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HPV Vaccine: Evolving Indications and Recommendations

Kenneth A. Alexander, MD, PhD

Human papillomavirus (HPV) is the most common sexually transmitted infection.¹ In the United States, approximately 20 million people are infected with HPV, with 6 million incident cases per year, and the lifetime risk of genital HPV infection is 80%. In 2006, a quadrivalent HPV vaccine (HPV4) was licensed for women; in 2009, a bivalent vaccine (HPV2) was licensed. In 2003-2004, the population-based National Health and Nutrition Examination Survey (NHANES) of 4,303 participants aged 14 to 59 years found that HPV seroprevalence in the United States for any vaccine type was 22.4% overall and 32.5% in females.² Studies have also shown that 18% of females aged 14 to 19 years are infected with HPV,³ emphasizing the need to vaccinate as early as possible, ideally at the targeted 11 to 12-year-old age group.

HPV Vaccine Indication Status

HPV vaccination has reached a crossroads. The notion of immunizing adolescent females against HPV is increasingly well-accepted, and most immunizers are now routinely offering HPV immunization to their adolescent female patients. The data, both medical and health-economic, supporting the utility and safety of HPV immunization of adolescent females are strong, and most payors, including the Vaccines for Children Program, are reimbursing immunizers. Nonetheless, some immunizers have not made HPV immunization a priority for their adolescent female patients.

Now, new data demonstrating the benefits of HPV immunization for protection of males against both anogenital warts and anal malignancies have become available. In response, the Food and Drug Administration (FDA) expanded the indications for HPV immunization to include immunization of males aged 9 to 26 years. Thus, the population recommended to receive HPV vaccines has grown from females only to males and females. To help immunizers understand the rationale for this expansion in vaccine indications, and to assist providers as they work promoting HPV immunization to their patients and in their communities, the facts and events leading to the expansion of HPV immunization indications will be reviewed.

The HPV4 (Gardasil, Merck) vaccine contains antigens for HPV types 6 and 11 to prevent genital warts, and antigens for HPV 16 and 18 to prevent anogenital cancers and precancers. The HPV2 vaccine (Cervarix, GlaxoSmithKline), which contains antigens for HPV 16 and 18, prevents genital precancers and cancers. Both vaccines were recommended by the Advisory Committee on Immunization Practices (ACIP) for routine use in girls 11 to 12 years of age, while allowing for vaccination of girls as young as 9 years of age, and catch-up immunization of females aged 13 to 26 years. In 2009, HPV4 received expanded FDA approval for use in boys and men 9 through 26 years of age for the prevention of genital warts caused by HPV types 6 and 11. This first approval for use of the HPV4 vaccine in males was followed in December 2010 by an indication for both genders aged 9 through 26 years for the prevention of anal cancer and associated precancerous lesions due to HPV types 6, 11, 16, and 18.⁴

Efficacy of these vaccines for prevention of precancers due to vaccine types has been as high as 100% in females 16 to 26 years of age.⁵ HPV immunization of females has been demonstrated to be cost-effective, and the community has become more accepting of female HPV immunization.

The consensus of regulatory agencies and advisory committees is that both vaccines are safe. Occasionally adolescent patients faint following HPV immunization. However, this is not specific to the HPV vaccine or to gender. Rather, these vasovagal events are a consequence of the immunization process itself, and rates of syncope with any vaccine are higher among adolescents. In pediatric practices, HPV immunization has become more routine and less of a topic for discussion. Insurance reimbursement is being provided in most cases for females and modestly for males. However, it is not included in all plans. Nonetheless, vaccine coverage remains suboptimal.

HPV Vaccination Coverage

Uptake of the vaccine in the United States remains modest.⁶ In 2008, female adolescent coverage rates were 37.2% and 17.9% for > 1 and > 3 doses of the vaccine, respectively. The increases in adolescent female HPV vaccine coverage rates to 44.3% and 26.7%, respectively, seen in 2009 suggest that some barriers to HPV immunization are being overcome, albeit slowly.

Of the more than 100 countries that have licensed one or both HPV vaccines, many (in particular, Canada, the United Kingdom, New Zealand, and Australia) have achieved immunization rates that are much higher than those in the United States. This discrepancy in HPV immunization rates is due primarily to the success in other countries of implementing aggressive school-based immunization programs. For example, in April 2007, Australia launched a government-funded National HPV Vaccination Program. As part of the program, an HPV immunization registry sends reminders to the patients when doses 2 and 3 are overdue.⁷ The Australian program achieved 75% to 80% vaccination coverage for all 3 doses among targeted girls in the first program year.⁸

Results from an Australian study also suggest that the HPV4 vaccine induces herd immunity.⁹ As immunization of young women increased, with a subsequent decline in genital warts diagnoses among young women, there was also a decline in genital wart-related clinic visits among young men, even though the men were rarely immunized.

HPV Infections in Men

As in women, HPV infections are common in men. The NHANES study reported that in 2003-2004, the prevalence of any of the quadrivalent vaccine types in men 14 to 59 years of age was 12.2%.² As in women, HPV infections cause many serious diseases in men, including:

• Genital warts
• Anal cancers
• Penile cancers
• Oropharyngeal and oral cavity cancers
• Recurrent respiratory papillomatosis

With 500,000 incident cases per year that result in more than $200 million in health care costs, genital warts are the most common disease caused by HPV infection of males.^10-13 Treatments for genital warts are expensive and are associated with undesirable side effects. Even with treatment, recurrence is common. A diagnosis of genital warts is also associated with a significant reduction in quality of life.^14-18

Incidence data for HPV-associated cancers in the United States are compiled from population-based cancer registries that participate in the National Program of Cancer Registries or from the Surveillance, Epidemiology, and End Results (SEER) Program, which together cover virtually the entire US population.^19-21 Although the combined incidence for all HPV-associated cancers is higher in women, the incidence rate of oropharynx and oral cavity cancer is higher in men.

The incidence of HPV-related oral squamous cell carcinomas increased 0.8% annually from 1973 to 2004 (P<. 001).²² Although the rate of oral malignancies attributable to HPV is decreasing for some sites (eg, the larynx), the incidence rate of tonsillar and base of the tongue cancer increased significantly for both men and women between 1998 and 2003, with a combined increased incidence of 3% annually.²³ If this trend of increasing incidence of tonsillar and base of tongue squamous carcinomas continues, the incidence of HPV-positive oral and oropharyngeal malignancies will soon exceed that of cervical malignancies.

Anal HPV infections in men are also common. Although anal cancers are rare, the incidence of HPV-associated anal cancers increased at an average rate of 2.6% per year from 1998 to 2003.²⁴ Women had a higher rate of invasive anal cancer than men in that study; 5-year anal cancer survival at all stages of the disease was lower for men than for women.

HPV4 Vaccine: Efficacy in Males

Studies on the immunogenicity of the HPV4 vaccine have demonstrated that 1 month after dose 3, seroconversion rates were > 99.5% for the 4 vaccine HPV types.²⁵ Furthermore, the geometric mean titers and seroconversion rates in boys aged 9 to 15 years were noninferior to those in girls of the same age group (P<. 001; Table 1).²⁵

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The geometric mean titers of anti-HPV antibodies in young boys and girls 10 to 15 years of age were shown to be 1.7-fold to 2.7-fold higher than those observed in females in the older age group (Table 2).²⁶ Because the antibody titers seen in boys and girls aged 9 to 16 years were not inferior to those in women aged 16 to 26 years, the FDA allowed licensure of the HPV4 vaccine on the basis of immunologic bridging.

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HPV4 vaccine and genital warts

Prelicensure studies of the HPV4 vaccine measured vaccine efficacy for preventing external genital lesions and condyloma (genital warts) caused by vaccine types. Among the study cohorts were a cohort of men and boys 16 through 26 years of age who were HPV-negative prior to vaccination. Per-protocol vaccine efficacy for prevention of genital warts and external genital lesions in this cohort was approximately 90% for both conditions.²⁷ Injection site pain was significantly more frequent among subjects receiving the HPV4 vaccine than among those receiving placebo (57% vs. 51%; P< .001).²⁸

In October 2009 and on the basis of these data, the FDA approved the expanded indication for the use of the HPV4 vaccine in males for the prevention of genital warts caused by HPV 6 and 11. Following the FDA’s approval of the expanded indications, the ACIP issued a permissive recommendation stating that the quadrivalent vaccine may be given to males 9 through 26 years of age to reduce the likelihood of acquiring genital warts.²⁹ As with HPV immunization of girls, the recommended age for immunization of boys was 11 to 12 years. Because the bivalent vaccine does not contain HPV 6 and 11 antigens, and therefore has no utility for prevention of most genital warts, the bivalent vaccine has not been approved for use in males.

HPV4 vaccine and anal cancer

In a substudy of the trial described above, 598 men who have sex with men (MSM) aged 16 to 26 years were randomized to receive the HPV4 vaccine or placebo according to the standard 3-dose immunization schedule (0, 2, and 6 months).^27,30 In the per protocol analysis after a median follow-up of 2.5 years, vaccine efficacy for prevention of anal intraepithelial neoplasia (AIN) and anal carcinoma caused by vaccine HPV types was 77.5% (95% CI, 39.6-93.3) for AIN 1/2/3 (Table 3); vaccine efficacy for prevention of the more advanced AIN 2/3 was 74.9% (95% CI, 8.8-95.4).

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In response to these data, on December 22, 2010 the FDA Vaccines and Related Biological Products Advisory Committee issued an approval letter supporting an indication for the quadrivalent vaccine use in males and females aged 9 through 26 years for prevention of anal intraepithelial neoplasias and anal cancers. Thus, in the 4 and a half years since the initial approval of the HPV4 vaccine for use in girls and young women, 3 expanded indications have been approved.

HPV4 vaccine and cancer at other sites

As noted above, HPV types, in particular HPV 16, play a significant role in the genesis of oral and oropharyngeal cancer, in particular tonsillar, base of tongue, and laryngeal squamous carcinomas. Because HPV vaccines confer immunity against HPV 16, it is conceivable (and indeed, hoped) that HPV vaccines might prevent the increasing number of head and neck malignancies anticipated. While pursuing an indication for prevention of these tumors would appear to be a logical next step, the imminent prospects for an FDA-granted indication for prevention of head and neck cancer are remote. Unlike HPV-associated genital and anal diseases that have well-characterized premalignant states that can be used as surrogate endpoints in clinical trials evaluating vaccine efficacy (ie, CIN 1, 2, and 3 for cervical cancer, and AIN 1, 2, and 3 for anal malignancies), there are no established premalignant states identified for head and neck squamous carcinomas. Given a lack of surrogate endpoints for HPV-associated head and neck squamous cancers, a vaccine efficacy trial would require cancer development as a study endpoint. Attaining such an endpoint could take 30 years or longer, precluding such a trial. If scientists able to identify and validate premalignant markers of head and neck squamous tumors, then a trial of HPV vaccines for prevention of head and neck malignancies could proceed. Alternatively, persistent infection could serve as a marker.

In conclusion, the utility of HPV immunization for prevention of cervical, vaginal, and vulvar disease is now generally accepted. Newer data indicate that HPV vaccines also prevent genital warts in males, and prevent anal malignancies in males and females. While not yet indicated for this purpose, it is likely that these vaccines will also prevent a portion of head and neck malignancies. Thus, as physicians consider HPV immunization of both their female and male patients, the broadening scope of genital wart and cancer prevention benefits of immunization must be considered.

References

1. Centers for Disease Control and Prevention. Genital HPV Infection—Fact Sheet. http://www.cdc.gov/std/HPV/STDFact-HPV.htm. Accessed January 10, 2011.
2. Markowitz LE, Sternberg M, Dunne EF, McQuillan G, Unger ER. Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey 2003-2004. J Infect Dis. 2009;200(7):1059-1067.
3. Forhan SE, Gottlieb SL, Sternberg MR, et al. Prevalence of sexually transmitted infections among female adolescents aged 14 to 19 in the United States. Pediatrics. 2009;124(6):1505-1512.
4. US Food and Drug Administration. Vaccines, Blood, and Biologics. Gardasil. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094042.htm. Accessed January 6, 2011.
5. Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005;6(5):271-278.
6. Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among adolescents aged 13-17 years—United States, 2009. MMWR Morb Mortal Wkly Rep. 2010;59(32):1018-1023.
7. The National Human Papillomavirus (HPV) Vaccination Program Register. http://www.hpvregister.org.au/Default.aspx. Accessed January 10, 2011.
8. Shefer A, Markowitz L, Deeks S, et al. Early experience with human papillomavirus vaccine introduction in the United States, Canada, and Australia. Vaccine. 2008;26(suppl 10):K68-K75.
9. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis. 2011;11(1):39-44.
10. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL. The estimated direct medical cost of sexually transmitted diseases among American youth, 2000. Perspect Sex Reprod Health. 2004;36(1):11-19.
11. Insinga RP, Dasbach EJ, Elbasha EH. Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature. Pharmacoeconomics. 2005;23(11):1107-1122.
12. Chesson HW, Ekwueme DU, Saraiya M, Markowitz LE. The cost effectiveness of HPV vaccination in the United States: estimates from a simplified model. Presented at: Annual Meeting of the International Society for Sexually Transmitted Diseases Research; July 31, 2007; Seattle, WA.
13. Hoy T, Singhal PK, Willey VJ, Insinga RP. Assessing incidence and economic burden of genital warts with data from a US commercially insured population. Curr Med Res Opin. 2009;25(10):2343-2351.
14. Woodhall S, Ramsey T, Cai C, et al. Estimation of the impact of genital warts on health-related quality of life. Sex Transm Infect. 2008;84(3):161-166.
15. Lawrence S, Walzman M, Sheppard S, Natin D. The psychological impact caused by genital warts: has the Department of Health's choice of vaccination missed the opportunity to prevent such morbidity? Int J STD AIDS. 2009;20(10):696-700.
16. Jeynes C, Chung MC, Challenor R. 'Shame on you'—the psychosocial impact of genital warts. Int J STD AIDS. 2009;20(8):557-560.
17. Ireland JA, Reid M, Powell R, Petrie KJ. The role of illness perceptions: psychological distress and treatment-seeking delay in patients with genital warts. Int J STD AIDS. 2005;16(10):667-670.
18. Mortensen GL. Long-term quality of life effects of genital warts—a follow-study. Dan Med Bull. 2010;57(4):A4140.
19. Joseph DA, Miller JW, Wu X, et al. Understanding the burden of human papillomavirus-associated anal cancers in the US. Cancer. 2008;113(10 suppl):2892-2900.
20. Centers for Disease Control and Prevention. National Program of Cancer Registries. US cancer statistics. http://apps.nccd.cdc.gov/uscs/. Accessed January 5, 2011.
21. National Cancer Institute. Surveillance Epidemiology and End Results (SEER). http://seer.cancer.gov/. Accessed January 5, 2011.
22. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.
23. Ryerson AB, Peters ES, Coughlin SS, et al. Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral cavity in the US, 1998-2003. Cancer. 2008;113(10 suppl):2901-2909.
24. Watson M, Saraiya M, Ahmed F, et al. Using population-based cancer registry data to assess the burden of human papillomavirus-associated cancers in the United States: overview of methods. Cancer. 2008;113(10 suppl):2841-2854.
25. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J. 2007;26(3):201-209.
26. Block SL, Nolan T, Sattler C, et al; Protocol 016 Study Group. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics. 2006;118(5):2135-2145.
27. Gardasil [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2010.
28. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med. 2011;364(5):401-411.
29. Makowitz LE. Update and recommendations: human papillomavirus vaccines. November 12, 2009. http://www.cdc.gov/vaccines/ed/ciinc/downloads/Nov_09/NICRDnetconf2009final.ppt. Accessed January 14, 2011.
30. Palefsky J. Efficacy of the quadrivalent HPV vaccine to prevent anal intraepithelial neoplasia among young men who have sex with men. Presented at: 26th International Papillomavirus Conference; July 3-8, 2010; Montreal, Canada. Abstract 456. http://hpv2010.org/main/. Accessed January 12, 2011.