Human Papillomavirus Infection: Current Approach to Prevention

Bryan Hess, MD

Resident

Internal Medicine Residency Program

Thomas Jefferson University Hospital

Rebecca Maury, MD

Instructor

Department of Internal Medicine

Jefferson Medical College of Thomas Jefferson University

Mark G. Graham, MD, FACP

Associate Director

Internal Medicine Residency Program

Thomas Jefferson University Hospital

Associate Professor of Medicine

Jefferson Medical College of Thomas Jefferson University

Director, Jefferson Hospital Ambulatory Practice

Philadelphia, Pa.

The human papillomavirus is the main cause of cervical cancer. About 20 million Americans are infected with one of the many serotypes of this virus, but because the infection is asymptomatic, many do not know they carry the virus and may infect their sexual partners. Although no cure is available for this infection, 2 new vaccines have shown good protection against it when administered to women before they become sexually active. Unlike available childhood vaccines, however, vaccination against the human papillomavirus is elective. To provide effective and accurate counsel to parents and young women, physicians must have a working knowledge of the epidemiology of the infection and its relationship to cervical cancer, as well as the efficacy and limitations of the new vaccines.

The Centers for Disease Control and Prevention estimates that about 20 million American men and women are infected with the human papillomavirus (HPV),¹ and the American Cancer Society indicates that nearly 3700 women die from cervical cancer annually in the United States.² Because the infection is asymptomatic, transmission occurs unwittingly among sexual partners. There is so far no cure for HPV infections.

The development of 2 new vaccines, Gardasil and Cervarix, against HPV infection has sparked a lively debate among clinicians and healthcare policymakers. Unlike childhood vaccines against polio, measles, mumps, rubella, tetanus, and diphtheria, HPV vaccination is elective. Clinicians are frequently called upon to guide parents and young women in this decision. To provide effective and accurate counsel, physicians must have a working knowledge of HPV infection, its epidemiology and relationship to cervical cancer, as well as the efficacy and limitations of the new HPV vaccines.

Virology and Epidemiology

HPV is an encapsulated, double-stranded, nonenveloped DNA virus.³ The different types of HPV are classified according to their nucleotide sequences, with more than 100 HPV types currently identified.³ Of these serotypes, more than 40 are known to infect the genital area (Table 1).⁴ HPV types are further categorized by their epidemiologic association with cervical cancer. Examples of low-risk HPV types, which are not considered carcinogenic, include HPV types 6 and 11; these have been associated with the majority of genital warts,⁵ as well as with low-grade cervical changes and recurrent respiratory papillomatosis. In contrast, high-risk types, including serotypes 16, 18, 31, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82, are strongly linked with cervical cancer,⁴ anal cancer, and other genital cancers.

The worldwide HPV presence in cervical cancer has been reported as high as 99.7%⁶; and 70% of these cancers have been associated with HPV types 16 and 18.^5,7 Therefore, HPV infection is considered necessary, but not sufficient, for the development of cervical cancer.⁸ Reports indicate that 70% of new HPV infections are cleared within 1 year, and 90% are cleared after 2 years.⁹ The median duration of a new HPV infection is 8 months.⁹

HPV is generally transmitted by sexual contact¹⁰ and, rarely, by perinatal transmission. As many as 6.2 million new HPV infections occur each year in the United States among persons aged 14 to 44 years.¹¹ Nearly 4.6 million (74%) of these cases involve young persons aged 15 to 24 years. The observed prevalence of all types of HPV infection was 26.9% in a representative, population-based study of sexually active women aged 18 to 25 years. HPV types 6 and 11 had a prevalence of 2.2%, whereas types 16 and 18 showed a prevalence of 7.8%.¹² A similar study examining women 14 to 59 years of age found an HPV prevalence of 26.8%. In this study, 20- to 24-year-old women demonstrated the highest HPV prevalence, at 44.8%.¹³

HPV acquisition is strongly associated with sexual debut. A prospective study of college women in the United States found a cumulative 38.9% probability of HPV infection within 24 months after first sexual intercourse.¹⁴ Transmission of HPV infection is difficult to prevent, even with the use of condoms. Proper condom use led only to a 70% reduction in HPV infection of newly sexually active college women.¹⁵

Screening for Cervical Cancer

The incidence of cervical cancer in the United States has decreased by approximately 70% since the introduction of the Papanicolaou (Pap) smear in the 1950s.¹⁶ Current estimates suggest that approximately 82.4% of women aged 25 years or older in the United States have had a Pap test in the past 3 years.¹⁷ Despite the availability of routine screening, approximately half of the women in the United States with newly diagnosed cervical cancer have not had a Pap test in the 3 years before diagnosis.¹⁸

The viral genomes of high-risk HPV types code for proteins that act to inhibit host p53 and Rb proteins. The inhibition of these tumor-suppressor proteins is a central component of the process of malignant transformation of cervical cells in cervical cancer.^19-21 The time interval between becoming infected with HPV and transformation to cervical cancer is usually more than 10 years, providing a window of opportunity to screen for dysplastic lesions in the uterine cervix. The tools available for screening the cervix for cancer are:

• Standard Pap smear
• Liquid-based cytology
• Testing for HPV DNA.

Pap smear

The conventional Pap smear examines for changes in the cells of the transformation zone of the cervix caused by HPV infection. A meta-analysis of studies on conventional cytology reveals a sensitivity range between 29% and 54% and a specificity between 97% and 99%.²² Another meta-analysis of the conventional cytology method for HPV screening revealed a false-negative rate of 42%, a majority of which were the result of sampling errors.²³

Liquid-based cytology

Thin-layer, liquid-based cytology (ThinPrep) is a newer technique in which the collected sample removed from the cervix is rinsed from the sampler into a vial, as opposed to a glass slide in the conventional method.²⁴ A meta-analysis of published studies has demonstrated that liquid-based gynecologic cytology preparations were between 73% and 94% sensitive for the detection of epithelial-cell abnormalities, making this technique superior to the conventional cytologic smear.²⁵

HPV DNA testing

Testing for HPV DNA is also available. The Hybrid Capture-II microtiter assay, which is approved by the US Food and Drug Administration (FDA), has been shown to have a sensitivity range of 85% to 100% for detecting cervical cancers and high-grade lesions.²⁴ Combined data from European and US studies of HPV testing for the detection of cervical intraepithelial neoplasia grade 2 or greater in women aged 35 or older have demonstrated a sensitivity of 95% and a specificity of 93%.²⁶ The combination of HPV testing with conventional cytology greatly improves the sensitivity of screening when compared with either method used alone, with a negative predictive value nearing 100%.^26,27

Screening recommendations

Table 2 summarizes current cervical cancer screening recommendations proffered by the American Cancer Society, the American College of Obstetricians and Gynecologists, and the United States Preventive Services Task Force. Screening should begin 3 years after commencement of sexual activity, or at age 21, whichever comes first.

A consensus statement for the management of women with abnormal cervical cancer screening tests, issued in 2006 by the American Society for Colposcopy and Cervical Pathology in association with other societies, was published in October 2007 (Table 3).²⁸ Although a full discussion on these new guidelines is beyond the scope of this article, HPV testing as a screening tool for the prevention of HPV infection and its potentially deadly outcomes is particularly relevant. The recommendations state that HPV testing should be used for routine screening only in patients aged 30 years or older,²⁸ because of the high prevalence of HPV infection in young women, as well as the high spontaneous clearance rate of early infection. Screening should only be performed for the high-risk HPV types. The current guidelines cite evidence from health policy studies that have demonstrated that combination HPV DNA testing with cytology at 3-year intervals in women aged 30 years or older is more beneficial or equivalent to annual conventional cytology.²⁹

The 2 HPV Vaccines

Gardasil

The FDA approved the first quadrivalent HPV vaccine (Gardasil) in June 2007. The vaccine incorporates the L1 major capsid as its antigen, and includes L1 proteins for HPV types 6, 11, 16, and 18. The L1 proteins are expressed in yeast, and the self-assembled viruslike particle is noninfectious.³⁰

A phase 2 randomized, double-blind, placebo-controlled study demonstrated that the combined incidence of persistent infection or disease with HPV type 6, 11, 16, or 18 was 90% lower in the group vaccinated with the quadrivalent HPV vaccine than that observed in the placebo group.³¹

A phase 3 randomized, double-blind, placebo-controlled study evaluated the quadrivalent HPV vaccine for the prevention of high-grade cervical lesions associated with HPV types 16 and 18.³² In this study, 12,167 women aged 15 to 26 years were enrolled to receive either 3 doses of the vaccine at the recommended intervals of day 1, month 2, and month 6, or placebo. All participants underwent a Pap smear test, cervicovaginal sampling for HPV DNA testing, and detailed genital inspection at day 1 and at months 7, 12, 24, 36, and 48. Referrals for colposcopy were standardized with the use of a mandatory Pap smear triage algorithm.

The primary end point for this study was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV type 16 or 18. According to the per-protocol analysis, vaccine efficacy for the prevention of the primary end point was 98%.³² The vaccine was well tolerated, with the most common adverse reaction being injection-site pain.³²

The FDA has not approved the administration of the quadrivalent HPV vaccine to females under the age of 9 or over the age of 26, or for males of any age. Gardasil is estimated to cost around $120 per injection.

Cervarix

A second vaccine currently under FDA review is the bivalent HPV vaccine that uses types 16 and 18 L1 viruslike particles and is known as Cervarix. This vaccine has been shown to be very effective against HPV infection types 16 and 18 and to possess an improved duration of action, presumably as a result of a novel vaccine adjuvant.³³ Human and animal studies have demonstrated an enhanced antibody response with this vaccine that persists for at least 3.5 years as compared with a vaccine that uses traditional aluminum salt conjugation.³³

In a large-scale follow-up study of a multicenter, double-blind, randomized, placebo-controlled trial, more than 98% seropositivity was maintained for HPV types 16 and 18 antibodies during the extended follow-up phase of 4.5 years.³⁴ With regard to HPV types 16 and 18 end points, vaccine efficacy was reported as 96.9% against incident infection, and 100% against cervical intraepithelial neoplasia.³⁴ A good long-term safety profile was also found in that study. Cervarix is already approved in Australia for women aged 10 to 45 years and was submitted for FDA review in March 2007.³⁵

It is important to note that neither Gardasil nor Cervarix is effective against HPV serotypes 31, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, 82?which are responsible for about 30% of the cervical cancer burden.

While Gardasil targets younger women, from adolescence to young adulthood, Cervarix has shown good efficacy in older women as well as in younger populations.

Recommendations for HPV Vaccination

The Advisory Committee on Immunization Practices (ACIP) now recommends routine vaccination of all females aged 11 to 12 years with 3 doses of the quadrivalent HPV vaccine via intramuscular injection at months 0, 2, and 6.³⁶ This series may be started in girls as young as 9 years of age. The ACIP also recommends HPV vaccination for females aged 13 to 26 years who have not been previously vaccinated or who have not yet completed the full series of injection. This recommendation includes sexually active females as well as those with previously documented HPV infection.

The cervical cancer screening recommendations for females who receive the HPV vaccine are the same as for women who have not been vaccinated. The ACIP also addressed the following special populations and clinical situations with respect to HPV vaccination³⁶:

• Women with equivocal/abnormal Pap smear tests, known HPV infection, or genital warts should still be vaccinated; however, it is recommended that these patients be informed that the evidence has not demonstrated that the vaccine will have any therapeutic effect on their existing conditions
• Lactating women can receive vaccine
• Immunocompromised women may be vaccinated, although it may be less effective; pregnant women should not be vaccinated due to insufficient safety data
• Severely ill women should defer HPV vaccination
• Women with immediate hypersensitivity to yeast should not be vaccinated
• HPV vaccination of males is currently not recommended.

Conclusion

Cervical cancer remains an important cause of morbidity and mortality in young women. HPV infection is a prerequisite for the development of cervical cancer but the infection does not always progress to cancer. HPV infection is prevalent in young women shortly after their sexual debut, is asymptomatic, and is easily spread unwittingly through sexual activity. It is difficult to prevent, even with condom compliance. Preventing HPV infection is tantamount to the eradication of cervical cancer. Widespread use of vaccination against HPV offers the best hope for preventing most cases of cervical cancer. Because the new vaccines are effective against some, but not all, high-risk serotypes, current cervical cancer screening guidelines should be followed carefully, regardless of HPV immunization status.

PRACTICE POINTS

Human papillomavirus infection can be transmitted between sexual partners even when a condom is used.

The infection is asymptomatic, and the high-risk serotypes are strongly linked to cervical, anal, and other genital cancers.

Because no cure is available, advising patients about prevention strategies is crucial.

Physicians are urged to recommend vaccination for young women, but screening for cervical cancer is appropriate even in those who receive the vaccine.

SELF-ASSESSMENT TEST

1. Of the more than 100 HPV serotypes, how many are known to infect the genital area?More than 50More than 40More than 30More than 10
2. Some 70% of cervical cancers worldwide have been associated with which HPV serotypes?14 and 3114 and 1816 and 1816 and 31
3. Which of the following statements about HPV infection is not true?Transmission is difficult to preventIt is necessary but not sufficient for the occurrence of cervical cancerThe use of condom is a good way to prevent the infectionThe majority of infected people worldwide are under age 24
4. All the following statements about cervical cancer screening are true, except:US incidence has been reduced by 70% with use of Pap smearAbout 50% of women diagnosed with cervical cancer were not screened for at least 3 yearsLiquid-based cytology and testing for HPV DNA are not as effective as Pap smear testingEven women who are vaccinated against HPV should be screened
5. The quadrivalent HPV vaccine is currently indicated for females aged:9 to 26 years9 to 24 years11 to 26 years11 to 24 years

(Answers at end of references list)

References

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Answers: 1. B; 2. C; 3. C; 4. C; 5. A.