warts or papillomas in the upper respiratory tract, particularly the larynx, and that is associated with extensive morbidity (Table 1). RISK FACTORS G

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1 CONCISE REVIEW FOR CLINICIANS HPV AND VACCINATION Human Papillomavirus and Vaccination CHRISTINE M. HUANG, MD On completion of this article, you should be able to (1) review pathophysiology and transmission of human papillomavirus, (2) cite efficacy and safety profile of the new human papillomavirus vaccine, and (3) summarize current guidelines for use of the vaccine. Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. Although most infections are transient and asymptomatic, persistent infection with high-risk types of HPV can lead to precancerous lesions and progress to cancer. In June 2006, the US Food and Drug Administration licensed the first vaccine to prevent cervical cancers and other diseases in women. This quadrivalent vaccine protects against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. Several studies have been published examining the vaccine s efficacy, duration, immunogenicity, and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses, and cost-effectiveness. Mayo Clin Proc. 2008;83(6): CI = confidence interval; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; Pap = Papanicolaou; QALY = quality-adjusted life-year; RRP = recurrent respiratory papillomatosis; VLP = viruslike particle Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States; an estimated 6.2 million new infections occur each year. 1,2 Although most infections are transient and asymptomatic, persistent infections with high-risk types of HPV can lead to cervical and anogenital cancers. Despite the decline in deaths due to cervical cancer in the United States since the widespread institution of Papanicolaou (Pap) testing, an estimated 11,070 new cases of invasive cervical cancer will be diagnosed and 3870 women will die of cervical cancer during Worldwide, cervical cancer remains a leading cause of death, with half a million new cases and a quarter of a million deaths each year. 1,2,4,5 Hence, the advent of a vaccine against the HPV virus has stirred much excitement as well as debate. PATHOPHYSIOLOGY Human papillomaviruses are small, nonenveloped, doublestranded DNA viruses; their 8-kB circular genome encodes the encapsulating structural proteins L1 and L2, as well as several early genes that enable viral transcription and replication and interact with the host genome. Approximately 100 types of HPV have been identified; those that infect the genital area have a predilection for mucous membranes. The low-risk types can cause benign or low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis (RRP). The high-risk types can cause low-grade and high-grade cervical cell abnormalities that are precursors to cervical and anogenital cancers. Most HPV infections are transient and asymptomatic; they can be associated with mild cytologic abnormalities but, in general, cause no clinical problems. Of new infections, 70% clear within 1 year, and 90% clear within 2 years, 6 with mean duration of 8 months. 7 However, persistent infection with high-risk types of HPV can progress to a precancerous lesion and eventually to cancer. CLINICAL SEQUELAE Since the 1950s, the number of deaths due to cervical cancer in the United States has decreased by more than 70% and continues to decline by nearly 4% a year, 3 with widespread use of Pap testing. This decrease has been observed primarily in squamous cell cancers rather than adenocarcinomas, which are more difficult to detect with Pap tests. The clinical sequelae of HPV infection are not limited to cervical cancer and its precursor lesions; they have also been associated with several other types of squamous cell carcinomas and their precursors at different sites. A recent study reported further evidence of an association between HPV and oropharyngeal cancer that was independent of tobacco and alcohol use (with HPV-16 found in 72% of 60 oropharyngeal cancers sampled) and suggested an association with sexual behavior. 8 Also caused by HPV are anogenital warts (condylomas), approximately 90% of which are associated with HPV-6 and HPV Infection with these low-risk HPV types rarely results in RRP, a disease that is characterized by recurrent From the Department of Internal Medicine, UCLA School of Medicine, VA Greater Los Angeles Healthcare System, West Los Angeles, California. Individual reprints of this article are not available. Address correspondence to Christine M. Huang, MD, Wilshire Blvd (PACC), Los Angeles, CA Mayo Foundation for Medical Education and Research Mayo Clin Proc. June 2008;83(6):

2 warts or papillomas in the upper respiratory tract, particularly the larynx, and that is associated with extensive morbidity (Table 1). RISK FACTORS Genital HPV infection is transmitted primarily by genital contact. Sexual activity remains the most consistent predictor of infection. In a study of women aged 18 to 25 years, HPV infection was found in 14.3% of women with 1 lifetime sex partner, in 22.3% of women with 2 lifetime sex partners, and in 31.5% of women with more than 3 lifetime sex partners. 6,9 In the 2002 National Survey of Family Growth, 24% of female respondents in the United States were sexually active by age 15 years, 40% by age 16 years, and 70% by age 18 years. The 2005 Youth Behavioral Risk Survey indicated that 3.7% of female students are sexually active before age 13 years. Of those sexually active, 5.7% of 9th-grade female students and 20.2% of 12th-grade female students had had at least 4 sex partners. 6 Acquisition of HPV infection occurs soon after onset of sexual activity. In a prospective study of college women in the United States, the cumulative probability of incident infection was 38.9% by 24 months after first sexual intercourse and more than 50.0% by 4 years. Of the 6.2 million new HPV infections each year, 74% occur among those aged 15 to 24 years. Modeling estimates suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years. In a study by Dunne et al 10 of population prevalence, overall prevalence of HPV (any type) was high at 26.8% in female participants aged 14 to 59 years, with nearly half of the cases occurring in those aged 20 to 24 years; however, combined prevalence of the 4 types (HPV-6, HPV-11, HPV-16, and HPV-18) targeted by the new vaccine was lower than expected at 3.4%. Human papillomavirus infection is also common among men, with a prevalence of more than 20% among heterosexual men. 6 If cumulative incidence rather than prevalence data were considered, these numbers might be even higher. A few prospective studies have shown that condoms help prevent genital HPV infection. For example, a study among newly sexually active college women showed that consistent and correct condom use reduced HPV infection by 70%. 11 Abstaining from sexual activity completely is the surest way to prevent infection. HPV VACCINE On June 8, 2006, the US Food and Drug Administration licensed the quadrivalent HPV vaccine by Merck and Co., Inc. Recombinant DNA technology is used to express the TABLE 1. Clinical Sequelae of Infection With HPV a Attributable to oncogenic Lesion HPV (%) Cervical cancers 100 b Anogenital cancers Anal 90 Vulvar 40 Vaginal 40 Penile 40 Oropharyngeal cancers 12 Anogenital warts (condyloma) 90 c Recurrent respiratory papillomatosis NA d a HPV = human papillomavirus; NA = not available. b HPV-16 and HPV-18 account for 70% of cases. HPV-6 and HPV-11. Mainly HPV-6 and HPV-11. L1 major capsid protein of HPV in yeasts (Saccharomyces cerevisiae), which self-assemble to form empty shells resembling a virus, called viruslike particles (VLPs). The VLPs have the same outer L1 protein coat as HPV but contain no genetic material. The vaccine uses these VLPs as antigens to induce a strong protective immune response; if an exposure occurs, the vaccinated person s antibodies against the L1 protein will coat the virus and prevent it from releasing its genetic material. Each 0.5-mL dose contains HPV-6, HPV-11, HPV-16, and HPV-18 L1 proteins. Available as a sterile suspension for injection in a single-dose vial or a prefilled syringe, the vaccine should be shaken well and administered intramuscularly into the deltoid muscle of the upper arm or higher anterolateral thigh as 3 separate 0.5-mL doses at 0, 2, and 6 months, with minimum intervals of 4 weeks between doses 1 and 2 and 12 weeks between doses 2 and 3. Four randomized, double-blind, placebo-controlled studies evaluated the efficacy of the HPV vaccine. A phase 2 study of a monovalent HPV-16 vaccine (protocol 005) and a phase 2 study of quadrivalent HPV-6/11/16/18 vaccine (protocol 007) evaluated the efficacy of the vaccine using an end point of persistent infection. Two phase 3 studies of the quadrivalent HPV vaccine (protocols 013 and 015) evaluated the efficacy of the vaccine on clinical lesions. Protocol 005 enrolled 2392 female participants aged 16 to 23 years (mean age, 20 years; 75.8% white) from 16 centers in the United States between October 1998 and November 1999; study participants were randomized to receive 3 doses of either placebo (1198 participants) or HPV-16 VLP vaccine (1194 participants). When persistent HPV-16 infection was taken as the primary end point, vaccine efficacy was shown to be 100% after median follow-up of 17.4 months. 12 A follow-up study 3.5 years after vaccination showed the vaccine to provide 100% protection against HPV-16 related cervical intraepithelial neopl asia (CIN) 2 and 3; efficacy against persistent infection decreased slightly to 94% (95% confidence interval [CI], 88%-98%) Mayo Clin Proc. June 2008;83(6):

3 TABLE 2. Summary Results of FUTURE I Trial a Vaccine Placebo No. of No. of % Efficacy Type of analysis participants Cases participants Cases (95% CI) Primary b Per-protocol susceptible population Cervical lesions (CIN 1-3 or AIS) (94-100) External anogenital and vaginal lesions (94-100) Unrestricted susceptible population Cervical lesions (CIN 1-3 or AIS) (92-100) External anogenital and vaginal lesions (87-99) Intention-to-treat population Cervical lesions (CIN 1-3 or AIS) (40-66) External anogenital and vaginal lesions (58-83) Second intention-to-treat c Cervical lesions (CIN 1-3 or AIS) (8-31) External anogenital and vaginal lesions (15-49) a AIS = adenocarcinoma in situ; CI = confidence interval; CIN = cervical intraepithelial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus. b Evaluated lesions associated with vaccine-type HPV. c Evaluated lesions associated with any HPV type. Protocol 007 assessed the efficacy of the quadrivalent vaccine targeting HPV-6, HPV-11, HPV-16, and HPV-18 in 1158 female participants aged 16 to 23 years (mean age, 20; 78% white) randomized to receive vaccine (277 participants) or placebo (275 participants). 14 Combined incidence of persistent infection with HPV-6, HPV-11, HPV- 16, or HPV-18 or associated cervical or genital disease, the primary end point of the study, decreased by 90% (95% CI, 71%-97%, P<.0001) in the vaccinated group. Interim analysis from this study 14 established the vaccine dosage used in the phase 3 studies. Once made available by the Centers for Disease Control and Prevention, the interim analyses from these larger, international phase 3 trials (including approximately 1.5 years of follow-up data) were used as part of the application for vaccine licensure. Further analyses, including an additional year of follow-up from the interim analyses, were published in 2007, known as Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I 15 and II. 16 In the ongoing, randomized placebo-controlled, double-blind FUTURE I trial, 5455 female participants aged 16 through 24 years (mean age, 20 years) were enrolled from 62 study sites in 16 countries from January 2002 through March 2003, randomized to receive vaccine (2723 participants) or placebo (2732 participants), and followed up for an average of 3 years after first vaccine dose. The vaccine showed 100% efficacy (95% CI, 94%-100%) against both cervical lesions and external anogenital and vaginal lesions in the per-protocol population. The term per-protocol population refers to participants who completed the vaccination regimen, did not violate protocol, were seronegative, and had negative findings on polymerase chain reaction for the HPV strains in the vaccine through 1 month after the third vaccine dose. In an unrestricted susceptible population that included all women who were seronegative and who had negative findings on polymerase chain reaction at baseline, some of whom might have violated protocol, vaccine efficacy was found to be 98% (95% CI, 92%-100%) against cervical lesions and 95% (95% CI, 87%-99%) against external anogenital and vaginal lesions. Vaccine efficacy was also estimated in an intention-to-treat population that included all participants who had undergone randomization regardless of their baseline HPV status, with efficacy of 55% (95% CI, 40%-66%) against cervical lesions and 73% (95% CI, 58%-83%) against external anogenital and vaginal lesions. A second intention-to-treat analysis was done to evaluate lesions associated with any HPV type; vaccine efficacy was found to be 20% (95% CI, 8%-31%) against cervical lesions and 34% (95% CI, 15%-49%) against external anogenital and vaginal lesions (Table 2). The study concluded that the quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. 15 FUTURE II examined vaccine efficacy against highgrade cervical lesions associated with HPV-16 and HPV-18. In this large, randomized placebo-controlled, double-blind trial, 12,167 female participants aged 15 through 26 years (mean age, 20 years) at 90 study sites in 13 countries were enrolled from June 2002 through May 2003, randomized to receive vaccine (6087 participants) or placebo (6080 participants), and followed up for an average of 3 years after the first vaccine dose. Similarly, in the per-protocol susceptible population, vaccine efficacy against CIN 2 and 3 or adenocarcinoma in situ was high at 98% (95% CI, 86%- 100%). Vaccine efficacy was 95% (95% CI, 85%-99%) in the unrestricted susceptible population, 44% (95% CI, 26%- 58%) in the intention-to-treat population, and 17% (95% CI, Mayo Clin Proc. June 2008;83(6):

4 TABLE 3. Summary Results of FUTURE II Trial a Vaccine Placebo No. of No. of % Efficacy Type of analysis participants Cases participants Cases (95% CI) Primary b Per-protocol susceptible population CIN 2 and 3 or AIS (86-100) Unrestricted susceptible population CIN 2 and 3 or AIS (85-99) Intention-to-treat population CIN 2 and 3 or AIS (26-58) Second intention-to-treat c CIN 2 and 3 or AIS (1-31) a AIS = adenocarcinoma in situ; CI = confidence interval; CI N = cervical intraepithe lial neoplasia; FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; HPV = human papillomavirus. b Evaluated lesions associated with HPV-16, HPV-18, or both. c Evaluated lesions associated with any HPV type. 1%-31%) in the second intention-to-treat analysis. When administered to those who had not been previously exposed to either HPV-16 or HPV-18, the HPV vaccine was highly effective in preventing related CIN 2 and 3 and adenocarcinoma in situ (Table 3). 16 In other words, the quadrivalent vaccine is prophylactic, not therapeutic. No evidence exists of protection against disease caused by vaccine types for which participants had positive results on polymerase chain reaction at baseline. Participants with positive results to 1 or more vaccine HPV types before vaccination were protected against disease caused by the other vaccine types. DURATION OF PROTECTION AND IMMUNOGENICITY Antibody titers of HPV-16 gradually decline after the third dose but appear to plateau by 24 months. At 36 months, anti HPV-16 geometric mean titers in vaccinees remained higher than those in the placebo group who were seropositive at baseline (vaccination produced antibody titers higher than those after natural infection). 17 No minimum protective titer has been determined. In a combined analysis of all participants through year 3 and a subset through 60 months, efficacy against vaccine-hpv type persistent infection or disease was 95.8% (95% CI, 83.8%-99.5%) and efficacy against vaccine-type related CIN or external genital lesions was 100% (95% CI, 12.4%-100%). 6,18 Longer follow-up studies are under way. To evaluate how the vaccine would perform in younger patients, immunogenicity studies in female children aged 9 to 15 years were conducted. 6,19 Anti-HPV responses in these patients were no lower after the third dose than those of female patients aged 16 to 26 years. In fact, at month 18, anti-hpv geometric mean titers in the younger patients remained 2 to 3 times higher than those in the older patients. SAFETY PROFILE Safety data on quadrivalent HPV vaccine are available from 7 clinical trials including 11,778 vaccine recipients and 9686 placebo recipients aged 9 to 26 years. Additional details were collected in a subset of patients randomized to receive either vaccine (5088 patients) or placebo (3790 patients) using report cards for 14 days after each injection. Injection site pain was the most common adverse event (in 83.9% of vaccinees vs 75.4% receiving aluminumcontaining placebo and 48.6% receiving saline placebo), followed by swelling (25%) and erythema (25%). Common systemic adverse effects included fever, nausea, and fainting, with similar occurrences in both vaccine and control groups. Most adverse events were mild to moderate. Serious adverse events occurred in less than 0.1% of patients (bronchospasm, gastroenteritis, headache with hypertension, vaginal hemorrhage, and injection site pain or impaired movement). In overall safety evaluation, 10 vaccine and 7 placebo recipients died during the course of the trials; none of the deaths was considered to be vaccine related. 6,19 The HPV vaccine is currently not licensed for use in female patients younger than 9 years or older than 26 years or for use in male patients. It is contraindicated in people with history of immediate hypersensitivity to yeast or to any vaccine component. The vaccine should be deferred in patients with moderate or severe acute illnesses. Patients should be observed for syncope for 15 minutes after vaccine administration. The vaccine is also not recommended for use in pregnant women. Although it has not been causally associated with adverse outcomes of pregnancy, data are limited. The vaccine is classified as Category B on the basis of animal studies in rats showing no evidence of impaired fertility or harm to the fetus. Any exposure to the vaccine during pregnancy must be reported to the vaccine 704 Mayo Clin Proc. June 2008;83(6):

5 pregnancy registry ( ). Lactating women can receive the HPV vaccine. Immunosuppressed female patients can receive the vaccine, but its efficacy and the degree of immune response it elicits could be poorer in this population. 19 ECONOMIC IMPACT The prevention and treatment of anogenital warts and cervical HPV-related disease imposes an estimated burden of more than $4 billion (2004 dollars) in direct costs in the United States each year, with $200 million attributable to management of genital warts, $300 to $400 million to treatment of invasive cervical cancer, and the remainder to routine cervical cancer screening, follow-up of abnormal Pap tests, and preinvasive cervical cancer. These figures do not include the costs of other HPV-related diseases (eg, vaginal and anal cancers, RRP). Markov models have suggested that vaccination of an entire cohort of female patients aged 12 years could significantly reduce lifetime risk of cervical cancer, as well as decrease Pap test abnormalities and cervical cancer precursor lesions. Models that incorporate HPV transmission dynamics suggest that vaccination could have an even greater effect. Since 2003, 4 studies have estimated the potential cost-effectiveness of routine HPV vaccination of female patients aged 12 years to range from $3000 to $24,300 per quality-adjusted life-year (QALY). 6 For example, one of the Markov model studies assumes 100% vaccine coverage with 90% vaccine efficacy against HPV-16 and HPV-18 and lifetime duration of protection at a cost of $377 per vaccine series; under these assumptions, an estimated 58% reduction in lifetime risk of cervical cancer for the vaccinated cohort would be achieved at a cost of $24,300 (2002 dollars) per QALY compared with no vaccination. Dynamic transmission models incorporating benefits of vaccination on HPV transmission in the population (herd immunity) can be used with varying assumptions. If one assumes inoculation at age 12 years with a targeted HPV-16 and HPV-18 vaccine ($300 per series) with 90% efficacy and 10-year duration of protection plus 10 additional years with a booster dose ($100 per booster), lifetime risk for cervical cancer among vaccinated female patients would be reduced by 62% at a cost per QALY of $14,600 (2001 dollars). A 75% reduction in cervical cancer at a cost of $3000 per QALY (in 2005 dollars) would be projected if one assumed inoculation at age 12 years or younger with an HPV-6/11/16/18 vaccine (average cost, $360 per series) that has 90% efficacy against infection and 100% efficacy against HPV-related diseases attributable to the targeted HPV types with lifelong duration of protection and 70% vaccine coverage. 6 The current market price of $360 for the vaccine series does fall within the range estimates used in these models; however, cost of vaccine administration, including physician s visits, increases actual cost. SUMMARY RECOMMENDATIONS The Advisory Committee on Immunization Practices currently recommends routine vaccination of female patients aged 11 to 12 years with 3 doses of the quadrivalent HPV vaccine. Vaccination can be given to female patients as young as 9 years, as well as to female patients aged 13 to 26 years who have not previously completed vaccination. Pap testing and screening for HPV DNA or HPV antibody before vaccination is not needed. Routine cervical cancer screening should be continued. 6 The American College of Obstetricians and Gynecologists recommends that HPV vaccination be offered to all female patients aged 9 to 26 years who have not been previously vaccinated and also emphasizes continued regular cervical cytology screening. 20 In contrast, the American Cancer Society does not consider existing evidence to be sufficient to recommend or warn against routine vaccination for women older than 18 years. Because women aged 19 to 26 years are more likely to have been exposed already to HPV, the American Cancer Society suggests that the decision to vaccinate women in this age range should be made on an individual basis. 4 LEGISLATION Three months after the Food and Drug Administration licensed Merck s HPV vaccine, Michigan lawmakers began proposing that vaccination be compulsory for girls entering the sixth grade. In February 2007, Texas became the first state to mandate it; however, this order was later overridden. At least 24 states and the District of Columbia have introduced legislation to specifically mandate the HPV vaccine for school. 21 Opponents of mandatory inoculation include antivaccine activists who argue that the vaccine has not been sufficiently tested in young girls, conservative Christian groups who oppose mandatory HPV vaccinations on moral grounds, and those generally distrustful of the pharmaceutical industry. 22 FURTHER STUDIES More research is needed regarding duration of protective immunity and need for booster, fu rther monitori ng for HPVassociated lesions, effect on prevalence and incidence of HPV types included in the vaccine, general safety and pregnancy outcomes, safety and immunogenicity of simultaneous administration with other vaccines, efficacy in female patients older than 26 years and in male patients, effect on cervical cancer screening prac tices and on saf e sex behavior, and further economic analysis. A bivalent vaccine directed against HPV-16 and HPV-18 by GlaxoSmithKline is expected to be on the market some time in Also Mayo Clin Proc. June 2008;83(6):

6 administered in 3 doses (at 0, 1, and 6 months), it has been reported to be highly immunogenic and safe. 23,24 Head-tohead trials are reportedly planned. CONCLUSION Human papillomavirus infection is the most common sexually transmitted infection in the United States. Persistent infection with high-risk types can lead to precancerous and cancerous lesions. The new quadrivalent HPV vaccine appears to confer a high degree of protection against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts. If the vaccine s duration of protection proves to be sufficient or can be maintained through booster vaccinations at costeffective levels, we can anticipate promising results with population-wide vaccination. REFERENCES 1. National Cancer Institute, US National Institutes of Health. Human papillomaviruses and cancer: questions and answers. /cancertopics/factsheet/risk/hpv. Accessed April 28, US Food and Drug Administration. FDA licenses new vaccine for prevention of cervical cancer and other diseases in females caused by human papillomavirus: rapid approval marks major advancement in public health. FDA News 2006 June 8. /NEW01385.html. Accessed April 28, American Cancer Society. Detailed guide: cervical cancer: what are the key statistics about cervical cancer? Revised Aug 4, _statistics_for_cervical _cancer_8.asp?sitearea=. Accessed May 7, Saslow D, Castle PE, Cox JT, et al, Gynecologic Cancer Advisory Group. American Cancer Society guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007;57(1): Pagliusi S, World Health Organization. Human papillomavirus infection and cervical cancer. Accessed April 28, Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2): /rr5602a1.htm. Accessed Apr 28, Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998; 338(7): D Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19): Manhart LE, Holmes KK, Koutsky LA, et al. Human papillomavirus infection among sexually active young women in the United States: implications for developing a vaccination strategy. Sex Transm Dis. 2006;33 (8): Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007;297(8): Winer RL, Hughes JP, Feng Q, et al. Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med. 2006;354 (25): Koutsky LA, Ault KA, Wheeler CM, et al, Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347(21): Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus- 16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial [published correction appears in Obstet Gynecol. 2006;107(6): 1425]. Obstet Gynecol. 2006;107(1): 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. 2005;6(5): Garland SM, Hernandez-Avila M, Wheeler CM, et al, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against the human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356(19): The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356 (19): Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine Jul 7;24(27-28): Epub 2006 May Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 viruslike particle vaccine though 5 years of follow-up. Br J Cancer Dec 4; 95(11): Epub 2006 Nov Gardasil [human papillomavirus quadrivalent (types 6,11,16,18) vaccine, Recombinant] [package insert]. Whitehouse Station, NJ: Merck & Co; Accessed Apr 28, American College of Obstetricians and Gynecologists. HPV Vaccine ACOG Recommendations. Accessed April 28, National Conference of State Legislatures. HPV vaccine legislation Updated Feb, Accessed April 28, Colgrove J. The ethics and politics of compulsory HPV vaccination. N Engl J Med. 2006;355(23): Harper DM, Franco EL, Wheeler CM, et al, HPV Vaccine Study Group. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367(9518): Paavaonen J, Jenkins D, Bosch F, et al, HPV PATRICIA Study Group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial [published correction appears in Lancet. 2007;370(9596):1414]. Lancet. 2007; 369(9580): CME Questions About HPV Vaccine 1. Which one of the following best describes the percentage of genital warts and cervical cancers covered by the quadrivalent vaccine s protection against HPV-6, HPV-11, HPV-16, and HPV-18? a. 70% of genital warts and 90% of cervical cancers b. 90% of genital warts and 70% of cervical cancers c. 30% of genital warts and 50% of cervical cancers d. 50% of genital warts and 30% of cervical cancers e. 100% of both genital warts and cervical cancers 2. Which one of the following is the most common mode of HPV transmission? a. Vertical transmission from mother to newborn b. Fecal-oral transmission c. Blood products d. Airborne vectors e. Genital contact 706 Mayo Clin Proc. June 2008;83(6):

7 3. Which one of the following is the most common adverse effect of the quadrivalent HPV vaccine? a. Injection site pain b. Nausea c. Swelling d. Erythema e. Myalgia 4. In which one of the following population groups do current guidelines recommend use of the quadrivalent HPV vaccine? a. Girls younger than 9 years b. Women older than 26 years c. Routine administration to girls aged 9 to 12 years; can be given up to age 26 years d. Newborns e. Male patients 5. Which one of the following statements is false? a. The HPV vaccine is prophylactic, not therapeutic b. The HPV vaccine has been shown to have an efficacy of 95% or more among women who have no evidence of infection with the vaccine HPV type at time of vaccination c. For the greatest effect, the vaccine ideally should be administered before sexual debut d. Testing for HPV before vaccination is neither needed nor recommended e. Recommended routine Papanicolaou testing intervals are longer for vaccinated women This activity was designated for 1 AMA PRA Category 1 Credit(s). Because the Concise Review for Clinicians contributions are now a CME activity, the answers to the questions will no longer be published in the print journal. For CME credit and the answers, see the link on our Web site at mayoclinicproceedings.com. Mayo Clin Proc. June 2008;83(6):