Human papillomavirus, vaccines and women's health: questions and cautions

We were disturbed by unfounded criticisms by Lippman et al. about HPV vaccination recently published in CMAJ [1]. We have followed the development and testing of HPV vaccines and new cervical cancer screening technologies, such as HPV testing, with much appreciation for the science propelling the evidence that will ultimately revolutionize cervical cancer control. The points of disagreement between our views, as McGill University epidemiologists working on cervical cancer etiology and prevention, and those in the commentary [1] are simply too many to fit in a letter. We trust that arguments against the commentary’s ill-conceived conclusions will be given by eminent groups such as the Society of Obstetricians and Gynaecologists of Canada and Society of Gynaecologic Oncologists of Canada, as well as by Canada’s National Advisory Committee on Immunization, all of which issued favourable positions concerning HPV vaccination. To summarize, we echo the concluding remarks from the meta- analysis of Rambout and Colleagues [2]: ”Vaccination appears to be well tolerated and safe. Data to help reconcile the gap between the impressive vaccine efficacy demonstrated in these trials and the potential effectiveness of vaccination at reducing the global burden of cervical cancer and death from the disease should be forthcoming from phase IV trials currently underway”.

As with most new vaccines, cost is a concern. With time, competition and economies of scale make vaccination policies more affordable. A paradigm change in cervical cancer screening based on the use of HPV testing technology is likely to take place in synergy with HPV vaccination and will help the case for cost-effectiveness [3]. Surely there are lessons to be learned but adjustments in policies can be made as the emerging science produces its dividends. What cannot be dismissed, however, is the fact that the quality and quantity of evidence already accrued in favour of HPV vaccination is just as good, if not better, than that for preventive strategies in any other area of cancer control. Seemingly cautious arguments to the effect that we do not know enough about vaccination of girls and adolescents are irrelevant and untenable. The vaccines have been (i) thoroughly tested in women at risk of HPV exposure (ages 15- 25 years) and proven safe and efficacious; (ii) immunobridging studies have shown that the immune response in adolescents is stronger than that in young and old adults; and (iii) to be of maximal benefit in reducing cervical cancer burden in the future vaccination should focus on pre- exposure prophylaxis. The argument about herd immunity is not yet one that we can use in cervical cancer prevention. Eventually, phase IV trials may point to policy revisions and male vaccination could become a complementary prevention strategy in the future. As for the argument that cervical cancer will not develop in most women infected with oncogenic HPVs, it ignores basic cancer epidemiology. Most smokers will not develop lung cancer, yet we hold smoking cessation in high esteem as cancer prevention target. More importantly, one can develop lung cancer despite never having smoked but an infection with an oncogenic HPV type is a necessary precursor for cervical cancer. Incidentally, safe sex is practically an oxymoron when it comes to preventing HPV infection; condom use is not protective [4].

Finally, we take issue with the argument that there is no cervical cancer epidemic in Canada to justify a sense of urgency in adopting new policies. Low fertility, universal access to care, and intensive screening with the relatively inefficient Pap test have collectively contributed to keep cervical cancer rates low in Canada, but the enormous cost and morbidity resulting from frequent screening and management of cervical cancer precursors are seldom appreciated. By analogy, childhood cancer mortality has declined but not fast enough. We believe one would not be arguing against a new federal policy that could reduce cancer risk in children by 50%-70%. Cervical cancer strikes relatively young women compared with other cancers. The 400 Canadian women who die of cervical cancer every year suffer unbearable pain, loss of function and form, and see their dignity slip away as the disease progresses and treatment fails. Pelvic exenteration, a heroic act by gynecology oncologists trying to rescue cervical cancer patients with locally advanced disease, is one of the most gruesome and complex among all surgical procedures and is psychologically devastating. No health economic analysis can assign a proper value to these procedures or, to the patient, the avoidance of what brought them so much suffering.

Eduardo L. Franco, Alexandra de Pokomandy, Andrea R. Spence, Ann N. Burchell, Helen Trottier, Marie-Hélène Mayrand, Susie Lau

Department of Epidemiology, Biostatistics, and Occupational Health McGill University, Montreal, Quebec

References:

1. Lippman A, Melnychuk R, Shimmin C, Boscoe M. Human papillomavirus, vaccines and women's health: questions and cautions. CMAJ. 2007 Aug 1; [Epub ahead of print]

2. Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ. 2007 Aug 1; [Epub ahead of print]

3. Franco EL, Cuzick J, Hildesheim A, de Sanjose S. Chapter 20: Issues in planning cervical cancer screening in the era of HPV vaccination. Vaccine. 2006 Aug 21;24 Suppl 3:S171-7.

4. Burchell AN, Richardson H, Mahmud SM, Trottier H, Tellier PP, Hanley J, Coutlee F, Franco EL. Modeling the sexual transmissibility of human papillomavirus infection using stochastic computer simulation and empirical data from a cohort study of young women in Montreal, Canada. Am J Epidemiol. 2006 Mar 15;163(6):534-43.

Conflict of Interest:

ELF has served as advisor to several companies involved with HPV diagnostics or vaccines. ELF and MHM have received unconditional research grants from Merck-Frosst.

Although there may be “only” 400 deaths annually in Canada from cancer of the cervix, it appears likely that in the long run, approximately 70% of these deaths could be prevented by current human papillomavirus (HPV) vaccines. If cancer of the cervix was an infection acquired in a more traditional manner and presenting more acutely, an opportunity to prevent that many deaths would be regarded as an irresistible prospect. More frequent screening of high-risk women for cervical intraepithelial neoplasia is suggested as an alternative strategy (1), but first we need a practical solution to the problem that these women classically access health care only during a crisis. The suggestion that promotion of good nutrition and smoking cessation will also be useful for preventing cancer of the cervix is not evidence-based (1).

It is suggested that HPV immunization may provide a false sense of security, encourage risky sexual practices, and discourage regular Pap smears (1). Surely concerns about pregnancy or infection with more commonly recognized sexually transmitted diseases such as human immunodeficiency virus predominate over fears of cancer of the cervix in the choices girls or women make about sexual activity. It seems unlikely they will discontinue having Pap smears unless health care workers promote this idea.

A further concern was that the age group targeted for routine immunization will be younger than in published studies, but here were over 1000 girls in the 9-15 year age group enrolled and their HPV titres were approximately double that achieved in the older age group (2). Accurate cost-effectiveness data will not be obtained until we know how many doses of vaccine are required to offer life-long protection, but extrapolation from preliminary data suggests that if immunity is life-long and efficacy is as predicted, it would cost approximately $162,000 to prevent one case of cancer of the cervix (based on 324 immunized females at a cost of approximately $500 for purchase and delivery of 3 doses of vaccine) (3), which is likely to be cost-effective given the costs of treatment and follow-up and the years of productive life lost to this disease.

References 1. Lippman A, Melnychuk R, Shimmin C, Boscoe M. Human papillomarivus, vaccines and women’s health: questions and cautions. CMAJ 2007;177:484-7. 2. Dawar M, Deeks S, Dobson S. Human papillomavirus vaccines launch a new era in cervical cancer prevention. CMAJ 2007;177:456-61. 3. Brisson M, Van de Velde N, De Wals P, Boily M. Estimating the number needed to vaccinate to prevent diseases and death related to human papillomavirus infection. CMAJ 2007;177:464-8.

Conflict of Interest:

None declared

The Commentary by Lippman et al. 1 on the planned human papillomavirus (HPV) vaccination of Canada’s 9-13 year-old girls raises “questions and cautions” 1 for physicians, parents, and citizens of Canada.

As a physician who trained in the late 1970s with gynecologic oncologist Hugh Allen,2 I have both witnessed the devastating effects of advanced cervical carcinoma and its dramatic reduction due to Pap smear screening.3 As a parent, I would worry that my 9-13 year old daughter (I have sons) could not give “informed” consent to HPV vaccination by herself,4 and, predicated on my feeling that she could be educated to the importance of Pap smear screening and safe sexual practices, and would comply at least with Pap smear screening, advise her that HPV vaccination is not necessarily in her best interest. As a citizen, I believe this important women’s health promotion funding should be designated to better education regarding Pap smear screening and safe sexual practices, as well as beginning public education toward the largely preventable BRCA gene- related breast and ovarian cancers,5 which are more common killers of women.

As a physician, parent and citizen, I support vaccination for “herd immunity”6; however, as a parent, my obligation to my daughter would supercede my obligation to others, and as a physician whose patient asks “What would you do if I (or my daughter) was your daughter?”, unlike my usual response “But you are not my daughter (or wife or sister)”, I would respond “I would be uncomfortable with you being vaccinated against HPV at this time.”

Jeff Nisker MD PhD Professor Obstetrics and Gynecology and Oncology Coordinator Health Ethics and Humanities Schulich School of Medicine & Dentistry University of Western Ontario

References

1. Lippman A, Melnychuk R, Shimmin C, Boscoe M. Human papillomavirus, vaccines and women’s health: questions and cautions. Can Med Assoc J 2007; 177(5): 484.

2. Allen HH, Nisker JA, Anderson RJ. Primary surgical treatment in one hundred and ninety-five cases of stage 1B carcinoma of the cervix. Am J Obstet Gynecol 1982;143(5):581-4.

3. Canadian Cancer Society, National Cancer Institute of Canada. Canadian Cancer Statistics 2007. National Cancer Institute of Canada. Available at http://www.ncic.cancer.ca/vgn/images/portal/cit_86751114/21/40/1835950430cw_2007stats_en.pdf [accessed Aug 29, 2007].

4. Nisker, J. Philip. Can Med Assoc J 2003; 168(6): 246-247.

5. Nisker J. The Need for Public Education: “Surveillance and Risk Reduction Strategies” for Women at Risk for Carrying BRCA Gene Mutations. J Obstet Gynaecol Can 2007; 29(6): 510-511.

6. Colgrove J “The Ethics and Politics of Compulsory HPV Vaccination” NEJM 2006; 355: 2389-2391.

Conflict of Interest:

None declared

The article by Lippman et al (1), regarding larger scale use of human papillomavirus (HPV) vaccine, which advocates a cautious approach to such use, contains several arguments that are not compelling.

Regarding the duration of vaccine-induced protection, other worthwhile vaccines have been introduced before this issue was resolved, e.g. hepatitis B vaccine (2). Withholding HPV vaccine pending resolution (which may take years) would disadvantage a substantial cohort of women.

Whether cervical cancer incidence and mortality warrant "urgency" depends on one's view. We think that 1,350 cases and 390 deaths a year (3), many of which will likely be preventable by vaccine, supports use of this vaccine. Further, while cervical cancer may currently rank (3) 13th and 15th respectively on the list of female cancer incidence and mortality, prevention of the higher 12 or 14 respectively, other than lung cancer and smoking, cannot be as uniquely or effectively targeted.

There is no confusion, at this time, as to the goal of larger scale use of HPV vaccine in Canada: it is to reduce cervical cancer incidence and mortality.

Other interventions, e.g. universal adolescent hepatitis B vaccine and sex education that is not restricted to abstinence, have raised concern regarding increasing unsafe sexual activity. However, to our knowledge, such a result has not been documented (4) and, it is highly suspected, will not happen with HPV vaccine.

While not the primary purpose of HPV vaccination, Lippman does not mention the likely substantial benefit that use of HPV vaccine will have on the incidence of genital warts among females, which cause substantial morbidity, often psychological (5).

HPV vaccine is highly efficacious (6) (for the serotypes in the vaccine) and will likely be highly effective. It should be used in publicly funded programs.

Martin Tepper, MD, MHSc, FRCPC (lead and corresponding author, tepper.ml@forces.gc.ca)

Barbara Strauss, BScN, RN, MSc

James Anderson, MD, MTM&H

Fiann Crane, BScN, RN, MSc

Directorate of Force Health Protection, Canadian Forces Health Services Group Headquarters, 1745 Alta Vista Drive, Ottawa, Ontario, K1A 0K6

The opinions expressed in this letter are those of the authors and not necessarily those of the Department of National Defence.

References:

1. Lippman A, Melnychuk R, Shimmin C and Boscoe M. Human papillomavirus, vaccines and women's health: questions and cautions. CMAJ 2007:177(5) (online at http://www.cmaj.ca/cgi/rapidpdf/cmaj.070944v1 ; accessed on 10 Aug 07).

2. Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Hepatitis B in Canada: the case for universal vaccination. CMAJ 1992;146(11):25-28.

3. Canadian Cancer Society. Canadian Cancer Statistics, 2007 (online at http://129.33.170.32/vgn/images/portal/cit_86751114/36/15/1816216925cw_2007stats_en.pdf ; accessed on 10 Aug 07).

4. Underhill K, Montgomery P and Operario D. Sexual abstinence only programmes to prevent HIV infection in high income countries: systematic review. BMJ 2007;335:248-252.

5. Maw RD, Reitano M and Roy M. An international survey of patients with genital warts: perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 1998;9(10):571-578.

6. Rambout L, Hopkins L, Hutton B and Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ 2007;155(5) (online at http://www.cmaj.ca/cgi/rapidpdf/cmaj.070948v1 ; accessed on 10 Aug 07)

Conflict of Interest:

None declared

I wish to comment on the commentary by Abby Lippman and colleagues which appears in the on-line version of the August issue of CMAJ, “Human papillomavirus vaccines and women’s health: questions and cautions” (1). According to the authors, their commentary was based on a careful review of the literature including that submitted by the manufacturer, Merck. To begin with, I fully agree with the issues raised by the authors about the “unknowns” of Gardasil®, including the duration of immune memory, long term efficacy and safety. These are certainly important issues, although they have been raised before not only by the manufacturer but also, by virtually all investigators who have published on the subject (2). It is comforting to know that there are a large number of ongoing, longitudinal studies worldwide to address these unknowns, the results of which will become available next year and in the years to come (3). On the other hand, I disagree with their suggestion that it is premature to recommend prophylactic HPV vaccination until long term data answers all the questions raised so far. The authors do not specify how long the public should wait for vaccination implementation.

However, I disagree with the authors’ position regarding the scientific merit of the “handful of randomized, controlled trials of efficient quality to qualify for review”. I am one of the members of the Pathology Quality Control Panel responsible for assessing vaccine efficacy in all Merck’s randomized, controlled clinical trials (RCT’s) on Gardasil®. Gardasil® has been studied in 27,000 women aged 15 to 26 years old in 33 countries at 130 investigation sites with the most rigorous design and statistical analysis one can achieve in modern, clinical research. The vaccine’s immunogenicity, safety and efficacy have been documented for 5.3 years not 1.8 years, quoted by the authors with a reference to the New York Times! The efficacy trials were analyzed in both ideal, per protocol as well as per intent-to-treat conditions, the latter being close to a real world situation. In both instances, vaccine efficacy–focused on preventing persistent vaccine-related HPV infections as well as their complications, e.g. high-grade squamous cell lesions and adenocarcinoma in -situ of the cervix, and squamous cell cancer precursors of the vulva and vagina–was over 90% to 100%. The primary objective of efficacy studies was disease rather than HPV infection prevention as per US FDA requirements.

The authors did not mention in their commentary the two other HPV genotypes carried in Gardasil®, namely 6/11. These are responsible for 95% of external genital warts in North America (2). Gardasil® prevented 99% of these lesions compared to placebo. I consider these to be Level I evidence-based studies.

I also disagree with their suggestion that studies independent of the manufacturer’s funding should be conducted to ascertain the true merits of the vaccine. It is true that all clinical trials so far were funded by the manufacturer. It is only normal that the company which developed the product be the first one to evaluate its performance. The same has been done for virtually all pharmaceutical products including penicillin, Aspirin®, Tamoxifen®, etc. To suggest, albeit indirectly, that studies carried out by a manufacturer are automatically biased in favour of the product is against all science. Common sense tells us that if there is a need for a new product, it is in the interest of the manufacturer to make it viable for long term use so that the tremendous amount of intellectual and physical efforts have not been spent in vain and the financial input for developing the product for the market is recovered. If the product proves to be very successful commercially and there is a financial gain for the company, so be it.

If the results of Merck’s randomized, clinical trials would have suffered from major, even minor pitfalls, the US Food and Drug Administration would not have approved Gardasil® and the Advisory Committee on Immunological Practices (ACIP) which advises the US Centers for Disease Control and Prevention would not have recommended it for vaccinating young girls and women aged 9 to 26 years old (4). Essentially, the same recommendations that have been formulated by the ACIP have been made by public health authorities in over 70 countries, including Canada.

Epidemiologists take the big picture approach to public health; however, the big picture is made of individuals. Epidemiologists are not clinicians; they do not face the three to four women diagnosed with invasive cervical cancer and one woman who will be buried due to the disease, every day. We, the physicians in the field, are the ones who deal with the worried patient who receives a positive Pap test and will have to go for colposcopy, cervical biopsies and many times, be subjected to various ablational and excisional therapies. The latter may lead to late gestational abortion or premature delivery (5). The estimated annual burden of HPV-related diagnoses in Canada includes 52,000 cases of new high-grade cervical cancer precursors, 177,000 low-grade cervical lesions and 36,000 external genital warts (6). While we do not know the exact prevalence of cancer precursors of the vulva, we know that most affect young women and require repeated treatments because of multiple recurrences (7). Some of these treatments lead to vulvar disfigurement and psychosexual distress of great severity.

The financial costs of HPV infections of the cervix alone including screening, diagnosing and treatment are substantial, on the order of an estimated $300 million yearly in Canada (7). It is true that cervical cancers and deaths in Canada are relatively rare from an epidemiological point of view; however, these represent 100% of disease for the affected individual. While Pap screening did reduce cervical cancer indeed, for the past 10 to 20 years there is no longer a decline and now it is a highly cost-ineffective means to prevent cervical cancer (8). I agree with Dr. Lippman et al that education on HPV is key to vaccine acceptance. Both healthcare professionals and the public must be alerted to HPV vaccines. HPV infection is one of the least well know STI’s particularly with respect to its relatedness to carcinogenesis of the lower genital and one- third of cancers of the upper aerodigestive tracts (2).

While obstetricians and gynaecologists may be familiar with the natural history of the disease, they are considerably less familiar with vaccines and the reverse is true for paediatricians. The best equipped for taking a large part in prophylactic HPV vaccination may well be the primary care physicians. Clinicians’ acceptance of medical practice in general is largely influenced by medical organization guidelines. The American College of Obstetricians and Gynecologists, the Academy of Family Physicians and the American Academy of Pediatricians all endorsed an HPV vaccination programme (4). Also, the American Academy of Pediatrics (9) and the Department of US Health and Human Services have also formulated HPV vaccination recommendations. These mandate each state in the United States to provide the HPV vaccine to children from low income families. Similar groups such as the National Advisory Committee on Immunization and the Society of Obstetricians and Gynecologists have produced recommendations (10). Why couldn’t we do the same in Canada?

Initially, the fact that a vaccine to prevent cancer was related to an STI caused concern and sometimes total rejection by a small segment of the population. Conservative, religious organizations were very vocal with their opposition fearing that HPV vaccination would lead to increased promiscuity among young teenagers. Following appropriate education, most groups have embraced HPV vaccination. To date, it appears that the population in most countries has accepted the HPV vaccine (11).

Not to introduce school-based, quadrivalent (6, 11, 16, 18) HPV vaccination programmes, at least as a starter for 12-year olds in Canada, is to say we are willing to ignore a vaccine preventable disease which otherwise carries substantial medical and financial costs as well as psychological suffering (12). The sooner we implement prophylactic HPV vaccination programmes, the sooner will we witness the reduction of morbidity, mortality and eventually, healthcare costs. In Merck’s multicountry RCT’s, the overall population impact at 3 years after vaccination in subjects aged 15 to 26 years, including those with previous HPV infection, was 46% and 76% for cervical cancer precursors and genital warts, respectively (13,14). The question really is not whether it is time to implement prophylactic HPV vaccination, rather should vaccination of 12 -year old girls be mandated at school or be on a voluntary basis at parents’ discretion. I agree with Abby Lippman and colleagues that vaccination should fully be supported by public funds and by inference, the $300 million of federal funding recently provided to the Provinces should be earmarked for instituting teen HPV vaccination programmes and funding be maintained for many years to come. In Italy, they have done so for all 12-year olds. The same is true for Australia and some US states, such as New Hampshire. We students interested in this challenging field of investigation consider the discovery and manufacturing of prophylactic HPV vaccines a technological triumph, if not the greatest milestone in cervical cancer prevention since the introduction of the Pap test 50 years ago. The status quo in cervical cancer prevention with Pap cytology alone is no longer acceptable.

References:

1.Lippman A, Melnychuk R, Shimmin C, Boscoe M. Human papillomavirus, vaccines and women’s health: questions and cautions. CMAJ 2007;177(5):online-1-4.

2.Ferenczy A, Franco EL. Prophylactic human papillomavirus vaccines: potential for sea change. Expert Rev Vaccines 2007;6(4):511-525.

3.Lehtinen M, Herrero R, Mayaud P, et al. Chapter 28: Studies to assess the long-term efficacy and effectiveness of HPV vaccination in developed and developing countries. Vaccine 2006 Suppl 24;S233-S241.

4.Centers for Disease Control. Quadrivalent human papillomavirus vaccine. MMWR Recommendations and Reports 56/RR02;1-24, March 23, 2007).

5.Samson S-L, Bentley JR, McKay D, Gill GH. The effect of loop electrosurgical excision procedure on future pregnancy outcomes. Obstet Gynecol 2005;105:325-332.

6.Brisson M, van de Velde N, Boily MC, et al. The health and economic burden of HPV infection, genital warts, cervical dysplasia and cervical cancer in Canada. Presented at the 23rd International Papillomavirus Conference and Clinical Workshop, Prague, Czech Republic, 2006.

7.Bruchim I, Gotlieb WH, Mahmud S, Tunitsky E, Grzywacz K, Ferenczy A. HPV-related vulvar intraepithelial neoplasia: outcome of different management modalities. Int J Gynaecol Obstet, epub April 2007. doi:10.1016/j.ijgo.2007.03.023.

8.Franco EL, Ferenczy A. Is HPV testing with cytological triage a more logical approach in cervical cancer screening? Lancet Oncology 2006;7:527-529.

9.American Academy of Pediatrics Committee on Infectious Diseases. Recommended immunization schedules for children and adolescents-United States, 2007. Pediatrics 2007;119(1):207-208.

10.Gynecologic oncologists strongly endorse NACI statement on HPV vaccination: HPV vaccine now standard of care for Canadian women and girls. http://www.sogc.org/media/pdf/articles/feb107hpvvaccgoce.pdf

11.Olshen E, Woods ER, Austin SB, Luskin M, Baucher H. Parental acceptance of the human papillomavirus vaccine. J Adolescent Health 2005;37(3):248-251.

12.Le T, Hopkins L, Menard C, Hicks-Boucher W, Lefebvre J, Fung Kee- Fung M. Psychological morbidities prior to loop electrosurgical excision procedures in the treatment of cervical intraepithelial neoplasia. Int J Gynecol Cancer 2006;16(3):1089-1093.

13.Garland SM, Hernandez-Avila M, Wheeler CM, and the FUTURE I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. New Engl J Med 2007;356(19):1928-1943.

14.Ault KA, and the Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in-situ: a combined analysis of four randomized clinical trials. Lancet 2007;369(9576):1861- 1868.

Conflict of Interest:

Dr. Ferenczy is a member of Merck's Pathology Panel.

No one would question the overall goal of reducing rates of mortality and morbidity associated with HPV infection and the urge to protect as many young women as possible is very understandable. Nevertheless, there is also the argument that not putting a system in place, capable of monitoring and evaluating an HPV vaccination program, is neither good science nor good public health ethics.

Seen from this perspective, the SOCG Statement is disappointing in not recognizing the importance of tracking what happens as HPV vaccination moves out of research and into use in the general population. A more specific criticism is the lack of support from the SOCG for testing for HPV infection prior to vaccination, (1) ,particularly in view of the new data from Costa Rica showing that women positive for HPV do not benefit from the vaccine. (2) The immediate cost of not testing is that a woman may be vaccinated not knowing that she is already infected and will not be protected. This may not matter if she does not change her regular pattern of screening, but may have serious consequences if she is in her early twenties, sexually active, not part of a monitoring program and goes five years or more without being alerted to her need for a screening test.

Unfortunately, the very high cost of adding HPV testing to the cost of the vaccine, coupled with the even higher costs of a surveillance system, will probably block their adoption. However, the ratio of risk to benefit may look quite different when applied to high risk populations. Canadian data show that the prevalence of HPV varies from 13% to 33% depending on the community. Aboriginal women make up 42% of the group at highest risk. (3) Sadly, their risk for cervical cancer approaches the rates found in some developing countries. Vaccination will help many, but not the women already infected with HPV. A program is needed which is fully comprehensive, has the strong support of Inuit and First Nations women, adequate funding, and a system of monitoring and evaluation acceptable to each community.

1. Canadian Consensus Guidelines on Human Papillomavirus Journal of Obstetrics and Gynecology of Canada, Supplement 3, Volume 29, Number 8. 2007

2. Hildesheim A, Herrero R, Wacholder S, Rodriguez A, Solomon D, et al. Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women with Preexisting Infection. JAMA 2007; 298: 743-753.

3. Canadian Human Papillomavirus Vaccine Research Priorities Workshop, Final Report. November 17-18, 2005, Quebec City. Canadian Communicable Disease Workshop 2006; 3251

Conflict of Interest:

None declared

I was surprised the Canadian Medical Association Journal, a respected peer-reviewed journal, would publish a commentary that focused exclusively on theoretical issues. Given the fact that the commentary is more of a negative visionary opinion piece than a scientific review of clinical evidence on the quadrivalent HPV vaccine and cervical cancer, I trust the editors of the CMAJ will allow me the space required to address with scientific evidence and rigour many of the issues raised.

Is cervical cancer an epidemic? Are we not over reacting by implementing provincial HPV vaccination programs?

The purpose of vaccines is to prevent disease. And while most HPV infections do clear on their own, the burden of HPV disease remains significant. HPV infections annually lead to approximately 400,000 abnormal Pap smear results , 85,000 consultations due to genital warts and 36,000 new cases of genital warts , as well as 1,400 cervical cancer diagnoses and 400 cervical cancer deaths . HPV is also linked to loss of female fertility and premature ovarian failure.

Clinical trials have shown that the quadrivalent HPV vaccine is 96 to 100 per cent effective at preventing infections from the HPV types that cause the most clinical diseases: HPV 6, 11, 16 and 18. These HPV types account for more than 90 per cent of genital warts, approximately 70 per cent of cervical and anogenital cancers and high-grade pre-cancers, 35 to 50 per cent of low-grade cervical, vaginal and vulvar lesions, and all four types cause abnormal Pap test results.

Lippman et al say the goal of the HPV vaccination program is not clear. Is the goal to eradicate high-risk HPV types or to reduce the number of deaths from cervical cancer? As discussed above, cervical cancer is by no means the only issue: the quadrivalent HPV vaccine is indicated for cervical cancer as well as several other diseases associated with HPV types 6, 11, 16 and 18, including vulvar and vaginal cancer, genital warts and the precursors to these diseases. As such, an effective preventative HPV vaccine program combined with ongoing cervical screening would have the ability to significantly reduce the overall burden of HPV related diseases.

What about the “real world” efficacy of the quadrivalent HPV vaccine?

The quadrivalent HPV vaccine is extremely effective at preventing disease, as shown in clinical research data, but does not alter the course of pre-existing infections. For example, in the results of the trials published in the May 10th issue of the NEJM, none of the 2,261 participants receiving the vaccine who were not already infected with the vaccine HPV types developed an HPV-related disease. And in the larger trial, one of the 5,305 participants receiving the vaccine who were not already infected with the vaccine HPV types developed an HPV-related disease. It is clear; the vaccine works when we vaccinate females before they come in contact with the virus that causes these diseases.

In the overall study populations (real life situations), efficacy increases over time as new infections occur in the placebo group but not in the vaccine group. The fact that we are seeing significant differences between the vaccinated and placebo groups in the overall population analyses after a short three years of follow-up, bodes well for the effectiveness of the quadrivalent HPV vaccine in public programs.

Is it really worth vaccinating girls at nine if the vaccine is only effective for five or six years?

Clinical data to date shows that the quadrivalent HPV vaccine is effective for five years and the immune response in nine year old girls was shown to be the strongest. Moreover, there is evidence of strong immune memory, a hallmark for long lasting protection. We continue to follow women in the studies to track longer-term efficacy.

Isn’t the data available about girls in the 9-13 age group thin?

The safety of the quadrivalent HPV vaccine was tested in over 3,000 girls and boys aged nine to 15. It is unethical and of no use to test the vaccine’s efficacy against a sexually transmitted disease in a population that is not likely to be engaging in sexual activity. Most of the participants in the clinical trials were therefore young women aged 16 through 26, the age at which the risk for HPV infection is highest. Since girls 9-13 are generally not sexually active, Health Canada agreed that efficacy findings in 16- to 26-year-olds can be applied to younger adolescents, since the immune response in young girls was higher than in adolescents and adults. This so-called immunogenicity “bridging” is an accepted surrogate for efficacy with most childhood vaccines.

The quadrivalent HPV vaccine is expensive and no cost-effectiveness studies have been carried out.

There have been extensive cost-effectiveness analyses of HPV vaccines from across the globe, all suggesting vaccination represents a cost- effective addition to cervical screening .One such cost-effectiveness analysis was conducted by Dr. Marc Brisson, who holds the Canada Research Chair in Mathematical Modeling and Health Economics of Infectious Diseases at Laval University. In it, Canadian age and type specific data for infection, cervical dysplasia, cancer and genital warts was modeled. This study suggests that vaccinating adolescent girls against HPV is likely to be cost-effective under current Pap testing programs in Canada.

Will HPV vaccination lead to reductions in safe sex practices and Pap screening?

There is no reason to believe that Canadians will think that an HPV vaccine will prevent all sexually transmitted diseases. As for Pap tests, Merck Frosst has always promoted a three-pronged approach: education, vaccination and continued Pap tests. In fact, we believe the vaccine has done much to raise awareness about the importance of Pap tests, what they are for and the relation between Pap testing and HPV. In a recent Ipsos- Reid survey, almost all (98%) Canadian parents knew that the vaccine is not a substitute for regular pap testing and recognized that pap testing for protection against cervical cancer is still necessary, even with the HPV vaccine.

Do we really need an HPV vaccine to prevent cervical cancer? Isn’t sex education and Pap screening enough?

We must first reiterate that the quadrivalent HPV vaccine is indicated for cervical cancer as well as several other diseases associated with HPV types 6, 11, 16 and 18, such as vulvar and vaginal cancer, genital warts and the precursors to these diseases.

Despite incredible advances in communication over the last 20 years and the vast improvement of Pap screening programs, according to the Society of Obstetricians and Gynaecologists of Canada, the incidence of cervical cancer is on the rise in Canada. And a study done by the Canadian Association for Adolescent Health (CAAH) showed that despite the extensive effort to communicate the importance of condoms, one quarter of sexually active adolescents failed to use a condom the last time they had sex.

Moreover, the trend in the incidence and prevalence of anogenital warts in Canada are on the rise over the past 20 years an indication that preventive measures comprised primarily of sexual education have been unsuccessful in stymieing the tide. Whereas, in excess of ninety percent of anogenital warts have been attributed to HPV -6 and -11, vaccination of pre-sexually active teens would have a very rapid impact on ano-genital warts8.

As stated previously, Merck Frosst therefore advocates a three- pronged approach: education, vaccination and continued Pap tests.

Could short-term immunity alter the natural history of the infection, such that the disease reappears to a different degree later in life?

As outlined in the CMAJ commentary, Lippman et al highlight the importance of the long-term duration of the immune response from a HPV vaccine. This is indeed an important consideration, however, at the start of any vaccination program, it is impossible to say whether boosting will be required; that is the role and the importance of post-vaccine surveillance. What we do know is that antibody concentrations remain from 10 to 20 times that found in natural infections for at least 5 years post- vaccination. Moreover, there is evidence that the vaccine elicits a strong immune memory, the later being the hallmark for long-term protection.

What about the marginalized and most vulnerable groups in society?

As expressed earlier, Merck Frosst is supportive of a national, three -pronged approach to battling HPV-related diseases: education, vaccination and continued Pap tests. We must execute on these three levels if we wish to reach all women across the country. As with evaluating the long-term duration of protection and the theoretical risk of type replacement or changes in the natural history of the infection, post-vaccine surveillance will evaluate the effective implementation of the vaccine for everyone.

Let me remind readers that Merck & Co. is conducting several studies to assess long-term safety and duration of efficacy, including following 35,000 subjects to evaluate general safety and pregnancy outcomes. A pregnancy registry will further monitor pregnancy outcomes in women who received the quadrivalent HPV vaccine. In addition, 5,500 trial participants will be followed throughout their lifetimes. Evaluation of the long-term safety and duration of efficacy of the quadrivalent HPV vaccine is also part of the Nordic Cancer Registry Program. Pap test and biopsy results can be tracked very closely in Scandinavia, where governments require reporting of results by national ID number.

In conclusion, the CMAJ-published Commentary destabilizes the public's confidence in the rigour of our national recommendations and expert opinions while adversely impacting women's health initiatives. The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public health advice relating to immunization and, as such, has recommended that all females aged 9 to 26 should receive the quadrivalent HPV (6, 11, 16 and 18) vaccine. This statement was endorsed by our country's leading medical societies namely, the Society of Obstetricians and Gynaecologists of Canada, the Gynaecologists Oncologists of Canada and the Society of Canadian Colposcopists. Immunization with the quadrivalent HPV vaccine coupled with proper education, continued Pap testing and ongoing post vaccination surveillance is the new standard of care in our country. ------------------------------------------------------------ References:

Statement by the Society of Obstetricians and Gynaecologists of Canada (SOGC) on CMAJ Commentary, “Human papillomavirus, vaccines and women’s health: questions and cautions”. (Accessed on August 14, 2007 at: http://www.sogc.org/media/guidelines-hpv-commentary_e.asp)

Brisson, M et al. The health and economic burden of HPV infection, genital warts, cervical dysplasia and cervical cancer in Canada. Presented at the 7th Canadian Immunization Conference (CIC) on December 3, 2006 in Winnipeg.

Public Health Agency of Canada, Cervical Cancer Screening in Canada: 1998 Surveillance Report, Executive Summary. (Accessed at http://www.phac- aspc.gc.ca/publicat/ccsic-dccuac/exec_e.html).

Statement by the Society of Obstetricians and Gynaecologists of Canada (SOGC) on CMAJ Commentary, “Human papillomavirus, vaccines and women’s health: questions and cautions”. (Accessed on August 14, 2007 at: http://www.sogc.org/media/guidelines-hpv-commentary_e.asp)

Efficacy of a Prophylactic Quadrivalent Human Papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine for Prevention of Cervical Dysplasia and External Genital Lesions (EGL). Presented by C. Sattler at the 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, DC.

Merck & Co. Q&A document developed for the ACIP Meeting and dated June 29, 2006.

Barnabas, R.V., Kulasingam, S.L.Economic Evaluations of Human papillomavirus vaccines, Expert Rev pharmacoeconomics Outcomes Res. 7(3) 2007.

Brisson, M et al., The potential cost-effectiveness of prophylactic human papillomavirus vaccines in Canada, Vaccine 25, 2007, 5399-5408.

Statement by the Society of Obstetricians and Gynaecologists of Canada (SOGC) on CMAJ Commentary, “Human papillomavirus, vaccines and women’s health: questions and cautions”. (Accessed on August 14, 2007 at: http://www.sogc.org/media/guidelines-hpv-commentary_e.asp)

Sexual Behaviour and Lack of Knowledge Threaten Health of Canadian Teens. Press release issued by Canadian Association for Adolescent Health (CAAH) on February 21, 2006.

Kliewer EV, Demers A, Elliott L, Brisson M. Twenty Year Trends (1985 -2004) in the incidence and prevalence of anogenital warts in Manitoba, Canada: Preliminary Results. In: 23rd International Papillomavirus Conference (Abstract P-341) 2006

Briefing Document presented to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the US FDA on May 18, 2006.

Conflict of Interest:

None declared

In May of 2007 Judicial Watch, a United States based public interest watchdog, reported 1,637 adverse reactions including three girls who died shortly after receiving the HPV vaccine.

Judicial Watch obtained the reports from the U.S. Food and Drug Administration using the Freedom of Information Act.

In Australia, 25 girls who had just received their first injection of the vaccine experienced headache, nausea, and dizziness. In some cases, the problems were so severe that they were hospitalized.

Shares of the vaccine's Australian developer, CSL, fell after the incident was reported in the Australian news media. (British Medical Journal June 92007;334:1182-1183)

The United States Food & Drug Administration and Health Canada meed to be held to account as to why they have allowed Merck to use a potentially reactive aluminum containing placebo as a control for most trial participants, rather than a non-reactive saline solution placebo.[1] A reactive placebo can artificially increase the appearance of safety of an experimental drug or vaccine in a clinical trial. Gardasil contains 225 mcg of aluminum and, although aluminum adjuvants have been used in vaccines for decades, they were never tested for safety in clinical trials. Merck and the FDA did not disclose how much aluminum was in the placebo.[2]

Animal and human studies have shown that aluminum can cause nerve cell death [3] and that vaccine aluminum adjuvants can allow aluminum to enter the brain, [4 5] as well as cause inflammation at the injection site leading to chronic joint and muscle pain and fatigue. [6 7] Nearly 90 percent of Gardasil recipients and 85 percent of aluminum placebo recipients followed-up for safety reported one or more adverse events within 15 days of vaccination, particularly at the injection site.[8] Pain and swelling at injection site occurred in approximately 83 percent of Gardasil and 73 percent of aluminum placebo recipients. About 60 percent of those who got Gardasil or the aluminum placebo had systemic adverse events including headache, fever, nausea, dizziness, vomiting, diarrhea, myalgia. [9 10] Gardasil recipients had more serious adverse events such as headache, gastroenteritis, appendicitis, pelvic inflammatory disease, asthma, bronchospasm and arthritis.

A vaccine should not only be effective but above all, it should be safe. The latter is simply not the case with the HPV vaccine and its variants now being hyper-marketed in the United States, Canada, Australia and elsewhere by the manufacturer Merck and its foreign licensees.

1. Merck & Co., Inc. 2006. Gardasil [Quadrivalent Human Papillomavirus Types 6,11,16,18) Recombinant Vaccine] product insert. Table 6.

2. Food and Drug Administration. May 18, 2006. FDA Background Document for Vaccines and Related Biological Products Advisory Committee: Gardasil HPV Quadrivalent Vaccine.

3. Kawahara M et al. 2001. Effects of aluminum on the neurotoxicty of primary cultured neurons and on the aggregation of betamyloid protein. Brain Res. Bull. 55, 211-217.

4. Redhead K. et al. 1992. Aluminum-adjuvanted vaccines transiently increase aluminum levels in murine brain tissue. Pharmacol. Toxico. 70, 278-280.

5. Sahin G. et al. 1994. Determination of aluminum levels in the kidney, liver and brain of mice treated with aluminum hydroxide. Biol. Trace. Elem. Res. 1194 Apr-May;41 (1-2):129-35.

6. Gherardi M et al. 2001. Macrophagaic myofastitis lesions assess long-term persistence of vaccine-derived aluminum hydroxide in muscle. Brain, Vol 124, No. 9, 1821-1831.

7. Shingde M eta la. 2005. Macrophagic myofastitis associated with vaccine derived aluminum. MJA, 183 (03):145-146.

8. Merck & Co. May 18, 2006. Merck briefing document for Vaccines and Related Biological Products Advisory Committee: Gardasil. Table 24.

9. Merck & Co., Inc. 2006. Gardasil product insert: Serious Adverse Experiences.

10. Food and Drug Administration. May 18, 2006. FDA Background Document for Vaccines and Related Biological Products Advisory Committee.: Gardasil. Table 32.

Conflict of Interest:

None declared

Research efforts in cancer treatment continue to confirm that the only way to reduce the impact of these diseases is to prevent not to treat cancer. We already see a >75% reduction in the incidence of cervical cancer cases in countries with PAP smear programs versus those without. HPV reduction is likely to impact on the other HPV associated diseases such as Head and Neck, Vulvar and Anal Canal carcinoma; all of these require extensively morbid chemo-radiotherapy treatments for control or cure. Why does there appear to be such resistance to low-morbidity prevention efforts when the human and monetary costs of these diseases is so extensive? A local Gynecologist has informed me that the teenage daughters of the majority of physicians in our community are vaccinated. If that $400 reduces their risk of ever having to see me or one of my colleagues it is a superior investment than a $10,000 chemotherapy that may extend life by 8-12 weeks, in my opinion.

Conflict of Interest:

None declared