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ARCHIVED - Statement on human papillomavirus vaccine

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Information identified as archived on the Web is for reference, research or recordkeeping purposes. It has not been altered or updated after the date of archiving. Web pages that are archived on the Web are not subject to the Government of Canada Web Standards. As per the Communications Policy of the Government of CanadaExternal link, you can request alternate formats on the "Contact Us" page.

Canada Communicable Disease Report

Canada Communicable Disease Report
Volume 33 • ACS-2
15 February 2007

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)*†

PDF Version
32 Pages -651 KB PDF


Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Introduction

Over 100 human papillomavirus (HPV) types have been described. These are virus particles consisting of circular DNA molecules wrapped in a protein shell. The shell is made up of two protein molecules, L1 and L2. These viruses infect differentiating epithelial cells of skin or mucosae. At least 40 HPV types are able to infect the genital tract. Studies over the past 15 years have revealed that almost all cervical cancers can be traced to infection with oncogenic HPV types, including types 16 and 18. These types are referred to as high risk (HR) because of their link to cervical cancer. The key role of HPV infection in the etiology of cervical cancer provides an opportunity to control this cancer through immunization against the most common HR HPV types.

In addition to the HR types, there are other HPV types, in particular 6 and 11, that are low risk (LR) for causing cancer, but cause the majority of genital warts; these are referred to as LR types. A quadrivalent HPV vaccine against types 6, 11, 16 and 18 (GardasilT, manufactured by Merck Frosst Canada Ltd.) has recently been approved for use in Canada.

This National Advisory Committee on Immunization (NACI) statement will concentrate on specific elements of the analytic framework for immunization programs in Canada developed by Erickson et al.1, in particular, burden of disease and vaccine characteristics. The statement will make recommendations about the use of HPV vaccine. It will also comment upon important research gaps for the optimal use of this vaccine in Canada. Other elements of the framework, such as cost-effectiveness, acceptability of vaccine programs and feasibility, will be addressed by the Canadian Immunization Committee.

Natural history of HPV infection

HPV is capable of causing benign and cancerous anogenital disease as well as benign and malignant head and neck lesions. HPV infections are transmitted sexually by direct epithelial (skin or mucosa) to epithelial contact and vertically to an infant exposed to the virus in the maternal genital tract; as well, transmission from oral mucosal contact in head and neck infections is likely.

Cervical dypslasia and cancer are the potential consequences of genital infection with HR oncogenic HPV subtypes. HPV 16 and 18 contribute to 70% of cervical cancer2, and these and other subtypes can result in infection of the cervical cells, primarily at the transformation zone between stratified squamous epithelium and endocervical columnar cells. To manifest the oncogenic potential, the viral genome integrates itself into the host cell genome and then develops a persistent infection. This infection must persist for years to permit progression to cancer. In the setting of cervical dysplasia or cancer development the mucosal immune function is likely impaired, with a decreased ability of the T cell helpers (Th1) to clear the HPV.

A key carcinogenic process is production of the E7 protein by the virus (one of its early proteins), which interferes with the host pRB (retinoblastoma protein) tumour-suppressor protein. This is one of the mechanisms that allows for disordered cell replication. The E6 protein of the virus is capable of destroying the p53 protein of the host cell, which prevents the cell from blocking accumulation of genetic mutations during replication, usually through apoptosis.

Cervical cancer appears to develop in a progressive fashion; usually mild dysplastic changes evolve into severe dysplastic changes and ultimately into in situ carcinoma and, if untreated, invasive squamous cell carcinoma. The ability of Papanicolaou (Pap) smear screening to detect cervical dysplastic changes prior to the development of carcinoma has led to dramatic reductions in invasive cancer in the developed world. Even with effective vaccine programs, until close to 100% coverage can be achieved for all oncogenic HPV types this ability to detect pre-invasive disease will remain critically important. It is of note that most immunologically competent women who are infected with oncogenic HPV will clear the infection without its progression to cervical carcinoma.

HPV has also been implicated in the much more rare cancers of the penis, anus, vulva and vagina, in which mechanisms of oncogenicity are presumed to be similar to those of the cervix, but the rapidly replicating nature of the cervical transformation zone appears to make this area more susceptible to its oncogenic influences. In addition, although squamous cell cancers of the mouth and oropharynx are rare, 35.6% (range 11% to 100%) of oropharyngeal, 23.5% (range 4% to 80%) of oral and 24% (range 0% to 100%) of laryngeal cancers have been associated with HPV3.

HPV infection, primarily due to types 6 and 11, can also result in anogenital warts. Genital warts are typically warty projections that can occur anywhere in the genital skin surface but primarily on the vulva, penis and perianal skin. They are usually self-limited lesions in immunocompetent individuals, resolving typically in 12 to 24 months. It is estimated that HPV 6 and 11 cause 90% of genital warts4. The virus enters the epithelium, usually through a break, and then infects and replicates in basal and parabasal cells. In this circumstance the virus is established as an episome in the human cell's nucleus. As these cells mature, translation of viral genome occurs with assistance from the host cell machinery; translation of early and then late genes occurs. This ultimately results in the creation of progeny virus, which are then shed at the epithelial surface. During the process there is over-replication of epithelial cells, and this can result in the heaped-up manifestations of genital warts.

Recurrent respiratory papillomatosis (RRP) is a rare condition, given the relatively ubiquitous nature of HPV in the female genital tract. It is characterized by recurrent warts or papillomas in the upper respiratory tract, particularly the larynx. Almost all cases of RRP are linked to HPV 6 and 115,6. On the basis of the age of onset, RRP is divided into juvenile onset, believed to be acquired from the mother at delivery, and adult forms5. The juvenile form, generally defined as onset before 18 years, is better characterized than the adult form. Malignant transformation occurs in 3% to 5% of RRP patients and is associated with the presence of HPV types 16 and 187,8. RRP can result in substantive morbidity as the papillomas can enlarge and result in respiratory compromise. This is managed by repeat laryngoscopy and bronchoscopy for wart removal / debulking every 2 to 3 months, or as often as weekly in times of rapid papilloma growth7,9. The clinical course is quite variable, requiring a median of 13 lifetime surgeries to remove warts and maintain an open airway(9). There is currently no curative treatment, but most people will ultimately clear these papillomas following recurrent debulking. There are likely many people with minor manifestations that never come to medical attention.

Pathophysiology of cervical cancer

Cervical cancer is a malignancy of the cells lining the surface of the cervix. The cervix is lined with two main types of cell: squamous and glandular mucus-secreting cells. The junction between the two types of cell is called the transformation zone (or squamo-columnar junction) and is an area of rapid cell turnover where benign and malignant cellular changes are most likely to occur.

Cervical cancers begin as asymptomatic pre-cancerous lesions and usually develop gradually over many years. The intraepithelial lesions are limited to the cervical epithelium, and as invasion occurs the neoplastic cells penetrate the underlying membrane with potential for widespread dissemination. Depending on their severity, lesions can resolve spontaneously or can progress to cancer.

Cervical lesions are described according to the degree of cytopathology found on Pap smear, with progression in degree of dysplasia. There are different classification systems used throughout Canada, but the most internationally accepted system is the Bethesda system10, in which the classifications include atypical squamous cells of undetermined significance (ASC-US); atypical glandular cells of undetermined significance (AGUS); atypical squamous cells of undetermined significance in which a highgrade squamous intraepithelial lesion cannot be excluded as a possibility (ASC-H); low-grade squamous intraepithelial lesions (LSIL); and high-grade squamous intraepithelial lesions (HSIL). When colposcopically directed biopsies are performed, the histopathologic result is the diagnosis of degree of dysplasia or carcinoma, which can range from mild to severe dysplasia, carcinoma in situ or invasive carcinoma. Low-grade lesions commonly regress, but high-grade lesions more commonly progress if untreated.

The likelihood of a lesion regressing or progressing depends on a number of factors. Low-grade lesions, particularly in young women, tend to be associated with self-limited HPV infection11. For reasons that are not fully understood, the time it takes for an infection to progress to invasive cervical cancer can vary widely, with typical progression estimated to take up to 10 years or longer12. In rare cases, however, lesions appear to progress rapidly with invasive cancer developing in < 1 year13. Screening may offer little benefit in such cases. In general, however, the vast majority of precancerous lesions, which progress slowly, can easily be detected and treated. Cervical cancer can also be more effectively treated when detected early.

HPV epidemiology

HPV infection is extremely common. The natural history and epidemiology of HPV infection will be described, followed by the burden of cervical cancer.

Canadian prevalence and incidence

HPV is often described as the most common sexually transmitted infection (STI)14. It is not a nationally notifiable disease in Canada and, to date, no population-based studies have been published. Estimates of HPV infection and associated disease burden are based on Canadian prevalence and incidence studies in select populations, such as patients in routine cervical screening clinics, family planning clinics, STI/HIV clinics and university health clinics. All published Canadian studies have been conducted in women.

Table 1 summarizes data from available Canadian HPV prevalence studies. The overall prevalence of HPV (any type) ranges from 10.8% to 29.0%. However, prevalence varies greatly within different age groups, ranging from 3.4% to 42.0%. The peak prevalence tends to occur in adolescents and young adults (around ≤ 25 years of age or younger) with a subsequent decrease with age. Because of differences in population selection criteria (e.g., age, recruitment site) and diagnostic testing methods, these studies may not be directly comparable or generalizable to the broader population. In addition, diagnostic testing and specimen collection techniques are an evolving science. The type of diagnostic test performed, the number of genotypes (high risk or low risk) included in the test, the sensitivity and specificity of the test, the site of specimen collection and the type of sampling device affects results and comparability.

Table 1. Reported point prevalence of cervical high–risk and low–risk HPV in Canadian studies using PCR or hybrid capture I (HC1) and/or II (HC2) methods

Study

Population

Age range, years

N

%HPV

Test

Sample

Healey et al.(15)

Women attending for routine cervical screening from 19 communities in Baffin/Keewatin regions of Nunavut; 86% Inuit

13-79
13-20
21-30
31-40
> 40

1,290
240
480
331
239

25.8 (HR)
42.1
31.3
13.9
15.1

HC2*

Residual liquid-based cytology medium (ThinPrep) after preparation of Pap smear

Moore et al.(16)

Routine cervical screening across British Columbia

15-69
<20

5,000

16.8 (HR, LR)
13.9 (HR)
26.9 (HR, LR)
20.6 (HR)

GP5+/6+†

Liquid-based cytology specimens

Ratnam et al.(17)

Routine cervical screening in 10 different regions in Newfoundland

18-69
<25
25-34
35-44
45+

2,098 401 1,098 536 59

10.8 (HR)
16.7
11.7
5.0
3.6

HC1** (69%), HC2* (31%)

Ecto-and endocervical specimens collected with spatula/cytobrush

Richardson et al.(18)

Women attending a university health centre in Montreal

Primarily 18-24
(with 3% > 30)

375

22.7 (HR, LR)
HR : 11.8
LR :6.2
UT : 7.1

MY09/11‡

Residual cervical cells after preparation of Pap smear, collected with spatula/cytobrush

Richardson et al.(19)

Women attending a university health centre in Montreal

17-42
Mean: 23
Median: 21

621

29.0 (HR, LR)
HR : 21.8
LR : 14.8

MY09/11‡;
HMB01

Second cervical brush sample (first sample used to prepare Pap smear)

Sellors et al.(20)

Family practice clinics for cytologic cervical screening - proportionate random sampling from each of the 6 health planning regions of Ontario

15-49
15-19
20-24
25-29
30-34
35-39
40-44
45-49
> 50

955
89
125
159
163
157
144
118
156

12.7 (HR)
15.7
24.0
16.4
12.3
9.6
8.3
3.4
8.3

HC2*

Cervical brush sample in Digene STM

Sellors et al.(21)

As described above

 

 

 

 

As described above

Young et al.(22)

Community health centre in a low-income inner city area of Winnipeg; 42% Aboriginal

Range not reported
(73% < 30)

1,263

33 (HR, LR)

MY09/11¶

Residual cells from spatula/brush after preparation of Pap smear

* HC2 for high-risk types 16,18,31,33,35,39,45,51,52,56,58,59,68
† General primer 5+/6+ (GP5+/6+) polymerase chain reaction (PCR) with bi-directional sequencing, comparing with known HPV types
** HC1 for high-risk types 16,18,31,33,35,45,51,52,56
‡ MY09/11 PCR with dot-blot hybridization for HR types 16,18,31, 33,35,39,45, 51,52,56,58,59, 68 and LR types 6,11, 26,40,42,53, 54,55,57,66, 73, 82 (MM4), 83 (MM7), 84 (MM8)
¶ MY09/11 PCR with dot-blot hybridization for HR types 16,18,31,33,35, LR types 6,11


Within Canada, HPV prevalence appears to vary with age, place of residence and ethnicity. Differences in reported prevalence of HPV may be partly attributed to laboratory detection methods: refinements in the technology for both PCR amplification and detection of the PCR products. In Montreal, the overall prevalence of HPV infection was found to be strongly associated with place of birth: women from western Canada, Ontario and Europe were more likely to be infected with any HPV than women born elsewhere18. The higher rates of HR HPV infection seen in Nunavut (86% Inuit)15 compared with other Canadian studies are consistent with the higher cervical cancer rates that have been reported elsewhere in the north24,25. It was also noted that HPV infection appeared to be acquired at an earlier age in Inuit versus non-Inuit, as seen by the higher prevalence in women aged 13 to 20 years (31.7% vs. 11.8%). The prevalence of any HPV among women attending an inner-city primary care clinic in Winnipeg did not differ significantly between Aboriginal and non- Aboriginal women22. It was found, however, that HPV type 18 was the most prevalent type in Aboriginal women, and it was significantly more common in Aboriginal than non-Aboriginal women.

A prevalence study in British Columbia (BC) conducted in 2004-2005 provides the most recent Canadian data16. HPV typing was completed on liquid-based specimens from a convenience sample of 8,700 women throughout BC who were attending for routine cytology screening at high-volume primary care screening sites. Specimens were received from every geographic health authority in BC and were representative of the over 500,000 women who receive Pap screening annually in the province. DNA was isolated from 5,000 samples, including all 620 samples with cytological abnormalities and 4,380 randomly chosen cytologically normal samples. HPV was detected by PCR. HPV typing was done by bi-directional sequencing of PCR products and comparison with known HPV types. The overall adjusted HPV prevalence for women 15 to 69 years of age for all HPV, any HR HPV, HPV-16 and HPV-18 was 16.8%, 13.9%, 10.6% and 3.5% respectively. The overall prevalence of the HR HPV subtypes that are contained in the vaccine (16 and/or 18) was 11.6% (95% confidence interval [CI]: 10.8% to 12.6%). Among women < 30 years of age, the prevalence of HR subtypes contained in the vaccine (16 and/or 18) was 16.7% (< 20 years), 13.7% (20 to 24 years) and 13.0% (25 to 29 years). Women < 20 years of age had the highest prevalence rates of any HPV (26.9%), any HR HPV (20.6%) and HPV-16 and/or HPV-18 (16.7%). HPV prevalence decreased with each older age stratum until age 69. In women with normal Pap smears, 8.7% and 3.0% respectively were positive for HPV-16 and HPV-18.

Despite the use of different methods, HPV-16 has consistently been found as the most common HPV infection in Canada16,18-20. In theWinnipeg study, type 16 was the most prevalent overall (12.5% of women tested); type 16 was the most prevalent in non-Aboriginal women, but type 18 was the most prevalent in Aboriginal women in Winnipeg22.

There are very few studies of HPV incidence in Canada, and all have been conducted in women.Women previously involved in a prevalence study in Ontario were invited to participate in a follow-up study 1 year later25. Among those 15 to 49 years of age (mean 32.7 years) with a mean interval of 14 months of followup (range 9 to 21.3 months), incident HR HPV infection was found in 11.1% of women who were initially HPV negative. The highest incidence was found among those aged 15 to 19 years (25.0%), followed by those 30 to 34 years (14.7%).

Female university students in Montreal with a mean age of 23 years (range 17 to 42 years) were followed at 6-month intervals for 24 months to determine incident infections in those HPV negative at baseline. The cumulative rate for new HPV infections was 36% during the 2-year period of the study, taking into account coinfection with more than one HPV type; 29.0% were infected with HR types and 23.7% with LR types. The most frequently detected incident HPV types were 16 (5.2 cases/1,000 woman-months), followed by 84, 51, 53 and 5419.

International prevalence and incidence

HPV prevalence estimates for women in countries around the world range from 2% to 44%, depending on the geographic region, population sampled and testing methodology26. A peak prevalence of HPV infection in women < 25 years of age has been demonstrated consistently, with a decreasing prevalence with age thereafter27. Herrero et al.28 found that among women < 25 years of age, oncogenic HPV types predominated, whereas in women > 55 years, non-oncogenic and uncharacterized types were the most common. A second peak in HPV prevalence among older women has also been found in some studies22,29, but this has not been seen consistently.

HPV infection is not reportable in the United States (US)29. Studies conducted in subsets of the general population, such as college and clinic populations, are limited in their generalizability30. The HPV prevalence reported in a systematic review of US studies in 2005 ranged from 14% to 90%, the highest prevalence of HPV being identified among college students and women attending STI clinics31. Among young college women in the US, HPV prevalence has ranged from 20% to 46%11,32,33, whereas in a high-risk urban adolescent clinic a prevalence of 64% was found34. In a review by the CDC in 2004, most studies were found to report a prevalence of HPV of > 30%35.

The International Agency for Research on Cancer's multi-centre cervical cancer studies have shown that, around the world, HPV type 16 is the most prevalent; 54.6% of HPV-infected patients with squamous cell cervical cancer were infected with type 16, as were 24.3% of HPV-infected controls. Types 16, 18, 45, 31 and 33 accounted for 80% of the type distribution in squamous cell carcinomas, and types 16, 18, 45, 59 and 33 accounted for 94% of the type distribution in adenocarcinomas26. These distributions are consistent with a meta-analysis of studies conducted worldwide36 and other published data37.

Although incidence studies are few, longitudinal cohort studies in the US and the United Kingdom (UK) have shown remarkably similar 36-month cumulative incidence rates for acquisition of any new HPV infection, ranging from 43% to 51%11,35,38-40 among women in their early 20s and younger. These figures are comparable to the Canadian study by Richardson et al.19 . Sellors et al.25 found a lower incidence in Ontario for the same age group, but a shorter follow-up period and a difference in testing methods may partly account for this.

Acquisition of HPV infection is high following sexual debut. In a study of female university students the cumulative incidence of HPV infection (in those initially determined to be HPV negative) was 38.8% (95% CI: 33.3% to 45.0%) in 24 months of follow-up for those who were sexually active at enrollment and 38.9% (95% CI: 29.4% to 50.3%) for those who were virgins at enrollment33. Incident infection with HPV type 16 was 10.4% and with HPV type 18 was 5.6%. The study found that any type of non-penetrative sexual contact was associated with an increased risk of genital infection in virgins. In a study of virgin women, 23 of the 65 women who became sexually active tested positive for HPV DNA at the follow-up examination (year 2), type 16 being the most commonly detected type42. In an analysis of 474 women recruited within 12 months of initiating sexual intercourse (only one partner) the cumulative risk of acquiring any HPV infection at 3 years after first intercourse was 45% (95% CI: 37.9% to 51.2%). HPV 16 was the most common type detected43.

Infections with multiple HPV types

There is relatively little information on the prevalence, incidence or natural history of multiple HPV infections. This information is important when considering multivalent vaccines. Epidemiologic studies have noted that infection with a given type does not decrease the probability of being infected by phylogenetically related types44.While studies have shown that 20% to 30% of women with cervical HPV infections have multiple types present, regardless of cytology/pathology, cervical cancer is typically a monoclonal event related to one HPV type45.

In the GardasilTM phase II and III trials 3,578 North American women aged 16 to 26 years with 0 to 5 or 1 to 5 lifetime sexual partners, depending upon the exact study, had baseline HPV status assessed by serologic and PCR testing of cervico-vaginal specimens. Only 1.1% were positive for three or more types, and only 0.1% were positive for all four types (Table 2). Only 1.0% of the study participants were positive for both HPV 16 and 18, the oncogenic types. Even in those women whose study baseline Pap test showed LSIL or worse (175 women) only 14 (8%) were positive for both HPV 16 and 18 (Dr. James Mansi, Merck Frosst Canada: personal communication, 22 November, 2006).

Table 2. Number of positive tests and types of HPV detected (by serology or PCR) during Gardasil™ trials* (n = 3,587 women)

 

Number positive at day 1 (%)

Positive to ≥ 1 type (HPV 6/11/16/18)

848 (23.7)

Positive to ≥ 2 types

213 (6.0)

Positive to exactly 2 types:

172 (4.8)

HPV 6 and 11

8 (0.2)

HPV 6 and 16

90 (2.5)

HPV 6 and 18

24 (0.7)

HPV 11 and 16

12 (0.3)

HPV 11 and 18

3 (0.1)

HPV 16 and 18

35 (1.0)

Positive to ≥ 3 types

41 (1.1)

Positive to exactly 3 types:

37 (1.0)

HPV 6, 11 and 16

9 (0.3)

HPV 6, 11 and 18

1 (0.0)

HPV 6, 16 and 18

24 (0.7)

HPV 11, 16 and 18

3 (0.1)

Positive to all 4 types

4 (0.1)

* Data on file,Merck Frosst Canada, Dr. James Mansi, November 22, 2006

Clearance and persistence of HPV

As previously noted, most HPV infections are transient. The persistence of an HPV infection can be defined as the detection of the same HPV type two or more times within a given time interval between examinations46. However, there is no uniformly accepted definition of the time interval over which an infection should be present to be considered persistent; most of the data refer to 6 months or 1 year apart. With the lack of a standard and reliable definition regarding the temporal association of events, results that report persistence vary according to study design. In general, HR infections tend to persist longer than LR infections44, but the effect of type-specific HPV infection on persistence is not consistently reported27. Across studies, individual episodes last between 4 and 20 months, less than half of infections still being present after 12 months in most studies44. For those infections that do clear, the reappearance of the same HPV genotype is not common46.

In Montreal university students, persistence of any HR HPV infection was found to be longer on average than persistence of LR HPV infection; the mean HR and LR retention times were 16.3 months and 13.4 months respectively19. The most persistent HR infections found included HPV-16 (mean 18.3 months), HPV-31 (mean 14.0 months) and HPV-18 (mean 11.6 months). The most persistent LR infection was HPV-54 (mean 13.2 months). The most transient infections were HPV-6 and 84 (both LR types) clearing with mean retention times of 8.7 and 9.9 months respectively19. Among Ontario women who were previously positive for an HR HPV infection, 51.9% appeared to have cleared the infection at a mean interval of 14 months25.

HPV infection in males

Epidemiologic studies in males are important to create not only a clear picture of transmission dynamics but also a clear understanding of the natural history of infection in males. To date, studies in males are less extensive than in females. Some of the main challenges in studying HPV infection in males lie in the selection of sampling site and technique27,47. Prevalence in males, as in females, varies according to the population studied, limiting the generalizability of results to the broader population. HPV prevalence among males has been shown to vary by the sex of their sexual partners48, the presence of cervical pathology in their partners49 and geographic region49. Despite the limitations in determining HPV infection status in males, infection and asymptomatic HPV infections appear to be common27,47,50,51. Weaver et al. compared a subset of males (18 to 20 years of age) and a previous study of females (18 to 20 years of age) attending the same US university and found a prevalence of 28% for both sexes52. A review of 12 studies by Partridge and Koutsky reported a prevalence HPV among males ranging from 3.5% to 45.0%47. The prevalence of HR types ranged from 2.3% to 34.8%, type 16 being the most prevalent in all but one study (type 59 was the most prevalent in the exception)47. The prevalence of LR infections ranged from 2.3% to 23.9%, and prevalence of multiple infections ranged from 3.4% to 22.6%47.

Epidemiology of anogenital warts

Most HPV infections are transient and asymptomatic. As noted previously, genital warts are caused primarily by infection with the LR HPV types 6 and 11. The presence of these HPV types in genital warts varies among studies, 90% being the proportion most frequently reported4. It has also been reported that 20% to 50% of genital wart lesions contain HR HPV co-infections53,54.

There are no published population-based studies on the disease burden of anogenital warts in Canada. In a sample of women 15 to 49 years of age attending cytology screening at family practice settings in Ontario, 1.1% were reported to have genital warts20. With the lack of published data in Canada, prevalence estimates are largely based on epidemiologic studies and on surveillance activities in other developed countries with similar trends in other reportable STI. In the UK, anogenital warts (first episode) are the most common viral STI diagnosed at genitourinary medicine clinics, accounting for 11% (79,678 of 753,075) of all diagnoses made in these clinics in 200455. In 2004, the highest rate of new cases (first episode) among males was found in 20 to 24-year olds (783/100,000), and among females the highest rate was found in 16 to 19-year olds (703/100,000)55. Among females, 30% of diagnoses were seen in those < 20 years of age, as compared with 11% among males55.

According to a US database of privately insured individuals in 2000 (n = 3,664,686), the incidence of anogenital warts was 1.67 and 1.65 per 1,000 person-years among males and females respectively; the highest incidence was among women 20 to 24 years of age (6.2 per 1,000 person years) and among men 25 to 29 years (5.0 per 1,000 person years)50.

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Epidemiology of RRP

There appears to be a bimodal age distribution of RRP, the first peak occurring in children < 5 years of age and the second peak between 20 and 30 years8. In Canada, there are relatively few data regarding the epidemiology of RRP. Estimates of the incidence of juvenile-onset RRP are relatively imprecise but range from 0.12 to 2.1 cases per 100,000 children < 18 years in two cities in the US56. RRP is reported as the most common benign neoplasm of the larynx in children57. A national survey of practising otolaryngologists in the US in 1993-1994 provided an estimated incidence of RRP among children and adults of 4.3/100,000 and 1.8/100,000 respectively58. In Denmark, the incidence of RRP in the pediatric population was reported to be approximately 3.5 per 100,000 and 7 per 1,000 among children whose mothers had vaginal condylomata57. The risk of RRP was 213.4 (95% CI: 135.3 to 395.9) times greater than the risk in newborn infants whose mother had no history of genital warts57.

Epidemiology of cervical cancer (cervical neoplasia)

Cervical cancer is estimated to be the second most common malignancy affecting women worldwide. In 2005, approximately 1 million women were estimated to have cervical cancer, and more than 250,000 deaths were attributed to the condition worldwide59. Older women in developing countries suffer disproportionately from cervical cancer. Among women aged ≥ 70 years the estimated incidence rate in 2005 was 70 per 100,000 and the estimated mortality rate 60 per 100,000.

As in other countries, the incidence of cervical cancer varies with age in the Canadian population. Incidence initially peaks among women in their 40s, then declines and peaks again among women ≥ 70 years of age (see Figure 1). Canadian incidence and mortality rates associated with cervical cancer have declined since the 1970s (Figure 2). Declines can be attributed to the success of Pap cytology screening efforts beginning in the 1960s.

Approximately 70% of cervical cancers arise from the squamous cells, and 18% to 20% arise from the glandular cells (adenocarcinomas). Adenosquamous carcinomas account for approximately 5% of cervical cancers and share features of both squamous cell carcinoma and adenocarcinoma. Other unspecified types of cervical cancer account for the remaining 5%2.

Despite the overall decline in the incidence of cervical cancers, a recent study of provinces with a complete and consistent registry of histological classification (Ontario, Saskatchewan and British Columbia) has shown that incidence rates of adenocarcinoma and adenosquamous carcinoma increased, from 1.30 and 0.15 per 100,000 women respectively in 1970-1972 to 1.83 and 0.41 per 100,000 women respectively in 1994-199660. These increases were mainly observed in women aged 20 to 49 years. The incidence rates of cervical adenocarcinoma among older women decreased slightly. Similar increases have been seen in other developed countries where cervical screening is well established60,61.

Although still relatively rare, the increasing incidence of adenocarcinoma is of concern because of the poorer prognosis compared with that for squamous cell carcinoma62,63. It also represents an additional challenge for screening, as clinical and epidemiologic studies suggest that the Pap test is less effective in detecting adenocarcinoma than squamous cell carcinoma because the former arise further in the endocervical canal. Cervical brushes, when used in combination with a spatula with an extended tip, are now known to be more efficient than spatulas alone in collecting the endocervical cells64-67.

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Figure 1. Cervical cancer incidence and mortality rates by age group in Canada, 2003

Figure 1. Cervical cancer incidence and mortality rates by age group in Canada, 2003
* Source: Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada

Figure 2. Age-standardized cervical cancer incidence and mortality in Canada, 1970-2006

Figure 2. Age-standardized cervical cancer incidence and mortality in Canada, 1970-2006
* Source: Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada

Screening and cervical cancer

Participation of Canadian women in Pap screening appears to be relatively high. In the 2003 Canadian Community Health Survey, 79% of eligible Canadian women aged 18 to 69 years reported having had a Pap test in the previous 3 years68. Therewas some variation by jurisdiction. However, self-reports may tend to over-estimate actual participation rates by 10% to 20%69. This suggests that a sizeable segment of the population goes unscreened or is underscreened.

In 1998, while approximately 40% of cervical cancer diagnoses occurred among women undergoing regular screening (every 3 years or more), the remaining 60% occurred among unscreened or underscreened women, making the failure to screen or to screen at the recommended interval the major risk factor for development of cervical cancer2. Screening does have limitations, however, even for those regularly screened. Conventional cytology is limited, as it depends on the abilities of both the clinician and the cytologist to collect an adequate specimen and interpret it correctly. Thereafter, follow-up and management need to be sufficient and appropriate.

Burden of cervical cancer and cervical screening

Some of the elements of organized screening programs (such as population-based information systems; supporting laboratory networks; quality assurance programs; methods for monitoring and evaluation; and participation and health promotion) exist in most jurisdictions, but only a few provinces/territories have implemented the majority of these elements. Therefore, screening in Canada remains largely opportunistic70.

Under the ideal conditions of an organized population-based screening program, Pap testing is recommended for women starting at age 18 (or at the age of sexual debut) as part of a routine health examination71. This age of onset varies from country to country, given the extremely low rates of invasive cancer among women in their early 20s. The test is repeated annually until two consecutive negative (normal) tests are complete. It is then generally recommended that screening be repeated every 3 years to age 69. Re-screening is not required for women who have never had sexual intercourse or for those who have had a total hysterectomy and previous normal tests. It is important to note that there is variation in the recommendations for screening among jurisdictions in Canada. Given the relatively low sensitivity and specificity of a single Pap test, many practitioners choose to screen annually or biennially after three consecutive normal annual tests.

In Western countries, for each new case of invasive cancer found by cytology there are approximately 50 to 100 other cases of precursor lesions that require follow-up or management72. Cytology results vary across the provinces and territories depending on reporting thresholds, age profile of the screened population and variations in the management or follow-up of low-grade abnormalities, which can range from immediate colposcopic examination to repeat Pap tests at 6 month intervals for up to 2 years. Higher grade abnormalities are typically referred for colposcopy and are assessed by biopsy if necessary, with treatment following on the basis of pathology.

Among jurisdictions that report the results of screening, BC typically reports some of the highest rates of cytological abnormalities. This is likely because BC is one of the few provinces with an organized Pap smear screening program. In 2004, the BC Cancer Agency Cervical Cancer Screening Program screened 539,309 women and reported findings of mild (low-grade) atypia at a rate of 44.7 per 1,000 and moderate (or more severe) atypia at a rate of 9.9 per 1,00073. Despite these efforts, an estimated 160 cervical cancers were diagnosed in BC in 200474.

The mechanisms for cervical cancer screening are under evaluation. Primary HPV testing and the role of liquid-based cytology are being assessed. Changes in screening approaches may be seen in the future.

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Risk factors for cervical cancer

Following infection with one or more oncogenic HPV types, the risk factors for cervical cancer can be considered to fall into two overlapping categories: risk factors for the progression of HPV infection to cervical cancer and factors associated with failure of cancer or pre-cancer detection and management.

Known risk factors for the progression of HPV infection to cervical cancer largely centre on individual susceptibility, robustness of immune function and factors that can mediate these. Such factors include immunosuppression, including HIV/AIDS75 and other conditions associated with immunosuppression (organ transplantation76-78, drug-induced immunosuppression79, lengthy corticosteroid use80), host human leukocyte antigen, p53 (tumour suppressor gene) polymorphism81,82, history of STI infection82, tobacco use83 and increased age2.

Risk factors associated with failure of cancer or pre-cancer detection and management include failure to screen, failure to screen at the recommended interval, false-negative results associated with screening and failure to receive appropriate follow-up of screen-detected abnormalities84. Failure to screen and failure to screen at the recommended interval are associated with low education and low socio-economic status85, rural/remote residenc 84 and ethnicity (Aboriginal people, African American and Hispanic)13,15,86. According to one US study of women with cervical cancer, 50% had never been screened, 10% reported > 5 years since screening, 30% had a false-negative Pap test, and 10% were errors in follow-up87.

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HPV risk factors

Among females, both prevalent and incident HPV infections have been associated with an increasing number of sexual partners, both lifetime3,22,25,27,33,34,38,42,88,89 and within the previous year11,22,25,34,38,41,89,90. Condom use provides some, but not absolute, protection11,22,33,90-92. Both current and past use of tobacco has been reported as a predictor of HPV infection, but that has not been consistent27,33,34. The use of marijuana has also been reported as a predictor of HPV infection34. The use of oral contraceptives has been reported both as a predictor of HPV infection27,29,33,88,93 and as a protective factor38.

Other factors that have been associated with an increased risk of HPV infection are previous infection with an STI, specifically chlamydia22,89,93 and herpes simplex virus38, history of sexual abuse22,34, early age of first sexual intercourse22,94, having never married88, not living with a sexual partner88, having never been pregnant or having been pregnant but never having delivered a child93, having immune suppression29 and having HIV95,96. Partner characteristics, including partner's number of lifetime sex partners, are also associated with increased risk88.

The risk factors for HPV infection in males have not been studied to the extent of those in females. An increasing number of previous sexual partners in the male has been identified as a risk33,38,49, both lifetime49,97 as well as recent98. Being uncircumcised was also found to be a risk in some studies97-99.

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Canadian sexual behaviour

When HPV immunization programs are being considered, it is important to understand when sexual activity begins among Canadian youth, as this is a risk factor for HPV infection. The Canadian Community Health Survey (CCHS) cycle 2.1100 asked participants whether they had had sexual intercourse and, if so, to indicate their age at first sexual intercourse. The survey found the average age of first sexual intercourse among those 15 to 19 years of age to be 15.7 years for both males and females. Among 15 to 19-year old females, 1.1% reported having had sex by the age of 12 years, 3.3% by the age of 13 years and 9.0% by the age of 14 years. Among 15 to 19-year old males, 1.1%, 3.7% and 9.0% reported having had sex by the age of 12 years, 13 years and 14 years respectively.

The Canadian Youth, Sexual Health and HIV/AIDS Study consists of a questionnaire administered to classrooms of grade 7, 9 and 11 students. Classrooms are selected from schools identified by a stratified random sampling method, according to school, language of instruction, size of community, geographic location and school size. In 2002, 19% of females and 23% of males in grade 9 reported having had vaginal intercourse at least once. This increased to 40% and 46% of grade 11 boys and girls respectively101.

The Health Behaviours in School-Aged Children survey is administered to a representative sample of students in grade 6, 7, 8, 9 and 10; sexual health questions are asked to students in grade 9 and 10. In 2001-2002, 17% of grade 9 girls and 19% of boys reported having had sexual intercourse. In grade 10, this increased to 25% of girls and 27% of boys. For students in grade 10, 4% of male respondents (n = 472) and 1% of female respondents (n = 623) indicated having had sexual intercourse at ≤ 11 years102.

In 2005, the Canadian Association for Adolescent Health and Ipsos Reid completed a national survey of teenagers; 27% of teens between the ages of 14 and 17 years reported being sexually active. Of these, 20% reported having had sexual activity by 15 years of age. Sexually active teens reported, on average, three partners, 24% reported that they did not use any protection against STI the last time they had engaged in sexual activity, and 16% reported that their partner had other sexual partners while they were dating103.

The initiation of sexual activity, as referred to in these studies, cannot be generalized to all youth and needs to be interpreted with caution. This may be especially relevant for subpopulations such as street youth or immigrants and refugees.

Education/school leaving

The age at which children and adolescents leave school is important if school-based vaccination programs are to be considered. In Canada, the age requirement for compulsory education varies according to region. Up until the late 1990s the standard minimum age to leave school was 16 years. Despite having compulsory attendance enacted in the various provinces and territories this is not always an option for some children and adolescents, especially high-risk groups. Street youth are part of a vulnerable population that is likely to leave school earlier than other youth. In the Enhanced Surveillance of Canadian Street Youth Study (E-SYS) Phase 4 (2003), 66.3% of male street youth 15 to 24 years of age (691/1,042) had left school permanently (had either dropped out or been expelled), 21% of those leaving before grade 8 and 12% leaving before grade 7. Among females in the same age group, 59.6% (366/614) had permanently dropped out of or had been expelled from school, 20.2% leaving before grade 8 and 9.6% leaving before grade 7104 (E-SYS unpublished data, Public Health Agency of Canada, 2006).

HPV quadrivalent vaccine: Gardasil™

Vaccine composition

The quadrivalent HPV vaccine, Gardasil™, consists of the L1 capsid protein of each of four HPV strains (types 6, 11, 16 and 18). A gene encoding the L1 protein of each type is expressed in the yeast Saccharomyces cerevisiae. The protein product self-assembles into a non-infectious virus-like particle (VLP) that is identical in shape and size to the natural virus. The vaccine is administered as a 0.5 mL dose, which contains the following:

HPV-6: 20 µg L1 protein
HPV-11: 40 µg L1 protein
HPV-16: 40 µg L1 protein
HPV-18: 20 µg L1 protein

The VLPs of each type are purified and adsorbed onto an aluminum-containing adjuvant (amorphus aluminum hydroxyphosphate sulfate 225 µg). The formulation also includes sodium chloride, L-histidine, polysorbate 80, sodium borate and water for injection. The product does not contain preservative or antibiotics, and the packaging is latex-free.

The vaccine should be stored at +2º C to +8º C and should not be frozen.

Vaccine efficacy

Immunogenicity: Immune correlates for protection against HPV are unknown. However, it is known that VLPs are highly immunogenic and that in studies reported to date VLP-immunized individuals have made anti-VLP antibody responses substantially greater than those identified in natural infections105. HPV serologic assays rely on detection of specific serum immunoglobulin G (IgG) anti-L1 VLP antibodies. Immunogenicity is measured using a specific assay for neutralizing antibodies against epitopes for each HPV genotype. Most studies have used a type-specific competitive Luminex immunoassay (cLIA)106. The results are consistent only with each HPV type and cannot be compared across types. Therefore, the geometric mean titres (GMTs) cannot be directly compared among types. These assays are not readily available and are, at present, only being done by the vaccine's manufacturer.

Immunogenicity and efficacy data are available for women aged 16 to 26 years through the Gardasil™ Phase II and Phase III trials. Immunogenicity data are also available for females aged 9 to 15 years from bridging studies. There are also bridging studies in males. Bridging studies attempt to determine whether the immunogenicity is the same in these younger populations as in the population for which both immunogenicity and efficacy data are available and are used to infer efficacy in the group in which only immunogenicity studies have been conducted. One month after the third dose in the series, almost all (≥ 99.5%) subjects in the studies had seroconverted to all four of the vaccine HPV types. The final antibody titres against all four vaccine HPV types 1 month after series completion (i.e., the third dose) were each 10 to 100 times higher than corresponding antibodies produced by natural infection. The bridging studies revealed that cLIA anti-HPV GMTs in adolescent boys and girls (9 to 15 years of age) were 2 to 3 fold higher than the GMTs in adults. Seroconversion rates in adolescents were over 99% for all four HPV vaccine types.

Efficacy: The efficacy of Gardasil™ was studied in four clinical trials in women 16 to 26 years of age (Table 3)105. This included a Phase II study of a monovalent HPV-16 vaccine107,108, Phase II study109 of the quadrivalent HPV vaccine Gardasil™ and then two Phase III studies105 of Gardasil™. These were randomized, double-blind, placebo controlled studies. The study populations were geographically widespread; subjects were enrolled in North America, Latin America, Europe and the Asian-Pacific regions. Participants had to have had a limited number of lifetime sexual partners (0 to 5 or 1 to 5 depending on the study).

Table 3. Gardasil™ clinical trials*

 

Number of subjects

Protocol

Vaccine

Placebo

005

Phase II monovalent HPV-16

1,193

1,198

007

Phase II quadrivalent HPV-6, -11, -16, -18

280

275

013

Phase III quadrivalent HPV-6, -11, -16, -18

2,717

2,725

015

Phase III quadrivalent HPV-6, -11, -16, -18

6,082

6,075

* Health Canada approved Gardasil™ Product Monograph105

Subjects were enrolled regardless of their baseline HPV status. Subjects identified as already infected with a vaccine HPV type were not eligible for prophylactic efficacy evaluations for that type of HPV, but they were eligible for other evaluations. This type of enrollment allowed for differing evaluations that might approximate how a prophylactic vaccine would be used in a population in which routine HPV detection and typing is not available. In the per protocol efficacy (PPE) evaluation, subjects were HPV naïve at day 1 and remained free of HPV infection throughout the vaccination series (i.e., three doses). Endpoint assessment started 7 months after the first dose (i.e., 1 month after series completion). This would approximate adolescents or adults who received a full course of vaccine prior to exposure to vaccine types. An HPV-naïve modified intention to treat (MITT) provided a supportive analysis. In this analysis, those who were naïve to relevant HPV types at day 1 were included, and case counting began at 1 month after the first dose of vaccine rather than 7 months after series completion. This analysis would approximate adolescents or adults who received one dose or more of vaccine prior to exposure to types of HPV that are contained in the vaccine. Endpoints between month 1 and month 7 were evaluated. A smaller sample of the population did not complete the protocol as specified, received fewer than three doses, had no follow-up after month 7 or were infected during the course of vaccination.

The primary endpoints for HPV-16- and HPV-18-related cervical cancer were HPV-16-related and HPV-18-related cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS). These were surrogate markers for cervical cancer as they are obligate precursors to cervical cancer caused by HR HPV types. Vaginal and vulvar cancer precursor lesions (vulvar intraepithelial neoplasia [VIN] and vaginal intraepithelial neoplasia [VaIN]) were also endpoints that were evaluated, as were genital warts. The follow-up period for the GardasilT Phase III trials was 36 months. Of the women who were enrolled and randomly assigned to conditions, 12% to 16% failed to complete the 3 years of follow-up.

Persistent HPV-6, -11, -16 or -18 infection was also a primary endpoint for analysis. This was defined as follows:

  1. two or more cervical, vaginal or external genital samples collected at consecutive visits at least 4 months apart testing positive by PCR assay for the same viral genotype (HPV-6, -11, -16, -18);

  2. a biopsy specimen showing an HPV-related lesion as well as HPV-6, -11, -16 or -18 DNA detected in the same lesion; or

  3. a cervical, vaginal or external genital sample positive for HPV -6, -11, -16 or -18 DNA at the last visit before being lost to follow-up.

These specific infection endpoints were evaluated in the two Phase II studies. The efficacy of prevention of persistent HPV 6, 11, 16 or 18 at the end of the study (about 2.5 years after series completion) was 89% (95% CI: 73% to 96%)

Efficacy against cervical cancer: In the composite Phase II and Phase III studies, prevention of HPV-16- and HPV-18-related cervical cancer surrogates (CIN 2, CIN3 or AIS) was 100% (95% CI: 93% to 100%) and 99% (95% CI :93% to 100%) in the PPE and MITT analyses respectively (Table 4)105.

Table 4. Gardasil™ clinical trials: efficacy, HPV-16 and HPV-18-related cervical cancer (protocols 005, 007, 013, 015)*

Pop

Endpoint

Gardasil™ Cases
(n = 9,342)

Placebo Cases
(n = 9,400)

Efficacy (95% CI)

PPE

HPV 16/18-related CIN 2/3 or AIS

0

53

100% (95% CI 93-100%)**

 

HPV 16-related CIN 2/3 or AIS

0

44

100% (95% CI 92-100%)

 

HPV 18-related CIN 2/3 or AIS

0

14

100% (95% CI 70-100%)

HN-MITT

HPV 16/18-related CIN 2/3 or AIS

1

81

99% (95% CI 93-100%)

CI = Confidence interval; PPE = Per Protocol Efficacy; HN-MITT = HPV-Naïve Modified Intention-to-treat
CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ
*data on file, Merck Frosst Canada, Dr. James Mansi, December 12, 2006
** Health Canada approved Gardasil™ Product Monograph105

Efficacy against external genital lesions (EGL) including genital warts, VIN and VaIN: In the combined data set from Phase II and Phase III studies, efficacy against EGL related to HPV-6, -11, -16 or -18, including warts, and to VIN and VaIN was 99% (95% CI: 95% to 100%) in the PPE and 95% in the MITT analysis (95% CI: 90% to 98%) (Table 5)105. Slight variations in the dosing regimen did not affect efficacy. The only dosing requirements for inclusion in the PPE population were receipt of three doses of vaccine or placebo within a 1-year time frame. Efficacy was observed uniformly across all the ethnic groups and sexual behaviour patterns and regardless of co-infection with other common STI pathogens.

Table 5. Gardasil™ clinical trials: efficacy against HPV 6/11/16/18-related external genital lesions (EGL) (protocols 007, 013, 015)*

Pop

Endpoint

Gardasil™ Cases
(n = 7,897)

Placebo Cases
(n = 7,899)

Efficacy
(95% CI)

PPE

HPV 6/11/16/18-related EGL

1

113

99% (95% CI 95-100%)

 

HPV 6/11-related EGL

1

97

99% (95% CI 94-100%)

 

HPV 16-related EGL

0

26

100% (95% CI 85-100%)

 

HPV 18-related EGL

0

9

100% (95% CI 50-100%)

 

HPV 6/11/16/18-genital warts

1

91

99% (95% CI 94-100%)**

HN-MITT

HPV 6/11/16/18-related EGL

9

174

95% (95% CI 90-98%)

*data on file, Merck Frosst Canada, Dr. James Mansi, December 12, 2006
** Health Canada approved Gardasil™ Product Monograph(105)

In summary, the prophylactic administration of vaccine had high efficacy in preventing persistent infection with HPV types contained in the vaccine, AIS and CIN 2/3 related to the vaccine types, as well as against EGL such as genital warts, VIN and VaIN.

Duration of protection: A subset of participants (n = 241) in the Phase II quadrivalent HPV vaccine study (protocol 007) has been followed for 60 months after dose 1 with high sustained vaccine efficacy and no evidence of waning immunity (Table 6)105,110.

From the peak antibody titres 1 month after dose 3, there is a detectable decline in antibody levels until about month 18, when the titres appear to plateau for the rest of the 5-year follow-up period. This plateau is well above the titres observed in women who have had naturally acquired HPV infection for types 11 and 16 but is approximately the same as for natural infection for types 6 and 18 (Figure 3)105.

Table 6. Efficacy of Gardasil™ over 5-year follow-up for per protocol participants (protocol 007)

Endpoint

Gardasil™ n

Gardasil™ Cases

Placebo n

Placebo Cases

Efficacy (95% CI)

Infection or disease

235

2

233

46

96% (95% CI 84-100%)

Infection

235

2

233

45

96% (95% CI 83-100%)

Disease

235

0

233

6

100% (95% CI 12-100%)

CIN 1-3

235

0

233

3

100% (<0-100%)

Condyloma

235

0

233

3

100% (<0-100%)

Endpoints by HPV type

 

 

 

 

 

HPV 6

214

0

209

17

100% (95% CI 76-100%)

HPV 11

214

0

209

3

100% (95% CI <0-100%)

HPV 16

199

1

198

28

97% (95% CI 79-100%)

HPV 18

224

1

224

11

91% (95% CI 36-100%)

Two vaccine cases:

  • HPV 18 infection at months 12 and 18, subsequent time points tested HPV DNA-negative
  • HPV 16(+) at the last visit on record (month 36) without confirmed persistence

*Adapted from Villa LL, Costa RLR, Petta CA et al.(110)

Figure 3. Antibody titres (cLIA) following vaccination or natural infection

Figure 3. Antibody titres (cLIA) following vaccination or natural infection

* Data on file, Merck Frosst Canada, Dr. James Mansi, 29 November, 2006

Efficacy in women who have had previous HPV infection or have current HPV infection: Because participants were enrolled into the clinical trials even if they were HPV DNA or antibody positive, it was possible to evaluate vaccine efficacy against cervical cancer surrogate CIN 2/3 in women already infected with a vaccine type at the time of vaccination. At baseline, 27% of participants in the clinical trials had evidence of past or current infection with a vaccine HPV type. There was no clear evidence that this vaccine protected against disease caused by HPV types for which the subjects were already seropositive and/or HPV DNA positive105. The use of prophylactic vaccine does not prevent the consequences of current HPV infection.

No efficacy has been demonstrated against disease due to HPV types not contained in the vaccine.

Vaccine safety and adverse events

Detailed safety data were acquired in clinical trials by use of a daily diary for 14 days after each injection. Table 7 lists the vaccine-related adverse experiences that were observed among female recipients of Gardasil™ at a frequency of at least 1.0% and at a greater frequency than observed among female placebo recipients. GardasilT is safe and well tolerated. Local injection site reactions included pain, redness or swelling and were reported more often among the recipients of the vaccine than among the recipients of the placebo. The majority (94%) of injection-site adverse experiences reported in female recipients of Gardasil™ were mild to moderate in intensity (Table 7)105. Systemic adverse events such as headache or fatigue were reported by a similar proportion in the vaccine and placebo recipients.

Table 7. Vaccine-related injection site and systemic adverse experience in female study participants*

 

Gardasil™
(n = 5,088) %

Aluminum-Containing Placebo
(n = 3,470) %

Saline Placebo
(n = 320) %

Adverse Experience (1 to 5 Days Postvaccination)
Injection Site

Pain

83.9

75.4

48.6

Swelling

25.4

15.8

7.3

Erythema

24.6

18.4

12.1

Pruritus

3.1

2.8

0.6

 
 

Gardasil™
(n = 5,088) %

Placebo** (n = 3,790) %

AdverseExperience(1 to15 Days Postvaccination)
Systemic

Fever (≥37.8oC)

10.3

8.6

Nausea

4.2

4.1

Dizziness

2.8

2.6

Diarrhea

1.2

1.5

* Health Canada approved Gardasil™ Product Monograph(105)
** Aluminum and non-aluminum containing placebo.

Serious adverse events were rarely related to the vaccine. The proportions of subjects reporting a serious adverse event were similar in the vaccine and placebo groups, as were the types of serious adverse event reported. There were five serious events among 11,640 Gardasil™ vaccine recipients and two among 9,578 placebo recipients that were considered possibly, probably or definitely related to the injection. The five in the Gardasil™ group were bronchospasm (possibly related), gastroenteritis (possibly related), headache/hypertension (defintely related), vaginal hemorrhage (probably related) and injection site pain/ movement impairment (probably related). There was no evidence that vaccination resulted in allergic reactions or other immune-mediated diseases.

During the course of the combined studies involving 21,464 male and female participants, 10 subjects in the vaccine group and seven in the placebo group died. None of these deaths were considered to be vaccine related. Deaths were due to trauma, suicide, pulmonary embolus, infection, cancer, a complication of cesarean section and an arrhythmia105.

New medical conditions: There was no difference between the vaccination and placebo groups with respect to development of new medical conditions during the course of the studies.

Vaccination during pregnancy: During the course of the Phase III studies there were 1,115 subjects who became pregnant in the Gardasil™ group and 1,151 in the placebo group. Pregnancy was an exclusion criterion for entering the trial, but these women were found to be pregnant during the study. Further vaccination was delayed until completion of the pregnancy. The proportion of spontaneous abortion was similar in both groups (26%). Congenital anomalies were noted in 15 of the vaccine group and 16 in the placebo group. None were considered to be related to the vaccine. These rates of congenital anomalies were the same as in surveillance registries.

Vaccination during breastfeeding: Breastfeeding during the vaccination period was reported by 995 subjects (500 in the vaccine, 495 in the placebo group). Seventeen (3.4%) of the breastfeeding infants in the Gardasil™ group and nine infants (1.8%) in the placebo group experienced a serious adverse event. However, these were mainly respiratory infections, gastroenteritis or diarrhea, and none were thought to be vaccine related.

Dosage and schedule

Gardasil™ is given as three separate 0.5 mL doses. The vaccine should be administered as an intramuscular injection in the deltoid muscle or the anterolateral upper thigh using a 0, 2 and 6 month schedule. The minimum interval between the first and second dose is 1 month.

Interrupted vaccine schedules

If the Gardasil™ vaccine schedule is interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be given as soon as possible, and the second and third doses should be separated by an interval of at least 12 weeks. If only the third dose is delayed, it should be administered as soon as possible.

Simultaneous administration with other vaccines

Concomitant administration of Gardasil™ vaccine and hepatitis B vaccine at all three doses does not diminish the response or GMTs to either vaccine. Studies with conjugate meningococcal vaccine and with adult/adolescent formulations of tetanus, diphtheria and acellular pertussis vaccines (Tdap) are under way.

Gardasil™ is not a live vaccine and has no components that have been found to adversely affect the safety or efficacy of other vaccines. Therefore, Gardasil™ vaccine can be administered at the same visit as other age-appropriate vaccines, such as the adolescent/ adult formulation of Tdap and meningococcal conjugate vaccines. Administering all indicated vaccines together at a single visit increases the likelihood that adolescents and young adults will receive each of the vaccines on schedule. Each vaccine should be administered using a separate syringe at a different anatomic site.

HPV testing

Currently, type-specific screening methods to determine whether an individual is currently or has previously been infected with HPV are not yet routinely used. Therefore, routine HPV testing is not recommended before or after immunization. In addition, serologic tests are not routinely available in Canada.

Contraindications and precautions

Gardasil™ is contraindicated for persons with a history of hypersensitivity to yeast or to any of the vaccine's components. Despite a theoretic risk for allergic reaction to vaccine in persons with allergy to Saccharomyces cerevisiae (baker's yeast), no adverse reactions have been documented after vaccination of persons with a history of yeast allergy.

Recommended use

  1. Females between 9 and 13 years of age. Gardasil™ is recommended for females between 9 and 13 years of age, as this is before the onset of sexual intercourse for most females in Canada, and the efficacy would be greatest. While efficacy of the vaccine in this age group has not been demonstrated, the immunogenicity bridging data implies that efficacy would be high.

  2. Females between the ages of 14 and 26 years would benefit from Gardasil™, even if they are already sexually active, as they may not yet have HPV infection and are very unlikely to have been infected with all four HPV types in the vaccine. It is therefore recommended that females in this age group receive the vaccine. However, women who are already sexually active may be infected with an HPV type contained in the vaccine, and there is no readily available screening method to determine this. Therefore, these women need to be aware of the possibility that they are already infected.

  3. Females between the ages of 14 and 26 years who have had previous Pap abnormalities, including cervical cancer, or have had genital warts or known HPV infection would still benefit from Gardasil™. These women may not have had infection with the HPV types included in the vaccine and are very unlikely to have been infected with all four HPV types contained therein. It is therefore recommended that these women receive the vaccine. However, they should be advised that there are no data to suggest that the vaccine will have any therapeutic effect on existing cervical lesions.

  4. Females > 26 years. Studies of Gardasil™ vaccine use in women > 26 years are ongoing. No recommendations can be made for the use of the vaccine in this age group at this time, although its use can be considered in individual circumstances.

  5. Females < 9 years of age. Immunogenicity or efficacy is not known for females < 9 years of age nor is the duration of protection from this vaccine. The vaccine is not recommended for this age group.

  6. Males. While immunogenicity data are available for boys and men, the efficacy of Gardasil™ vaccine in males is as yet unknown. The vaccine cannot be recommended for males at this time.

  7. Immunocompromised persons. Because Gardasil™ is a subunit vaccine, it can be administered to persons who are immunosuppressed as a result of disease or medications; however, the immunogenicity and efficacy in this population are not known, and individuals should be aware that immune response to the vaccine might be less than that in persons who are immunocompetent.

  8. Pregnancy. Gardasil™ vaccine is not recommended for use in pregnancy. Although the vaccine has not been causally associated with adverse outcomes of pregnancy or adverse events to the developing fetus, the data on vaccination in pregnancy are limited. Until further information is available, initiation of the vaccine series should be delayed until after completion of the pregnancy. If a woman is found to be pregnant after initiating the vaccination series, completion of the three-dose regimen should be delayed until after pregnancy. If a vaccine dose has been administered during pregnancy, there is no indication for any intervention.

Other considerations

Cervical cancer screening in women who have received quadrivalent HPV vaccine: While Gardasil™ has been shown to be highly effective against cancer precursors caused by HPV-16 and 18, these two HR types of HPV are responsible for about 70% of cervical cancer. Women who have been vaccinated will still be susceptible to other HR HPV types. Even if those types are less prevalent than HPV-16 or 18 these women should still expect to take part in the currently recommended cervical cancer screening programs.

Women who were already sexually active before receiving vaccine may already have been infected with HPV-16 or 18, and therefore any sexually active woman should continue to take part in the routine cervical cancer screening program.

As more females receive the vaccine the screening programs may be modified in either type and/or frequency of screening. This is an area requiring careful research and surveillance before guidelines can change.

Research questions: The knowledge and infrastructure gaps in Canada related to how the HPV vaccine can be best used was the subject of a Canadian HPV Vaccine Research Priorities workshop in late 2005. The results of the workshop are posted at:
http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/06vol32/32s1/index.html
and were published in the CCDR111. The 10 research questions ranked the most highly were as follows:

  1. Most efficient way to deliver an HPV vaccination program

  2. Knowledge, attitudes and beliefs and acceptability of HPV vaccination programs in recipients, providers, parents

  3. Vaccine program delivery costs

  4. Immunogenicity of two-dose HPV vaccine schedule

  5. Impact of vaccination programs on cervical screening programs

  6. How to promote HPV vaccine in an acceptable and effective way

  7. Co-administration with other vaccines and effect on safety and immunogenicity

  8. Economic burden of HPV-related diseases and conditions in Canada

  9. Efficacy/effectiveness of a two-dose HPV vaccine schedule

  10. As vaccine programs progress, what will be observed with cervical screening programs.

As the immunogenicity and efficacy in the immunocompromised population is not known, this is an important area for further research. In addition, more information regarding Aboriginal populations would be of assistance.

Infrastructure gaps

It is essential for evaluation of vaccine effectiveness and the impact on cervical cancer screening that Pap smear screening databases, cervical cancer registries and vaccine registries be developed and linked. These would need to be accessible and linked in order to maximize the ability to do accurate clinical service delivery and program evaluation.

In addition, networks of researchers and mathematical modelers from the different disciplines of HPV disease evaluation, cervical cancer screening and treatment, public health and vaccinology would need to be expanded.

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* Members: Dr. M. Naus (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Tan, Dr. B.Warshawsky.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. D. Money (SOGC), Dr. P. Orr (AMMI Canada), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. J. Smith (CDC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE).

Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB), Dr. J.W. Anderson (DND).

†This statement was prepared by Simon Dobson, Shelley Deeks and Deborah Money. NACI gratefully acknowledges the work of Robert Lerch, Maritia Gully and Jay Onysko for their contribution to the development of the statement.


[Canada Communicable Disease Report]