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The Quadrivalent Human Papillomavirus Vaccine: Potential Factors in Effectiveness
The Quadrivalent Human Papillomavirus Vaccine: Potential Factors in Effectiveness Nancy J. Zonfrillo, MSN, APRN-BC, RNC, and Barbara Hackley, CNM, MSN Cervical cancer, caused by human papillomavirus (HPV) infection, is the second most common female cancer in the world, causing over a quarter of a million deaths worldwide every year. The quadrivalent HPV vaccine (Gardasil) has the potential to significantly reduce morbidity and mortality associated with cervical disease. However, a variety of factors affect the vaccine’s success, including exposure to HPV prior to vaccination, duration of protection provided by the vaccine, the in vivo interaction between HPV serotypes, and variation in HPV serotype prevalence worldwide. This article describes the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine’s effectiveness in reducing cervical cancer rates, and recommendations for maximizing this effectiveness. J Midwifery Womens Health 2008;53:188 –194 © 2008 by the American College of Nurse-Midwives. keywords: cervical cancer, genital warts, human papillomavirus, vaccination
INTRODUCTION Genital human papillomavirus (HPV) is the most common sexually transmitted infection, accounting for an estimated 6.2 million new infections in the United States annually.1 Over 40 identified types of HPV have been linked to genital warts and cervical cancer.2,3 Cervical cancer is the second most common female cancer in the world, resulting in over a quarter of a million deaths worldwide every year.4 Use of the Pap smear has significantly reduced the incidence and mortality of cervical cancer in women who have regular screening and follow-up.5 However, the test has been inadequate in universally preventing cervical cancer. Pap smear sensitivity is poor, ranging from 50% to 74%, depending on the methodology.6 In addition, the test is not sufficiently used. An analysis of the 1998 National Health Interview Survey by the Centers for Disease Control and Prevention of more than 100,000 individuals revealed that only 83% of women aged 40 to 64 years reported Pap testing in the previous 3 years.7 Screening rates are lower among women who are uninsured, younger, poorer, and less educated,7,8 likely contributing to the higher cervical cancer mortality in minority groups such as African Americans.9 Even among women who have screening, approximately 40% with abnormal Pap smear results fail to return for additional testing.10 Routine Pap testing is also problematic in developing countries where there are often limited resources for technology, laboratories, and screening programs.11 These challenges suggest a preventative strategy may be more effective in reducing precancerous lesions and cervical cancer. One potential approach is the use of the quadrivalent
Address correspondence to Nancy J. Zonfrillo, MSN, APRN-BC, RNC, 33 West Durham Street, Philadelphia, PA 19119. E-mail: nancyzonfrillo@aya. yale.edu
188 © 2008 by the American College of Nurse-Midwives Issued by Elsevier Inc.
HPV vaccine (Gardasil, Merck & Co., Inc.), which was approved by the Food and Drug Administration in June 2006.12 Several clinical studies have demonstrated vaccine efficacy in protecting against infection with the four HPV types (6, 11, 16, and 18) associated with approximately 70% of all cervical cancer cases and more than 90% of genital warts.13–16 The vaccine has the potential to significantly reduce morbidity and mortality associated with cervical disease. The purpose of this review is to describe the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine’s effectiveness in reducing cervical cancer rates, and recommendations on how to maximize this effectiveness. BACKGROUND Human papillomavirus is a nonenveloped doublestranded DNA virus that infects mucosal epithelial cells via microabrasions that provide the virus with access to the constantly dividing basal cell layer.17 Specific oncogenes E6 and E7 (“early” viral genes), which comprise part of the viral DNA, are expressed and hinder the functional abilities of the human tumor-suppressing genes p53 and RB.18 With the inhibition of these genes, human cells are unable to perform apoptosis, resulting in overgrowth of infected cells.18 This proliferation ultimately results in various mucosal cellular changes, ranging from genital warts to transient mild dysplasia and carcinoma in situ. The 40 known types of genital HPV are divided into high-risk and low-risk serotypes.3 Table 1 summarizes serotype classification for 35 types. Serotype classification as high risk or low risk relates to the correlation with mucosal cellular changes, as well as the severity of these changes. Low-risk HPV serotypes tend to induce genital warts.3 High-risk HPV serotypes are more often associated with cervical cellular changes, including low-grade Volume 53, No. 3, May/June 2008 1526-9523/08/$34.00 • doi:10.1016/j.jmwh.2007.12.015
Table 1. HPV Serotype Risk Classification
HPV serotype
High Risk
Probable High Risk
Low Risk
Undetermined Risk
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
26, 53, 66
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108
34, 57, 83
HPV ⫽ human papillomavirus. Source: Munoz et al.3
lesions (such as cervical intraepithelial neoplasia 1 [CIN 1]), high-grade lesions (such as CIN 2 and 3), and squamous cell carcinoma.3,19 Higher grade lesions carry an increased risk for developing into cervical cancer.20 VACCINE DEVELOPMENT In 1992, Kirnbauer et al.21 found that a major capsid protein of HPV could be expressed in cultured cells and self-assemble into viruslike particles. These particular particles morphologically resembled HPV virions and were highly antigenic, but did not contain the oncogenic DNA of HPVs.22 Several studies involving injection of the viruslike particles into various animal species and subsequent challenges with high doses of homologous virus within 1 month of the last booster vaccination demonstrated more than 90% protection from infection.23–26 These studies provided the platform to launch human trials. To date, at least 10 human randomized controlled clinical trials have been conducted or are currently in progress, evaluating a 3-dose vaccine to protect against HPV types 6, 11, 16, and 18.13 Outcomes for these trials have included 1) clinical efficacy in preventing cervical and genital disease, 2) duration of protection, 3) immunogenicity, and 4) safety and tolerability. Clinical efficacy endpoints differed slightly across the trials and included persistent HPV infection, CIN, adenocarcinoma in situ, cervical cancer, external genital lesions or warts, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, vulvar cancer, and vaginal cancer.13 The studies also differed with regard to which serotypes were included in the vaccine, dosing levels, sample characteristics such as age and gender, and what outcome measures were examined. The phase 1, phase 2, and ongoing phase 3 trials have included more than 24,000 participants from 22 countries since 1997.13,14 Of these, clinical efficacy has been analyzed in more than 20,800 females aged 16 to 26 years.14 Because the vaccine is intended to be prophylactic, efficacy analyses largely focused on partic-
Nancy J. Zonfrillo, MSN, APRN-BC, RNC, is a 2007 graduate of Yale University School of Nursing. Barbara Hackley, CNM, MSN, is on faculty at Yale University School of Nursing and is in clinical practice at the Women’s Health Service at Montefiore South Bronx Health Center for Children and Families.
Journal of Midwifery & Women’s Health • www.jmwh.org
ipants who were completely HPV naive (both seronegative and polymerase chain reaction negative) at baseline. Participants who showed evidence of current or prior infection with a vaccine-relevant HPV type represented approximately 27% of all participants in the phase 2 and 3 trials and were included in a subset of efficacy analyses. Overall, these trials have demonstrated strong efficacy in preventing cervical, vaginal, and vulvar disease in the female who is HPV naive and less so in the female who has HPV infection. Efficacy rates among these populations are listed in Table 2 according to endpoint measured. The data show promise in the vaccine’s ability to decrease rates of cervical cancer. However, the suboptimal results among the general population are not insignificant. Although the vaccine proved to be at least 95% effective in preventing cervical lesions caused by HPV types 6, 11, 16, or 18 in females who were HPV naive and received all three injections, it was only 36% effective in preventing such lesions in the general population.13,14 This disparity can be attributed to the presence of infection at the time of the initial injection.14 This finding strongly emphasizes the need for females to be fully vaccinated prior to sexual initiation to realize maximum efficacy. The age of female sexual initiation has gradually increased over time, indicating that teenage girls are delaying sexual activity until they are somewhat older.27 Still, nearly 43% of females in grades 9 through 12 reported having ever had sexual intercourse in 2001.27 Therefore, a relatively large proportion of females eligible for vaccination may have been already exposed to HPV, and as a result, may not fully benefit from the vaccine. Long-term efficacy data for the vaccine are limited. To date, only two studies have evaluated duration of protection after completion of the vaccination series.28,29 One study of 2391 women with a monovalent vaccine28 against HPV type 16 and another of 241 women receiving the quadrivalent vaccine29 found that protection lasted through the study periods of 3.5 and 5 years, respectively. Given the relatively short follow-up time and small sample sizes, it is unclear how durable protection will be and whether booster injections will be needed. The pharmaceutical company Merck is conducting ongoing research in the Nordic region (including Sweden, Norway, Iceland, and Denmark) to better understand long-term 189
Table 2. HPV Vaccine Efficacy Rates Among Three Different Study Populations According to Endpoint Measured Population
Endpoint
Relevant HPV Types
Efficacy %
95% Confidence Interval
HPV naive at baseline, received three required doses and followed protocol exactly
CIN/AIS VIN 2/3 or VaIN EGL CIN 2/3 or AIS
6, 11, 16, 18 16, 18 6, 11, 16, 18 16, 18
95 100 99 100
87%–99% 83%–100% 95%–100% 93%–100%
Infected with one vaccine-relevant type but naive to other types; efficacy evaluated only for naive types
CIN or AIS EGL
6, 11, 16, 18 6, 11, 16, 18
89 91
64%–98% 64%–99%
General population: received at least one dose and one follow-up, irrespective of baseline HPV status
CIN 2/3 or worse EGL
6, 11, 16, 18 6, 11, 16, 18
36 70
19%–50% 61%–78%
HPV ⫽ human papillomavirus; CIN ⫽ cervical intraepithelial neoplasia; AIS ⫽ adenocarcinoma in situ; VIN ⫽ vulvar intraepithelial neoplasia; VaIN ⫽ vaginal intraepithelial neoplasia; EGL ⫽ external genital lesions. Source: US Food and Drug Administration.13,14
vaccine effectiveness.30 The research will evaluate vaccine durability over a period of 14 years.30 Although vaccine immunogenicity (the ability to induce an anti-HPV neutralizing antibody response) has been studied in females younger than 16 years, clinical efficacy has not.13,14 Postvaccination immune response in females aged 9 to 15 years was compared with that of females aged 16 to 23 years via measurement of geometric mean titers.13,31 Overall, the younger group was found to generate antibody responses that were 1.67 to 2.02 times higher than those in the older group, and 100% of the younger females seroconverted by 1 month after the final dose.31 Therefore, it has been presumed that the vaccine will have comparable clinical efficacy in younger females and in older women. However, this hypothesis should be held with caution until formally studied. Detailed vaccine safety data, including injection-site reactions, systemic adverse events, and new medical conditions presenting postvaccination, have been evaluated. A total of 5088 vaccine recipients and 3470 placebo recipients recorded vaccination report cards for 14 days postinjection.32 More vaccine recipients (83.9%) than placebo recipients (73.3%) reported injection site pain. Swelling and erythema were also more common in vaccine recipients (25.4% and 24.6%, respectively) than in placebo recipients (15.8% and 18.4%, respectively).32 Rates of systemic adverse reaction (primarily pyrexia) were relatively similar between the vaccine group (10.3%) and placebo group (8.6%).32 Serious adverse events (including death) were rare in both groups (⬍0.1%), and no deaths were determined to have been caused by the vaccine or placebo.32 Data on the development of new medical conditions were gathered through 4 years after vaccine receipt, and rates of autoimmune disorders (such as systemic lupus erythematosus and rheumatoid arthritis) were not different between vaccine and placebo recipients.32 The vaccine’s manufacturer (Merck) is cur190
rently conducting a safety surveillance study to assess whether the vaccine presents short-term safety concerns or causes systemic immune disorders,30 a potential concern with some vaccines.33 Animal reproduction studies have demonstrated no adverse effects of the vaccine on fertility or on fetuses exposed in utero.34 Although women known to be pregnant were not included in the human clinical trials, 2516 pregnancies were reported in women who inadvertently received the vaccine in early pregnancy.14 Rates of live birth, fetal loss, and congenital anomalies were similar between the vaccine and placebo groups.14 There was no evidence that the vaccine adversely affected fertility, pregnancy, or infant outcomes.14,34 Additionally, although 995 women were breastfeeding infants at the time of vaccination, few infants had serious adverse experiences (3.4% for vaccine and 1.8% for placebo), none of which were deemed to be vaccine related.34 The Food and Drug Administration has classified the vaccine as a pregnancy Category B medication.35 However, the Advisory Committee on Immunization Practices does not recommend vaccination during pregnancy because of lack of available data on safety in pregnancy.32 If a woman is found to be pregnant after the vaccination series is initiated, it is recommended that the series be completed when the woman is no longer pregnant. FACTORS IN VACCINE EFFECTIVENESS Several factors may impact the clinical effectiveness of the HPV vaccine. One consideration is whether coinfection with multiple serotypes would enhance or diminish vaccine effectiveness. There may be an in vivo interaction between HPV serotypes that could be synergistic or competitive in nature. A synergistic interaction would occur if two serotypes shared genetic qualities, thus allowing one serotype to facilitate infection with the second.36 In this case, a vaccine specific to one type may Volume 53, No. 3, May/June 2008
induce antibodies to other, genetically related serotypes, thus reducing infection acquisition of multiple HPV strains.36 However, although there may be some antibody cross-reactivity between HPV types, immunity is thought to be largely type specific, suggesting that most serotypes act competitively.36,37 If this is true, then decreasing the prevalence of one serotype may trigger the process of “competitive release” and subsequent proliferation of another serotype.36 For example, removing serotype A from a large proportion of the population may actually promote proliferation of serotype B, which was previously limited by A. This situation may have significant implications for women infected with multiple HPV strains. A study of nearly 2500 Brazilian women revealed coinfection with multiple serotypes in approximately 2% to 3% of women at any one visit, and in more than 12% cumulatively over 1 year.38 Coinfection was found to markedly increase the risk for high-grade lesions.38 Additionally, coinfection has also been demonstrated in 8% of women with confirmed cervical cancer.3 Furthermore, an increased risk for concurrent and sequential infection has been observed in some women, suggesting some degree of inherent predisposition to infection acquisition.39 Therefore, if the vaccine does initiate a competitive release of other, potentially more virulent strains, protection may be incomplete and the vaccine may be less effective than anticipated. The variation in HPV prevalence between countries may also affect vaccine effectiveness. For example, the prevalence (age standardized) in Nigeria is 25.6%, whereas in Spain it is as low as 1.4%.40 Additionally, the varied prevalence of individual HPV serotypes and their contribution to cervical cancer cases may influence effectiveness.37,40 Although HPV types 16 and 18 have been implicated in a majority of cervical cancer cases worldwide (53.5% and 17.2%, respectively), the specific regional prevalence of additional HPV types and their contribution to cervical cancer cases varies.37,40 Given the variation in both HPV prevalence and serotype distribution worldwide and the possibility that women could become infected by serotypes not targeted by the vaccine, it is difficult to predict the vaccine’s worldwide impact. One analysis estimates that a vaccine against only serotypes 16 and 18 could prevent 71% of cervical cancers globally.37 Protection could increase to approximately 87% by including the seven most common cancer-causing serotypes (types 16, 18, 45, 31, 33, 52, and 58).37 However, a heptavalent vaccine would likely be costly to produce, and the added benefit of the five additional cancer-causing serotypes would be difficult to establish.37 Overall, vaccination could decrease detected cytologic abnormalities by 20% including: a 10% reduction in atypical squamous cells, a 25% reduction in low-grade squamous intraepithelial lesions, and a 50% reduction in high-grade squamous intraepithelial lesions.41 InterestJournal of Midwifery & Women’s Health • www.jmwh.org
ingly, vaccination implementation would actually decrease the utility of screening by eliminating higher grade abnormalities.41 For example, in reducing detection of high-grade squamous intraepithelial lesions, which are more likely to progress to cancer than the other grades, the positive predictive value of an abnormal Pap smear for predicting CIN 3 and cancer would decrease.41 Additionally, decreasing the prevalence of HPV type 16 would lower the positive predictive value of colposcopy, as this serotype typically leads to the most identifiable lesions on colposcopic exam.41 Another consideration is the impact that vaccination could have on overall Pap smear testing volume. One analysis suggests that if vaccination were widely implemented among females aged 11 to 12 years old, the most cost-effective screening strategy would be to delay initial Pap testing until 24 years of age, and then continue screening on a biennial basis.42 Assuming all females were vaccinated, this delay in testing would result in a 43% reduction in overall Pap volume 20 years postimplementation.42 Several studies have modeled the overall cost-effectiveness of the quadrivalent vaccine and have found that savings per quality-adjusted life year range from $3000 to $24,300.32 This figure could be even higher if vaccine use was expanded to include women in developing countries where 83% of cervical cancer cases occur.4 However, these cost-effectiveness analyses assume a vaccine efficacy rate of 75% to 90%, which may be significantly overstated if virginal females are not reached. Additionally, each injection of the vaccine costs approximately $120 in addition to the cost of an office visit.43 It is unclear whether vaccination-related fees will limit vaccine implementation. SUMMARY AND RECOMMENDATIONS Although the quadrivalent HPV vaccine has demonstrated effectiveness in preventing acquisition of HPV infection in the HPV-naive female, some argue that it may not have the impact on morbidity and mortality of cervical disease that marketers claim.44 Vaccination of females who are already infected, a detail which may not be known at the time of vaccination, will decrease effectiveness. Additionally, even if HPV-naive females are vaccinated, it is unclear at this early stage how long protection lasts. The detail is important as, on average, CIN 3 progresses to cervical cancer over a period of 8.1 to 12.6 years.45 Therefore, protection against infection acquisition must be long lasting. To maximize the vaccine’s impact, several implementation strategies need to be used. Early Vaccination The vaccine has been approved for use in females aged 9 to 26 years, and current guidelines of the Advisory 191
Committee on Immunization Practices recommend routine vaccination for girls aged 11 to 12 years, with “catch-up” vaccination for adolescents and women aged 13 to 26 years.32 Policy statements and/or recommendations supporting vaccination according to these guidelines have been issued by the American College of Obstetricians and Gynecologists, the American College Health Association, the American Academy of Family Physicians, the American Academy of Pediatrics, and the Society for Adolescent Medicine.46 –50 Ongoing research will ultimately determine any role for booster vaccinations. Immunize Without Prescreening for Vaccine Serotypes At this time, neither the American College of Obstetricians and Gynecologists nor the American Cancer Society recommend HPV screening prior to vaccination.46,51 Cytologic HPV testing would only detect current infections, and serologic testing that could detect past infections is unreliable.46 The American College of Obstetricians and Gynecologists also states that implementing screening prior to vaccination would decrease overall cost-effectiveness.46 In cases of older patients and/or those with a high likelihood of or known HPV infection, health care providers may need to decide on a individual basis if vaccination would be cost-effective. Wide Vaccination The issues of mandatory vaccination and parental consent prior to vaccination are under debate in the United States and are beyond the scope of this review. However, research has shown that parents are generally favorable toward HPV vaccination.52 Parents who were unfavorable toward the vaccine often did not have a comprehensive understanding of the infection, or of the need to vaccinate prior to sexual initiation.52 This highlights the role of health care providers to educate parents and recommend the vaccine when appropriate.52 Additionally, it seems particularly important that the vaccine be made available in developing countries bearing the burden of cervical-related morbidity and mortality. Given the lack of resources available in these countries as well as concerns about the need for early vaccination, implementation may be difficult. Continue Regular Cervical Cancer Screening The vaccine protects against only two of the HPV types that cause cervical cancer and against two that cause genital warts. Although types 16 and 18 are responsible for the majority of cervical cancer, females will continue to be susceptible to other virulent strains. Therefore, the vaccine cannot be used as a replacement for cervical cancer screening. 192
Monitor Safety Data Although clinical trial data have shown similar rates of serious reactions in vaccine and placebo groups, ongoing postmarketing surveillance is needed to monitor vaccine safety because long-term safety data are limited. Providers should report suspected vaccine reactions to the Vaccine Adverse Events Reporting System, which collects safety data on vaccines after licensure. Complete and accurate reporting to the Vaccine Adverse Events Reporting System is essential to evaluate whether serious adverse events are occurring at higher-than-expected rates. If so, further research may be warranted to determine if these events are causal or coincidental. Additionally, health care providers and consumers should report outcomes to the pregnancy registry for Gardasil in cases where vaccination has occurred during pregnancy or within 1 month prior to conception.35 CONCLUSION The quadrivalent HPV vaccine has the potential to reduce the devastating gynecologic sequelae associated with genital HPV infections, thereby lessening a considerable amount of physical pain, emotional toll, and medical cost. However, although the vaccine has been shown to be highly effective in preventing infection with four serotypes, it is difficult to predict the magnitude of its impact on cervical cancer rates. Vaccine use may change the epidemiology of infection, and other equally oncogenic serotypes could replace the four serotypes targeted by the vaccine. Therefore, continued adherence to Pap smear screening recommendations will be needed to reduce cervical cancer deaths. Universal implementation of HPV vaccination at an early age and careful follow-up monitoring will also be required. Women’s health care providers who offer HPV vaccination and adapt their practices to incorporate the newest recommendations for vaccine use and Pap smear screening can be instrumental in reducing the burden associated with HPV infection. REFERENCES 1. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: Incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004;36:6 –10. 2. deVilliers EM. Taxonomic classification of papillomaviruses. Papillomavirus Rep 2001;12:57– 63. 3. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518 –27. 4. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74 –108. 5. National Cancer Institute. Cervical Cancer Screening (PDQ®). 2007. Available from: www.cancer.gov/cancertopics/
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19. Schiffman MH, Castle P. Epidemiologic studies of a necessary causal risk factor: Human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst 2003;95:E2. 20. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999;91:252– 8. 21. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into viruslike particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992;89:12180 – 4. Journal of Midwifery & Women’s Health • www.jmwh.org
35. Merck & Co., Inc. Merck pregnancy registries. 2006. Available from: www.merckpregnancyregistries.com/gardasil.html [Accessed August 14, 2007]. 36. Elbasha EH, Galvani AP. Vaccination against multiple HPV types. Math Biosci 2005;197:88 –117. 37. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004;111:278 – 85. 38. Trottier H, Mahmud S, Costa MC, et al. Human papilloma-
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virus infections with multiple types and risk of cervical neoplasia. Obstet Gynecol Surv 2006;61:706 –7. 39. Mendez F, Munoz N, Posso H, et al. Cervical coinfection with human papillomavirus (HPV) types and possible implications for the prevention of cervical cancer by HPV vaccines. J Infect Dis 2005;192:1158 – 65. 40. Clifford GM, Gallus S, Herrero R, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: A pooled analysis. Lancet 2005;366:991– 8. 41. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer 2007; 111:145–53. 42. Eltoum IA, Roberson J. Impact of HPV testing, HPV vaccine development, and changing screening frequency on national Pap test volume: Projections from the National Health Interview Survey (NHIS). Cancer 2007;111:34 – 40. 43. Vu A. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil®). 2006. Available from: http://uuhsc.utah.edu/pharmacy/bulletins/gardasil.html [Accessed May 1, 2007]. 44. Carreyrou J. Questions on efficacy cloud a cancer vaccine. The Wall Street Journal Online. 2007;A1. Available from: http://online.wsj.com/article/SB117668541991270825.html?mod⫽ googlenews_wsj [Accessed May 11, 2007]. 45. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 66, September 2005. Management of abnormal cervical cytology and histology. Obstet Gynecol 2005;106:645– 64.
46. American College of Obstetricians and Gynecologists. HPV Vaccine - ACOG recommendations. Available from: www. acog.org/departments/dept_notice.cfm?recno⫽7&bulletin⫽3945 [Accessed August 6, 2007]. 47. American College Health Association Vaccine Preventable Diseases Committee. Recommendations for institutional prematriculation immunizations. 2006;1–7. Available from: www.acha.org/info_resources/RIPIstatement.pdf [Accessed August 6, 2007]. 48. American Academy of Family Physicians. AAFP policy statement regarding consideration of the mandated use of HPV for school attendance. 2007. Available from: www.aafp.org/online/en/ home/clinical/immunizationres/mandatedhpv.html [Accessed August 26, 2007]. 49. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of human papillomavirus infection: Provisional recommendations for immunization of females with quadrivalent human papillomavirus vaccine. 2007;1–7. Available from: www.cispimmunize.org/ill/pdf/HPVprovisional.pdf [Accessed August 26, 2007]. 50. Friedman LS, Kahn J, Middleman AB, Rosenthal SL, Zimet GL. Human papillomavirus (HPV) vaccine: A position statement of the Society for Adolescent Medicine. Available from: www. adolescenthealth.org/PositionStatement_HPV_Vaccine.pdf [Accessed August 26, 2007]. 51. Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7–28. 52. Zimet GD. Improving adolescent health: focus on HPV vaccine acceptance. J Adolesc Health 2005;37:S17–23.
Share With Women There is a Share With Women patient handout in this issue of JMWH about human papillomavirus (HPV) infection and prevention. There are more than 30 women’s health topics addressed in previous Share With Women columns, including the following infectious disease topics: ● ● ● ● ● ● ● ●
Genital Warts (Volume 49, Number 1) Group B Strep in Pregnancy (Volume 47, Number 6) Hepatitis C (Volume 50, Number 4) HPV, Cervical Cancer, and You Immunizations for Adults (Volume 52, Number 2) Sexually Transmitted Diseases (Volume 48, Number 2) Tuberculosis and Pregnancy (Volume 52, Number 4) Urinary Tract Infections (Volume 50, Number 6)
Share With Women columns are available for download from www.jmwh.org and are copyright free, which means they can be reproduced and Shared With Women!
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Volume 53, No. 3, May/June 2008
INTRODUCTION Genital human papillomavirus (HPV) is the most common sexually transmitted infection, accounting for an estimated 6.2 million new infections in the United States annually.1 Over 40 identified types of HPV have been linked to genital warts and cervical cancer.2,3 Cervical cancer is the second most common female cancer in the world, resulting in over a quarter of a million deaths worldwide every year.4 Use of the Pap smear has significantly reduced the incidence and mortality of cervical cancer in women who have regular screening and follow-up.5 However, the test has been inadequate in universally preventing cervical cancer. Pap smear sensitivity is poor, ranging from 50% to 74%, depending on the methodology.6 In addition, the test is not sufficiently used. An analysis of the 1998 National Health Interview Survey by the Centers for Disease Control and Prevention of more than 100,000 individuals revealed that only 83% of women aged 40 to 64 years reported Pap testing in the previous 3 years.7 Screening rates are lower among women who are uninsured, younger, poorer, and less educated,7,8 likely contributing to the higher cervical cancer mortality in minority groups such as African Americans.9 Even among women who have screening, approximately 40% with abnormal Pap smear results fail to return for additional testing.10 Routine Pap testing is also problematic in developing countries where there are often limited resources for technology, laboratories, and screening programs.11 These challenges suggest a preventative strategy may be more effective in reducing precancerous lesions and cervical cancer. One potential approach is the use of the quadrivalent
Address correspondence to Nancy J. Zonfrillo, MSN, APRN-BC, RNC, 33 West Durham Street, Philadelphia, PA 19119. E-mail: nancyzonfrillo@aya. yale.edu
188 © 2008 by the American College of Nurse-Midwives Issued by Elsevier Inc.
HPV vaccine (Gardasil, Merck & Co., Inc.), which was approved by the Food and Drug Administration in June 2006.12 Several clinical studies have demonstrated vaccine efficacy in protecting against infection with the four HPV types (6, 11, 16, and 18) associated with approximately 70% of all cervical cancer cases and more than 90% of genital warts.13–16 The vaccine has the potential to significantly reduce morbidity and mortality associated with cervical disease. The purpose of this review is to describe the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine’s effectiveness in reducing cervical cancer rates, and recommendations on how to maximize this effectiveness. BACKGROUND Human papillomavirus is a nonenveloped doublestranded DNA virus that infects mucosal epithelial cells via microabrasions that provide the virus with access to the constantly dividing basal cell layer.17 Specific oncogenes E6 and E7 (“early” viral genes), which comprise part of the viral DNA, are expressed and hinder the functional abilities of the human tumor-suppressing genes p53 and RB.18 With the inhibition of these genes, human cells are unable to perform apoptosis, resulting in overgrowth of infected cells.18 This proliferation ultimately results in various mucosal cellular changes, ranging from genital warts to transient mild dysplasia and carcinoma in situ. The 40 known types of genital HPV are divided into high-risk and low-risk serotypes.3 Table 1 summarizes serotype classification for 35 types. Serotype classification as high risk or low risk relates to the correlation with mucosal cellular changes, as well as the severity of these changes. Low-risk HPV serotypes tend to induce genital warts.3 High-risk HPV serotypes are more often associated with cervical cellular changes, including low-grade Volume 53, No. 3, May/June 2008 1526-9523/08/$34.00 • doi:10.1016/j.jmwh.2007.12.015
Table 1. HPV Serotype Risk Classification
HPV serotype
High Risk
Probable High Risk
Low Risk
Undetermined Risk
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
26, 53, 66
6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP6108
34, 57, 83
HPV ⫽ human papillomavirus. Source: Munoz et al.3
lesions (such as cervical intraepithelial neoplasia 1 [CIN 1]), high-grade lesions (such as CIN 2 and 3), and squamous cell carcinoma.3,19 Higher grade lesions carry an increased risk for developing into cervical cancer.20 VACCINE DEVELOPMENT In 1992, Kirnbauer et al.21 found that a major capsid protein of HPV could be expressed in cultured cells and self-assemble into viruslike particles. These particular particles morphologically resembled HPV virions and were highly antigenic, but did not contain the oncogenic DNA of HPVs.22 Several studies involving injection of the viruslike particles into various animal species and subsequent challenges with high doses of homologous virus within 1 month of the last booster vaccination demonstrated more than 90% protection from infection.23–26 These studies provided the platform to launch human trials. To date, at least 10 human randomized controlled clinical trials have been conducted or are currently in progress, evaluating a 3-dose vaccine to protect against HPV types 6, 11, 16, and 18.13 Outcomes for these trials have included 1) clinical efficacy in preventing cervical and genital disease, 2) duration of protection, 3) immunogenicity, and 4) safety and tolerability. Clinical efficacy endpoints differed slightly across the trials and included persistent HPV infection, CIN, adenocarcinoma in situ, cervical cancer, external genital lesions or warts, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, vulvar cancer, and vaginal cancer.13 The studies also differed with regard to which serotypes were included in the vaccine, dosing levels, sample characteristics such as age and gender, and what outcome measures were examined. The phase 1, phase 2, and ongoing phase 3 trials have included more than 24,000 participants from 22 countries since 1997.13,14 Of these, clinical efficacy has been analyzed in more than 20,800 females aged 16 to 26 years.14 Because the vaccine is intended to be prophylactic, efficacy analyses largely focused on partic-
Nancy J. Zonfrillo, MSN, APRN-BC, RNC, is a 2007 graduate of Yale University School of Nursing. Barbara Hackley, CNM, MSN, is on faculty at Yale University School of Nursing and is in clinical practice at the Women’s Health Service at Montefiore South Bronx Health Center for Children and Families.
Journal of Midwifery & Women’s Health • www.jmwh.org
ipants who were completely HPV naive (both seronegative and polymerase chain reaction negative) at baseline. Participants who showed evidence of current or prior infection with a vaccine-relevant HPV type represented approximately 27% of all participants in the phase 2 and 3 trials and were included in a subset of efficacy analyses. Overall, these trials have demonstrated strong efficacy in preventing cervical, vaginal, and vulvar disease in the female who is HPV naive and less so in the female who has HPV infection. Efficacy rates among these populations are listed in Table 2 according to endpoint measured. The data show promise in the vaccine’s ability to decrease rates of cervical cancer. However, the suboptimal results among the general population are not insignificant. Although the vaccine proved to be at least 95% effective in preventing cervical lesions caused by HPV types 6, 11, 16, or 18 in females who were HPV naive and received all three injections, it was only 36% effective in preventing such lesions in the general population.13,14 This disparity can be attributed to the presence of infection at the time of the initial injection.14 This finding strongly emphasizes the need for females to be fully vaccinated prior to sexual initiation to realize maximum efficacy. The age of female sexual initiation has gradually increased over time, indicating that teenage girls are delaying sexual activity until they are somewhat older.27 Still, nearly 43% of females in grades 9 through 12 reported having ever had sexual intercourse in 2001.27 Therefore, a relatively large proportion of females eligible for vaccination may have been already exposed to HPV, and as a result, may not fully benefit from the vaccine. Long-term efficacy data for the vaccine are limited. To date, only two studies have evaluated duration of protection after completion of the vaccination series.28,29 One study of 2391 women with a monovalent vaccine28 against HPV type 16 and another of 241 women receiving the quadrivalent vaccine29 found that protection lasted through the study periods of 3.5 and 5 years, respectively. Given the relatively short follow-up time and small sample sizes, it is unclear how durable protection will be and whether booster injections will be needed. The pharmaceutical company Merck is conducting ongoing research in the Nordic region (including Sweden, Norway, Iceland, and Denmark) to better understand long-term 189
Table 2. HPV Vaccine Efficacy Rates Among Three Different Study Populations According to Endpoint Measured Population
Endpoint
Relevant HPV Types
Efficacy %
95% Confidence Interval
HPV naive at baseline, received three required doses and followed protocol exactly
CIN/AIS VIN 2/3 or VaIN EGL CIN 2/3 or AIS
6, 11, 16, 18 16, 18 6, 11, 16, 18 16, 18
95 100 99 100
87%–99% 83%–100% 95%–100% 93%–100%
Infected with one vaccine-relevant type but naive to other types; efficacy evaluated only for naive types
CIN or AIS EGL
6, 11, 16, 18 6, 11, 16, 18
89 91
64%–98% 64%–99%
General population: received at least one dose and one follow-up, irrespective of baseline HPV status
CIN 2/3 or worse EGL
6, 11, 16, 18 6, 11, 16, 18
36 70
19%–50% 61%–78%
HPV ⫽ human papillomavirus; CIN ⫽ cervical intraepithelial neoplasia; AIS ⫽ adenocarcinoma in situ; VIN ⫽ vulvar intraepithelial neoplasia; VaIN ⫽ vaginal intraepithelial neoplasia; EGL ⫽ external genital lesions. Source: US Food and Drug Administration.13,14
vaccine effectiveness.30 The research will evaluate vaccine durability over a period of 14 years.30 Although vaccine immunogenicity (the ability to induce an anti-HPV neutralizing antibody response) has been studied in females younger than 16 years, clinical efficacy has not.13,14 Postvaccination immune response in females aged 9 to 15 years was compared with that of females aged 16 to 23 years via measurement of geometric mean titers.13,31 Overall, the younger group was found to generate antibody responses that were 1.67 to 2.02 times higher than those in the older group, and 100% of the younger females seroconverted by 1 month after the final dose.31 Therefore, it has been presumed that the vaccine will have comparable clinical efficacy in younger females and in older women. However, this hypothesis should be held with caution until formally studied. Detailed vaccine safety data, including injection-site reactions, systemic adverse events, and new medical conditions presenting postvaccination, have been evaluated. A total of 5088 vaccine recipients and 3470 placebo recipients recorded vaccination report cards for 14 days postinjection.32 More vaccine recipients (83.9%) than placebo recipients (73.3%) reported injection site pain. Swelling and erythema were also more common in vaccine recipients (25.4% and 24.6%, respectively) than in placebo recipients (15.8% and 18.4%, respectively).32 Rates of systemic adverse reaction (primarily pyrexia) were relatively similar between the vaccine group (10.3%) and placebo group (8.6%).32 Serious adverse events (including death) were rare in both groups (⬍0.1%), and no deaths were determined to have been caused by the vaccine or placebo.32 Data on the development of new medical conditions were gathered through 4 years after vaccine receipt, and rates of autoimmune disorders (such as systemic lupus erythematosus and rheumatoid arthritis) were not different between vaccine and placebo recipients.32 The vaccine’s manufacturer (Merck) is cur190
rently conducting a safety surveillance study to assess whether the vaccine presents short-term safety concerns or causes systemic immune disorders,30 a potential concern with some vaccines.33 Animal reproduction studies have demonstrated no adverse effects of the vaccine on fertility or on fetuses exposed in utero.34 Although women known to be pregnant were not included in the human clinical trials, 2516 pregnancies were reported in women who inadvertently received the vaccine in early pregnancy.14 Rates of live birth, fetal loss, and congenital anomalies were similar between the vaccine and placebo groups.14 There was no evidence that the vaccine adversely affected fertility, pregnancy, or infant outcomes.14,34 Additionally, although 995 women were breastfeeding infants at the time of vaccination, few infants had serious adverse experiences (3.4% for vaccine and 1.8% for placebo), none of which were deemed to be vaccine related.34 The Food and Drug Administration has classified the vaccine as a pregnancy Category B medication.35 However, the Advisory Committee on Immunization Practices does not recommend vaccination during pregnancy because of lack of available data on safety in pregnancy.32 If a woman is found to be pregnant after the vaccination series is initiated, it is recommended that the series be completed when the woman is no longer pregnant. FACTORS IN VACCINE EFFECTIVENESS Several factors may impact the clinical effectiveness of the HPV vaccine. One consideration is whether coinfection with multiple serotypes would enhance or diminish vaccine effectiveness. There may be an in vivo interaction between HPV serotypes that could be synergistic or competitive in nature. A synergistic interaction would occur if two serotypes shared genetic qualities, thus allowing one serotype to facilitate infection with the second.36 In this case, a vaccine specific to one type may Volume 53, No. 3, May/June 2008
induce antibodies to other, genetically related serotypes, thus reducing infection acquisition of multiple HPV strains.36 However, although there may be some antibody cross-reactivity between HPV types, immunity is thought to be largely type specific, suggesting that most serotypes act competitively.36,37 If this is true, then decreasing the prevalence of one serotype may trigger the process of “competitive release” and subsequent proliferation of another serotype.36 For example, removing serotype A from a large proportion of the population may actually promote proliferation of serotype B, which was previously limited by A. This situation may have significant implications for women infected with multiple HPV strains. A study of nearly 2500 Brazilian women revealed coinfection with multiple serotypes in approximately 2% to 3% of women at any one visit, and in more than 12% cumulatively over 1 year.38 Coinfection was found to markedly increase the risk for high-grade lesions.38 Additionally, coinfection has also been demonstrated in 8% of women with confirmed cervical cancer.3 Furthermore, an increased risk for concurrent and sequential infection has been observed in some women, suggesting some degree of inherent predisposition to infection acquisition.39 Therefore, if the vaccine does initiate a competitive release of other, potentially more virulent strains, protection may be incomplete and the vaccine may be less effective than anticipated. The variation in HPV prevalence between countries may also affect vaccine effectiveness. For example, the prevalence (age standardized) in Nigeria is 25.6%, whereas in Spain it is as low as 1.4%.40 Additionally, the varied prevalence of individual HPV serotypes and their contribution to cervical cancer cases may influence effectiveness.37,40 Although HPV types 16 and 18 have been implicated in a majority of cervical cancer cases worldwide (53.5% and 17.2%, respectively), the specific regional prevalence of additional HPV types and their contribution to cervical cancer cases varies.37,40 Given the variation in both HPV prevalence and serotype distribution worldwide and the possibility that women could become infected by serotypes not targeted by the vaccine, it is difficult to predict the vaccine’s worldwide impact. One analysis estimates that a vaccine against only serotypes 16 and 18 could prevent 71% of cervical cancers globally.37 Protection could increase to approximately 87% by including the seven most common cancer-causing serotypes (types 16, 18, 45, 31, 33, 52, and 58).37 However, a heptavalent vaccine would likely be costly to produce, and the added benefit of the five additional cancer-causing serotypes would be difficult to establish.37 Overall, vaccination could decrease detected cytologic abnormalities by 20% including: a 10% reduction in atypical squamous cells, a 25% reduction in low-grade squamous intraepithelial lesions, and a 50% reduction in high-grade squamous intraepithelial lesions.41 InterestJournal of Midwifery & Women’s Health • www.jmwh.org
ingly, vaccination implementation would actually decrease the utility of screening by eliminating higher grade abnormalities.41 For example, in reducing detection of high-grade squamous intraepithelial lesions, which are more likely to progress to cancer than the other grades, the positive predictive value of an abnormal Pap smear for predicting CIN 3 and cancer would decrease.41 Additionally, decreasing the prevalence of HPV type 16 would lower the positive predictive value of colposcopy, as this serotype typically leads to the most identifiable lesions on colposcopic exam.41 Another consideration is the impact that vaccination could have on overall Pap smear testing volume. One analysis suggests that if vaccination were widely implemented among females aged 11 to 12 years old, the most cost-effective screening strategy would be to delay initial Pap testing until 24 years of age, and then continue screening on a biennial basis.42 Assuming all females were vaccinated, this delay in testing would result in a 43% reduction in overall Pap volume 20 years postimplementation.42 Several studies have modeled the overall cost-effectiveness of the quadrivalent vaccine and have found that savings per quality-adjusted life year range from $3000 to $24,300.32 This figure could be even higher if vaccine use was expanded to include women in developing countries where 83% of cervical cancer cases occur.4 However, these cost-effectiveness analyses assume a vaccine efficacy rate of 75% to 90%, which may be significantly overstated if virginal females are not reached. Additionally, each injection of the vaccine costs approximately $120 in addition to the cost of an office visit.43 It is unclear whether vaccination-related fees will limit vaccine implementation. SUMMARY AND RECOMMENDATIONS Although the quadrivalent HPV vaccine has demonstrated effectiveness in preventing acquisition of HPV infection in the HPV-naive female, some argue that it may not have the impact on morbidity and mortality of cervical disease that marketers claim.44 Vaccination of females who are already infected, a detail which may not be known at the time of vaccination, will decrease effectiveness. Additionally, even if HPV-naive females are vaccinated, it is unclear at this early stage how long protection lasts. The detail is important as, on average, CIN 3 progresses to cervical cancer over a period of 8.1 to 12.6 years.45 Therefore, protection against infection acquisition must be long lasting. To maximize the vaccine’s impact, several implementation strategies need to be used. Early Vaccination The vaccine has been approved for use in females aged 9 to 26 years, and current guidelines of the Advisory 191
Committee on Immunization Practices recommend routine vaccination for girls aged 11 to 12 years, with “catch-up” vaccination for adolescents and women aged 13 to 26 years.32 Policy statements and/or recommendations supporting vaccination according to these guidelines have been issued by the American College of Obstetricians and Gynecologists, the American College Health Association, the American Academy of Family Physicians, the American Academy of Pediatrics, and the Society for Adolescent Medicine.46 –50 Ongoing research will ultimately determine any role for booster vaccinations. Immunize Without Prescreening for Vaccine Serotypes At this time, neither the American College of Obstetricians and Gynecologists nor the American Cancer Society recommend HPV screening prior to vaccination.46,51 Cytologic HPV testing would only detect current infections, and serologic testing that could detect past infections is unreliable.46 The American College of Obstetricians and Gynecologists also states that implementing screening prior to vaccination would decrease overall cost-effectiveness.46 In cases of older patients and/or those with a high likelihood of or known HPV infection, health care providers may need to decide on a individual basis if vaccination would be cost-effective. Wide Vaccination The issues of mandatory vaccination and parental consent prior to vaccination are under debate in the United States and are beyond the scope of this review. However, research has shown that parents are generally favorable toward HPV vaccination.52 Parents who were unfavorable toward the vaccine often did not have a comprehensive understanding of the infection, or of the need to vaccinate prior to sexual initiation.52 This highlights the role of health care providers to educate parents and recommend the vaccine when appropriate.52 Additionally, it seems particularly important that the vaccine be made available in developing countries bearing the burden of cervical-related morbidity and mortality. Given the lack of resources available in these countries as well as concerns about the need for early vaccination, implementation may be difficult. Continue Regular Cervical Cancer Screening The vaccine protects against only two of the HPV types that cause cervical cancer and against two that cause genital warts. Although types 16 and 18 are responsible for the majority of cervical cancer, females will continue to be susceptible to other virulent strains. Therefore, the vaccine cannot be used as a replacement for cervical cancer screening. 192
Monitor Safety Data Although clinical trial data have shown similar rates of serious reactions in vaccine and placebo groups, ongoing postmarketing surveillance is needed to monitor vaccine safety because long-term safety data are limited. Providers should report suspected vaccine reactions to the Vaccine Adverse Events Reporting System, which collects safety data on vaccines after licensure. Complete and accurate reporting to the Vaccine Adverse Events Reporting System is essential to evaluate whether serious adverse events are occurring at higher-than-expected rates. If so, further research may be warranted to determine if these events are causal or coincidental. Additionally, health care providers and consumers should report outcomes to the pregnancy registry for Gardasil in cases where vaccination has occurred during pregnancy or within 1 month prior to conception.35 CONCLUSION The quadrivalent HPV vaccine has the potential to reduce the devastating gynecologic sequelae associated with genital HPV infections, thereby lessening a considerable amount of physical pain, emotional toll, and medical cost. However, although the vaccine has been shown to be highly effective in preventing infection with four serotypes, it is difficult to predict the magnitude of its impact on cervical cancer rates. Vaccine use may change the epidemiology of infection, and other equally oncogenic serotypes could replace the four serotypes targeted by the vaccine. Therefore, continued adherence to Pap smear screening recommendations will be needed to reduce cervical cancer deaths. Universal implementation of HPV vaccination at an early age and careful follow-up monitoring will also be required. Women’s health care providers who offer HPV vaccination and adapt their practices to incorporate the newest recommendations for vaccine use and Pap smear screening can be instrumental in reducing the burden associated with HPV infection. REFERENCES 1. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: Incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004;36:6 –10. 2. deVilliers EM. Taxonomic classification of papillomaviruses. Papillomavirus Rep 2001;12:57– 63. 3. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518 –27. 4. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74 –108. 5. National Cancer Institute. Cervical Cancer Screening (PDQ®). 2007. Available from: www.cancer.gov/cancertopics/
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22. Tewari KS, DiSaia PJ. Primary prevention of uterine cervix cancer: Focus on vaccine history and current strategy. Obstet Gynecol Clin North Am 2002;29:843– 68. 23. Breitburd F, Kirnbauer R, Hubbert NL, et al. Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol 1995;69:3959 – 63. 24. Suzich JA, Ghim SJ, Palmer-Hill FJ, et al. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A 1995;92:11553–7.
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31. Block SL, Nolan T, Sattler C, et al. 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;118:2135– 45.
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19. Schiffman MH, Castle P. Epidemiologic studies of a necessary causal risk factor: Human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst 2003;95:E2. 20. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 1999;91:252– 8. 21. Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into viruslike particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992;89:12180 – 4. Journal of Midwifery & Women’s Health • www.jmwh.org
35. Merck & Co., Inc. Merck pregnancy registries. 2006. Available from: www.merckpregnancyregistries.com/gardasil.html [Accessed August 14, 2007]. 36. Elbasha EH, Galvani AP. Vaccination against multiple HPV types. Math Biosci 2005;197:88 –117. 37. Munoz N, Bosch FX, Castellsague X, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004;111:278 – 85. 38. Trottier H, Mahmud S, Costa MC, et al. Human papilloma-
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virus infections with multiple types and risk of cervical neoplasia. Obstet Gynecol Surv 2006;61:706 –7. 39. Mendez F, Munoz N, Posso H, et al. Cervical coinfection with human papillomavirus (HPV) types and possible implications for the prevention of cervical cancer by HPV vaccines. J Infect Dis 2005;192:1158 – 65. 40. Clifford GM, Gallus S, Herrero R, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: A pooled analysis. Lancet 2005;366:991– 8. 41. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer 2007; 111:145–53. 42. Eltoum IA, Roberson J. Impact of HPV testing, HPV vaccine development, and changing screening frequency on national Pap test volume: Projections from the National Health Interview Survey (NHIS). Cancer 2007;111:34 – 40. 43. Vu A. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil®). 2006. Available from: http://uuhsc.utah.edu/pharmacy/bulletins/gardasil.html [Accessed May 1, 2007]. 44. Carreyrou J. Questions on efficacy cloud a cancer vaccine. The Wall Street Journal Online. 2007;A1. Available from: http://online.wsj.com/article/SB117668541991270825.html?mod⫽ googlenews_wsj [Accessed May 11, 2007]. 45. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 66, September 2005. Management of abnormal cervical cytology and histology. Obstet Gynecol 2005;106:645– 64.
46. American College of Obstetricians and Gynecologists. HPV Vaccine - ACOG recommendations. Available from: www. acog.org/departments/dept_notice.cfm?recno⫽7&bulletin⫽3945 [Accessed August 6, 2007]. 47. American College Health Association Vaccine Preventable Diseases Committee. Recommendations for institutional prematriculation immunizations. 2006;1–7. Available from: www.acha.org/info_resources/RIPIstatement.pdf [Accessed August 6, 2007]. 48. American Academy of Family Physicians. AAFP policy statement regarding consideration of the mandated use of HPV for school attendance. 2007. Available from: www.aafp.org/online/en/ home/clinical/immunizationres/mandatedhpv.html [Accessed August 26, 2007]. 49. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of human papillomavirus infection: Provisional recommendations for immunization of females with quadrivalent human papillomavirus vaccine. 2007;1–7. Available from: www.cispimmunize.org/ill/pdf/HPVprovisional.pdf [Accessed August 26, 2007]. 50. Friedman LS, Kahn J, Middleman AB, Rosenthal SL, Zimet GL. Human papillomavirus (HPV) vaccine: A position statement of the Society for Adolescent Medicine. Available from: www. adolescenthealth.org/PositionStatement_HPV_Vaccine.pdf [Accessed August 26, 2007]. 51. Saslow D, Castle PE, Cox JT, et al. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7–28. 52. Zimet GD. Improving adolescent health: focus on HPV vaccine acceptance. J Adolesc Health 2005;37:S17–23.
Share With Women There is a Share With Women patient handout in this issue of JMWH about human papillomavirus (HPV) infection and prevention. There are more than 30 women’s health topics addressed in previous Share With Women columns, including the following infectious disease topics: ● ● ● ● ● ● ● ●
Genital Warts (Volume 49, Number 1) Group B Strep in Pregnancy (Volume 47, Number 6) Hepatitis C (Volume 50, Number 4) HPV, Cervical Cancer, and You Immunizations for Adults (Volume 52, Number 2) Sexually Transmitted Diseases (Volume 48, Number 2) Tuberculosis and Pregnancy (Volume 52, Number 4) Urinary Tract Infections (Volume 50, Number 6)
Share With Women columns are available for download from www.jmwh.org and are copyright free, which means they can be reproduced and Shared With Women!
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Volume 53, No. 3, May/June 2008