disease in Men

Evidence that the quadrivalent vaccine can prevent HPV-related disease in MSM (n=602, 16 to 26 years of age) was reported here for the first time by Dr. Joel Palefsky, University of California, San Francisco. At a mean follow-up of 31 months, the vaccine proved 77.5% effective against HPV 6-, 11-, 16- and 18-related anal intraepithelial neoplasia (AIN) and anal cancer in the PPP, which was the closest investigators could get to the ideal target population for male vaccination. It was also 100% effective against condyloma, 73% effective against AIN1 and 74.9% against AIN2+.

Encouragingly, efficacy seen in the full analysis data set (ITT population) was still good, at 50.3% against vaccine type-related AIN or anal cancer, 57.2% against condyloma, 49.6% against AIN1 and 54.2% against AIN2+. Overall, the safety profile was similar to that reported in females, the majority of adverse events being local injection site reactions with no serious vaccine-related adverse events. “If you look at AIN2 or worse, we saw a 75% reduction [in the PPP] which was statistically significant and even in the ITT population, it was surprisingly good too,” Dr. Palefsky told delegates, “If the vaccine works the way we expect it will, we can expect it will show a substantial reduction in anal cancer over time and I think this is one of the most important health advances for MSM we have seen so far.”

PISCES and HITCH

The psychological ramifications of HPV infection should not be trivialized either, as several speakers here indicated. Measures of psychological distress have shown that having genital warts is as distressing for patients as having CIN2/3. This was corroborated by Canadian investigators who, as results from the PISCES (Psychological Impact of Cervical Screening and Condylomas: An Epidemiology Study) indicate, men and women with genital warts reported considerably more anxiety and depression than Canadian norms. The impact on quality of life also lasted far longer for men (210 days) than it did for women (90 days), likely because men are slower to seek medical care for genital warts than women.

Data from the Canadian HITCH (HPV Infection and Transmission Among Couples Through Heterosexual Activity) study also indicate that HPV transmission is very likely in new couples. If transmission does not occur within the first four months, there is a 21% chance of males infecting their female partners within the next five months and a 28% chance of females infecting their male partners. Researchers reminded delegates that HPV transmission is very common among couples and the rate of concordance is also very high.

Summary

As Dr. Marc Steben, Institut national de santé publique du Québec, Montreal, reminded delegates, “Once patients have one HPV lesion, they are at very high risk to have another lesion elsewhere.” The reality of this reverberates in international statistics where it is estimated that 80% to 90% of anal cancer is HPV-related, as is 40% to 50% of penile cancer and some 25% of oral and oropharyngeal cancers. Prevention of non-cervical HPV-related disease therefore has potentially enormous public health implications for both women and men.