Tuesday, August 18, 2009

A New Study Examines the HPV Vaccine

Is the HPV Vaccine Safe?

Watch CBS Videos Online

"Is the HPV Vaccine Safe?" CBS reports:

CBS) When Barbara Archiello's doctor recommended a vaccine to prevent cancer of the cervix, she jumped at the chance.

"I think it's just a great thing for women to have," Archiello said.

But the most comprehensive look at the side-effects of since the HPV vaccine was approved in 2006 raises questions about its safety, reports CBS News medical correspondent Dr. Jon LaPook.

In Tuesday's Journal of the American Medical Association, the CDC reported more than 12,000 side effects after 23 million doses were distributed. Ninety-four percent of the problems were not serious but 6 percent were, including patients who were hospitalized, permanently disabled or died. There were 32 deaths - one in over 700,000 doses.

"It really isn't an increase with what we've seen with other vaccines and what is seen regularly with people of that age group," said Dr. Barbara Slade, with the CDC.

But problems that did occur more frequently than expected were fainting - about once every 12,000 doses, and blood clots, once every 500,000 doses.

"The reporting on blood clots was concerning to CDC, concerning in the way that we think it needs further investigation," Slade said.

Critics question the vaccine maker's aggressive ad campaign, because it paid medical societies to help spread the word, and underplayed the importance of evaluating the vaccine's risks and benefits.

"It screeched the message, 'all women are at equal risk, protect yourself from cervical cancer, and this is the way to do it,'" said Dr. Sheila Rothman, author of the JAMA article. "The fact that the medical societies repeated this message is what concerns us."

Merck says after reviewing the new report of adverse events, it continues to be confident in the safety of the vaccine. While the CDC and FDA continue to recommend its use, doctors say they'll look at the HPV vaccine for girls and women on a case-by-case basis.

"If you're going to administer the vaccine, you should discuss these risks with your patient and do a risk assessment." Said Dr. Daniel Smith, with Hackensack University's Medical School.

Something else to consider for parents uncertain about whether to have their daughters vaccinated - Routine pap smears can also help prevent cervical cancer.

In a related story, Kare11.com reports:

As parents across the country try to decide whether to get the human papillomavirus (HPV) vaccine for girls as young as 11, a new study on the shots' side effects, may help some families make up their minds.

Gardasil is recommended by the Centers for Disease Control and Prevention and the American Academy of Pediatrics to help protect against cervical cancer and genital warts.

But many parents have been leery of getting it out of concern that it may promote sexual activity and concern about its side effects since it hasn't been on the market that long.

However, three years and over 23 million doses later, a new study does have something to say about its safety record. So just how safe is the HPV vaccine? That new study examined data from the CDC's Vaccine Adverse Events Reporting System, also called VAERS, to find out. Dr. Barbara Slade with the CDC says, "For 23 million doses that have been sent out, we've received 12,424 reports of adverse events in the VAERS system."

The study, published in the Journal of the American Medical Association (JAMA,) shows of those reports, 772 were classified as serious including 32 deaths. But Kris Ehresmann with the Minnesota Department of Health says, "I do think that the data is very useful but we do sort of have to keep it in context." Ehresmann, who is division director for infectious disease, says that VAERS is set up so that anybody, a parent, a doctor, anyone, can call in to report a problem. Details of those reports are investigated later. So, she says, its possible problems and deaths reported may not always be a direct result of the vaccine. She says, "Is it really because the child was vaccinated or were they hit by a car?

And literally those kinds of things are in that system." The study did find nearly two-thousand girls fainted after getting the HPV vaccine, which is information Ehresmann says is helpful to doctors. She says, "It's useful to know that because then you can say, 'You know what? You've gotten your HPV vaccine. We want you to sit here 15 minutes before we let you go to avoid some of those consequences.'" Compared to other vaccines, she says the HPV vaccine appears just as safe. Ehresmann says, "If there was a concern about a safety signal, the Advisory Committee on Immunization Practices, of which I'm a member, would be getting together and talking about, 'Do we need to change the recommendations?'" She says the HPV vaccine is safe enough for her family saying, "I'm still going to have my daughter vaccinated." Other adverse events reported include dizziness, nausea, headaches and injection site reactions. The HPV vaccine is recommended for women age 11 to 26.

See http://www.kare11.com/news/health/takekare/takekare_article.aspx?storyid=822358&catid=20


The full text of the study published in the Journal of the American Medical Association (JAMA) is provided as follows:

The Risks and Benefits of HPV Vaccination
Charlotte Haug, MD, PhD, MSc

JAMA. 2009;302(7):795-796.

When do physicians know enough about the beneficial effects of a new medical intervention to start recommending or using it? When is the available information about harmful adverse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a complicated process because medical knowledge is typically incomplete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent disease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point.

zur Hausen, winner of the Nobel Prize in Physiology or Medicine in 2008, discovered that oncogenic HPV causes cervical cancer.1-4 His discovery led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and eventually to the development of prophylactic vaccines against HPV infection.

The theory behind the vaccine is sound: If HPV infection can be prevented, cancer will not occur. But in practice the issue is more complex. First, there are more than 100 different types of HPV and at least 15 of them are oncogenic. The current vaccines target only 2 oncogenic strains: HPV-16 and HPV-18. Second, the relationship between infection at a young age and development of cancer 20 to 40 years later is not known. HPV is the most prevalent sexually transmitted infection, with an estimated 79% infection rate over a lifetime5-6 The virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system.7-8 In a few women, infection persists and some women may develop precancerous cervical lesions and eventually cervical cancer. It is currently impossible to predict in which women this will occur and why. Likewise, it is impossible to predict exactly what effect vaccination of young girls and women will have on the incidence of cervical cancer 20 to 40 years from now. The true effect of the vaccine can be determined only through clinical trials and long-term follow-up.

The first HPV vaccine was licensed for use in the United States in June 2006,9 and the Advisory Committee on Immunization Practices recommended routine vaccination of girls aged 11 to 12 years later that same month.10 However, the first phase 3 trials of the HPV vaccine with clinically relevant end points—cervical intraepithelial neoplasias grades 2 and 3 (CIN 2/3)—were not reported until May 2007.11 Previously only reduction in the prevalence of persistent infection and CIN from the 2 virus strains included in the vaccine had been reported. The results were promising, but serious questions regarding the overall effectiveness of the vaccine for protection against cervical cancer remained to be answered, and more long-term studies were called for.12 However, no longer-term results from such studies have been published since then.

So how should a parent, physician, politician, or anyone else decide whether it is a good thing to give young girls a vaccine that partly prevents infection caused by a sexually transmitted disease (HPV infection), an infection that in a few cases will cause cancer 20 to 40 years from now? Two articles in this issue of JAMA13-14 present important data that may influence, and probably already have influenced, such decisions about HPV vaccination.

The report by Rothman and Rothman13 demonstrates how the vaccine manufacturer funded educational programs sponsored by professional medical associations in the United States. The article illustrates how the Society of Gynecologic Oncology, the American Society for Colposcopy and Cervical Pathology, and American College Health Association helped market the vaccine and influenced decisions about vaccine policy with the help of ready-made presentations, slide sets, e-mails, and letters. It is of course reasonable for professional medical associations to promote medical interventions they believe in. But did these associations provide members with unbiased educational material and balanced recommendations? Did they ensure that marketing strategies did not compromise clinical recommendations? These educational programs strongly promoting HPV vaccination began in 2006, more than a year before the trials with clinically important end points were published. How could anyone be so certain about the effect of the vaccine? This matters because the voices of experts such as the professional medical associations are especially important with a complex issue such as this.

In another article, Slade and colleagues14 from the US Centers for Disease Control and Prevention and the US Food and Drug Administration describe the adverse events that occurred 2.5 years following the receipt of quadrivalent HPV vaccine that were reported through the US Vaccine Adverse Events Reporting System (VAERS). Even though most of the reported adverse events were not serious, there were some reports of hypersensitivity reactions including anaphylaxis, Guillain-Barré syndrome, transverse myelitis, pancreatitis, and venous thromboembolic events. VAERS is a passive, voluntary reporting system, and the authors call attention to its limitations. They point out that only systematic, prospective, controlled studies will be able to distinguish the true harmful effects of the HPV vaccine. These limitations work both ways: it is also difficult to conclude that a serious event is not caused by the vaccine.

Whether a risk is worth taking depends not only on the absolute risk, but on the relationship between the potential risk and the potential benefit. If the potential benefits are substantial, most individuals would be willing to accept the risks. But the net benefit of the HPV vaccine to a woman is uncertain. Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened.15 So rationally she should be willing to accept only a small risk of harmful effects from the vaccine.

When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.


Corresponding Author: Charlotte Haug, MD, PhD, MSc, The Journal of the Norwegian Medical Association, Akersgata 2, Oslo 0107, Norway (charlotte.haug@legeforeningen.no).

Financial Disclosures: None reported.

Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.

Author Affiliation: The Journal of the Norwegian Medical Association, Oslo, Norway.


1. zur Hausen H. Human papillomaviruses and their possible role in squamous cell carcinomas. Curr Top Microbiol Immunol. 1977;78:1-30. PUBMED
2. Tsunokawa Y, Takebe N, Nozawa S; et al. Presence of human papillomavirus type-16 and type-18 DNA sequences and their expression in cervical cancers and cell lines from Japanese patients. Int J Cancer. 1986;37(4):499-503. ISI | PUBMED
3. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342-350. FULL TEXT | ISI | PUBMED
4. Nobelförsamlingen 2008: the discoveries of human papilloma viruses that cause cervical cancer and of human immunodeficiency virus. http://nobelprize.org/nobel_prizes/medicine/laureates/2008/adv.pdf. Accessed July 16, 2009.
5. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7(1):11-22. FULL TEXT | ISI | PUBMED
6. Woodman CB, Collins S, Winter H; et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet. 2001;357(9271):1831-1836. FULL TEXT | ISI | PUBMED
7. Syrjänen K, Hakama M, Saarikoski S; et al. Prevalence, incidence, and estimated life-time risk of cervical human papillomavirus infections in a nonselected Finnish female population. Sex Transm Dis. 1990;17(1):15-19. ISI | PUBMED
8. Human papillomavirus (HPV) natural history. http://www.asccp.org/hpv_history.shtml. Accessed July 16, 2009.
9. FDA. June 8, 2006 approval letter: human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm111283.htm. Accessed July 24, 2009.
10. Markowitz LE, Dunne EF, Saraiya M; et al, Advisory Committee on Immunization Practices (ACIP). Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1-24. PUBMED
11. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915-1927. FREE FULL TEXT
12. Sawaya GF, Smith-McCune K. HPV vaccination: more answers, more questions. N Engl J Med. 2007;356(19):1991-1993. FREE FULL TEXT
13. Rothman SM, Rothman DJ. Marketing HPV vaccine: implications for adolescent health and medical professionalism. JAMA. 2009;302(7):781-786. FREE FULL TEXT
14. Slade BA, Leidel L, Vellozzi C; et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302(7):750-757. FREE FULL TEXT
15. Sawaya GF, Brown AD, Washington AE, Garber AM. Current approaches to cervical-cancer screening. N Engl J Med. 2001;344(21):1603-1607. FREE FULL TEXT

See http://jama.ama-assn.org/cgi/content/full/302/7/795


For additional information contact:

Alan L. Morton
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