By Molly A. Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington

Dr. Brewer reports no financial relationships relevant to this field of study.

Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States and causes cervical, vaginal, some vulvar, anal, penile, and oropharyngeal cancers. The strongest association for the development of cancer is with the high-risk HPV (hrHPV) subtypes. Low-risk subtypes are associated with anogenital warts, with HPV 6 and 11 causing 90% of these warts. The link between HPV and cervical cancer was confirmed in the 1990s,1-5 when epidemiologic studies with advanced molecular detection techniques showed that there was a causative association between cervical cancer and hrHPV infections. Anywhere from 90-100% of paraffin-embedded specimens of cervical cancer were positive for HPV. This was landmark breaking news, since this was the first cancer to be strongly associated with a viral infection.6-7

Cervical cancer remains a major public health problem. It is the fourth most common cancer affecting women worldwide, with 528,000 cases in 2012 and 266,000 deaths.8 It is most prevalent in Asia and Africa, and 85% of the cases occur in less developed countries where access to screening is minimal. The United States has a lower incidence of cervical cancer, with approximately 12,000 cases and 4,100 deaths yearly. However, the cost of following abnormal Pap smears is enormous, and efforts have been made to decrease screening and increase vaccination rates. Given that this cancer is such a world health problem and the cost of screening is large and unreliable, HPV vaccines should substantially reduce the incidence and cost of both screening for and treating hrHPV-related diseases.

The first HPV vaccine was introduced in the United States in 2006, and it contained HPV 6, 11, 16, and 18 (Gardasil-4vHPV). Cervarix (2vHPV), which vaccinates against 16 and 18, was approved in 2009. Both vaccines were approved for males in 2009. Gardasil 9 (9vHPV), which vaccinates against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, was approved in 2014. In 2007, the CDC recommended that all females between the ages of 9-26 years be vaccinated against HPV. Realizing the major health benefit, in 2011, the CDC recommended that all males be vaccinated against HPV. In 2015, the CDC recommended that all women between the ages of 11-26 be vaccinated with one of the three vaccines, and males between ages 11-21 years receive either the 4vHPV or the 9vHPV. Although the vaccine is approved starting at 9 years, the Advisory Committee on Immunization Practices recommends starting vaccinations at age 11.9 Despite these recommendations, the rates of vaccination remain relatively low compared to other countries. In 2016, the National Cancer Institute-designated cancer centers released a statement that according to a 2015 CDC report, only 40% of girls and 21% of boys in the United States receive the recommended three doses of the HPV vaccine.10 In 2016, the American Society of Clinical Oncology published a statement on HPV vaccination for cancer prevention. It stated that “Despite the almost certainty that cancers caused by oncogenic HPV types would be dramatically reduced, the use of HPV vaccination is low (36% and 14% of girls and boys, respectively, age 11-13 years have received all three doses)” in 2013.11 In 2014, the vaccination rates had risen to 60% and 41.7% among girls and boys, respectively. Medicaid patients were almost twice as likely to receive vaccines compared to private insurance.12 Although no studies have used cervical cancer as the endpoint of vaccine efficacy, there are substantial data showing that vaccination against HPV 16 and 18 offers protection for at least five years in HPV-naïve women against these HPV types.13 It is extrapolated that just vaccinating against 16 and 18 would reduce the incidence of cervical cancer by as much as 70% as well as reduce the incidence of oropharyngeal cancer, anal cancer, vaginal cancer, vulvar cancer, and penile cancer.11

Barriers to HPV vaccination are multiple. Lack of education of parents by healthcare professionals has been the major barrier to vaccination in the United States. Additional barriers include parental concern about sexual activity in their child, safety concerns, and lack of reimbursement. Given that HPV is not a life-threatening condition, there is a long lag-period for manifestation of infections, and the progression to cancer is low even with HPV 16 and 18 infections. Parents have not been adequately educated about the benefits of vaccine.

One study showed that pediatricians discussing vaccination with parents often left discussion of the HPV vaccine last, so parents had the perception that it was less important.14 Another study showed that pediatricians believed that having to discuss HPV vaccines was burdensome, that they did not have adequate time to discuss the vaccine, and that parents were less supportive of these vaccines. The study showed that a majority of physicians (59%) used a risk-based approach to recommending HPV vaccine, and about half (49%) usually did not recommend same-day vaccination. A substantial minority also reported weaker recommendation practices in the areas of timeliness for males.15-17 Many other countries have used school-based programs that have resulted in much larger rates of vaccination, such as Australia, which provided a nationally financed program; Rwanda, where free vaccines were provided; and the United Kingdom, where school-based vaccination programs were instituted.10 These countries have 75-90% vaccination rates compared to the much poorer rates in the United States. The ideal age to vaccinate is before the age of sexual activity so they are HPV naïve. Better immunity occurs in the younger age groups, which may be due partially to lack of exposure to HPV and partially to improved immunity prior to the age of 15 years.

A 2016 study by Paskett et al investigated methods to increase vaccination rates among adolescent girls.18 The researchers studied groups in Appalachia, OH, which is an area associated with poor vaccine rates and negative attitudes toward the HPV vaccine among parents. This area is considered to be underserved and to have a lower socioeconomic status than other parts of the Midwest. The researchers hypothesized that they could improve vaccine rates by engaging clinics and providers in this effort. Despite extensive educational efforts on multiple occasions for parents and providers, only 17% received vaccination compared to 9% in the comparison group, showing the challenge of improving the vaccine rate among adolescents. Although this was an improvement, it was not close to what other countries have achieved.

A recent study showed that despite poor vaccine rates, there has been a substantial reduction in the rate of HPV infections in the United States, with 11.5-4.3% reduction in the 4vHPV women ages 14-19 years and 18.5-12.1% decrease in women ages 20-24 years. Despite the relatively low vaccination rate, there has been a substantial reduction in the hrHPV infections.19 In addition, the 9vHPV vaccine, which is more expensive than the 4vHPV and 2vHPV vaccines, was cost effective when modeled nationally.19 They estimated that using 2vHPV and 4vHPV would reduce the cervical cancer incidence by 63% and death rate by 43%. Switching to the 9vHPV is hypothesized to reduce the incidence by 73% and the death rate by 49%. Vaccinating 11% more of the population with the 2vHPV or 4vHPV would cost $2.7 billion more than increasing this coverage with the 9vHPV vaccine.

COMMENTARY

The ability to prevent cancer is truly a new phenomenon. In the 1980s and 1990s, there was substantial work to link HPV to cervical cancer and precancer, and in the 2000s, there was substantial work that linked high-risk HPV, particularly 16 and 18, to the highest risk of cancer. There are now three vaccines that provide excellent protection against both 16 and 18 as well as 9vHPV, which is estimated to reduce the incidence of cervical cancer with a lower cost than the first two vaccines developed.

Why are all young people between the ages of 9 and 15 years not being vaccinated? The most common reason is physicians are not giving parents adequate information about the importance of the vaccine and the long-term reduction in morbidity. Pediatricians are the most common physicians to care for these young people, and they often are overburdened with sick patients and long hours. Putting this vaccine program into schools has been the most successful type of program worldwide, yet there was large pushback from parents in states that tried to mandate the vaccine. We need to better educate parents that preventing the diseases associated with hrHPV will keep their children healthier into adulthood. As a nation, we are afraid of discussing a sexually transmitted disease with our adolescents. It’s time to work harder educating about this preventable disease.

REFERENCES

  1. Syrjänen K, Mäntyjärvi R, Väyrynen M, et al. Human papillomavirus (HPV) infections involved in the neoplastic process of the uterine cervix as established by prospective follow-up of 513 women for two years. Eur J Gynaecol Oncol 1987;8:5-16.
  2. Franco EL. The sexually transmitted disease model for cervical cancer: Incoherent epidemiologic findings and the role of misclassification of human papillomavirus infection. Epidemiology 1991;2:98-106.
  3. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes Most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993;85:958-964.
  4. Bosch FX, Lorincz A, Muñoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244-265.
  5. zur Hausen H. Papillomavirus causing cancer: Evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000;92:690-698.
  6. van den Brule AJ, Meijer CJ, Bakels V, et al. Rapid human papillomavirus detection in cervical scrapes by combined general primer mediated and type-specific polymerase chain reaction. J Clin Microbiol 1990;28:2739-2743.
  7. Gravitt PE, Manos MM. Polymerase chain reaction-based methods for the detection of human papillomavirus DNA. IARC Sci Publ 1992;(119):121-133.
  8. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available at: http://globocan.iarc.fr. Accessed May 26, 2016.
  9. Markowitz LE, Dunne EF, Saraiya M, et al.; CDC. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2014;63(No. RR-05):1–30.
  10. NCI-designated Cancer Centers Urge HPV Vaccination for the Prevention of Cancer. Available at: https://www.mdanderson.org/content/dam/mdanderson/documents/prevention-and-screening/NCI_HPV_Consensus_Statement_012716.pdf. Accessed May 26, 2016.
  11. Bailey HH, Chuang LT, duPont NC, et al. American Society of Clinical Oncology Statement: Human Papillomavirus Vaccination for Cancer Prevention. J Clin Oncol 2016;34:1803-1812.
  12. Ng J, Ye F, Roth L, et al. Human Papillomavirus Vaccination Coverage Among Female Adolescents in Managed Care Plans - United States, 2013. MMWR Morb Mortal Wkly Rep 2015;64:1185-1189.
  13. Maine D, Hurlburt S, Greeson D. Cervical cancer prevention in the 21st century: Cost is not the only issue. Am J Public Health 2011;101:1549-1555.
  14. Bratic JS, Seyferth ER, Bocchini JA Jr. Update on barriers to human papillomavirus vaccination and effective strategies to promote vaccine acceptance. Curr Opin Pediatr 2016;28:407-412.
  15. Gilkey MB, Malo TL, Shah PD, et al. Quality of physician communication about human papillomavirus vaccine: Findings from a national survey. Cancer Epidemiol Biomarkers Prev 2015;24:1673-1679.
  16. Gilkey MB, Moss JL, Coyne-Beasley T, et al. Physician communication about adolescent vaccination: How is human papillomavirus vaccine different? Prev Med 2015;77:181-185.
  17. Thomas R, Higgins L, Ding L, et al. Factors associated with HPV vaccine initiation, vaccine completion, and accuracy of self-reported vaccination status among 13- to 26-year-old men. Am J Mens Health 2016; Apr 22.
  18. Paskett ED, Krok-Schoen JL, Pennell ML, et al. Results of a multilevel intervention trial to increase human papillomavirus (HPV) vaccine uptake among adolescent girls. Cancer Epidemiol Biomarkers Prev 2016;25:593-602.
  19. Markowitz LE, Liu G, Hariri S, et al. Prevalence of HPV after introduction of the vaccination program in the United States. Pediatrics 2016;137:1-9.
  20. Durham DP, Ndeffo-Mbah ML, Skrip LA, et al. National- and state-level impact and cost-effectiveness of nonavalent HPV vaccination in the United States. Proc Natl Acad Sci U S A 2016;113:5107-5112.