Vaccinating against cervical cancer
From the March ACP Observer, copyright © 2007 by the American College of Physicians.
By Stacey Butterfield
Until recently, the general public was little-aware of human papilloma virus. A 2005 survey of American women found that only 40% had ever heard of HPV and less than 20% knew that the virus could cause cervical cancer.
Last year's release of a quadrivalent human papillomavirus recombinant vaccine (Merck & Co.'s Gardasil), triggered a dramatic increase in public awareness of the virus. Even before the FDA's June 2006 approval of the vaccine for women age nine to 26, the manufacturer had unleashed an advertising campaign to publicize the link between the virus and cervical cancer.
That publicity, coupled with the CDC's subsequent recommendations, is having a major impact on internists, especially those specializing in adolescent medicine. In addition to fielding questions from patients, many internists have concerns of their own, such as how much vaccine to keep on hand and whether routine vaccination will discourage women from having regular Pap smears.
Nadja Peter, ACP member, who works in adolescent medicine and family planning at the University of Pennsylvania, has been getting several questions a week about the vaccine from women of all ages. While misperceptions are common, she said, the sudden interest in prevention is positive.
Many women do at first believe that the vaccine prevents all cervical cancer, said Dr. Peter. "But if the advertisement brings people into the office to ask about the vaccine, it gives you the opportunity to explain what it does."
Who to vaccinate
The CDC's Advisory Committee on Immunization Practices (ACIP) went a step further than the FDA approval by specifically urging vaccination for girls at 11 and 12 years old, with vaccination possible for girls as young as nine.
Vaccinating women at a young age is important, explained Janet R. Gilsdorf, MD, chair of the ACIP's HPV Vaccine Workgroup, because the vaccine doesn't protect against cancer caused by a virus the woman has acquired before vaccination. (It would protect against other strains not acquired before vaccination.)
It's also "a natural time for young people to visit their primary health care physicians," she said. "They're just on the brink of adolescence and there's an effort to try to promote a routine health care visit within that age group. Putting all that together, we thought that would be a good time."
The ACIP also suggested catch-up vaccinations for females between 13 and 26 years old.
The American Cancer Society, however, recently broke with ACIP's findings and recommended against routine vaccination for women over 18. Because women 19 to 26 are more likely to have already been exposed to HPV, the ACS suggests that physicians and patients in this age range determine whether to vaccinate on an individual basis.
"We would predict that the older women are, the less benefit they would receive from the vaccine because they would already have been infected," said Dr. Gilsdorf. "That doesn't say what would be right or wrong for an individual woman."
By age 50, at least 80% of sexually active women in the U.S. will have acquired an HPV infection.
According to the CDC, more than 20 million Americans are infected with one of the 40 anogenital HPV types at any given time, and by age 50, at least 80% of sexually active women in the U.S. will have acquired an HPV infection that has cleared.
Amid the public and government enthusiasm, the limitations of the vaccine are being largely ignored, said Diane M. Harper, MD, a researcher at Dartmouth Medical School involved in the vaccine's clinical trials. She doesn't believe that HPV vaccination needs to be mandatory and worries that women will become overconfident in the abilities of the vaccine, and not understand the continuing risk of cervical cancer and need for Pap tests. (See sidebar)
"The worst thing that could happen is that a whole bunch of 11- and 12-year-olds get vaccinated and then they decide they never want to go in for a gynecological exam and you're going to have increases in the number of cervical cancers," said Dr. Harper.
Individual physicians will play an important role in making sure that doesn't happen. "We want to emphasize that women will need to continue to have Pap smears," said Dr. Gilsdorf.
The issue of whether to mandate vaccination is currently a topic of debate in state legislatures around the country. In February the Governor of Texas by-passed his legislature and mandated by executive order vaccination for sixth-grade girls. At press time, 20 states and Washington, D.C., had pending or drafted legislation which would mandate vaccination for girls.
The political debate in D.C. has made patients and their parents a little more hesitant about the vaccine, said Lawrence J. D'Angelo, FACP, chief of adolescent and young adult medicine at Children's National Medical Center.
"They're aware of the controversy and there's a sense of uneasiness, although most of them can't articulate what the concern is," he said.
Some political opponents of the vaccine have argued that it will encourage sexual activity among young teens, but Dr. D'Angelo has not found that to be an issue with his patients' parents. "No one has said to us, 'If you give my daughter this shot, I'm afraid she'll become promiscuous,'" he said.
Sexual activity doesn't even need to come up in discussions about the vaccine, said Theresa Rohr-Kirchgraber, FACP, an internist in Atlanta, Ga.
"I don't go into this big explanation about sex. It's a vaccine to stop a virus that causes cancer," she said. Out of about 50 patients to whom Dr. Rohr-Kirchgraber suggested vaccination, only one declined, because of concerns that the vaccine was too new.
A bigger issue for patients is the cost of the vaccine. At the Cincinnati Children's Hospital where internist Corinne E. Lehmann, FACP, practices, the charge for the vaccine is $260 per shot. She notifies self-pay patients, especially, of the cost when offering them the vaccine. "Most of them say, 'Whoa, let me think on that,'" Dr. Lehmann said.
The vaccine is now covered by almost all private health insurers, and has been added to the federal government's Vaccines for Children program, which funds vaccinations for uninsured children.
Based on mathematical models and the vaccine's catalog price of $360 per series, ACIP found the vaccine's cost-effectiveness for women 9 to 26 to be in the range of other recommended vaccines, noted Dr. Gilsdorf.
Cost has been an issue for some physicians as well. Because the vaccine is so new, many providers are not yet certain how much reimbursement insurers will provide. Dr. Rohr-Kirchgraber, who has been giving the vaccine since August, said that cost has not been a problem for her practice. Reimbursements from the third-party payers she works with have been sufficient to cover the full expense of the vaccines.
On the other hand, Steven Mussey, ACP member, a general internist in Fredericksburg, Va., did some advance research and determined that his practice cannot afford to offer the vaccine.
He found that although the vaccine would cost $140 or more from suppliers, Anthem and Aetna would reimburse only $128 per shot. Dr. Mussey has found a way to provide the vaccine to his patients, though. "What we have done is to write a prescription for the vaccine, let the patient fill it, and then come back to the office so we can give it," he said. "This avoids the tremendous issue of having to put out so much money which may or may not be reimbursed."
Physicians who do stock the vaccine have to decide how much to keep on hand. Because the vaccine requires refrigeration, a practice's backstock represents a financial investment that is potentially vulnerable to power outages or other temperature fluctuations.
Richard Neubauer, FACP, a general internist in Anchorage, Alaska, said that he and other physicians in his office discussed this issue when deciding how much vaccine to order from their supplier. "At least right now, we're going to have a limited supply and try and order it once we have a number of patients lined up," he said.
One of the patients Dr. Neubauer lined up was his 19-year-old daughter, who he vaccinated shortly after the vaccine became available. "I definitely wanted her to get it," he said.
Physicians will also need to stay on top of administration of the vaccine, which requires three doses over six months. "One of the real challenges with this vaccine is actually administering three doses of it to people in whom there's not a routine time to visit the physician," said Dr. Gilsdorf.
Dr. Rohr-Kirchgraber hasn't had problems getting patients to come back for a nurse visit to get the follow-up shots. Patients schedule the visit on their way out from the first shot, and get a phone call if they don't show up. "It can be done after school, before school. It's two minutes and they're out," said Dr. Rohr-Kirchgraber.
Future of the vaccine
Almost as soon as physicians and patients have figured out the current vaccine, a new option is expected to hit the market.
GlaxoSmithKline has developed another HPV vaccine, called Cervarix, which is expected to be submitted to the FDA for approval this April. If the vaccine is approved, ACIP and the CDC will have to reevaluate their vaccination recommendations, said Dr. Gilsdorf.
The vaccines are very similar, Dr. Harper said. Both are designed to protect against the cancer causing HPV types 16 and 18, which cause about 70% of the cervical cancers. HPV 16 and 18 also account for about half of the HPV types that cause abnormal Pap tests. Gardasil also protects against HPV types 6 and 11, which cause genital warts.
The main difference between Cervarix and Gardasil is the adjuvant used to ensure immunologic memory, Dr. Harper added. Gardasil uses an aluminum salts adjuvant, and other vaccines that have that adjuvant require booster shots. Cervarix uses an adjuvant with greater immune response, and may not require any booster shots.
"We know we have protection for five years with both vaccines; beyond that we need more data," said Dr. Harper. Trials are underway to determine how long each vaccine remains effective.
In an effort to uncover the differences between the vaccines, GlaxoSmithKline has announced plans to sponsor a head-to-head clinical trial of the two products. Company officials said that they hope to prove that Cervarix has stronger immune response and broader protection than Gardasil.
Researchers are also investigating whether the vaccines may have some effectiveness against other HPV types.
"There is potential that even though the vaccines only cover 16 and 18 directly, they may have some indirect protection against HPV types 45 and 31," said Dr. Harper. The cross protection data for Cervarix shows protection from incident infections caused by HPV 45 and 31; Gardasil has not yet shown this extended protection.
What is clear, Dr. Harper said, is that the HPV vaccines will not eliminate cervical cancer because of the number of other HPV types that cause disease. Even with 100% vaccination of boys and girls and complete Pap screening of all women at all intervals, 3,000 women would still get cervical cancer every year in the U.S., she said.
Other ongoing trials for both drugs are looking at vaccinating men. HPV causes cancers of the head, neck, mouth and anus in men, but overall males represent less than 5% of HPV-related cancers. Although the vaccine's efficacy at preventing cancer in men is still in question, vaccinating men could turn out to be an effective way to disrupt transmission of the virus and therefore have important public health implications, Dr. Harper said.
While it could be 15 or 20 years before all these questions are answered, physicians should feel comfortable administering the vaccine today, agreed Dr. Harper and Dr. Gilsdorf. "Everything we've seen shows there's no harm caused by the vaccines," said Dr. Harper. "We may not know the endpoint yet, but that's OK, because we know it's safe."
Merck's vaccine targets HPV types 16 and 18, the two most common causes of cervical cancer, and types 6 and 11, which cause genital warts. The vaccine is available as a vial or a syringe and is administered in three separate 0.5-mL intramuscular injections over a six-month period, as is Cervarix.
The FDA's approval of the vaccine for females age nine through 26 was based on a series of double-blind randomized trials. Four studies, one in the United States and three multinational, were conducted in 21,000 subjects to show how well Gardasil worked in women between the ages of 16 and 26 by giving them either the vaccine or placebo.
Two studies were also performed to measure the immune response to the vaccine among younger females aged nine to 15 years. Their immune response was as good as that found in 16-26 year olds, indicating that the vaccine should have similar effectiveness when used in the 9-15 year age group, according to the FDA.
The studies found that the vaccine prevented 100% of HPV 16 and 18-related cervical pre-cancers and non-invasive cervical cancers and 95% of low-grade cervical dysplasia and pre-cancers caused by HPV 6, 11, 16 or 18. The vaccine also prevented 99% of cases of genital warts caused by HPV 6 or 11.
In the U.S., approximately 10,000 women develop cervical cancer every year, over a million have abnormal Pap tests or cervical lesions; and less than 100,000 women have genital warts, said Diane M. Harper, MD, a researcher involved in the vaccine trials.
"The vaccine will reduce the number of women with abnormal Pap smears. It will mean less women that we have to do little surgical procedures on. It will reduce the number of high-grade lesions by about half," she added.
But she cautioned that all women must continue Pap testing.
"Vaccinated women will still develop cervical cancer, and vaccinated women will still develop cervical cancer precursors caused from the other oncogenic HPV types not covered by the vaccine," she said.
On June 8, 2006, the U.S. Food and Drug Administration approved Gardasil for vaccination of females nine to 26 years of age for prevention of cervical cancer, genital warts and precancerous or dysplastic lesions caused by Human Papillomavirus (HPV) Types 6, 11, 16 and 18:
The efficacy of the vaccine was studied in four randomized, double-blind, placebo-controlled trials enrolling a total of 20,541 females between the ages of 16 and 26. Subjects were randomized to receive three doses of the vaccine at baseline, two and six months or placebo. Protocols required individuals receive all three vaccinations within one year of enrollment and be naive to the relevant HPV types prior to the first dose through one month after the third dose. In the per-protocol population, the efficacy of the vaccine was:
- 100% (95% CI: 92.9%, 100%) for prevention of HPV 16- or 18- related CIN 2/3 or AIS;
- 95.2% (95% CI: 87.2%, 98.7%) for prevention of HPV 6-, 11-, 16- or 18- related CIN or AIS;
- 100% (95% CI: 55.5%, 100%) for prevention of HPV 16- or 18-related VIN 2/3 or VaIN 2/3; and
- 98.9% (95% CI: 93.7%, 100%) for prevention of HPV 6-, 11-, 16- or 18- related genital warts.
In the general study population, (females with any HPV status at baseline who received at least one vaccine dose with case counting started at 1 month Postdose 1), the prophylactic efficacy of the vaccine was:
- 39.0% (95% CI: 23.3%, 51.7%) for prevention of HPV 16- or 18- related CIN 2/3 or AIS;
- 46.4% (95% CI: 35.2%, 55.7%) for prevention of HPV 6-, 11-, 16-, or 18- related CIN and AIS;
- 69.1% (95% CI: 29.8%, 87.9%) for prevention of HPV 16- or 18-related VIN 2/3 and VaIN 2/3; and
- 68.5% (95% CI: 57.5%, 77%) for prevention of HPV 6-, 11-, 16- or 18- related genital warts.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available online.
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