CPhA

2007

Home Study Program

Human Papillomavirus Vaccine

Essential Information for Pharmacists
Janice Meisner, BSc(Pharm), PharmD

This program has been approved for 1.0 CEUs by the Canadian Council on Continuing Education in Pharmacy CCCEP #500-1206 This lesson is valid until January 15, 2010

EP
Suggested retail price: $15 plus GST for CPhA members, $25 plus GST for non-members. This lesson is available from the CPhA Online Learning Centre, with online marking at www.pharmacists.ca. If online access is not available to you, contact CPhA at 1-800- 917-9489.

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Lesson description

Learning objectives

ith approval in 2006 of a quadrivalent vaccine for human papillomavirus (HPV) in Canada, and the anticipated approval of a bivalent HPV vaccine in 2007, pharmacists will be faced with questions about vaccine safety and efficacy as well as about HPV and its connection with cervical cancer. This lesson will review the pathophysiology, epidemiology, transmission, complications, and prevention of HPV as well as the safety and efficacy of preventative vaccines in order to prepare community pharmacists with the answers to the questions of parents and young women. Case studies and post-lesson questions are utilized to reinforce the pharmaceutical care process.

hen you have completed this lesson, you should be able to:

state the clinical implications of infection with high- and low-risk HPV virus types describe how HPV is transmitted describe the natural history of HPV state the differences between the quadrivalent HPV vaccine and the bivalent HPV vaccine state the recommendations for the quadrivalent vaccine issued by the CDC discuss the effects of the HPV vaccine on cervical cancer screening programs

Disclaimer
e have done our best to produce an accurate, timely, and educational Learning Series. However, MediResource Inc., the Canadian Pharmacists Association, the sponsors, the authors, the reviewers, and the editors assume no responsibility for any errors or consequences arising from the use of information contained within this program. With the constant changes in practice and regional differences, it remains the responsibility of the

readers as professionals to interpret and apply this lessons information to their own practices. All rights reserved. For this lesson, in compliance with sections 10.2 and 10.3 of the Guidelines and Criteria for CCCEP Accreditation, the author, expert reviewers, and MediResource Inc. report no real or potential conflict of interest with their involvement in this lesson.

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Author
Janice Meisner, BSc(Pharm), PharmD Janice has a BSc(Pharm) and hospital residency certificate from Dalhousie University and a PharmD from the University of Toronto. Janice has over 15 years of experience in retail, hospital, and industrial pharmacy and has clinical experience in oncology, infectious disease, and ambulatory care. Janice practiced at The Halifax Infirmary and The Montreal General where she provided clinical services in oncology and infectious disease. Janice also gained additional experience in these areas through the clinical rotations as part of the Doctor of Pharmacy program. Janice has diverse experience in teaching both at the undergraduate level and through continuing education lectures. At Dalhousie University, Janice taught an undergraduate course and acted as a preceptor for many students. She also held an Adjunct professor position at Dalhousie University and Memorial University from 1998 until 2002. During her career in the pharmaceutical industry, Janice conducted many lectures in the area of health economics for pharmacists across the country. Currently, Janice provides consultative services in the areas of continuing medical and pharmacy education and health economics.

Expert reviewers
Zubin Austin, BScPhm, MBA, MISc, PhD Zubin Austin is Assistant Professor at the Leslie Dan Faculty of Pharmacy, University of Toronto. He is coordinator of introductory courses in clinical pharmacology and senior level courses in pharmacy practice. He is also a clinical pharmacist working at Mount Sinai Hospital. He has experience working in both ambulatory and family medicine practices, and has worked with health promotion teams working with at-risk populations. He is currently an investigator in the IMPACT (Integrating family Medicine and Pharmacy to Advance primary Care Therapeutics) project, a primary health care transitions fund project examining collaboration between physicians and pharmacists in family health teams. Kathryn Slater, BScPharm, PharmD Dr. Kathy Slayter is currently Assistant Professor, Faculties of Medicine and Health Professions, and Clinical Pharmacy Specialist with the Division of Infectious Diseases, Department of Medicine at the Queen Elizabeth II Health Sciences Centre. She provides care to inpatients through the Infectious Diseases Consult Service and at the HIV and hepatitis C outpatient clinics, and she is a consultant for the sexually transmitted diseases clinic. Kathy has a very keen interest in the area of vaccinology and is the primary investigator on a national study of pneumococcal conjugate vaccine in HIV-infected individuals. In addition, she is on the Editorial Board for Immunizations for the Compendium of Pharmaceuticals and Specialities (CPS) and on the Editorial Advisory Board for the Ontario Anti-infective Guidelines for the Treatment of Community-Acquired Infections (which inclues sexually transmitted diseases). Finally, Kathy is a reviewer for the vaccine, infectious diseases, and HIV chapters for Therapeutic Choices 2007. She has done numerous presentations on immunizations and infectious diseases.

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Contents
1 1 1 1 1 2 2 3 3 4 5 5 1. Introduction 2. Primer on HPV and cervical cancer 2.1 HPV types, epidemiology, transmission and natural history Table 1. Epidemiologic classification of HPV types Figure 1. Cumulative percentages and numbers of cervical cancer cases attributed to the most frequent HPV genotypes 2.2 Cervical cancer epidemiology, classification, and natural history Figure 2. The natural history of HPV infection and cervical cancer 3. HPV vaccines Gardasil and Cervarix Table 2. Descriptive diagnoses from cytology-based screening (Pap test) 3.1 Safety and efficacy of Gardasil Table 3. Clinical trial efficacy of Gardasil Table 4. Clinical trial efficacy of Gardasil

6 3.2 Safety and efficacy of Cervarix 6 Table 5. General population impact for Gardasil 7 3.3 Practical application of clinical trial results 7 Table 6. Clinical trial efficacy for Cervarix 7 Table 7. Overview of combined initial and extended follow-up Cervarix efficacy against cytological abnormalities 8 3.4 Cost-effectiveness considerations 8 3.5 Reminder on vaccine cold chain 9 4. Centers for Disease Control and Prevention statement on HPV vaccine recommendations 9 4.1 Cervical cancer screening is still required in vaccinated women 9 5. HPV myths 10 6. Unresolved issues 10 6.1 Duration of vaccination immunity 10 6.2 Vaccination of males 10 6.3 Developing countries 10 7. Summary 10 References 12 Questions

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1. Introduction

uman papillomavirus (HPV) is a common sexually transmitted virus that causes benign genital warts and virtually all cases of cervical cancer.13 Although most infections are self-limiting, persistent infection with certain types of HPV is associated with the development of cervical and other anogenital cancers.46 In 2006, a three-dose quadrivalent HPV vaccine was approved for use in females 9 to 26 years of age in Canada and the United States, as well as other countries around the world. The quadrivalent vaccine immunizes against four types of HPV (HPV 16, 18, 6, and 11). HPV 16 and HPV 18 are causal agents in about 70% of cervical cancer cases,3,7,8 while HPV 6 and HPV 11 are responsible for more than 90% of cases of genital warts.9 A second vaccine, bivalent against HPV 16 and 18, is anticipated in 2007. Public awareness of HPV and its association with cervical cancer is increasing. The pharmacist is well placed to assist patients in accessing and interpreting information on HPV, cervical cancer, and vaccination.

a prescription for her asthma, you see her pick up one of the pamphlets you have on HPV, genital warts, and cervical cancer. If Chantal were to ask you about the natural history of HPV and how it might affect her life, what information would you need to know?

2. Primer on HPV and cervical cancer

2.1 HPV types, epidemiology, transmission and natural history

Case 1

hantal is a 35-year-old woman who is well informed about health issues. She often asks your advice and opinion on diverse issues of health, natural remedies, and nutrition. One day, while Chantal is waiting for

Table 1. Epidemiologic classification of HPV types3,5

High-risk 16, 18, 31, 33, 35, 39, 45, 51, 52, (i.e., carcinogenic) 56, 58, 59, 68, 73, and 82 Probably high-risk Low-risk Undetermined risk 26, 53, and 66 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81 34, 57, and 83

More than 100 different HPV genotypes have been defined, of which about 40 infect the genital tract.10 Genital HPV types are classified as low- or highrisk by their tendency to cause cervical cancer.1113 Low-risk types, typified by HPV 6 and HPV 11, produce benign genital warts, condyloma acuminata.12 Genital HPV types do not cause common skin or plantar warts. High-risk types, most notably HPV 16 and HPV 18, are considered a necessary cause of cervical cancer.13,14 HPV 16 accounts for over half of all cervical cancers, while HPV 18 accounts for an additional 1220%.7,8 Together HPV 16 and HPV 18 account for about 70% of cervical cancers; see Figure 1. In addition to HPV 16 and HPV 18, there are at least 15 types of HPV known to be oncogenic; see Table 1.3,5 HPV is a highly contagious virus that is transmitted by skin-to-skin sexual contact with or without vaginal penetration.1517 HPV infects the mucosal areas of the cervix, vagina, vulva, and anus.18 It is considered the most prevalent sexually transmitted infection worldwide, with as many as 80% of Canadian women of reproductive age (and probably an equal percentage of men)5 having had an infection with HPV at some time in their lives.15 The Society of Obstetricians and Gynaecologists of Canada (SOGC) estimates that, at any given time, 1030% of the Canadian adult population is infected with HPV.15 Prevalence of HPV infection is highest for younger women and decreases in middle age; see Figure 2.6,1922 Infection generally occurs shortly

Figure 1. Cumulative percentages and numbers of cervical cancer cases attributed to the most frequent HPV genotypes (adapted from reference 8)
84.1% 85.6% 86.8% +56 +35 81.2%

cumulative percentage

65.4%

71.5% 77.1%

87.8%

genotypes

16

+18

+33

+31 +45

+52

No. of women: 428,848,000 No. of cases: 79,772 Human Papillomavirus Vaccine

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after initiation of sexual activity. In one study, 20% of young women became infected with HPV within 12 months of initiating sexual activity.16 Longitudinal research has consistently shown that the majority of HPV infections are resolved by the immune system such that HPV is no longer detectable within 12 years.5,18,19,22 Only about 1020% of HPV-infected women develop a persistent infection.5 Persistent infection is required in order for cervical cancer to develop.4,18,19 Infections with high-risk types of HPV persist longer than lowrisk infections. HPV 16 has been shown to persist longer than other types, and this may account for

its ability to cause cancer.2325 Persistent HPV infection accounts for the rise in prevalence of cervical cancer in later years, some 1015 years after the peak of HPV infection prevalence; see Figure 2. However, time to progression from HPV infection to pre-malignant lesions is highly variable, with a significant fraction of cases occurring within the first years of persistency.22

2.2 Cervical cancer epidemiology, classification, and natural history

In Canada in 2001, more than 1350 women were diagnosed with cervical cancer and 400 women

Figure 2. The natural history of HPV infection and cervical cancer (reprinted with permission from reference 6)

Viral persistence and progression Normal HPV-infected Precancerous cervix cervix lesion Regression Clearance HPV

Cancer Invasion

Precancer

Cancer

15 years

30 years

45 years

Pap tests

HPV vaccination

HPV test 1 HPV test 2

The peak prevalence of transient infections with carcinogenic types of HPV (blue line) occurs among women during their teens and 20s, after the initiation of sexual activity. The peak prevalence of cervical precancerous conditions occurs approximately 10 years later (green line), and the peak prevalence of invasive cancers occurs at 40 to 50 years of age (red line). (The peaks of the curves are not drawn to scale.) The conventional model of cervical-cancer prevention is based on repeated rounds of cytologic examination, including Papanicolaou smears, and colposcopy (small blue arrows). Alternative strategies include HPV vaccination of adolescents (large beige arrow), one or two rounds of HPV screening at the peak ages of treatable conditions and early cancer (large reddish-brown arrows), or both. Human Papillomavirus Vaccine
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Table 2. Descriptive diagnoses from cytology-based screening (Pap test)28

1. atypical squamous cells of undetermined significance (ASCUS) 2. low-grade squamous intraepithelial lesion (LSIL) cervical intraepithelial neoplasia (CIN 1) 3. high-grade squamous intraepithelial lesion (HSIL) cervical intraepithelial neoplasia 2 (CIN 2) cervical intraepithelial neoplasia 3 (CIN 3) 4. squamous cell carcinoma died from it.26 After breast cancer, cervical cancer is the most common cancer in Canadian women between the ages of 20 and 44.27 Cytology-based cervical screening with Papanicolaou (Pap) testing, introduced some 50 years ago, decreased the incidence of cervical cancer by up to 75% in countries able to implement and sustain good screening programs.5 Then in the 1980s the link was made between HPV and cervical cancer.5 Currently, we have the benefit of 20 years of biologic and epidemiologic research that has clearly demonstrated that infection with specific carcinogenic types of HPV is essential for the development of cervical cancer.13,7,8,1114 Some 1218 types of HPV are classified as known human carcinogens, with HPV 16 and 18 accounting for approximately 70% of squamous cell cervical cancers and 86% of adenocarcinomas3,7,8; see Figure 1. HPV is also implicated in a considerable proportion of the cancers of the vulva, vagina, anal canal, perianal skin, and penis.11 Furthermore, HPV likely plays a role in nonmelanoma skin cancers and oral cavity cancers.11 Several pre-malignant stages can be identified with Pap testing before the development of invasive carcinoma, including cervical intraepithelial neoplasia grades 1-3 (CIN 1-3); see Table 2. The majority of CIN 1 lesions regress spontaneously and only a few lesions persist or progress to CIN 2/3 and invasive carcinoma.5 Squamous cell cervical cancer is the most common cervical cancer. The other histologic type of cervical cancer is cervical adenocarcinoma and its precursor lesion adenocarcinoma in situ (AIS). In an international survey of cervical cancer specimens, 96% of cervical cancers were squamous cell and 6% were adenocarcinoma.8 Thus, it has been established that HPV is a necessary cause of cervical cancer.13,7,8,1113 The concept of necessary cause means that cervical cancer does not and will not develop in the absence of the persistent presence of HPV. That being said, it is essential to understand that while persistent HPV infection is a necessary cause of cervical cancer, HPV alone is not a sufficient cause cofactors are necessary for

progression from cervical HPV infection to cancer.14 Established cofactors are high parity, smoking, and long-term use of oral contraceptives. Other possible cofactors include infection with Chlamydia trachomatis, herpes simplex virus-2, immunosuppression, and certain dietary deficiencies.4

Case 1 contd
When Chantals prescription is ready, she takes the opportunity to ask you about the HPV pamphlet. She understands that HPV infection is the most commonly sexually transmitted disease worldwide and that persistent HPV infection causes cervical cancer. She asks what her signs and symptoms would be if she indeed had a persistent infection with HPV. You are able to tell Chantal that most women are exposed to HPV shortly after becoming sexually active and most infections spontaneously clear on their own and do not go on to cause cancer. You are also able to tell her that while HPV infection may cause noticeable genital warts, many infections are not noticeable at all, even persistent infections. The way women know if they have a persistent infection is by having regular Pap tests according to the frequency recommended by their family doctor. The Pap test is intended to pick up the cell changes that occur with persistent HPV infection long before they go on to become cervical cancer.

3. HPV vaccines Gardasil and Cervarix

In Canada, the US, and other countries around the world, a quadrivalent HPV vaccine (Gardasil, Merck and Co., Inc.) has recently been approved for use in girls and young women ages 9 through 26 for the prevention of infection caused by HPV types 6, 11, 16, and 18 and the following diseases associated with these HPV types29: cervical cancer vulvar and vaginal cancer genital warts (condyloma acuminata) cervical adenocarcinoma in situ (AIS) cervical intraepithelial neoplasia (CIN) grade 2 and grade 3 vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3 vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 cervical intraepithelial neoplasia (CIN) grade 1 A second vaccine, bivalent against HPV 16 and 18, is expected in 2007 (Cervarix, GlaxoSmithKline).30

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Both vaccines are manufactured using recombinant technology to produce virus-like particles that resemble the L1 protein on the outer capsule of the virus.13,31 These virus-like particles are recognized by the immune system, resulting in antibody levels that are substantially greater than those produced during natural infections.5,31 The virus-like particles are able to elicit an immune response specific to the HPV type, yet because they are devoid of any viral nucleic acid, they are completely non-infectious and non-replicating.13,31 Safety and efficacy trials have been conducted with both vaccines. In order to critically evaluate the clinical trials, the following points are useful: 1. For practical and ethical reasons, end-points used in clinical trials are surrogates for the end-point of cervical cancer. These surrogate end-points include HPV infection, through the detection of antibodies or viral DNA, HPV persistence, through the detection of infection over a specified number of evaluations, and cervical, vaginal, and vulvar low- and high-grade lesions detected through Pap test and vaginal/ external genital samples. Since many HPV infections spontaneously resolve, HPV persistence is a more relevant outcome than infection, assuming an adequate duration of observation.6 And since many lesions can spontaneously regress, higher-grade lesions (CIN 2/3, AIS) are more relevant than low-grade lesions with respect to cervical cancer, again assuming an adequate duration of observation.6 All lesions are relevant when considering cost-effectiveness as all lesions require follow-up and/or treatment. The occurrence of genital warts is a relevant endpoint with respect to esthetics and cost-effectiveness, since these lesions require treatment and sometimes recur after treatment. The occurrence of genital warts is only relevant to the quadrivalent vaccine, since the bivalent vaccine does not protect against HPV 6 and 11, which are responsible for 90% of genital warts. 2. Exclusion criteria are different in the design of the quadrivalent and bivalent vaccine trials. The quadrivalent vaccine trials did not pre-screen women before enrolment. As a result, women who were positive for HPV antibodies and/or DNA for HPV types 6, 11, 16, and/or 18, as well as other high-risk types, were enrolled in the quadrivalent vaccine trials and analyzed separately from HPV-nave women. This design provides useful information with respect to generalizability and duration of immunity. The bivalent vaccine trials pre-screened and excluded prior to enrolment women positive

for HPV 16 or 18 and also for 12 other high-risk HPV types including types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Women positive for HPV types 16 and 18 on the initial trial visit (i.e., who were negative at pre-screening but positive at the time of enrolment) were analyzed separately from the HPV-nave women. 3. Efficacy measures in the clinical trial are of three types: According-to-protocol, where women were nave to the vaccine-relevant HPV type at enrolment, remained free of infection with HPV types contained in the vaccine through the completion of the vaccination regimen, and received all 3 doses of vaccine or placebo within 1 year of enrolment, and where evaluation of cases started at 1 month after the third dose (month 7); Intention-to-treat, where women were nave to the vaccine-relevant HPV type on day 1 and received at least 1 dose, and where evaluation of cases started at day 1 or 1 month after day 1; General-population, where women were both HPV-nave and HPV-infected/exposed at the time of enrolment. In the case of the quadrivalent vaccine, they were not prescreened for non-vaccine-related high-risk types. In the case of the bivalent vaccine, they were pre-screened and excluded for vaccine and non-vaccine-related high-risk types.

3.1 Safety and efficacy of Gardasil

The safety and efficacy of the quadrivalent vaccine was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical trials involving over 18,000 patients.29,3234 Overall, the combined efficacy in clinical trials demonstrated that the quadrivalent vaccine was 100% efficacious in preventing HPV16- or 18related high-grade cervical lesions, 95.2% efficacious in preventing HPV 6-, 11-, 16-, or 18-related low-and high-grade lesions, and 98.9% efficacious at preventing HPV 6-, 11-, 16-, or 18-related genital warts relative to placebo; see Table 3.29 These efficacy results were in women nave to vaccinerelated HPV types at enrolment, who remained HPV-nave throughout the vaccination period and who received all 3 doses within 1 year of enrolment. Efficacy was also evaluated in women nave to vaccine-related HPV types on day 1 and who received at least 1 dose. This is a more generalizable population than above. The quadrivalent vaccine was 98.8% effective at preventing HPV 16- or 18-related high-grade cervical lesions, 100% effective at preventing HPV 16- or 18-related

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Table 3. Clinical trial efficacy of Gardasil (adapted from reference 29)

Outcome/Study Gardasil n Number of cases Placebo n % Efficacy Number (95% CI) of cases

Women HPV-nave to HPV types 6, 11, 16, and 18 and who received all 3 doses within 1 year of enrolment HPV 16- or 18-related high-grade lesion Combined protocols HPV 6-, 11-, 16-, 18-related low- or high-grade lesion Combined protocols HPV 6-, 11-, 16-, or 18-related genital warts Combined protocols 8487 7858 7897 0 4 1 8460 7861 7899 53 100.0 (92.9, 100.0) 83 95.2 (87.2, 98.7) 91 98.9 (93.7, 100.0)

High-grade lesions = cervical intraepithelial neoplasia 2 or 3 (CIN 2/3) or adenocarcinoma in situ (AIS); Low-grade lesions = CIN 1.

Table 4. Clinical trial efficacy of Gardasil (adapted from reference 29)

Outcome Gardasil n Number of cases 1 0 9 9 Placebo n % Reduction Number (95% CI) of cases 81 98.8 (92.9, 100.0) 24 100.0 (83.3, 100.0) 143 93.7 (87.7, 97.2) 136 93.4 (87.0, 97.0)

Women HPV-nave to HPV 6, 11, 16, and 18 at day 1 and who received at least 1 vaccination HPV 16- or 18-related high-grade cervical lesion HPV 16- or 18-related high-grade vaginal or vulvar lesion HPV 6-,11-, 16-, 18-related low- and high-grade cervical lesions HPV 6-, 11-, 16-, or 18-related genital warts 9342 8641 8625 8760 9400 8667 8673 8786

Highgrade cervical lesions = cervical intraepithelial neoplasia 2 or 3 (CIN 2/3) or adenocarcinoma in situ (AIS); Low-grade cervical lesions = CIN 1.

vaginal or vulvar high-grade lesions, 93.7% effective at preventing HPV 6-, 11-, 16-, or 18-related low- and high-grade lesions, and 93.4% effective at preventing HPV6-, 11-, 16-, or 18-related genital warts relative to placebo; see Table 4.29 Finally, the quadrivalent vaccine was assessed in the general population of women all of whom received at least 1 vaccination on day 1 regardless of HPV status (i.e., both nave and non-nave to vaccine-related HPV types and other high-risk types). The quadrivalent vaccine was found to decrease the incidence of HPV 16- or 18-related high-risk cervical lesions by 39%, HPV 16- or 18related high-risk vaginal or vulvar lesion by 69%, HPV 6-, 11-, 16-, or 18-related low- or high-grade lesions by 46.4% and HPV 6-, 11-, 16-, or 18-related genital warts by 68.5%.29 In this population the quadrivalent vaccine reduced the incidence of surgical excision of high-grade cervical lesions by 16.5% and surgery to excise external genital lesions by 26.5% compared to placebo for all HPV-related diseases; see Table 5.29

The studies mentioned above were conducted in young women aged 16 to 26 years at the time of enrollment. In order to bridge the efficacy results to girls and boys aged 9 to 15 years, immunogenicity studies were conducted.29 The quadrivalent vaccine was administered at 0, 2, and 6 months. Antibody titres against each HPV type were measured. In both boys and girls, the geometric mean titres for antibodies against all vaccine HPV types were higher than those achieved in the Phase III studies. Based on these results, the efficacy in 9- to 15-yearold girls is considered comparable. Efficacy in boys is still being investigated in further trials. In published clinical trials, the quadrivalent vaccine appears to be safe and generally well tolerated, though long-term data are currently not available.30,34 The most common adverse event reported in clinical trials was mild-to-moderate pain and swelling at the injection site, 15 days after the administration of the vaccine.29 Pain, swelling, and redness was experienced in over 80%, 25%, and 25% of patients, respectively, compared with 49%,

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Table 5. General population impact for Gardasil (adapted from reference 29)
Endpoints Analysis Gardasil n Cases HPV 16- or18-related high-grade HPV 16- and/or cervical lesion 18-positive at day 1 Gen pop impact* HPV 16- or 18-related highgrade vaginal or vulvar lesion HPV 16- and/or 18-positive at day 1 Gen pop impact* HPV 6-, 11-, 16-, 18-related lowor high-grade lesion HPV 6-, 11-, 16-, and/or 18-positive at day 1 Gen pop impact* HPV 6-, 11-, 16-, or 18-related genital warts HPV 6-, 11-, 16-, and/or 18-positive at day 1 Gen pop impact* 9831 8954 8814 8954 121 122 8 8 161 170 49 58 Placebo n Cases 9896 8962 8846 8962 120 201 2 26 174 317 48 184 68.5 (57.5, 77.0) 46.4 (35.2, 55.7) 69.1 (29.8, 87.9) 39.0 (23.3, 51.7) % Reduction (95% CI)

*General population impact Includes all subjects who received at least 1 vaccination (regardless of baseline HPV status at Day 1). Case counting started at 1 month post dose 1.

7%, and 12%, respectively, of those receiving saline injection. Systemic adverse events, including fever, headache, fatigue, and gastrointestinal symptoms, were reported in a similar proportion of vaccine and placebo recipients.29,34 The quadrivalent vaccine is contraindicated in patients who are hypersensitive to the active substances or to any of the excipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of quadrivalent vaccine should not receive further doses.29 The quadrivalent vaccine is intended for intramuscular injection as 3 separate 0.5 mL doses administered at 0, 2, and 6 months. Each dose contains approximately 20 g each of HPV 6 and HPV 18 L1 protein and 40 g each of HPV 11 and HPV 16 L1 protein. (L1 protein is the major capsid protein of the HPV virus.) It is supplied as single-dose vials and pre-filled syringes and requires shaking immediately before administration to maintain the suspension of the vaccine. Vials and pre-filled syringes are latex free. Gardasil is to be stored in the refrigerator between 2C and 8C, protected from freezing, and protected from light.

versity nearby and you see her often in your store. Her prescription file shows she has been taking the pill for at least 3 years. Apart from her birth-control prescription she has no other remarkable information in her file. Belinda tells you she has heard of the HPV vaccine and wonders if she is a candidate for vaccination. Given that she is on the pill, you mention that you are assuming she is sexually active. She tells you she has been sexually active for 3 years. What information can you offer to Belinda? Belinda may already have been exposed to HPV, as studies show that the highest prevalence is in women in the months and years after initiating sexual activity. The vaccine will not protect her from HPV types she might already have been exposed to, but will protect against any type contained in the vaccine to which she has yet to be exposed, assuming the three doses are administered as directed. Emphasize that regular cervical cancer screening (Pap testing) is still required in vaccinated women.

3.2 Safety and efficacy of Cervarix

Case 2

elinda is a 20-year-old woman who comes in to pick up her prescription for Alesse. She attends the uni-

Efficacy of the bivalent vaccine in the prevention of infection and persistence with HPV 16 and/or 18 was reported in a Phase II trial.35 The study enrolled 1113 women between the ages of 15 and 25 years. Women were eligible if they were cyto-

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Table 6. Clinical trial efficacy for Cervarix (adapted from reference 35)
Trial/Analysis Phase II35 HPV 16, 18 ATP analysis ITT analysis Incident HPV Infection, % (95% CI) 73.6 (49.786.1) p < 0.0001 67.6 (48.979.4) p < 0.0001 Persistent HPV Infection, % (95% CI) 100 (76.8100) p < 0.0001 87.5 (64.695.6) p < 0.0001 Cytologic Abnormalities, % (95% CI) 93.5 (51.39.1) p = 0.0002 (ASCUS/LSIL/HSIL)

ASCUS = atypical squamous cells of undetermined significance; ATP = according-to-protocol; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial lesions; ITT = intent-to-treat; LSIL = low-grade squamous intraepithelial lesions.

Table 7. Overview of combined initial and extended follow-up Cervarix efficacy against cytological abnormalities (adapted from reference 36)
HPV type HPV 16/18 Endpoint ASCUS LSIL CIN 1+ CIN 2+ Independent of HPV DNA status ASCUS LSIL CIN 1+ CIN 2+ Vaccine efficacy, % (95% CI) 95.7 (83.599.5) 92.6 (70.599.2) 100.0 (42.4100.0) 100.0 (-7.7100.0) 39.8 (20.954.4) 44.6 (17.463.3) 51.5 (-0.977.9) 73.3 (-1.095.2) p <0.0001 <0.0001 0.0035 0.0292 0.0002 0.0034 0.0418 0.0327

ASCUS = atypical squamous cells of undetermined significance; CIN 1+ = cervical intraepithelial neoplasia1, 2, 3, and invasive carcinoma; CIN 2+ = CIN2, CIN3, and invasive carcinoma; HPV = human papillomavirus; LSIL = low-grade squamous intraepithelial lesions.

logically negative, seronegative for HPV 16 and 18 antibodies, and DNA-negative for 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) within 90 days prior to enrollment. In women nave to all high-risk HPV types at the beginning of the study and in whom all 3 doses were administered according to the study protocol, the efficacy of the bivalent vaccine to prevent infection with HPV 16 and 18 was 73.6% compared to placebo. The efficacy of the bivalent vaccine to prevent persistent infection with HPV 16 and 18 was 100% in all samples compared to placebo. The efficacy of the bivalent vaccine to prevent cytologic abnormalities was 93.5% compared to placebo; see Table 6. In women nave to all high-risk HPV types at the beginning of the study and in whom at least 1 dose was administered, the efficacy of the bivalent vaccine to prevent infection with HPV 16 and 18 was 67.6%. The efficacy of the bivalent vaccine to prevent persistent infection with HPV 16 and 18 was 87.5%; see Table 6.

A long-term follow-up study enrolled 776 women for a mean follow-up time of 47.7 months.36 Vaccine-induced geometric mean titres at 5153 months were about 17-fold and 14-fold higher for HPV 16 and HPV 18 antibodies, respectively, than noted for natural infection. Efficacy against cytologic abnormalities according to lesion type and HPV type is presented in Table 7. The bivalent vaccine is also formulated with recombinant virus-like particles. Each dose contains 20 g each of HPV 16 and 18.35 Approval in Canada is expected in 2007. Cervarix uses a novel adjuvant, AS04, which has been reported to produce higher and persistent antibody titres, which may result in an enhanced immune response.36

3.3 Practical application of clinical trial results

A three-dose regimen of the quadrivalent or the bivalent vaccine has been shown to be highly efficacious in preventing HPV 16 and 18 persistent infections and related cervical lesions. The

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quadrivalent vaccine protects against infection and related lesions with HPV 16 and 18 and also HPV 6 and 11, the viruses most commonly associated with genital warts, and thus may be preferred by patients. Both vaccines are highly immunogenic, producing antibody titres well above that seen with natural infection. The bivalent vaccine has shown that immunogenicity and protection against infection is sustained up to 4.5 years. When generalizing clinical trial results to a broader population, some differences in study design are noteworthy. The bivalent trials prescreened and excluded any women positive for 14 high-risk HPV types, whereas the quadrivalent trials did not pre-screen. In both cases, the efficacy results are reported for HPV-nave women. The real-world population that most closely resembles this study group is girls and young women who are not yet sexually active. The clinical trials also present general population analyses (or analyses independent of HPV type status). These results would be appropriate when generalizing to a real-world population of young women who are sexually active.

by Goldie et al.40 An incremental cost-effectiveness ratio of less than US$60,000 per quality-adjusted life year was obtained with the model scenario of vaccinating girls at age 12 years with triennial conventional cytologic screening beginning at age 25 years. The model was sensitive to the frequency of cervical cancer screening, as this is the most costly aspect of cervical cancer prevention. Because genital warts caused by HPV 6 and 11 result in healthcare resource utilization for diagnosis and treatment, the cost-effectiveness of a vaccine against HPV 16, 18, 6, and 11 would be expected to be at least as cost-effective as a vaccine for HPV 16 and 18 alone.

3.5 Reminder on vaccine cold chain

3.4 Cost-effectiveness considerations

In Canada, the Cervical Cancer Screening Surveillance Report estimated that approximately 50% of women between the ages of 20 and 40 underwent an annual Pap test in 1998.38 The percentage of women with a low-grade and high-grade abnormality, respectively, was 13.7% and 1.4% in British Columbia, 4.5% and 1% in Ontario, and 2% and 0.5% in Nova Scotia.38 All women with an abnormal Pap test routinely undergo continued follow-up and/or outpatient surgical treatment, depending on the lesion.5 The annual health-care costs for HPV-related screening and treatment was assessed in a US healthcare setting.39 The overall annual cervical cancer prevention and treatment cost was US$26,415 per 1000 female enrollees, with routine cervical cancer screening accounting for 65% of the costs. The management of cervical precancers accounted for 17% of costs, while management of invasive cervical cancer and false-positive Pap tests accounted for 10% and 9% of costs, respectively. Introduction of HPV vaccines would be expected to decrease the amount of healthcare costs associated with the management of cervical pre-cancers and the management of invasive cervical cancer. The quadrivalent vaccine would also be expected to decrease healthcare costs associated with the diagnosis and excision of genital warts. The cost-effectiveness of a vaccine against HPV 16/18 vaccine in conjunction with an organized cervical cancer screening program was evaluated

The CDC has published guidelines for maintaining proper vaccine temperatures during storage and handling to preserve potency (i.e., maintaining the cold chain).41 As a brief reminder, for vaccines recommended to be stored at 28C, it is essential not to freeze the vaccines. Certain freeze-sensitive vaccines contain an aluminum adjuvant that precipitates when exposed to freezing temperatures, resulting in a loss of the adjuvant effect and vaccine potency. Vaccines should not be stored near the cold air outlet from the freezer to the refrigerator but rather stored centrally in the refrigerator compartment. Likewise, storage temperatures that are too warm can adversely affect vaccine potency. Vaccines that have been mishandled with respect to the cold chain should not be administered.

Case 3

rs. McDonald is with her 10-year-old daughter. They have just come from the pediatricians office next door and Mrs. McDonald is studying a pamphlet on the HPV vaccine. Mrs. McDonald is upset that her pediatrician would be recommending a vaccine against a sexually transmitted disease for her 10-year-old daughter. You are able to direct Mrs. McDonald to the Society of Obstetricians and Gynaecologists of Canada website15 and the CDC website,42 where all their recommendations can be viewed. While some parents may be apprehensive about the vaccine because of the association with sexual transmission, the focus is better placed on the fact that we now have a primary prevention for cervical cancer. In addition, while the guidelines from the CDC suggest vaccinating girls as young as 9, the parent needs to be aware that for maximum efficacy the three doses must be administered prior to the commencement of sexual activity. With this knowledge, some parents may choose to delay vaccination.

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4. Centers for Disease Control and Prevention statement on HPV vaccine recommendations
The Advisory Committee on Immunization Practices (ACIP) advises the Center for Disease Control (CDC) on the use of vaccines. The ACIP issued a recommendation for the quadrivalent vaccine.42 The ACIP recommends the following: The vaccine is recommended for 11- to 12-yearold girls, but can be administered to girls as young as 9 years of age. The vaccine is recommended for 13- to 26-yearold females who have not yet received or completed the vaccine series. Ideally, the vaccine should be administered before the onset of sexual activity. However, females who are sexually active also may benefit from vaccination. Females who have not been infected with any vaccine HPV type would receive the full benefit of vaccination. Females who already have been infected with one or more HPV type would still get protection from the vaccine types they have not acquired. The vaccine can be administered at the same visit as other age-appropriate vaccines, such as Tdap, Td, MCV4, and hepatitis B vaccines. Lactating women can receive the vaccine. Immunocompromised females, either from disease or medication, can receive the vaccine; however, the immune response to vaccination and vaccine efficacy might be less than immunocompetent females. The HPV vaccine is not recommended in pregnancy. The vaccine has not been causally associated with adverse outcomes of pregnancy or adverse events to the developing fetus. However, data on vaccination in pregnancy are limited, and any exposure to vaccine in pregnancy should be reported to the vaccine pregnancy registry (800-986-8999). The HPV vaccine is contraindicated for persons with a history of immediate hypersensitivity to yeast or any vaccine component. Cervical cancer screening recommendations have not changed for females who receive the HPV vaccine. The Society of Obstetricians and Gynaecologists of Canada (SOGC) are currently working on a clinical guideline on the appropriate usage of the vaccine, including information on screening, diagnosis, and treatment of HPV. The guideline is expected early in 2007.

4.1 Cervical cancer screening is still required in vaccinated women

It is important to note that cervical cancer screening is still required in vaccinated women. This is because the vaccine will not provide protection against all types of HPV that cause cervical cancer. The HPV types not covered by the vaccines are still responsible for causing 30% of cervical cancer. Also, women who do not complete the vaccine series or who have already acquired a vaccine HPV type may not receive the full benefit and may still be at risk for cervical cancer.

Case 4

r. Xian has a patient in her office to whom she wants to administer the first dose of quadrivalent HPV vaccine. The patient is also due for her final dose of hepatitis A and B vaccine (Twinrix). Dr. Xian wants to know if they can be given, in two injections, at the same visit. Also, due to school-related travel, the patient will be away for 3 months. What should be done about the second dose of quadrivalent HPV vaccine? The safety and immunogenicity of co-administration of the quadrivalent vaccine with recombinant hepatitis B vaccine was evaluated in a clinical trial. The immune response and safety profile for both vaccines were similar whether they were administered at the same visit or a different visit.29 Co-administration with other vaccines has not been studied. The immune response data suggests that schedule flexibility of 1 month for dose 2 and 2 months for dose 3 does not affect the immune response to the quadrivalent vaccine.29

5. HPV myths
HPV infection implies sexual promiscuity or infidelity As with other sexually transmitted infections, the risks associated with HPV acquisition are related to sexual behaviours such as age of onset of sexual activity, number of lifetime sexual partners, and number of recent sexual partners. However, positive HPV status does not imply multiple sexual partners (as rates of HPV infection have been shown to be 20% to 46% among women with only one lifetime partner43) and is not a marker for current sexual activity (as manifestations of persistent HPV infection on a Pap test can represent an infection acquired many years ago6). HPV infection is synonymous with cancer Anhang R et al. published results of 8 focus group discussions with 48 ethnically diverse, low-income

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women in Massachusetts.44 Most women overestimated the likelihood that women with HPV would develop cancer. Women also struggled to balance the anxiety of knowing that HPV infection causes cervical cancer with information that HPV infection often regresses without treatment. The majority of HPV infections are handled by the immune system and regress without consequence.5,18,19,22

References
1. Walboomers JMM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12 19. 2. Bosch FX, Lorincz A, Muoz N, Meijer CJLM, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244265. 3. Muoz N, Bosch FX, Sanjos SD et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518527. 4. Moscicki AB, Schiffman M, Kjaer S, Villa LL. Chapter 5: Updating the natural history of HPV and anogenital cancer. Vaccine 2006;24S3:S3/42S3/51. 5. Wright TC, Bosch FX, Franco EL et al. Chapter 30: HPV vaccines and screening in the prevention of cervical cancer; conclusions from a 2006 workshop of international experts. Vaccine 2006;24S3:S3/251 S3/261. 6. Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med 2005;353:2101. 7. Clifford GM, Smith JS, Plummer M, Muoz, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. British Journal of Cancer 2003;88:6373. 8. Muoz N, Bosch FX, Castellsagu X et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004;111:278285. 9. Von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001;11:598 604. 10. The Society of Gynecologic Oncologists Education Resource Panel. Cervical cancer prevention in the era of prophylactic vaccines: A preview for gynecologic oncologists. Gynecologic Oncology 2006;102:552562. 11. Bosch FX, Muoz n. The viral etiology of cervical cancer. Virus Research 2002;89:183190. 12. Mnger K, Baldwin A, Edwards KM et al. Mechanisms of human papillomavirus-induced oncogenesis. Journal of Virology 2004;78:1145111460. 13. Roden R, Wu T-C. How will HPV vaccines affect cervical cancer? Nature Reviews 2006;6:753763. 14. Muoz N, Castellsagu X, Berrington de Gonzlez A, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine 2006;24S3:S3/1S3/10. 15. The Society of Obstetricians and Gynaecologists of Canada (SOGC) Position Statement. www.sexualityandu.cahpvinfo/professionals accessed October 31, 2006. 16. Winer RL, Shu-Kuang Lee, Hughes J, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol

6. Unresolved issues
6.1 Duration of vaccination immunity
Long-term trials are required to evaluate whether immunity to HPV is long lasting and whether the occurrence of cervical cancer continues to decrease throughout a womans life.

6.2 Vaccination of males

The quadrivalent vaccine is not approved in males. The vaccine appears to be highly immunogenic and safe in men.29 The estimated prevalence of HPV in men is similar to the prevalence in women.45 Certainly, men and boys can benefit from a vaccine, as HPV is linked to genital warts as well oropharnygeal, esophageal, penile, and anal cancers.46 Vaccination of boys and men may also prevent transmission to women.

6.3 Developing countries

Approximately 80% of cervical cancer cases occur in less developed countries, mostly due to the fact that women have limited access to screening and treatment.5 Access to vaccines in such countries is limited. Additionally, the fact that HPV is a sexually transmitted infection and that vaccination will mostly target females may be problematic in some cultures.

7. Summary
The development and approval of the quadrivalent HPV vaccine, and the anticipated approval of the bivalent vaccine, represent a significant advancement in womens health, as we now have a primary prevention strategy for cervical cancer. Public education on the benefits and proper use of the vaccine along with continued screening for cervical cancer are essential to achieving the goal of reducing cervical cancer.

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2003;157:218226. 17. Shin H-R, Franceschi S, Vaccarella S, Roh J-W et al. Prevalence and determinants of genital infection with papillomavirus, in female and male university students in Busan, South Korea. J Infect Dis 2004;190:468476. 18. Burchell AN, Winer RL, de Sanjos, Franco EL. Chapter 6: Epidemiology and transmission dynamics of genitial HPV infection. Vaccine 2006;24S3:S3/52S3/61. 19. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423428. 20. Sellors JW, Mahoney JB, Kaczorowski J, Lytwyn A et al. Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. CMAJ 2000;163:503508. 21. Schlecht NF, Kulaga S, Robitaille J, Ferreira S et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 2001;286:31063114. 22. Winer RL, Kiviat NB, Hughes JP, Adam DE et al. Development and duration of human papillomavirus lesions, after initial infection. JID 2005;191:731738. 23. Peto J, Gilham C, Deacon J, Taylor C et al. Cervical HPV infectionan d neoplasia in a large populationbased prospective study: the Manchester cohort. British Journal of Cancer 2004;91:942953. 24. Castle PE, Solomon D, Schiffman M, Wheeler CM for the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 2005;97:10661071. 25. Wheeler CM, Hunt WC, Schiffman M, Castle PE for ALTS Group. Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer. J Infect Dis 2006;194:12911299. 26. Canadian Cancer Society. Canadian Cancer Statistics 2005. 27. Marrett LD. Cancer incidence in young adults in Canada: Preliminary results of a cancers urveillance project. Chronic Dis Can 2002;23:5864. 28. Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, ed. Harrisons principles of internal medicine. 16th edition. Toronto: McGrawHill; 2005. 29. Gardasil product monograph. Merck frosst Canada Ltd; July 10,2006. 30. Schmiedeskamp MR, Kockler DR. Human papillomavirus vaccines. Ann Pharmacother 2006;40:1344 1352. 31. Stanley M, Lowy DR, Frazer I. Chapter 12: Prophylactic HPV vaccines: Underlying mechanisms. Vac-

cine 2006;24S3:S3/106S3/113. 32. Koutsky LA, Ault KA, Wheeler CM, Brown DR et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002;347:16451651. 33. Villa LL, Costa RLR, Petta CA, Andrade RP et al. Prophylactic quadrivalent human papillomavirus (types 6,11,16, and 18) L1 virus-like particle vaccine in young women: a randomized double-blind placebo-controlled multicentre phse II efficacy trial. Lancet Oncol 2005;6:271278. 34. Koutsky LA, Harper DM. Chapter 13: Current findings from prophylactic HPV vaccine trials. Vaccine 2006;24S3:S3/114S3/121. 35. Harper DM, Franco EL, Wheeler C, Ferris DG et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet 2004;364:17571765. 36. Harper DM, Franco EL, Wheeler CM, Moscicki AB et al. 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 randomized control trial. Lancet 2006;367:12471255. 37. Chesson HW, Blandford JM, Gift TL, Toa G, Irwin KL. The estimated direct medical cost of sexually transmitted diseases among American youth, 2000. Perspect Sex Reprod Health 2004;36:1119. 38. Cervical cancer screening in Canada: 1998 Surveillance report. www.phac-aspc.gc.ca/pulicat/ccsicdccuac/index.html accessed November 22, 2006. 39. Insinga Rp, Glass AG, Rush BB. The health care costs of cervical human papillomavirus-related disease. Am J Obstet Gynecol 2004;191:114120. 40. Goldie SJ, Kohli MK, Grima D, Weinstein MC, et al. Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst 2004;96:604615. 41. Guidelines for maintaining and managing the vaccine cold chain. MMWR 2003;52(42):10231025. 42. www.CDC.gov/std/HPV/STDFact-HPV-vaccinehcp.htm accessed October 26, 2006. 43. Collins S, Mazloomzadeh S, Winter H, et al. High incidence of human papillomavirus infection in women during their first sexual relationship. Br J Obstet Gynaecol 2002;109:9698. 44. Anhang R, Wright TC, Smock L, Goldie SJ. Womens desired information about human papillomavirus. Cancer 2004;100:315320. 45. Dunne EF, Nielson CM, Stone KM, Markowitz LE, Giuliano AR. Prevalence of HPV infection among men: A systematic review of the literature. JID 2006;194:10441057. 46. Gillison ML, Koch WM, Capone RB, Spafford M et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709720.

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Questions
1. Which of the following statements is false with respect to HPV? a. There are more than 100 different HPV genotypes. b. Some 40 HPV types infect the genital tract. c. There are at least 15 types of HPV known to be oncogenic. d. Genital HPV types also cause common skin or plantar warts. 2. HPV type 16 and 18 are: a. low-risk viruses responsible for up to 90% of genital warts b. high-risk viruses responsible for causing ~70% of cervical cancers c. only transmitted by sexual intercourse d. carcinogenic and always lead to cancer 3. HPV type 6 and 11 are: a. low-risk viruses responsible for up to 90% of genital warts b. two of the viruses covered by Gardasil c. two of the viruses covered by Cervarix d. both a & b 4. The link between cervical cancer and HPV: a. has only recently been made b. was made some 20 years ago c. is most strongly associated with HPV type 34 d. is weak 5. Prevalence of HPV infection is: a. highest for younger women and decreases in the middle age groups b. highest 10 to 15 years after a young woman becomes sexually active c. significantly higher in women than men d. significantly higher in men than women 6. Which of the following statements is false? a. HPV is transmitted by skin-to-skin sexual contact. b. HPV is the most prevalent sexually transmitted infection worldwide. c. As many as 80% of Canadian women of reproductive age have had an HPV infection at some point. d. Pap tests will no longer be required if the HPV vaccine is used widely. 7. Which of the following statements is/are true? a. Pap testing has decreased the incidence of cervical cancer by up to 75% in areas with good screening programs. b. Squamous cell cervical cancer is the most common cervical cancer. c. Most HPV infections are cleared by the immune system. d. 1020% of HPV infections become persistent and may lead to cancer. e. All of the above. 8. Which of the following statements is false? a. HPV is considered a necessary cause of cervical cancer. b. HPV infection always leads to cancer. c. HPV alone is not a sufficient cause to produce cancer. d. Most HPV infections spontaneously clear. 9. Established and possible cofactors in the progression from cervical HPV infection to cancer are: a. high parity b. smoking c. long-term use of oral contraceptives d. infection with Chlamydia trachomatis e. a, b, c, and d 10. Which of the following statements is false with respect to persistent HPV infection? a. HPV 16 has been shown to persist longer than other HPV types. b. The time to progression from HPV infection to pre-malignant lesions is well established at 10 years. c. The time to progression from HPV infection to pre-malignant lesions is highly variable. d. A significant fraction of pre-malignant lesions occur within the first years of persistency. 11. Which of the following cervical lesions is/are considered low-grade? a. ASCUS b. CIN 1 c. CIN 2 d. CIN 3 e. a and b

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12. Which of the following statements is true with respect cervical screening and cervical cancer? a. In Canada in 2001, more than 1350 women were diagnosed with cervical cancer and 400 women died from it. b. After breast cancer, cervical cancer is the most common cancer in Canadian women between the ages of 20 and 44. c. The cost of screening represents the largest cost component in cervical cancer prevention and treatment. d. All of the above. 13. Which of the following statements is true with respect to recombinant technology used for HPV vaccine production? a. Recombinant technology is used to produce a live-virus HPV vaccine. b. Recombinant technology is used to produce an attenuated live-virus HPV vaccine. c. Recombinant technology is used to produce virus-like particles (VLP) that resemble the HPV major capsid antigen L1. Questions 1418 are specific to Cases 2 and 3 mentioned in the text. The pediatricians in the clinic next to your pharmacy have informed you that they are discussing HPV vaccination with all their female patients and parents during check-ups. In the last week youve had at least two patients from their practices asking about the HPV vaccine Belinda from Case 2 and Mrs. McDonald and her 10-year-old daughter from Case 3. 14. In your discussion with Belinda about whether or not she is eligible for HPV vaccine you emphasize the continued importance of Pap testing. Belinda responds that part of the reason she wants to get the vaccine is so she wont have to get Pap tests anymore. What information would you present to Belinda? a. The HPV vaccines currently, and soon to be, available are effective for preventing 70% of cervical cancers. Pap testing is still required for the early detection of cervical and vaginal lesions in the other 30% of cases. b. Belinda is already sexually active and may already have been exposed to a high-risk HPV type. If thats the case, the vaccine will not protect her against cancer for that type and Pap testing is required. c. All three doses are required over a 1-year period in order to obtain maximum protection. d. All of the above.

15. Belinda asks if her boyfriend should have the vaccine as well. What information can you provide at this point? a. HPV does not affect males. b. HPV vaccine is approved for use in males. c. HPV infection is probably similar in males but as yet the vaccine is not approved for males. d. HPV is not contagious. 16. Belinda has read that some vaccines contain live virus. She is worried that the HPV vaccine may give her the virus. What information is essential to give to Belinda? a. The risk of infection has not been quantified. b. The risk of infection outweighs the risk of cancer. c. The vaccine is made with virus-like particles that are empty inside (i.e., contain no DNA or RNA) and thus are in no way infective. d. You dont know so she should check with her doctor. 17. The next month, when Belinda comes in to pick up her Alesse prescription, she mentions that she read on the internet about two HPV vaccines Gardasil and Cervarix. She asks what the difference is between the two. Which statement(s) is/are true: a. Gardasil protects against 4 HPV types (6, 11, 16, 18). Together these HPV types are responsible for 70% of cervical cancers and 90% of genital warts. b. Cervarix protects against 2 HPV types (16 and 18). These HPV types are responsible for 70% of cervical cancers. c. There are no differences between the vaccines. d. a and b 18. When Mrs. McDonald initially heard about the HPV vaccine from the pediatrician she was upset about immunizing her 10-year-old daughter against a sexually transmitted infection. After you provided her with some information on the CDC recommendations she calmed down. As you continued to talk with her, she asked about the safety of Gardasil. How do you respond? a. You dont know and refer her to her doctor. b. You say that the safety is not known until long-term trial results are available. c. You ask her if she is aware of any allergies in her daughter. d. In the studies, the most common side effect was pain at the injection site. Patients also complained of headache, fatigue, and gastrointestinal symptoms, but no more than did patients who received placebo. e. c and d

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19. With respect to the clinical trial results for Gardasil, which of the following statements is false? a. Efficacy endpoints were cervical and vaginal cell changes and genital warts related to vaccine HPV types. b. Efficacy ranged from 90% to 100% compared to placebo. c. No data is available on the immunogenicity of the vaccine in girls or boys younger than 16 years. d. The vaccine produced levels of neutralizing antibody substantially greater than those produced during natural infection. 20. With respect to the clinical trial results for Cervarix, which of the following statements is false? a. Efficacy endpoints were incident HPV infection, persistent HPV infection, and cytologic abnormalities related to vaccine HPV types. b. Efficacy ranged from 74% to 100% for infections and from 92% to 100% for cytologic abnormalities. c. AS04 is a novel adjuvant reported to produce higher and persistent antibody titres. d. There is no data on the vaccine-induced antibody titres past 36 months. 21. With respect to interpretation of vaccine clinical trial results to the general population, which of the following statements is true? a. The efficacy results can only be expected if all 3 doses of vaccine are administered within 1 year. b. The efficacy results are most applicable for girls in whom sexual activity has not yet started. c. The general population results (or results independent of HPV status) are most applicable to women who are already sexually active. d. All of the above. 22. Which of the following statements is false? a. Each dose of Gardasil contains 20 g of L1 protein for each HPV type (6, 11, 16, and 18). b. Each dose of Cervarix contains 20 g of L1 protein for each HPV type (16, 18). c. Gardasil is intended for i.m. injection as 3 separate 0.5 mL-doses administered at 0, 2, and 6 months. d. Cervarix approval is expected in 2007.

23. With respect to the statement from the CDC Advisory Committee on Immunization Practices, which of the following is correct? a. The HPV vaccine is only recommended in girls 11 to 12 years old. b. The HPV vaccine is not recommended once young women are sexually active. c. Immunocompromised females can receive the vaccine. d. Frequency of cervical screening can be decreased in vaccine recipients. 24. Which of the following statements is true with respect to the HPV vaccine and pregnancy? a. HPV vaccine is not recommended in pregnancy. b. The vaccine has not been causally associated with adverse outcomes in pregnancy. c. Exposure to vaccine in pregnancy can be reported to a vaccine pregnancy registry (800986-8999). d. All of the above. 25. Gardasil: a. is supplied as single-dose vials and pre-filled syringes b. requires shaking immediately before administration c. vials and pre-filled syringes are latex free d. requires refrigeration e. all of the above

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