SAN FRANCISCO — A multinational study of 11,502 young women showed for the first time that a vaccine for human papillomavirus can prevent precancerous cervical lesions and early in situ cervical cancers, Laura A. Koutsky, Ph.D., reported.
The recombinant vaccine against HPV types 6, 11, 16, and 18 was 100% effective in preventing cervical intraepithelial neoplasia (CIN) grades 2 and 3 and adenocarcinoma in situ (AIS) related to HPV 16 or 18 in 5,301 women who completed a three-shot vaccination regimen and were negative for the HPV types at the start and end of vaccinations. HPV 16 and 18 cause approximately 70% of invasive cervical cancers worldwide.
Among 5,258 females who received three placebo shots, 1 developed AIS, 15 developed CIN3, and 5 developed CIN2 during an average 17-month follow-up, Dr. Koutsky said at the annual meeting of the Infectious Diseases Society of America.
The data came from a planned interim analysis of the ongoing Females United to Unilaterally Reduce Endo-Ectocervical Disease study (FUTURE II), a randomized, double-blind, phase III clinical trial of the vaccine made by Merck & Co., said Dr. Koutsky, professor of epidemiology at the University of Washington, Seattle. Dr. Koutsky has received grants and research funding from Merck, which funded the trial.
The company plans to apply by the end of this year for Food and Drug Administration approval to market the vaccine, which has been given the trade name Gardasil.
A secondary analysis intended to reflect more real-world conditions found the vaccine was 97% effective in preventing CIN2/CIN3 and AIS in women who received at least one of the three intended vaccinations. In this secondary analysis, 1 of 5,736 women in the vaccine group became infected with HPV 16 and developed CIN2. Among 5,766 women in the placebo group, 4 developed AIS, 23 developed CIN3, and 9 developed CIN2 related to HPV 16 or 18 over a 2-year follow-up starting 30 days after the first vaccination.
CIN2/CIN3 and AIS are accepted as surrogates for invasive cervical cancer for research purposes by regulatory agencies.
Study participants averaged 16–26 years of age and resided in 13 countries. HPV infection most commonly occurs in the late teens and early 20s. The vaccine is likely to be targeted to females before they become sexually active.
“Cervical cancer kills at a relatively early age,” Dr. Koutsky noted. Among U.S. women, the median age of death from cervical cancer is age 57, compared with a median age of death of 72 for all other cancer patients. Low-grade cervical lesions take 10–20 years to progress to cervical cancer, so a vaccine's effects on cancer incidence would not be felt for decades.
The interim data do not indicate how long immunity from Gardasil might last. An earlier phase II clinical trial of a monovalent HPV 16 vaccine showed that antibody titers decreased initially but then stabilized and were maintained out to 48 months, she said.
Women in the current trial underwent a Pap test and collection of cervical specimens for HPV DNA testing on the first visit. These tests were to be repeated at months 6, 12, 24, and 36; a 48-month follow-up lies ahead. The three-shot regimen of vaccine or placebo was to be given on day 1 and during months 2 and 6.
In addition to causing most invasive cervical cancers worldwide, HPV 16 and 18 cause a portion of cancers of the vagina, vulva, anus, penis, and head and neck. HPV 6 and 11 cause about 90% of anogenital warts. Investigators are analyzing the interim data to assess the vaccine's effectiveness against genital warts and its effects on the overall burden of HPV-related clinical disease, Dr. Koutsky said.
Approximately 20 million U.S. women and men are infected with HPV, which causes an estimated 10,400 cases of cervical cancer and 3,700 deaths from cervical cancer each year in the United States. Worldwide, approximately 290,000 women die each year of cervical cancer. HPV also can cause anal cancer in men and especially is a problem in men with immunosuppression from HIV infection.
Gardasil is one of two HPV vaccines currently in phase III clinical trials. The other, called Cervarix, immunizes against HPV 16 and 18 and uses a novel adjuvant that may boost the immune response and provide some cross-coverage against other types of cancer-causing HPV. GlaxoSmithKline Inc., which makes Cervarix, is likely to seek approval for its vaccine in 2006.
Both Gardasil and Cervarix are subunit vaccines that contain just one protein of the virus and induce antibodies that protect against infection.
HPV infection is very common, therefore abnormal Pap results are common. In the United States, about one in five women with abnormal Pap results will have biopsy-confirmed CIN that requires additional management and, often, treatment. About 1 in 135 women in countries with Pap screening and 1 in 20–30 women in countries without Pap screening will develop cervical cancer.
Serious adverse events were rare and relatively evenly divided between the vaccine group (three events) and placebo group (two events). None led to discontinuation from the study. Two patients in the vaccine group died, but the deaths were deemed unrelated to the vaccine.
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