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Human papillomavirus infection and the HPV vaccine: What are the facts?

If administered before sexual activity has begun, the HPV vaccine can prevent an estimated 7 of 10 cases of cervical cancer. Why, then, has it caused so much controversy?

Melissa Renee Conner, MPAS; Miranda Merandi Collins, MEd, MPAS, PA-C

Melissa Conner was a student in the PA program at Marietta College, Marietta, Ohio, when she wrote this article. Miranda Collins is a faculty member in the program and practices at MedExpress Urgent Care in Marietta. The authors have indicated no relationships to disclose relating to the content of this article.

Human papillomavirus (HPV) causes the most common sexually transmitted infection (STI) in the United States. Approximately 20 million people are currently infected with HPV, with 6.2 million people acquiring it each year.¹ Estimates are that more than 80% of sexually active females will have HPV by the time they reach age 50 years.² Most HPV infections are asymptomatic and self-limited. However, persistent infections have been proven to lead to cervical cancer in women and to other anogenital cancers and genital warts in both men and women.²

Cervical cancer is the second most common cancer in females worldwide.³ Eighty percent of cases occur in developing countries, where cervical cancer is the most common cancer in women.³ During 2007, cervical cancer was diagnosed in more than 500,000 women around the world and in more than 11,000 in the United States.^2,4 An estimated 300,000 deaths occurred worldwide, with approximately 3,700 of these in the United States.^2,4

In June 2006, a quadrivalent HPV vaccine (Gardasil) was licensed for use in females aged 9 to 26 years for the prevention of cervical cancer, cervical cancer precursors, vulvar and vaginal cancers, and anogenital warts caused by HPV types 6, 11, 16, and 18.² A bivalent HPV vaccine (Cervarix), not yet approved for use in the United States, protects against HPV types 16 and 18.⁵ HPV types 16 and 18 account for approximately 70% of HPV-associated cervical cancer. HPV types 6 and 11 account for approximately 90% of genital warts.⁵

Since the quadrivalent vaccine became available, state- mandated HPV vaccination has become a highly debated and controversial topic, with as many as 41 states introducing legislation to require, fund, or educate the public about the available vaccine.⁶ Some critics of this trend are concerned that a vaccine that protects against an STI will increase teenage sexual promiscuity. Others feel that mandating any vaccine is an intrusion on parental and individual rights. This article reviews the basic information PAs need in order to answer questions patients have about HPV or the vaccine. It also discusses the controversy over state- mandated HPV vaccination, parental attitudes toward the vaccine, and where states currently stand on the issue.

HPV INFECTION

The human papillomaviruses are nonenveloped, double-stranded DNA viruses in the family Papillomaviridae.² More than 100 types have been identified, differing by the epithelium they infect. Forty of these strands have been found to infect the anogenital epithelium. Genital HPV types are further divided into low-risk and high-risk strands. High-risk strands are oncogenic or have been associated with cancer. Low-risk strands are nononcogenic and are mainly found in genital warts.⁵ A study of the epidemiologic classification of HPV types associated with cervical cancer identified 15 HPV types as high risk for this disease.³ Of these, the most commonly occurring were types 16 and 18. HPV type 16 has been found to be more oncogenic than any other high-risk strand of HPV.² Twelve strands were classified as low risk,³ the most commonly occurring of these being types 6 and 11. Low-risk strands are far less common than high-risk strands.³

Transmission and prevention Studies have consistently indicated that HPV is predominantly transmitted through penetrative sexual intercourse.⁷ Thus, sexual behavior is the most important risk factor in the acquisition of HPV infection.⁵ Although rare, other modes of transmission have been implicated; these include oral-genital, manual-genital, and genital-genital nonpenetrative contact,⁵ but their role in cervical cancer is probably minimal.⁷ Nonsexual routes of transmission include transmission from mother to newborn during delivery, which can lead to a rare condition called recurrent respiratory papillomatosis (RRP).² The possibility for transmitting HPV transplacentally or via finger-genital contact has been suggested but is unproven.⁷ HPV is very unlikely to be transmitted through blood or breast milk.⁷

Strategies for preventing HPV infection include sexual abstinence, being in a monogamous relationship with an uninfected person, condom use, or vaccination. Sexual abstinence is by far the most effective way to prevent the transmission of genital HPV. For persons who are sexually active, a monogamous relationship with an uninfected partner will prevent future HPV infection.² Condom use has also been shown to lower the risk of transmission. A study following 82 female university students showed that consistent condom use appeared to reduce the transmission of genital HPV by 70%.⁸ For sexually naïve females, vaccination will prevent infection with HPV types 6, 11, 16, and 18. In females who have already had sexual contact, vaccination will prevent infection with HPV types to which they have not already been exposed.

Persistent infection In most women infected with HPV, the infection will not persist and serious clinical complications will not develop because the host immune system will clear the infection.¹ According to the CDC, approximately 70% of new HPV infections clear within 1 year, and around 90% will clear within 2 years.⁵ The median duration of infection is 8 months.⁵

Only about 10% of infections will persist,⁵ which is important because persistent infection with a high-risk type of HPV is required for the development of cervical cancer or its precursors. Factors that make persistent infection more likely include cigarette smoking, long-term use of oral contraceptives, coinfection with other STIs, increased parity, increased age, nutritional factors, immunosuppression from any cause, and lack of screening for cervical cancer.⁵ According to the National Institutes of Health, approximately half of women who receive a diagnosis of cervical cancer have never been screened for the disease.⁵ Patients should understand too that vaccination does not eliminate the need for cervical cancer screening. Women who have been vaccinated still need regular Pap smears.⁵

Persistent high-risk HPV infections have also been associated with several less common cancers in both men and women. These include vulvar, vaginal, penile, and anal cancers.⁵ Some cancers of the oral cavity, oropharynx, and conjunctiva have also been associated with high-risk types of HPV.⁷ A study by Mork and colleagues found that squamous cell carcinoma of the head and neck had a significant association with HPV type 16.⁹

Persistent infection with low-risk types of HPV is associated with genital warts in men and women and with RRP in infants and children.⁵ RRP is a rare, potentially life-threatening condition primarily associated with low-grade HPV types 6 and 11. RRP is characterized by recurrent papillomas in the upper respiratory tract, especially in the larynx.² It is unclear if cesarean delivery prevents RRP in infants and children because transplacental transmission is a possibility.⁷

HPV VACCINES

The quadrivalent HPV vaccine—the first to be developed and approved—was designed to protect against HPV types 6, 11, 16, and 18, which account for 70% of cervical cancers and 90% of genital warts. The bivalent HPV vaccine that protects against HPV types 16 and 18, which cause 70% of cervical cancers, has not yet been approved by the FDA. A study by Dempsey and colleagues found that among parents who would consider vaccinating their children, most would prefer that their child receive a vaccine that protects against both genital warts and cervical cancer rather than one that protects against cervical cancer alone.¹⁰

Dosage and administration The quadrivalent vaccine, made from noninfectious viruslike particles,⁵ was licensed by the FDA on June 8, 2006. On June 29, 2006, the Advisory Committee on Immunization Practices (ACIP) voted to recommend that the quadrivalent HPV vaccine be administered to females aged 9 to 26 years. It is administered in three IM injections, 0.5 mL each, at intervals 0, 2, and 6 months.^2,5 The preferred site of injection is the deltoid muscle. The second dose should not be given any sooner than 8 weeks after the first. The third should not be given any sooner than 12 weeks after the second. Doses that are given at shorter than recommended intervals and doses that are inadequate should be readministered. Catch-up vaccinations should be given to females aged 13 to 26 years who have not previously been vaccinated or who have not completed all three doses. It is not necessary to repeat doses if there is a long interval between doses. The next dose should be given as soon as possible and the schedule resumed appropriately.²

The ACIP recommends that females between the ages of 11 and 12 years be vaccinated routinely; however, the quadrivalent vaccine is approved for use in girls as young as 9 years and women as old as 26 years. Because the vaccine is prophylactic and because HPV is usually acquired soon after sexual activity begins, vaccination should ideally be complete before a girl has become sexually active. Females who are not yet sexually active will receive full benefit from the vaccine, although those who are having sex will still receive at least partial benefit. Studies have indicated that only a small percentage of sexually active females have been infected with all four HPV types covered by the vaccine.² Most people infected with HPV are infected with only one type, 16 being the most common.³ Between 5% and 30% of people are infected with two or more types.⁵

Gardasil is pregnancy category B, but the ACIP does not recommend administering the vaccine to pregnant females. Pregnancies that occurred during studies of the vaccine have not been causally associated with any adverse events, but data are limited. If pregnancy does occur while the vaccine series is being administered, completion of the series should be delayed until after delivery. If a dose is administered during pregnancy, intervention is not needed. Lactating women can be vaccinated.²

Females who are immunocompromised as a result of medication or disease can receive the HPV vaccine. However, the immune response and the efficacy of the vaccine might be decreased.²

Although the quadrivalent vaccine is not licensed for use in men, there is a potential benefit for males, including reduction in the incidence of genital warts and penile and anal cancers. There is also a potential indirect benefit for women if males are vaccinated because this will reduce HPV transmission.⁵ Data on immunogenicity and safety are available for males aged 9 to 15 years, but studies on the efficacy of the quadrivalent vaccine in men are still under way.² It is unknown when or if the vaccine will be approved for males.

Coadministration of the quadrivalent HPV vaccine with hepatitis B vaccine has been determined to be safe. No data exist on administering the HPV vaccine with other vaccines, but because Gardasil is not a live virus vaccine, the ACIP has suggested that it can be administered at the same time as other age-appropriate vaccines, including the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and the quadrivalent meningococcal vaccine.²

Safety and efficacy Safety data are available from seven clinical trials that included more than 11,000 females. The quadrivalent vaccine was found to be safe and to cause no serious side effects. The most common adverse events have been pain, swelling, and erythema at the injection site, which were reported to be mild. Clinical trials involving HPV-naïve females demonstrated that Gardasil had 100% efficacy in preventing cervical cancer precursor lesions and nearly 100% efficacy in preventing vaginal and vulvar precancers and genital warts caused by HPV types 6, 11, 16, and 18.

The duration of protection from the vaccine is unclear at this time. Current data show the vaccine to be effective for at least 5 years without evidence of waning.^2,5 Follow-up studies are planned to determine duration of protection. Approximately 5,500 women are enrolled in one of the phase III studies and will be followed for a minimum of 14 years.²

Cost The three-dose series of Gardasil costs about $360 and is covered by most large insurance companies. For those without insurance or whose insurance does not cover the vaccine, options are available. Some states provide free or low-cost vaccines at public health departments to those without insurance coverage. The federal Vaccines for Children Program provides free vaccination for those younger than 19 years who are uninsured, Medicaid-eligible, American Indian, or Native Alaskan. This program also provides free vaccines to children and adolescents if their private insurance does not cover the vaccine. The vaccines are administered through Federally Qualified Health Centers or Rural Health Centers.⁵

THE CONTROVERSY

Mandating the HPV vaccine Despite a unanimous vote by the ACIP to recommend that girls aged 11 to 12 years routinely receive the HPV vaccine, the topic has become highly debated among lawmakers and parents alike. Concern has focused on legislature mandates that girls receive the vaccine before entering the 6th grade. For more than a century, states have had the power by law to require people to be vaccinated, allowing them to deny unvaccinated children access to public schools. Each individual state decides which vaccines should be mandatory. The requirements vary, but they are usually based on the recommendations of the ACIP. However, most states allow parents to opt out of vaccinating their children on religious, medical, or philosophical grounds.¹¹

In September 2006, Michigan became the first state to introduce legislation requiring that girls entering the 6th grade receive the HPV vaccine, but the bill has yet to be enacted. In February 2007, Texas became the first state to mandate HPV vaccination for girls entering the 6th grade by executive order from the governor. After much controversy, legislators overrode this order. Also in 2007, Virginia passed legislation requiring the vaccine for girls, but it is currently considering a bill that would delay that requirement. At this time, many states are considering legislation or have enacted some kind of vaccine-related legislation, such as insurance coverage mandates, funding for vaccination, or public education.⁶ However, states seem to be pulling away from compulsory HPV vaccination. The manufacturer of the quadrivalent vaccine has even announced that it will stop lobbying states to require the vaccine in view of the controversy such efforts have generated among the media, parents, and consumers.

This is not the first time that compulsory vaccination has come under fire. Even vaccinations against diseases such as polio, measles, and pertussis have been resisted on a wide range of grounds. Some of this opposition has come from unproven theories connecting vaccines with disorders such as autism, diabetes, and multiple sclerosis. Opposition to the HPV vaccine comes in many forms, including opposition from groups that do not object to the vaccine but do object to making it mandatory, which they consider an intrusion on individual and parental rights. Others are concerned that a vaccine to prevent an STI will undermine abstinence-based prevention messages. They believe endorsing the vaccine is like endorsing sexual activity. Others worry that vaccination will reduce Pap test screening or will prove ineffective over time.¹²

Parental acceptance According to the CDC, 13% of American girls are sexually active by the age of 15 years; at age 17 years, this number grows to 43%, and by 19 years, 70% of girls are sexually active.¹¹ These figures helped to determine the ideal age—11 to 12 years—for administering the HPV vaccine. Although some parents have been reluctant to vaccinate their children against an STI at such a young age, fearing that doing so may be interpreted as condoning or promoting earlier sexual activity, overall parental attitudes toward the vaccine have been broadly positive in the United States, Canada, Mexico, and the United Kingdom.^10,13-17 Most parents said they intended to have their daughters vaccinated. In addition, most agreed that even though the quadrivalent vaccine is not licensed for use in males and they would benefit from it less directly, they should still be vaccinated.^13,15,16

CONCLUSION

HPV infection is the most common STI in the United States and is responsible for more than 500,000 cases of cervical cancer diagnosed every year worldwide. HPV infection has also been linked to other anogenital cancers and to genital warts in men and women. The quadrivalent HPV vaccine has been proven to be safe and effective in preventing infection with HPV types 6, 11, 16, and 18 in girls aged 9 to 26 years who have not already been exposed to the virus. These HPV types cause 70% of cervical cancers, and 90% of genital warts.

Many states have attempted to mandate the quadrivalent vaccine for girls entering the 6th grade, a requirement that has caused considerable controversy. The result has been that states have since backed away from requiring the vaccine. Despite the controversy, however, parental attitudes towards the vaccine have remained largely positive.

Continued research is needed to investigate the efficacy of the HPV vaccine in males, the duration of efficacy in persons vaccinated, and the possible impact the vaccine might have in women who already have cervical cancer and in preventing noncervical types of HPV-induced cancers. The impact of the HPV vaccine will not be fully apparent for decades. In the meantime, it is important to continue to educate the public about the sequelae of persistent HPV infections, the facts about the vaccine, and the benefits of vaccination. The controversy should not keep us from recognizing the potential good that vaccination against HPV can do in our own country and around the world. JAAPA

REFERENCES

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