First HPV Vaccine a Milestone in Women's Health

Prevents Cervical Cancer, Precancerous Changes, Genital Warts

Kevin A. Ault, MD

The approval of the first human papillomavirus (HPV) quadrivalent vaccine (Gardasil; Merck) represents a quantum step toward not only preventing infection with HPV but also preventing many of the almost 10,000 new cases of cervical cancer and 3700 cervical cancer?related deaths that occur each year in the United States.

"HPV is the most common sexually transmitted infection," said Kevin A. Ault, MD, associate professor, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Ga. "In addition to more than 6 million new cases every year, about 20 million people in the United States are infected at any given time."

He notes that some infected women will develop abnormal Pap smears and precancerous changes, and a minority will develop cervical cancer. Cancer of the cervix is unique among cancers, Dr Ault points out, "in that it is almost 100% due to an infectious disease."

The vaccine covers HPV types 6, 11, 16, and 18; these were selected, he says, "based on a cost-benefit analysis showing they represented the greatest burden of disease. HPV types 16 and 18 are responsible for about 70% of cervical cancers, while HPV types 6, 11, 16, and 18 are responsible for 90% of genital warts and about 10% of abnormal Pap smears."

Other HPV vaccines are also in the works, with GlaxoSmithKline's version, which contains HPV types 16 and 18, being furthest along in development and is expected to be submitted for FDA review by the end of this year.

The Road to Rapid Approval

The approval of the HPV quadrivalent vaccine came after only 6 months of FDA review under its recently introduced priority-review system, which was designed to speed the process for drugs with significant health benefits.

N Engl J Med

Dr Ault was an investigator in an early study (. 2002;347: 1645-1651) that examined an HPV type 16 vaccine and provided "the first inkling we had that there was going to be such good protection. What we found was 100% protection from type 16 infections."

Since that time, the vaccine has been evaluated in more than 20,500 women aged 16 to 26 years. The FDA based their approval on data from the 2 large phase 3 FUTURE (Females United to Unilaterally Reduce Endo-Ectocervical Disease) studies. "The big news from these trials," says Dr Ault, "was that precancerous changes can be prevented by the vaccine, as well as genital warts" (Table).

There was, however, a subgroup in the FUTURE I study who already had persistent infection with HPV vaccine types and whose disease may have worsened after receiving the vaccine. But Dr Ault believes that this "probably will not be a problem, because that was one small subset, and there were a lot of other cofactors in that particular study. When you took all 21,000 women who received the vaccine, you certainly did not see that as an effect. Those women [whose disease worsened] probably did not get any benefit from the vaccine, but they probably did not get any harm from it either."

In fact, women who are already infected with HPV may derive substantial benefits from the quadrivalent vaccine, based on data presented at the latest European Research Organization on Genital Infection and Neoplasia (EUROGIN) meeting.

Investigators randomized a subgroup of 4727 phase 2/3 study participants who were infected with 1 of the 4 HPV vaccine types to either placebo or active vaccine (Ferris D, for the FUTURE II Study Group. Efficacy of a quadrivalent HPV [types 6/11/16/18] L1 virus-like particle [VLP] vaccine in women with virologic evidence of HPV infection: a combined analysis. Presented at the EUROGIN meeting; Paris, France; April 26, 2006).

At an average of 2 years of follow-up, results showed that vaccination protected women infected with 1 HPV vaccine type from the other 3 HPV types in the vaccine. The efficacy of the vaccine was 88% in preventing all grades of cervical intraepithelial neoplasia (CIN), 91% in preventing genital warts, and 100% in preventing the precursors of invasive cervical cancer (ie, high-grade CIN and adenocarcinoma in situ) and vulvar and vaginal cancer (ie, high-grade vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia).

Also announced at the EUROGIN meeting were the results of the long-term follow-up of all participants in a phase 3 study showing no cases of CIN or genital warts at up to 5 years after vaccination.

Who Should Be Vaccinated?

The HPV quadrivalent vaccine is indicated for girls and women aged 9 through 26 years. It is administered as 3 separate 0.5-mL intramuscular injections, with the second dose given 2 months after the first, and the third dose 6 months after the first. Each dose is expected to cost around $120.

On June 29, 2006, a mere 3 weeks after the FDA announced its approval of the HPV vaccine, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices(ACIP) voted in favor of routine vaccination for all girls aged 11 or 12 years, although immunization can begin as early as 9 years at the discretion of the physician.

The ACIP also recommended vaccination for girls and women aged 13 to 26 years who have not completed the vaccine series, ideally before they become sexually active, although women who are already sexually active should still be immunized.

Why not vaccinate boys as well? "That's a good question," responds Dr Ault. "Certainly other vaccines that have been single gender have not done that well as far as preventing disease, for example, the rubella vaccine in Sweden and Britain in the 1970s and 1980s." He said that the bottom line is that "there just wasn't efficacy data for boys and young men, although studies are ongoing to determine whether the vaccine will prevent disease in this group."

He adds that even though all the participants in the recent phase 2 and 3 studies were aged 16 to 26 years at enrollment, "I think we know a little bit about the immunogenicity in younger girls. "In 9- to 15-year-olds, studies have shown very good antibody responses in both adolescent boys and girls." And trials are ongoing in women older than 26 years.

Contraindications and Caveats

The only contraindication to the vaccine is hypersensitivity to the active substances or excipients of the vaccine. If a patient develops symptoms suggestive of hypersensitivity after receiving a dose of the vaccine, additional doses should not be given. Injection-site reactions are the most common adverse events, but only about 0.1% of study participants stopped receiving doses because of side effects.

The product labeling indicates that the vaccine does not protect women who are already infected with HPV, despite the preliminary results suggesting beneficial effects in such women. Since the quadrivalent vaccine does not prevent less common HPV types, routine Pap screening and consistent condom use are still recommended.

When asked how he would approach discussions with parents about the importance of their daughters receiving the HPV vaccine, Dr Ault points out that "every day, 10 women die of cervical cancer in the United States. If 10 women were dying every day of measles, we wouldn't be having this discussion. We'd be giving measles vaccine out in pharmacies, and theaters, and schools, and everywhere else we could get our hands on people to vaccinate."

He continues: "The overwhelming reason to give this vaccine is to protect young women against cervical cancer as well as abnormal Pap smears and precancerous changes of the cervix. HPV infection has deadly consequences. You have to remember just how common HPV infection is. Certainly the lifetime risk for sexually active people is 70%, maybe greater. So if you choose to be sexually active, it will be hard to avoid this virus."