HPV vaccination could be extended to adult women.

ATLANTA -- Adult women in their mid-20s to mid-40s could become the next group recommended for .human papillomavirus vaccination.

The currently licensed quadrivalent HPV vaccine (Merck & Co.'s Gardasil) is indicated for the prevention of cervical cancer in girls and women aged 9-26 years. It is recommended for routine use in girls aged 11-12 years and for "catch-up" vaccination in 13-to 26-year-olds. At press time, the Food and Drug Administration had begun a priority review of Merck's application for an expanded indication for women ages 27 through 45.

Another candidate HPV vaccine, GlaxoSmithKline Inc.'s bivalent Cervarix, is not yet licensed but the company has submitted data to the FDA from clinical trials in girls and women aged 10-55. Both companies ultimately hope to receive indications for use of their vaccines in women in their mid-20s and beyond.

At its winter meeting, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention heard presentations on clinical trial data from representatives of both companies, along with information from CDC staff on the cost-effectiveness of vaccination and the possible approaches ACIP might take toward recommending the vaccine for the 20s-40s age group.

Pending FDA action, ACIP could vote in June 2008 on recommendations for the use of the quadrivalent vaccine in women aged 27-45, and in either October 2008 or February 2009 on the bivalent vaccine in girls and women.

Dr. Richard M. Haupt of Merck Research Laboratories presented efficacy and safety data from placebo-controlled studies on Gardasil, including one involving a total of 3,819 women aged 24-45 years. All were nonvirgins at baseline, with a median age of 18 years at sexual debut. Two-thirds of the women were negative for all four HPV serotypes (6, 11, 16, and 18) contained in the vaccine, while about one-third were positive for one or more HPV vaccine serotypes. However, the majority of those were positive for only one, and only 0.4% of the vaccine recipients and 0.3% of the controls were positive for all four.

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"There's still a lot of opportunity to prevent the other types from being acquired," Dr. Haupt noted.

Moreover, just 1% of vaccine recipients and 1.6% of controls were positive for the cervical cancer serotypes 16 and 18. "Less than 2% were infected with 16 and 18. ... 98% would derive benefit from the vaccine," he said.

In the per-protocol analysis with a mean follow-up of 2.2 years, primary efficacy of the vaccine against persistent infection, cervical intraepithelial neoplasia (CIN), or external genital lesions (EGL) caused by any of the four vaccine strains was 92% among subjects aged 24-34 years and 89% among 35-to 45-year-olds. For disease caused by just HPV 16 or 18, primary efficacy was 85% among subjects aged 24-34 years and 81% among 35-to 45-year-olds. Efficacy against just CIN or EGL caused by any of the four vaccine serotypes was 92% (88% for 16 and 18, 100% for 6 and 11).

Safety profiles were similar to those seen in the 16- to 26-year age group, with no serious vaccine-related adverse events and significantly more reports of injection site problems--including erythema, pain, and swelling--among the vaccine recipients (76%), compared with those who received a control vaccine (64%).

Merck is conducting a 4-year "population benefit" analysis to determine the impact of vaccinating 24- to 45-year-old women. At baseline, the prevalence of HPV DNA among the study subjects was 6.1% for 16 and 2.5% for 18 among the 24-to 34-year-olds, compared with just 2.8% and 1.6%, respectively, for 35-to 45-year-olds. Rates of HPV antibody seroprevalence were higher, 14.9% for 16 and 5.7% for 18, in the 24-to 34-year-olds, compared with 14.5% (16) and 5.2% (18) for the 35-to 45-year-olds. Seroprevalence might represent a better approximation than does DNA of HPV exposure, but it's still an underestimate because not all infected women develop a measurable antibody response, he noted.

Acquisition of infection in the placebo arm over the course of the study in the 24-34 age group was 3.4 per 100 person-years for HPV 16 and 1.1 per 100 for 18. In the 35-to 45-year-olds, the rates were 1.1 per 100 person-years for 16 and 0.7 per 100 for 18. Persistent infection, a closer marker for the likelihood of disease, was 1.5 per 100 person-years for HPV 16 and 0.6 per 100 for 18 in the younger group and 0.6 per 100 (16) and 0.2 per 100 (18) for the older women.

Although lifetime sexual partners, new partners, and marital status were also associated with the likelihood of acquiring new infections, "you can't use them to define who should or shouldn't get the vaccine," Dr. Haupt said.

Dr. Gary Dubin, GlaxoSmithKline's vice president and director of clinical development and medical affairs, prophylactic vaccines, gave a shorter presentation of preliminary data on the use of the bivalent Cervarix in separate studies of women aged 15-25 and 26-55. Prospective data from the control arm in more than 8,000 15-to 25-year-olds suggest that those who were exposed to HPV 16 or 18 but not infected remain at risk for subsequent reinfection.

In a mean follow-up of 15 months, reinfection occurred in 3.8%, compared with 4.6% of those who were initially seronegative. Infection persisted up to 12 months in 1.0% of those who were seropositive vs. 0.8% who were initially seronegative, and 0.35% (seropositive) vs. 0.2% (seronegative) developed CIN1 +.

Harrell Chesson, Ph.D., a health economist at the CDC, summarized a series of analyses demonstrating that the cost-effectiveness of HPV vaccination declines with increasing age. However, the age at which the vaccine is no longer "cost-effective" remains unclear, because of uncertainty about the natural history of HPV and differences in assumptions and methods used in the statistical models.

In general, routine HPV vaccination of 12-year-old girls is considered cost effective, at about $3,000-$24,000 per quality-adjusted life year (QALY) gained, depending on whether HPV 6 and 11 and indirect effects such as herd immunity are included in the analysis). Data from Merck suggested that vaccinating females aged 12-24 years costs $4,700/QALY (Emerg. Infect. Dis. 2007;13:28-41).

According to different models, that dollar figure rises to $130,600-$226,100 per QALY when the age cutoff is raised to 34 years, and in Merck's model, to $225,300 for vaccinating women up to 44 years of age. More cost-effectiveness analyses are underway, Dr. Chesson said.

BY MIRIAM E. TUCKER

Senior Writer