From MedscapeCME Clinical Briefs
News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD
July 29, 2010 — Human papillomavirus (HPV) quadrivalent vaccine offers prolonged protection against anogenital warts and low-grade cervical, vulvar, and vaginal neoplasias, according to the results of 2 randomized controlled trials reported in the July 21 issue of the BMJ.
Latest Efficacy Data Presented
"This study gives us the latest and most comprehensive data on the efficacy of the quadrivalent HPV vaccine in protecting against low grade precancerous lesions of the cervical, vulva and vagina, and anogenital warin young women, over a longer period of follow-up than previously reported," Karen Canfell, PhD, a cancer epidemiologist at the Cancer Epidemiology Research Unit Cancer Council in New South Wales, Sydney, Australia, told Medscape Medical News when asked for independent comment. "The results confirm that the quadrivalent vaccine is highly effective in protecting against low grade disease and anogenital warts directly related to the vaccine-included HPV types in women who have not previously been exposed to these types, and this protection is sustained for at least 4 years. However, in the case of cervical low grade lesions, the protective effect against the entire spectrum of lesions is lower, because these can be caused by a variety of high risk and low risk HPV types."
The goal of the FUTURE I/II Study, by Joakim Dillner, from Lund University and Malmö University Hospital in Malmö, Sweden, and colleagues, was to determine the prophylactic efficacy of HPV quadrivalent vaccine in preventing low-grade intraepithelial neoplasias and condyloma acuminata (anogenital warts). FUTURE I (protocol 013) and FUTURE II (protocol 015) were designed to last for 4 years; this analysis was from final study data with follow-up of 42 months.
At primary care and university or hospital-associated medical centers in 24 countries and territories worldwide, 17,622 women aged 16 to 26 years were enrolled from December 2001 through May 2003. Pregnant women and those with a history of more than 4 sexual partners in their lifetime or abnormal cervical smear test results were excluded.
"Data are pooled from 2 randomized controlled trials of quadrivalent vaccine conducted in over 17,000 women aged 16-26 years, and there was an average of about 4 years of follow-up information," Dr. Canfell said.
At day 1, month 2, and month 6, participants received 3 doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo, and the primary study endpoints were vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade 1 and condyloma. Main analysis was per protocol among susceptible participants given all 3 vaccine doses who tested negative for the relevant vaccine HPV types at day 1 and whose test results remained negative through month 7 and who had no major protocol violations. The investigators also performed intent-to-treat analyses and studied generally HPV-naive and unrestricted susceptible populations.
For lesions related to the vaccine HPV types, efficacy in the per-protocol susceptible population was 96% for cervical intraepithelial neoplasia grade 1 (95% confidence interval [CI], 91% - 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade 1 (95% CI, 74% - 100% and 95% CI, 64% - 100%, respectively), and 99% for condyloma (95% CI, 96% - 100%).
In the generally naive population, vaccine efficacy against lesions of any HPV type was 30% (95% CI, 17% - 41%), 75% (95% CI, 22% - 94%), and 48% (95% CI, 10% - 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade 1, respectively, and 83% (95% CI, 74% - 89%) for condyloma.
Limitations of this study include testing of the HPV-naive population only for 4 vaccine HPV types and 10 other HPV types prevalent in cervical cancer. In addition, rate estimates of disease depend on the intensity of assessment.
"The study found that in women who were negative to the vaccine-included types at baseline, the efficacy of protection against cervical low grade lesions caused by one of the vaccine-included types was ~96%," Dr. Canfell said. "However, when the protective effect against all types was considered in women not previously exposed to any HPV types, the vaccine protected against 30% of cervical low grade cervical lesions. In the overall study population (some of whom had been previously exposed to HPV), the protective effect against all cervical low grade lesions was 20%, [and] protection against warts in the overall study population was estimated to be 62%."
Assuming the vaccine will have long-duration protection, Dr. Canfell noted that the results in this group approximate the effect that will be seen on low-grade lesions "down the track" for the preadolescent girls (usually 12 -13 years old) who are vaccinated in routine vaccination programs.
"However, the effect of the vaccine in preventing high grade lesions and cervical cancer will be much greater in this group, because a higher proportion of these are caused by the HPV types in the vaccine," she explained. "In the overall study population, the protective effect against all low grade lesions was reduced to 20%, because some women had already been exposed to HPV. This approximates the effect we will see in vaccination program 'catch-up' cohorts."
Similarly, the 61% protection against condyloma approximates that expected to be seen in catch-up cohorts. This is in line with ecologic data from Australia, which has high vaccination coverage, showing that presentations for genital warts have decreased in young women since the vaccination catch-up program was implemented. These results also suggest that approximately 70% to 80% of cervical low-grade lesions will not be prevented by the vaccine, even if very high rates of vaccination coverage are achieved.
"Therefore, dramatic reductions in the number of cervical low grade precancerous lesions in vaccinated populations are not expected, especially if catch-up vaccination coverage is relatively low," Dr. Canfell said. "However, a modest reduction in the rate of cervical low grade lesions should be observed in young women in countries with high levels of vaccination coverage. The good news is that the remaining low grade lesions will be generally less likely to progress to cervical cancer, because the vaccine will have decreased the size of the subgroup of low grade lesions related to HPV 16/18, which are the types involved in the majority of cervical cancers."
When asked about the need for additional research, Dr. Canfell recommended surveillance of cervical low-grade lesion rates in young women in countries that have implemented vaccination catch-up programs. However, she noted that this will only be possible in settings that have comprehensive and accurate data on screening behavior, because cervical precancerous lesions are only detected via screening. Therefore, it will be important to take into account any future changes in screening behavior. She also recommended surveillance of genital wart presentations in at least some of the countries that have implemented HPV vaccination.
"In countries with high coverage levels in catch-up programs, we expect to see a decreasing rate of genital wart presentations in both females and also in heterosexual males; the effect on males will be seen even without male vaccination, because there will be fewer HPV infections circulating in the population," Dr. Canfell said. "The best way to monitor the impact on genital warts will be by using routinely collected data in settings that allow assessments of genital wart presentations in vaccinated and unvaccinated individuals to be performed. This will allow the protective effect of vaccination to be further quantified in the context of actual vaccination programs, which will add to the evidence from the clinical trials."
Merck & Co supported this study, employs 9 of the study authors, and has various financial relationships with some of the other study authors. A complete description of other various financial relationships is available in the original article. Dr. Canfell has disclosed no relevant financial relationships.
BMJ. 2010;340:c3493. Abstract
The HPV quadrivalent vaccine has proven to be effective in the prevention of high-grade cervical dysplasia as well as the prevention of genital warts, but the role of the 4 HPV types contained in the vaccine (6, 11, 16, and 18) is less well established for low-grade cervical intraepithelial dysplasia. Many women clear their initial infection with HPV, and low-grade neoplasia often regresses spontaneously. Moreover, although at least 1 of the 4 HPV types contained in the vaccine are present in 25% to 50% of low-grade cervical and vulvovaginal neoplasias, these lesions frequently contain multiple HPV types, making causality difficult to prove.
One means to do so is to perform a placebo-controlled trial of the quadrivalent HPV vaccine in the prevention of low-grade disease. The results of this study are presented in the Study Highlights section.