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PRIORITY PRESS - 25th International Papillomavirus Conference

Malmö, Sweden / May 8-14, 2009

The promise of the two human papillomavirus (HPV) vaccines is already registering across communities most affected by HPV infection and expectations are high that infection rates will drop dramatically once target populations have been successfully vaccinated.

The Australian Experience

Australian investigators presented some of the most striking evidence here during the scientific sessions. Their research demonstrated that the quadrivalent vaccine against HPV types 6, 11, 16 and 18 produced rapid and marked reductions in the community incidence of 6- and 11-related disease. Prior to the introduction of the quadrivalent vaccine in April 2007 for 12- to 18-year-old girls and in July 2007 to women up to the age of 27, rates of genital warts had been increasing by about 2% a year, according to data collected by the Melbourne Sexual Health Centre (MSHC). Approximately 70% of adolescent girls received the vaccine upon its introduction as did between 65% and 75% of older females.

A comparison was conducted of the incidence of genital warts among those attending the MSHC between 2004 and 2007 with its incidence in 2008 to year’s end. Findings indicated that the proportion of patients diagnosed with genital warts at the MSHC was significantly lower in 2008 than in previous years, especially among females under the age of 28, in which there was a 25% decline in genital wart incidence in each quarter throughout 2008.

This protective effect was also seen in heterosexual men as well who experienced a 5% drop in the incidence of genital warts per quarter over the same year. In contrast, there was no change in 6- and 11-related disease in women over the age of 28 who were not eligible for the free vaccination program, nor was there any change in homosexual men.

“No other country has seen this yet, as no other country has vaccinated such a high proportion of women under the age of 28,” stated Dr. Christopher Fairley, MSHC, who reported the group’s findings. “And what is really surprising is the speed at which the incidence of genital warts is falling so you can only imagine what is going to happen over the next few years.” Both vaccines are highly effective against high-grade cervical lesions but their most tangible and more immediate impact will continue to be felt against low-grade lesions, abnormal Pap cytology and associated cervical procedures.

FUTURE Data Analysis

In a pooled analysis of the FUTURE (Females United to Unilaterally Reduce Endo/Ectocervical Disease) studies, investigators first observed that there was an annual 2% incidence of any cervical intraepithelial neoplasia (CIN) among placebo controls over a mean of 3.6 years of follow-up, a 1.8% annual rate of CIN1 and a 1.1% annual incidence of genital warts. The annual incidence of vulvar intraepithelial neoplasia (VIN1) and vaginal intraepithelial neoplasia (VaIN 1) among placebo controls was 0.3%. With protection rates among the HPV-naïve cohort in the FUTURE studies of 95.9% for CIN1, 100% for both VIN1 and VaIN1, and 99% for genital warts in the HPV-naïve cohort, investigators estimated that the quadrivalent vaccine would reduce CIN1 lesions by approximately 30%, early-grade vulvar lesions by 75%, early-grade vaginal lesions by 48% and condylomas by 83% if mass vaccination were introduced in the key target population. “Through only 44 months of follow-up, we had very strong protection against HPV 6, 11, 16 and 18 low-grade disease,” concluded Dr. Joakim Dillner, Lund University, Sweden.

This impact rapidly translated into reductions in abnormal Pap smears and referrals for colposcopy and cervical procedures in both pivotal vaccine trials. Among HPV-naïve recipients in the FUTURE studies, the quadrivalent vaccine reduced the number of abnormal Pap tests by 17% to 45%, depending on the abnormality, regardless of HPV type, reported Dr. Jorma Paavonen, University Hospital, Helsinki, Finland. Colposcopies were reduced by 20% during the FUTURE studies, cervical biopsies by 22% and definitive therapy 42%. “We must keep in mind how important this reduction in definitive therapy is, since these are young women whose fertility is always at stake,” he told delegates. Cervical procedures to eliminate dysplastic lesions have been associated with an increased risk of preterm delivery.

In PATRICIA (Papilloma Trial to Prevent Cervical Cancer in Young Adults), which evaluated the bivalent vaccine, investigators also observed a 20% reduction in colposcopy referrals among HPV-naïve vaccine recipients and a 68% reduction in cervical excision procedures. “These results provide strong evidence that vaccination programs in adolescents and young women will result in a notable reduction in cervical and cytological abnormalities as well as diagnostic and therapeutic procedures related to precursor lesions,” Dr. Paavonen concluded.

Cross-protection Added Value

Not only have both vaccines proven highly efficacious against HPV types contained within the respective vaccines, but significant cross-protection against oncogenic non-HPV vaccine types has also been observed, especially with the bivalent vaccine. As reported by Dr. Rachel Skinner, Children’s Hospital at Westmead, Australia, vaccine efficacy against HPV 31 and 45, the two most frequent oncogenic non-vaccine types implicated in cervical cancer, was 100% in the HPV-naïve PATRICIA cohort. The same vaccine was 68% effective at preventing infection with HPV types 31, 33, 45, 52 and 58, also in the HPV-naïve population. “Overall, vaccine efficacy against CIN2+ [the primary end point of the PATRICIA trial] associated with 14 oncogenic types including HPV 16 and 18 was 77.7%,” Dr. Skinner said, “and cross-protection against CIN2+ lesions associated with non-vaccine types is expected to contribute to meaningful reductions in the incidence of both cervical cancer and pre-cancer.” Other important reductions in HPV-related disease were reported to occur in men who received the quadrivalent vaccine, including men who have sex with men (MSM). Much like other FUTURE trial designs, 3463 heterosexual men and 602 MSM between the ages of 16 and 26 naïve to HPV at baseline were randomized to three doses of the quadrivalent vaccine or placebo and were followed for a mean of 24 months’ post-dose. The primary end point of this study was the incidence of vaccine-type related external genital lesions including external genital warts, penile, perineal or perianal intraepithelial neoplasia (PIN) and penile, perineal and perianal (PPP) cancer. As reported by Dr. Anna Giuliano, H. Lee Moffitt Cancer Center, Tampa, Florida, investigators observed only three cases of external genital lesions in the HPV-naïve vaccine group vs. 31 in the placebo cohort, for a vaccine efficacy rate of 90.4%. There were no cases of PIN 1, 2, or 3 and no cases of PPP among vaccine recipients vs. two cases of PIN 1 in placebo recipients. Vaccine efficacy against persistent infection—a clinically relevant end point—was 85.6% against the four vaccine types. In the smaller MSM cohort, the vaccine proved 79% effective against the same end points while it was 94.4% effective against persistent infection. By month 7, between 89.5% and 97.4% of MSM had seroconverted to the four HPV vaccine types.

Condom Use and Circumcision

Several speakers here also presented data supporting a protective benefit of circumcision against HPV infection as well as consistent condom use. In one US study, for example, multicentre investigators found that 40% of heterosexual men who reported using condoms less than half of the time were infected with at least one oncogenic HPV type compared to fewer than 20% of men who reported always using a condom. The protective effect of consistent condom use was particularly evident among men who reported having multiple sexual partners. Consistent condom use was also reported to significantly reduce the risk of HPV-related anal cancer in MSM. “There is a high incidence of anal HPV infection in highly-active MSM,” Dr. Peter Chin-Hong, University of California, San Francisco, reminded delegates, “and we now have a menu of strategies to prevent HPV infection in men including circumcision, condoms and vaccines. Condom use to prevent anogenital HPV acquisition could bolster messages for its use in HIV prevention as well.”