Authors and Disclosures
February 11, 2010 — The quadrivalent vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (Gardasil, Merck & Co) results in statistically significant reductions of HPV-associated genital diseases, such as warts and cervical dysplasia, in young women who receive it, according to the final analysis of 2 randomized placebo-controlled efficacy trials.
The HPV vaccine also statistically significantly reduces Pap test abnormalities, procedures such as colposcopy, and definitive cervical therapy, compared with placebo, report the study authors, led by Nubia Muñoz, MD, from the National Institute of Cancer, in Bogota, Colombia.
The study, which was sponsored by Merck, was published online February 5 in the Journal of National Cancer Institute. The average follow-up was 3.6 years for the 17,622 young women (aged 16–26 years) in the trials.
The prophylactic efficacy of the vaccine was best when the genital lesions and diseases being evaluated were related to HPV 6, 11, 16, and 18. When the researchers considered lesions caused by all types of HPV, the efficacy rate fell.
The efficacy was also better when the population being evaluated was that of young women who tested negative for a range of HPV types before vaccination, and thus approximated women who were "sexually naïve" — compared with a "mixed" population of HPV-exposed and -unexposed women that approximated sexually active women.
Impact on Everyday Clinical Practice
For clinicians who regularly take care of women, the results mean that everyday practice will eventually be affected in countries where the vaccine has been widely administered, suggested a study coauthor.
"I'm a gynecologist and, to me, the most important thing in these results is the reduction in the number of abnormal Pap smears, related biopsies and colposcopies, and follow-up visits," said Kevin Ault, MD, associate professor of obstetrics and gynecology at Emory University in Atlanta, Georgia.
"Most gynecologists spend a lot of time counseling women about minor abnormalities," continued Dr. Ault in an interview with Medscape Oncology.
Before this current study was published, another expert in HPV vaccination made similar comments, albeit from a patient perspective.
"In developed countries where Pap screening systems have been effective for decades, the biggest value of the HPV vaccine will not be in preventing deaths from cervical cancer. The true value of the HPV vaccine will be to provide women with a greater reassurance that their future Pap screens will more likely be normal," Diane Harper, MD, from the University of Missouri–Kansas City School of Medicine, previously told Medscape Oncology.
At the time, Dr. Harper also reminded clinicians that ongoing Pap testing was needed for all women, whether they receive the vaccine or not, because the vaccine does not protect against all types of HPV infection that cause cervical cancer.
Dr. Ault suggested that healthcare systems should see a return on their investment in the vaccination in the coming years. In the United States, for example, there are annually "several hundred thousand cases of cervical dysplasia" and "millions of abnormal Pap smears," he said.
"We should see a big reduction in these costly items in the next few years," Dr. Ault argued, referring to diagnostic and therapeutic care related to such clinical events.
Dr. Ault noted that so far "about 40%" of American teenaged girls have received 1 or more vaccine shots. The uptake of the vaccine in the United States has been comparable to that of the booster for pertussis, tetanus, and diphtheria, he observed.
Eventually, the reductions seen in HPV-related genital diseases in young women in this new study should affect cervical cancer incidence, note the authors. "It is anticipated that these reductions will eventually translate into lower rates of cancer of the cervix, vulva, and vagina," they write.
The authors highlighted several important limitations of the study.
Only 14 of the 40 HPV types that infect the genital tract were assessed; thus, 26 types of HPV were not assessed. As a result, "there may have been prevalent HPV infections or disease that were not detected," concede the authors.
The mixed or intention-to-treat population was not entirely representative of the general population because of inclusion/exclusion criteria, say the authors. Study participants were required to have had no more than 4 sex partners and no previous abnormal Pap test or external genital abnormality.
Results for the Sexually Naïve Population
The women in the current study were enrolled in 1 of 2 randomized double-blind placebo-controlled trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I and II.
In FUTURE, the impact of the HPV 6/11/16/18 vaccine was investigated in 2 different populations of women.
In one population, the women were described by the investigators as approximating sexually naïve women because they tested negative for 14 HPV types (sexually naïve group) before vaccination.
The other was a mixed population of HPV-exposed and -unexposed women (mixed group) that approximated sexually active women, said the investigators.
All women underwent cervicovaginal sampling and Pap testing on day 1 and every 6 to 12 months thereafter. They were administered either placebo or vaccine on day 1, month 2, and month 6.
In the sexually naïve group, vaccination was up to 100% effective in reducing the risk for HPV 16/18–related high-grade cervical, vulvar, and vaginal lesions and for HPV 6/11–related genital warts.
For example, in the sexually naïve group, only 5 of 4689 vaccinated women eventually tested positive for genital warts related to HPV 6, 11, 16, and/or 18, whereas 140 of 4735 women who received placebo did. Thus, the vaccine reduced the risk for these specific types of genital warts by 96.4% (95% confidence interval [CI], 91.4% - 98.9%).
Prophylactic vaccination resulted in a 92% reduction in HPV 16–related Pap test abnormalities and a 97% reduction in HPV 18–related Pap test abnormalities.
But, as expected, the impact on Pap test abnormalities, irrespective of causal HPV type, was less, with an overall reduction of only 17.1%; however, the reduction was still statistically significant, report the investigators.
Prophylactic vaccination in this sexually naïve population also statistically significantly reduced the risk for any colposcopy by 19.8%, any cervical biopsy examination by 22.0%, and any cervical definitive therapy by 42.3%, write the investigators.
Results for the Mixed Population
In the mixed population, vaccination was, predictably, not as powerful because of individuals' varying exposures to different types of HPV. The efficacy, as noted above, dropped further when lesions caused by all types of HPV were considered.
Still, in this population, statistically significant reductions were observed for all disease end points, irrespective of causal HPV type, with the exception of adenocarcinoma in situ.
The end points that were statistically significantly reduced include any high-grade cervical lesions (19%), vulvar and vaginal lesions (50.7%), genital warts (62.0%), Pap test abnormalities (11.3%), and cervical definitive therapy (23.0%).
With this 4-year study now complete, the researchers are looking at the possibility of second-generation vaccinations that protect against types of HPV not currently covered by the quadrivalent vaccine, said Dr. Ault.
Dr. Muñoz reports receiving lecture fees, advisory-board fees, and consultancy fees from Merck and Sanofi Pasteur. Dr. Ault reports receiving consultancy and advisory-board fees from Merck during the study, and previously receiving funding from his former institution to conduct HPV vaccine studies for GlaxoSmithKline. He reports currently receiving funding from Merck and Co. for another HPV vaccine trial.
J Natl Cancer Inst. Published online February 5, 2010. Abstract