HPV Vaccination in Québec: Knowledge Update and Expert Panel Proposals
The human papillomavirus (HPV) belongs to the Papillomaviridae family, which includes at least 100 genotypes affecting the skin and mucous membranes. Of these, about 40 affect the anogenital area in particular, and approximately 15 are oncogenic. Genotypes 16 and 18 are responsible for 70-76% of cervical cancer cases worldwide. Genotypes 6 and 11 are non-oncogenic but are responsible for most cases of condyloma (anogenital warts [AGW]).
HPV prevalence and incidence data are estimated on the basis of epidemiological studies and are better documented in women than men. HPV prevalence varies widely by geographic region, age, the selected subpopulation and HPV detection method. In women, the overall age-adjusted prevalence of genital infections worldwide is estimated at 11.7%. It peaks in young women aged 20-24 and declines subsequently with age. The risk of acquiring HPV infection is particularly high in the first few years after sexual activity begins. According to some estimates, more than 70% of sexually active women will contract an HPV infection at some time in their lives. Among men, the prevalence of genital infection is just as high, if not higher, but varies less with age.
HPV is usually transmitted sexually, and the risk of contracting the infection is largely determined by sexual behaviour, including the number of sexual partners. While the infection is common in the population, the majority of infections will clear spontaneously. A persistent infection increases the risk of progression to cancer, but this process takes many years, which explains why cervical cancer is rare before the age of 30 and practically non-existent before the age of 20. The precursor stages of cervical cancer can be detected by cytological screening (Pap test), and there are effective treatments for halting the progression to cancer. However, over half of cervical cancer cases are currently associated with inadequate screening.
A number of cancers are caused by HPV. In Québec, from 2004 to 2007, there were an average of 281 new cervical cancer cases and 69 deaths per year. HPV is also associated with a certain proportion of cancers of the anogenital area, including cancers of the anus (83%), vulva (66%), vagina (70%) and penis (49%). It is also found in cases of oropharyngeal cancer (47%) and, to a lesser extent, in cancers of the oral cavity (16%) and larynx (14%). HPV 16 is the genotype most frequently associated with these types of cancer.
When the proportion of cancers attributable to HPV and especially to genotypes 16 and 18 (as estimated from the data in the literature) is applied to those cancers associated with HPV1 that were reported during the 2004-2007 period, the number of potentially vaccine-preventable cancer cases is 356 per year in women and 179 in men. Excluding cancers of the oral cavity and larynx (whose causal link with HPV infection is still under study), the number of potentially preventable cancers is 339 in women and 129 in men.
In estimating this clinical burden, one must also include the substantial resources allocated to cervical cancer screening. Over 1 million cervical cancer screening tests are performed every year in Québec, not to mention the resources devoted to the assessment of abnormal results and the treatment of precursor stages.
The non-oncogenic HPV types also contribute to the burden of disease. AGW, usually associated with genotypes 6 and 11, affect both men and women with peak incidence observed before the age of 30. In Canada, only Manitoba and British Columbia currently have population-based data on the incidence and prevalence of this disease, estimated from the number of medical visits for the condition. In Manitoba, women aged 20-24 (5.7/1,000 person-years) and men aged 25-29 (4.6/1,000 person-years) had the highest rates. In British Columbia, between 1998 and 2006 the standardized incidence rate was 1.3/1,000 person-years among men and 1.2/1,000 person-years among women. Applying these data to the Québec population yields an estimated 14,000 cases of AGW diagnosed annually in Québec men and women.
Recurrent respiratory papillomatosis (RRP), which is also associated with genotypes 6 and 11, can affect both adults and young children. In Canada, the incidence of the juvenile form is estimated at 0.24 per 100,000 child-years among children under the age of 14 (there are approximately two new cases per year in Québec). While rare, the disease can lead to a high level of morbidity and repeated surgery in some individuals.
Vaccines
Immunogenicity
The two HPV vaccines approved for use in Canada have proven to be immunogenic in the short and medium term. Both vaccines are more immunogenic and better tolerated when administered in preadolescence and adolescence. Two doses of the bivalent or quadrivalent vaccine administered at 6-month intervals to individuals aged 9-14 induce antibody titres similar to or higher than those observed after three doses of vaccine administered to individuals aged 15-26 in whom clinical efficacy has been demonstrated. There are no important differences in vaccine immunogenicity between males and females of the same age. Most of the data from clinical studies conducted by the vaccine manufacturers are difficult to compare. Only one study directly compares the immunogenicity of the two vaccines, and it shows that the bivalent vaccine is more immunogenic for HPV 16, HPV 18 and certain other HPV types (HPV 31, HPV 33, HPV 45) closely related genetically to the two included in both vaccines. However, the quadrivalent vaccine induces additional immunity against HPV 6 and HPV 11, which are responsible for non-cancerous lesions associated with HPV (primarily AGW and RRP).
Efficacy
Vaccine efficacy data are limited to individuals aged 15 and over. In women, both vaccines have proven efficacious in preventing:
- cervical, vulvar and vaginal cancers and their precursors caused by HPV 16 and HPV 18, and
- cervical adenocarcinoma in situ.
In both males and females the quadrivalent vaccine is also efficacious in preventing AGW caused by HPV types 6 and 11 as well as anal cancers and their precursors caused by HPV 16 and HPV 18.
Approval of the vaccines for individuals under the age of 15 has been based exclusively on bridging immunogenicity studies.
Vaccine efficacy appears to decline with age at administration. There are two possible explanations for the decline in efficacy with age: 1) a weaker immune response and 2) a higher percentage of individuals who are infected before receiving the vaccine.
The duration of clinical vaccine efficacy as currently known is at least nine years in females and at least three years in males.
There are no head-to-head comparisons of the efficacy of the two vaccines. The study eligibility criteria, the point at which infections and lesions are counted, and the way in which the results are analyzed and presented are different for the two vaccines. In the medium term, some fairly similar cohort analyses show excellent efficacy of both vaccines against persistent infections and lesions due to the HPV types included in the vaccine. Both vaccines have also shown some degree of cross-protection. The existing data seem to show greater cross-protection after administration of the bivalent vaccine. The duration of protection against the vaccine HPV types and the duration of cross-protection are still unknown.
The population-level impact of immunization two to four years after implementation of a program with the quadrivalent vaccine has been reported for AGW. Ecological data from some sexually transmitted disease clinics in Australia show a decrease of up to 90% in the percentage of individuals with a diagnosis of AGW. While it is difficult to extrapolate these data to the general population, they do indicate the possibility that implementing a vaccination program with the quadrivalent vaccine will result in a considerable decrease in AGW within a relatively short period of time.
There have been relatively few studies on the efficacy of a reduced number of doses. However, the limited available data on the immunogenicity and efficacy of schedules that include only two doses are encouraging.
The efficacy of both HPV vaccines in reducing the number of cytological abnormalities and subsequent procedures has also been demonstrated and ranges from 20% to 33%.
It is plausible that both HPV vaccines protect against certain non-anogenital cancers associated with HPV 16 and HPV 18 and that the quadrivalent vaccine protects against RRP as well. However, there are currently no clinical data on the impact of vaccination on these diseases.
On the basis of the existing data, the two HPV vaccines approved for use in Canada are efficacious in the short and medium term, and both could be used in the publicly funded vaccination program. However, only the quadrivalent vaccine protects against AGW.
Safety
Both vaccines are well tolerated. Mild and moderate injection site reactions are apparently more frequent following administration of the bivalent vaccine. There is no increase in adverse reactions with the number of vaccine doses administered.
Acceptability, feasibility and ethical issues
Acceptability
Recent data show that the majority of both the general public and health care professionals favour the vaccination of girls aged 9-17. They also approve of vaccinating boys, as well as women aged 18-26. The cost of the vaccine is the greatest barrier, and a physician's recommendation is the most decisive factor in the acceptability of vaccination.
In Québec, in 2010-2011, HPV vaccine coverage rates in elementary grade 4 and Secondary III (grade 9) exceeded 75%, indicating high acceptability of vaccination among parents for their daughters and among teenaged girls.
The results of the survey of Québec health care professionals, while requiring cautious interpretation because of the low response rate, indicate significant interest in the vaccination of boys, although women aged 18-26 were selected as the first priority if the publicly funded vaccination program were expanded.
Feasibility
Organizing the delivery of vaccination services is a major challenge for any vaccination program aimed at women in the 18-26 age group, who generally cannot be reached through school-based programs. However, the vaccination of school-aged boys appears to be easier to achieve. Indeed, expanding HPV vaccination to the entire school population rather than targeting just girls could be done fairly easily. In both cases, it would be essential to devote more effort to informing and educating the public and health care professionals about the important role of vaccines in preventing diseases caused by HPV, and it can be assumed that vaccine coverage in boys would be comparable to that in girls.
Ethical issues
Several ethical issues have already been raised in connection with HPV vaccination. More issues will arise with approval of the bivalent vaccine for girls and women aged 10-25 and of the quadrivalent vaccine both for women over the age of 26 and for boys and young men aged 9-26.
First, the lack of a publicly funded HPV vaccination program aimed at women over the age of 18 and at young men raises ethical issues of social justice. As well, there are risks of stigmatization if, for epidemiological or logistical reasons, HPV vaccines were offered free of charge only to certain subgroups of the population (men who have sex with men [MSM] and HIV-positive individuals). Lastly, choosing the objective of the publicly funded vaccination program could raise the issue of whether it adheres to the principle of utility (cost/benefit).
Economic analyses
School vaccination for girls with the bivalent or quadrivalent vaccine is highly cost-effective, and the cost-effectiveness ratio of the quadrivalent vaccine continues to be lower than that of the bivalent vaccine in almost all the scenarios that have been analyzed, assuming that vaccine costs are equal.
In all the scenarios analyzed, the cost-effectiveness ratio of vaccinating only girls with the bivalent or quadrivalent vaccine is below the generally accepted Québec cost-effectiveness threshold. The existing vaccination program for girls is therefore considered cost-effective. In almost all these scenarios, the estimated cost-effectiveness ratio for the bivalent vaccine is higher than for the quadrivalent vaccine, assuming that vaccine costs are equal. The difference is mainly attributable to the burden of AGW prevented with the quadrivalent vaccine. The bivalent vaccine would therefore have to cost less than the quadrivalent vaccine in order for it to represent an economically worthwhile alternative to the quadrivalent vaccine.
Adding the vaccination of boys to the existing vaccination program for girls would likely not be cost-effective and would provide very few additional benefits to women and heterosexual men; most of the benefits would go to MSM.
The analyses predict that in heterosexual men, there will be a significant reduction in the burden related to diseases caused by HPV through the indirect protection (herd immunity) conferred on them by the vaccination of girls with the quadrivalent vaccine. Most of the benefits of the vaccination of boys would go to MSM, who presumably are unprotected by the vaccination of girls but who represent a small percentage of the male population. For all the scenarios considered, the economic analyses predict that adding the vaccination of boys to that of girls would result in cost-effectiveness ratios far higher than the generally accepted Québec threshold.
Proposals
The objective that most of the participants in the Ad Hoc Scientific Committee agreed on is the following:
Reduce the incidence, morbidity and mortality of cancers, precancerous lesions and other diseases associated with HPV.
The Committee believes that the available information on the immunogenicity and clinical efficacy of the quadrivalent HPV vaccine and the preliminary results of Phase IV studies in other countries demonstrate that the Québec program, consisting of routine vaccination of girls in grade 4 and a catch-up program up to the age of 18 with a quadrivalent vaccine, will be effective in reducing the burden of precancerous lesions and cancers attributable to HPV, as well as AGW, in the target population. The vaccine coverage currently achieved (± 80%) in girls is also expected to have a considerable indirect impact on the male heterosexual population, with respect to both AGW and certain cancers. Modelling results also indicate that the program will be cost-effective (< $20,000/quality-adjusted life-year [QALY]) on the basis of the standards generally accepted in Québec.
Replacing the quadrivalent vaccine (Gardasil®) with the bivalent vaccine (CervarixTM) would mean abandoning the goal of preventing diseases caused by HPV types 6 and 11, such as AGW and potentially laryngeal papillomatosis. However, the prevention of cancers would be slightly improved should the bivalent vaccine confer greater cross-protection against certain oncogenic types. Economic analyses conducted in Québec show that to be as cost-effective as the quadrivalent vaccine, the bivalent vaccine would have to cost considerably less. The majority of the members of the Ad Hoc Scientific Committee expressed reservations about the possibility of abandoning protection against AGW (both in girls through direct protection and in boys through herd immunity). Abandoning such protection could also trigger negative reactions from health care professionals and the public. On the other hand, replacing the quadrivalent vaccine with the bivalent vaccine could minimize program costs should the bivalent vaccine prove to cost significantly less than the quadrivalent vaccine.
The efficacy of the quadrivalent vaccine in men has been well demonstrated. However, adding universal vaccination of preadolescents would have only a marginal impact on the male heterosexual population, as long as vaccine coverage in the female population is maintained. The major benefit of a free vaccination program for boys would be to reduce the burden of AGW and certain cancers in men who will later have sexual relations with men, because they will have been vaccinated at the time when vaccine efficacy is highest (i.e. Before the start of sexual relations). However, at the current cost of the quadrivalent vaccine, extending the program to all preadolescent boys in order to provide more protection to a minority of them would not be cost-effective (> $180,000/QALY) according to generally accepted standards. A free vaccination program for all boys could be justified by political and equity considerations, primarily with respect to MSM, but not by arguments of significant epidemiological impact or efficiency of the program. In the event of a substantial reduction in the cost of the quadrivalent vaccine, such conclusions could change.
Extending the existing program in order to provide free vaccination to women aged 18 and over would probably have a limited impact on the burden of diseases caused by HPV in this population. The magnitude of the reduction is difficult to determine for each age group. Vaccine efficacy declines when vaccination takes place after the start of sexual activity. Approximately 50% of women aged 18-20 are already vaccinated, since they have been targeted by the catch-up program since 2008. Extending the existing program would be quite expensive, because three doses of the vaccine would have to be administered outside the school environment. The cost-effectiveness ratios of such an extension would definitely be less favourable than those achieved by the existing school-based program aimed at girls under the age of 18. There is also considerable uncertainty about the feasibility of such an addition to the program and the level of vaccine uptake that could be achieved.
The implementation of pilot projects for targeted vaccination of MSM could be explored, since free vaccination of all preadolescents is not an efficient strategy with the current cost of the vaccines. The scientific evidence suggests that the effectiveness of such a strategy, whereby the vaccine would in most cases be administered after the start of sexual relations, may be limited. Furthermore, the feasibility, acceptability and cost of such a program have not been carefully evaluated. Studies would have to be conducted to examine these aspects.
The vaccination of certain other population subgroups deemed at greater risk of acquiring HPV-associated diseases (e.g. Aboriginal people) or of experiencing complications (e.g. people with certain chronic diseases) could also be explored. A careful and specific analysis of this issue, which was not possible within the framework of this advisory report, should be understaken.
1The term “cancers associated with HPV” refers here to a whole category, even though not all the cancer cases in this category are caused by HPV.
