SEXUALLY TRANSMITTED DISEASES: HPV Vaccine Update

Jason Eberhart-Phillips, MD, MPH

Vaccines have recently become targets of controversy, but none have stimulated more debate than the two vaccines now approved to prevent cervical and other anogenital cancers caused by specific types of the human papillomavirus (HPV). Former presidential candidate Michele Bachmann, a US representative from Minnesota, drew attention last fall when she called the HPV vaccine “a dangerous drug” and repeated on national media a woman’s claim that her child had become mentally retarded as a result of getting the vaccine. Most controversial have been efforts to make HPV vaccination mandatory, as was attempted in Texas under a 2007 executive order by Gov. Rick Perry. Before dropping out of the race for president in January, Perry faced repeated attacks from his presidential rivals over his failed mandate. Rick Santorum, another presidential hopeful and a former US senator from Pennsylvania, said, “There is no government purpose served for having little girls inoculated at the force and compulsion of the government.”

Just as the political rancor about the HPV vaccine peaked last October, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention expanded its recommendations for routine use of quadrivalent HPV vaccine, also known as Gardasil, to include males aged 11 or 12 years. The ACIP also recommended catch-up vaccination for unimmunized males aged 13 to 21 years and for men who have sex with other men up to age 26 years. This recommendation brought the guidance for boys and men into greater alignment with that first given for girls and women in 2007.

The remainder of this article addresses some of the basic questions local physicians may have about HPV vaccination.

Q: How common is HPV infection in the United States? In Marin County? What are the consequences of such infection?

HPV is the most common sexually transmitted infection in the United States. About 20 million Americans are currently infected with genital HPV, and the CDC estimates that there are 6.2 million new infections each year, with 75% of these occurring in people 15 to 24 years of age.[1] Infection with HPV often comes soon after the initiation of sexual activity. In one prospective study of female college students, 39% of women who were virgins at the start of the study had become infected with HPV within 24 months of first intercourse.[2]

The vast majority of genital HPV infections are unnoticed and resolve spontaneously, but some infections can become persistent, and those due to more than a dozen so-called “high-risk” types may lead over time to precancerous changes in cells of the cervix, vulva, vagina, anus or penis. The American Cancer Society estimates that about 12,710 new cases of cervical cancer were diagnosed in the United States in 2011, and that about 4,290 American women die from the disease each year.[3] Nearly all these cases are thought to be due to HPV infection, with types 16 and 18--the oncogenic types covered by both vaccines--accounting for 70% of the total. High-risk HPV types are also responsible for about 90% of anal cancers, about 40% of vulvar, vaginal and penile cancers, and about 12% of oral and pharyngeal cancers. In addition, more than 90% of genital warts, which affect about 1% of the sexually active population, are associated with HPV types 6 and 11, both of which are covered by the quadrivalent vaccine (HPV4).

There is no population-based system to measure HPV infection in Marin County, but there were 27 cases of invasive cervical cancer diagnosed in the county from 2007 to 2009. This represents an annual age-adjusted rate of 5.97/100,000, compared to 8.18/100,000 for California as a whole. The county’s annual death rate from cervical cancer has averaged 1.52/100,000 since 2000, compared to 2.43/100,000 statewide.[4]

Q: How effective is HPV vaccine in preventing infection in women? In men?

Both HPV4 and the bivalent vaccine (HPV2, also called Cervarix) are inactivated subunit vaccines produced by recombinant DNA technology, and both are highly immunogenic in uninfected recipients. Within a month of completing the three-dose series, more than 99% of recipients show evidence of antibodies to each of the vaccine virus types with which they have not already been infected. In clinical trials, both vaccines were found to be highly efficacious in preventing cervical disease associated with HPV-16 and 18. The efficacy of HPV4 has been measured at 98% against vaccine type-specific cervical intraepithelial neoplasia grades 2 or 3 and adenocarcinoma in-situ, after a mean follow-up time of 42 months.[5] The efficacy of HPV2 was 93% against the same endpoints after a mean follow-up of 35 months.[6] In males the efficacy of HPV4 against genital warts is thought to be nearly 90%.[7] Among men who have sex with men, HPV4’s efficacy against vaccine type-specific anal intraepithelial neoplasia has recently been estimated at 78%.[7] In either sex, the duration of protection against HPV after immunization is unknown. There is no known serologic correlative of immunity, but a subset of trial participants has shown no waning of protection after more than five years.

As effective as the vaccine can be in clinical trials, there is no evidence of efficacy against disease caused by a type of HPV with which a patient is already infected. The vaccines are prophylactic; they have no therapeutic effect on existing infections or disease. Given how quickly infection with HPV can occur following sexual debut, the vaccine is maximally effective if given before an adolescent becomes sexually active. For this reason the recommended age for completing the three-dose course is 11 or 12 years. The vaccines can be given later (up to age 26 years for HPV4 and 25 years for HPV2), but population benefits decrease with increasing age of administration.

Q: What are the main arguments for and against HPV vaccination?

The main arguments in favor of HPV vaccination center on effectiveness and safety. While it is too early to see a significant reduction in the burden of invasive HPV-related cancers, the vaccine’s high efficacy against intermediate endpoints demonstrated in clinical trials suggests that over time it will become an important tool for preventing cervical cancer and other anogenital cancers. This promising outcome is being achieved with a strong record of safety. More than 35 million doses of HPV vaccine have been given so far with no increased risk of serious adverse reactions, based on monitoring by the CDC.[8] Local reactions such as pain, redness or swelling at the site of injection do occur, but they resolve quickly.

On the other side are a number of arguments questioning whether enough is known about the vaccine’s effectiveness to justify the cost and effort of a universal vaccination program. While the vaccine is highly effective in reducing precancerous cervical lesions caused by types 16 and 18, there is still no conclusive evidence that it can prevent cervical cancer or deaths. There is also no assurance that the duration of immunity will be long enough after age 11 or 12 years to protect recipients throughout their sexually active lives. Since 30% of cervical cancers are associated with types not covered by the vaccine, use of the vaccine does not eliminate the need for regular cervical cancer screening with the Pap test. Some critics argue that with effective screening there is no need for immunization, and that vaccination may even be harmful if some women falsely believe that they need not bother with continued screening. Critics also argue that over time the effectiveness of the vaccine may be lost if the selective pressure it exerts on the virus leads to the emergence of other oncogenic strains not covered by the vaccine.[9] There is no evidence that HPV immunization is associated with increased sexual risk-taking among adolescents, but this too is a concern that many parents share.

With all the doubts about the vaccine--and its cost of about $130 per dose--it is no surprise that only about one-third of US teenage girls have been fully vaccinated against HPV, and that fewer than half have even begun the series.[10]

Q: Should HPV vaccination be mandated for girls and women? For boys and men?

The lack of acceptance of the HPV vaccine by large segments of the general population should give us pause in using the law to reduce HPV-related cancers. Public discourse on HPV vaccine mandates inevitably raises divisive questions about adolescent sex, parental responsibility, the role of government in family decision-making, and the reported influence of the pharmaceutical industry on the political process. It would be far better if parents and adolescents themselves understood the risks that HPV infections pose and appreciated the benefits of receiving the vaccine well before exposure occurs. If that happens, we might see a higher uptake of vaccine, making mandates less important.

Q: In the absence of mandates, what can physicians and other agencies do to stop HPV infection?

Physicians can use their enormous influence to educate parents and their children alike on the risks of not being immunized, and the need to consider HPV vaccine at the 11- or 12-year-old visit. For a parent who believes the vaccine is unnecessary because they are certain their child will delay sexual activity until marriage, it may be helpful to explain that without the vaccine the child will one day be at risk of exposure if the future spouse has ever had sex before. Other parents may be persuaded if they are reminded that in America today more than one-quarter of boys and girls have had sexual intercourse by age 16.[11] It might be helpful to add that HPV can be transmitted through nonpenetrative sexual activity, which is common among adolescents, and that using condoms does not eliminate risk.

Q: How does the HPV vaccine fit into the larger debate about vaccinations? Is it as important as other vaccinations? Should certain vaccinations have priority?

I would hesitate to say one vaccine is more important than another. Is it better to die from measles, meningitis or cervical cancer? They are all equally bad outcomes, and the best evidence we have is that these diseases, like many others, are preventable when people follow the guidelines and accept the vaccines being offered.

Q: What is the role of the drug companies in this debate? How do they stand to profit from the HPV vaccine? What influence do they have on public policy?

The two HPV vaccines were developed and manufactured by two of the world’s largest pharmaceutical companies. These companies certainly expect to recover their costs and earn their shareholders a profit, as they do with any other product. Having said that, revelations about lobbying by one of those companies for compulsory vaccination laws may have tarnished the public’s confidence in the public health value of the HPV vaccine. Perceptions of unseemly political interference by the pharmaceutical industry are never helpful in encouraging vaccine uptake.

Q: What is the status of vaccination efforts in California?

The recent pertussis outbreak, and the new state law requiring the Tdap booster, have awakened a new consciousness in many parents that the task of getting their kids vaccinated does not end at kindergarten. Physicians have an important role in reminding parents of the need for a preteen visit that includes vaccines like that for HPV. Physicians should also be aware that under a new California statute, signed into law by Gov. Jerry Brown last October, they may provide the HPV vaccine to minors without parental consent. In an ideal world, adolescents and parents would both understand the importance of getting the vaccine, but that’s not always possible.

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Dr. Eberhart-Phillips is the former public health officer for Marin County.

 

Email: eberhartphillips@gmail.com

References

1. CDC, “Genital HPV Infection Fact Sheet,” www.cdc.gov/std/HPV/STDFact-HPV.htm (2011).

2. Winer R, et al, “Genital human papillomavirus infection incidence and risk factors in a cohort of female university students,” Am J Epidemiol, 157:218-226 (2003).

3. American Cancer Society, Cancer Facts & Figures 2011, ACS (2011).

4. California Cancer Registry (2012).

5. Kjaer SK, et al, “Pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (types 6/11/16/18) vaccine against high-grade cervical and external genital lesions,” Cancer Prev Res, 2:868-878 (2009).

6. Paavonen J, et al, “Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types,” Lancet, 374:301-314 (2009).

7. FDA, “Highlights of prescribing information: Gardasil,” www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm111263.pdf (2012).

8. CDC, “Reports of health concerns following HPV vaccination,” www.cdc.gov/vaccinesafety/vaccines/hpv/gardasil.html (2011).

9. Haug CJ, “Human papillomavirus vaccination--reasons for caution,” NEJM, 359:861-862 (2008).

10. CDC, “National and state vaccination coverage among adolescents aged 13 through 17 years--United States, 2010.” MMWR, 60:1117–23 (2011).

11. Abma JC, et al, “Teenagers in the United States: Sexual activity, contraceptive use, and childbearing” Vital Health Stat, 23:24 (2004).