Optimism is growing that a new HPV vaccine will drastically decrease the number of cases of pediatric recurrent respiratory papillomatosis (RRP), a rare but devastating disease.
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July 2010Regulators have proclaimed the vaccine safe, but experts on the disease and the vaccine say that more widespread use is needed to wipe out the disease. In addition, experts say, the medical culture in the U.S., traditionally hesitant with regard to adolescent vaccinations that are not mandated, might be a stumbling block.
RRP afflicts about four of every 100,000 children. Interferon and other drugs help to slow the spread of the lesions, but patients usually have to undergo multiple surgeries, sometimes dozens, to remove the lesions.
About 2,000 cases of pediatric RRP are reported each year in the U.S., almost all of them caused by the HPV 6 and HPV 11 strains.
The children at greatest risk are the firstborn children of young women who have genital warts during delivery. Still, the disease occurs in only about 0.5 percent of children whose mothers have condylomata during their pregnancies.
Two HPV vaccines, one developed by Merck and one by GlaxoSmithKline, have been approved for prevention of cervical cancer.
Use of the vaccine to prevent the spread of new lesions in those already afflicted has sparked interest among researchers, but otolaryngologists say controlled trials must be done to ground such treatment in solid science. There is growing hope, however, that preventive use of the Merck vaccine, Gardasil, can profoundly decrease the number of pediatric RRP cases. Gardasil is the only vaccine that targets HPV 6 and 11. It also protects against HPV 16 and 18, while the GlaxoSmithKline product, Cervarix, only protects against strains 16 and 18.
Beginning of the End
Michael Zacharisen, MD, a professor of pediatrics at the Medical College of Wisconsin who specializes in immunology and has studied RRP, said he hopes the vaccine is the beginning of the end for the affliction. “My impression would be that, with widespread immunization, RRP might become of historical interest only,” he said. “It’s not very common to begin with, but to those kids who have it it’s a huge problem, a chronic problem and a life-threatening problem.”
Craig Derkay, MD, professor of otolaryngology and pediatrics at Eastern Virginia Medical School and chair of the RRP Task Force, which is sponsored by the American Society of Pediatric Otolaryngology, said the vaccine should have a big effect. “If we get some herd immunity and vaccinate a large portion of the population before they become sexually active, then when their babies are born they will not be passing through birth canals that have been infected with the human papillomavirus,” he said.
He hoped for results similar to those from the influenzae type b (Hib) vaccine. “We saw a dramatic decrease in the amount of acute epiglottitis,” he said. “We’re hoping that the same kind of monumental change occurs with the HPV vaccine.”
Vaccination Barriers
The latest study on Gardasil found an efficacy rate up to 100 percent in preventing genital warts among those not yet infected. That analysis included 17,622 females aged 15-26 enrolled in one of two randomized, controlled efficacy trials, with the vaccine or placebo given at day one, month two and month six. The average follow-up was 3.6 years (J Natl Cancer Inst. 2010;102(5):325-339).
Gardasil was approved in the U.S. in 2006 for females ages 9 to 26, and in 2009 for males ages 9 to 26. In Europe, it is approved for females ages 9 to 26 and males 9 to 15. The vaccine is also approved in many other countries.
The main target group in the U.S. includes teenage girls aged 11 and 12, so that they can be vaccinated before becoming sexually active. Studies have shown the risk of HPV infection in the U.S. soars after a young girl’s first intercourse, and 70 percent of girls have had sex by age 18 (BJOG. 2002;109(1):96-98; Adv Data. 2005;362:1-55).
But, as of the end of 2008, only 37.2 percent of girls in the U.S. aged 13 to 17 had received one or more Gardasil vaccinations, according to the Centers for Disease Control and Prevention’s (CDC) Morbidity and Mortality Weekly Report. Experts say there is hesitation among some primary doctors to encourage the vaccination, either because of lack of knowledge or concerns about safety.
As of Jan. 31, there were 15,829 reports of adverse events following Gardasil vaccination, recorded in the Vaccine Adverse Event Reporting System, an early warning system for possible harmful effects of vaccinations. But 92 percent of the events were non-serious, ranging from fainting to headache to nausea.
—Farrel Buchinsky, MD
The 8 percent of effects that were serious include Guillain-Barré Syndrome; deep vein thrombosis; and 49 deaths in females who have received Gardasil. The CDC issued a statement in April vouching for the safety of Gardasil.
“Experts have not found a common medical pattern to the reports of serious adverse events reported for Gardasil that would suggest that they were caused by the vaccine,” according to the CDC website. But there is still considerable hesitation about the vaccine, and vaccines in general, say doctors who treat RRP.
“There are some primary care physicians who still will agree with families that it’s okay not to get them,” Dr. Zacharisen said. “It’s sometimes not getting through to the physicians, and if it doesn’t get through to the physicians, it’s not going to get through to the children and the families.”
There is some disagreement among otolaryngologists about the role they should play in promoting use of the vaccine.
“We should be encouraging our patients to have the vaccine or at the least making the parents aware of it,” said Farrel Buchinsky, MD, assistant professor of surgery at Drexel University College of Medicine, whose research includes the anti-HPV immune response in people with RRP, including those who had the HPV vaccine. “Primary prevention is not usually the role of the specialist, but that does not mean we cannot talk to parents of our ‘tweener’ patients about the vaccine.”
Dr. Buchinsky said otolaryngologists should also point out that the Merck vaccine is the only one that targets the HPV strains that cause RRP.
Dr. Derkay said that, at this point, he would hesitate to promote the vaccine for uses other than prevention of some types of cervical cancer.
“Until there is more science behind the vaccine’s efficacy for RRP, I would be reluctant, off label, to push the vaccine to the public,” he said, adding that he would encourage the use of Gardasil over Cervarix.
Douglas Lowy, MD, chief of the Laboratory of Cellular Oncology, part of the National Cancer Institute, said the resistance to vaccinations is a cultural hurdle that has to be overcome. “As a country, we don’t vaccinate particularly well when it comes to adolescent vaccines that are not required,” he said, pointing out that he was speaking for himself and not for the government agency.
Dr. Lowy said there might be more widespread use of the vaccine if it could almost completely eliminate the risk of cervical cancer, but the Merck vaccine doesn’t cover strains that cause about 30 percent of cervical cancer cases. “The vaccine is not perceived by some people as much of an advance as it might be if you could basically eliminate the risk of cervical cancer,” he said. “My own feeling is that a second-generation vaccine that has a broader efficacy is more likely to have a dramatic impact.”
But Dr. Buchinsky said he is not so sure the extra coverage would make much of a difference. “I doubt that the public and primary care doctors are going to have more acceptance just because it has a higher prevention rate,” he said. “The current vaccine’s likely cervical cancer prevention rate is pretty darn good.”
Therapeutic Possibilities
Gardasil is proven to prevent genital warts in those not yet infected with HPV 6, 11, 16 and 18, but there are questions about whether it could help slow the spread of recurrent respiratory papilllomatosis (RRP) lesions even in those already afflicted.
Experts say that no evidence from Merck’s trials has shown this to be the case, but it is theoretically possible that the vaccine might have a therapeutic effect.
Douglas Lowy, MD, an expert on the HPV vaccine for the National Cancer Institute, called on otolaryngologists to test the possibility in controlled trials. “What I do think would be worthwhile for the otolaryngology community to consider is the possibility of a controlled trial in children with newly diagnosed RRP, a controlled trial of the vaccine,” Dr. Lowry said. “The goal would be to try to reduce the likelihood of spread to new areas,” he said, pointing out that he was speaking for himself and not the government. “I have no idea whether it would work or it wouldn’t work but it seems to me that this is a serious enough condition that… it would be worth considering it.”
Farrel Buchinsky, MD, assistant professor of surgery at Drexel University College of Medicine, is now studying antibody response in both vaccinated and unvaccinated RRP patients. He hopes the study can show whether further work investigating a therapeutic use of the vaccine is worthwhile.
“We have the data, and I’m busy analyzing,” said Dr. Buchinsky, who anticipates finishing a manuscript for the study in the coming months. “Even if there is great data, it still may or may not work. What this data will do is serve to increase or decrease enthusiasms for a therapeutic trial.”
Experts on the disease agree that the vaccine should not be used for preventing the spread of lesions until solid research has been finished.
“When people inquire to me about this,” said Craig Derkay, MD, professor of otolaryngology and pediatrics at Eastern Virginia Medical School, “I tell them that we really should study this in a way that we pool the data and answer this in a scientific fashion. There have been a lot of false starts in the treatment of RRP over the years.”
—Thomas R. Collins