Reports

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Based on articles from: CMAJ August 2007;177(5):Online 1-4 Maclean’s Magazine August 27, 2007, pp. 38-42

August 2007

Editorial Overview:

Alex Ferenczy, MD Professor of Pathology and Obstetrics and Gynecology McGill University and the Sir Mortimer B. Davis-Jewish General Hospital Montreal, Quebec

and

Eduardo L. Franco, PhD Director, Division of Cancer Epidemiology Professor of Epidemiology and Oncology McGill University Montreal, Quebec

A commentary by Lippman et al. (CMAJ 2007, August 1:177(5):Online 1-4) has raised a number of issues concerning the use of the quadrivalent human papillomavirus (HPV) vaccine as recommended by the National Advisory Committee on Immunization (NACI) and supported by the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the Society of Gynaecologic Oncologists of Canada, paramount among which is the uncertainty concerning the vaccine’s ability to prevent HPV-related disease. The Canadian Cancer Society also applauded the $300 million allocated by the federal government for the HPV vaccination program, calling it a “positive development” in the fight against cancer. Federal regulatory officials in this and 80 other countries as well have approved the vaccine based on results from randomized, placebo-controlled trials—the highest standard available—involving approximately 27,000 participants of which a subset of women was followed for at least 5.3 years. Based on these studies, the vaccine is currently approved for use in females between nine and 26 years of age for the prevention of cervical, vulvar and vaginal cancer, as well as precancerous lesions at these sites and genital warts.

Keeping in mind that the approval of the vaccine was based on the ability of the vaccine to reduce HPV-related disease and not the incidence of persistent HPV infection, key findings from primarily the FUTURE I (Females United to Unilaterally Reduce Endo/Ectocervical Disease) and FUTURE II trials follow:

• Overall efficacy data based on four clinical trials demonstrated that vaccination of young women was 96% to 100% effective in preventing cervical, vulvar and vaginal precancerous lesions as well as genital warts related to the four vaccine types.

• Results held true for women who were naïve to all four HPV types at baseline, as well as women who had not been exposed to at least one of the target types.

• Of those women who were seronegative and who received all three doses of the vaccine, the vaccine was 100% effective in preventing vaginal, vulvar, perineal and perianal intraepithelial lesions and genital warts caused by vaccine-type HPV. The vaccine was also 100% effective in preventing cervical intraepithelial neoplasia (CIN) grades 1 to 3 as well as adenocarcinoma in situ from vaccine HPV types.

• The vaccine was 95% effective against all grades of external anogenital or vaginal lesions combined; 98% effective against all grades of cervical lesions combined; and 91% effective against high-grade vulvar or vaginal lesions in women who were naïve to vaccine types at study entry but whose Pap smear results may have been abnormal on day 1 and who may have incurred protocol violations. It was also 100% effective against adenocarcinoma in situ in the same cohort.

• Even among real-world women who may have had vaccine-type HPV infection or disease prior to vaccination and who may have also sustained protocol violations, the vaccine was 73% effective against all vaccine-type HPV-related grades of external anogenital or vaginal lesions combined, and 55% effective against all grades of cervical lesions combined, regardless of HPV types.

• Immune responses in all of these trials were either the same as or higher than those found in women who had been infected naturally with HPV. A booster dose at five years significantly increased the already high immune response levels seen at that time. This indicates that the immunogenicity of the vaccine persists for at least five years, demonstrating an immune memory response.

It is also important to appreciate that the vast majority—over 70% of the cohort involved in these studies—were naïve to HPV infection at baseline. The remainder had already been exposed to between one and four of the HPV vaccine types. However, of this subgroup, the majority were only “non-naïve” to one of the four types, meaning that only 0.1% of sexually active women enrolled in these clinical trials had neutralizing HPV antibodies to all four HPV types contained in the quadrivalent vaccine.

It was this finding that prompted NACI to recommend young women be vaccinated not only prior to their sexual debut but following initiation of sexual activity because chances of any woman being infected with all four vaccine types are remarkably low, at least up to 26 years of age. NACI also recommends vaccination for females even if they have already had an abnormal Pap smear or other evidence of HPV infection. Currently, both the quadrivalent and the bivalent vaccine against HPV types 16 and 18 are being evaluated in women up to the age of 55, as it is believed they will prevent HPV infection in these women as well. Even in this cohort, there are more women who are naïve to all four HPV types than partially naïve or non-naïve.

Much was made over the potential safety of the quadrivalent vaccine in a recently published Maclean’s article (August 27, 2007, pp. 38-42). As active participants in the vaccine studies or as individuals intimately familiar with their development and design, we can reassure physicians that no untoward side effects were seen with the quadrivalent vaccine in the pivotal clinical trials. There were some transient effects, including fever, headache and elevations in blood pressure; injection-site reactions were also predictable and as expected with any intramuscular injection.

But among all of the women who received the vaccine, there was only a 0.04% incidence of severe side effects and no vaccine recipient developed any major side effect which impaired their well-being. There were some deaths during the vaccine trials, but none were attributable to the vaccine. Also, the incidence of post-marketing adverse events including severe types is not higher than what is expected in vaccinees in general and no adverse event has been related to the vaccine itself.

Thus, there is absolutely no doubt in our minds that the data upon which the quadrivalent vaccine was approved by both our and many other regulatory officials is of excellent quality and that it can indeed be concluded the quadrivalent vaccine is immunogenic, efficacious and safe.

CERVICAL CANCER NOT THE SOLE ISSUE

The authors of the CMAJ commentary also pointed out that only about 400 women die from cervical cancer each year in Canada, making it the 13th most common cause of cancer-related death. They also maintain that both the incidence of and mortality from cervical cancer has been declining over past decades. But as the SOGC countered in response to the CMAJ commentary, cervical cancer is the second most common cancer in young Canadian women between the ages of 20 and 44, precisely at a time when women arguably are the most active in society and certainly most valuable to their children and families.

Statistics Canada reports that on average, 128 Canadian women die from vulvar or vaginal cancer each year. It is also estimated that between 325,000 and 400,000 abnormal Pap smears are generated every year here in Canada and many women will be required to proceed to colposcopy, biopsies and treatment as a result. Furthermore, an estimated 36,000 new cases of genital warts occur each year, resulting in some 85,000 medical consultations. Anyone who treats genital warts knows that the treatment course is frequently prolonged, that the warts often recur and that the psychological effects of having genital warts—the majority of which occur in young adults—can be potentially devastating. In one study in which Canadian investigators are now evaluating the psychological impact of genital warts, preliminary results suggest that their psychological impact is actually greater than that associated with an abnormal Pap test.

Relatively recently, it has also been estimated that between 25% and 30% of oral cancers seen in the upper aerodigestive tract are caused by HPV, particularly HPV 16, and that while rare, 100% of laryngeal papillomas in infants are caused by HPV types 6 or 11 infection. Treatment of these growths is frequently complex and can be associated with significant morbidity and psychological distress for both the child and the parent.

Then there is the argument concerning Pap screening and its ability to keep the mortality rate in check. In Canada, this holds true for women who are the least likely to develop cervical cancer but it does not protect women who are most likely to develop the disease, namely, the poor, the poorly educated and the marginalized. It is they who now develop cervical cancer in disproportionate numbers, even when Pap screening is widely available, as it is in many countries outside of Canada. Although cervical cancer rates might have decreased over the years, one must realize that among cancers, it is the one—along with head and neck cancers—that causes the greatest hardship to the patient and her family as she dies. Contrary to the CMAJ commentary that invasive cervical cancer usually follows a slowly progressive course, its natural history is actually among the most rapidly progressive of all cancers. It can lead to an extremely painful death, as many of us who have witnessed patients with terminal disease can sadly attest. It is probably the worst form of cancer death; it produces a foul smell, excruciating pain and loss of vital functions. Cervical cancer, unlike others, robs a woman’s dignity.

As concerns HPV-related penile and anal cancer, it is known that males are vectors of HPV and that they are capable of transmitting the virus not only to females but to men who have sex with other men as well. Currently, the incidence of anal cancer among gay men is about the same as the incidence of cervical cancer among women who do not undergo Pap tests. If men are HIV-positive, their risk of anal cancer is doubled. Given these epidemiological realities, it is likely that even selected uptake of the HPV vaccine by young gay men will be associated with a substantial decrease in anal, penile and other HPV-related cancers in men.

PREVENTING FUTURE DISEASE

Authors of the CMAJ commentary correctly point out that most HPV infections clear spontaneously: within two years, approximately 90% of infections are gone. But during this two-year window, people remain highly infectious—in fact, HPV is the most frequent sexually transmitted infection (STI) in individuals between the ages of 15 and 24 years, 100 times more infectious than HIV, for example. It can be on the same order of magnitude as some bacterial STIs, including gonorrhea and chlamydia.

Unlike most other STIs, HPV can also be transmitted through skin-to-skin contact, and continued transmission most assuredly will contribute to the burden of disease all around. If, on the other hand, we consider what could happen should HPV vaccination be taken up as currently recommended by the NACI, reductions in all HPV-related disease burden—not just cervical cancer—could be dramatic. For example, estimates suggest that up to 70% of genital warts could be prevented in as little as three years following the introduction of vaccination programs in 12-year-old girls.

Depending on the age at which females are vaccinated, a reduction in precancerous disease could take perhaps a decade but there is no doubt that widespread uptake of these vaccines will lead to substantial reductions in precancerous anogenital disease and its inevitable sequelae. The emergence of accurate HPV-DNA testing, expected to supplant Pap cytology as a screening test in the not-too-distant future, could also reduce the need for Pap testing by up to 90%, which has staggering implications in terms of healthcare costs alone. (Consider that the detection and management of these lesions costs roughly $500 million a year in Canada already.)

A more immediate impact on the incidence of precancerous lesions could also be observed should older women take advantage of “catch-up” HPV vaccination as recommended by the NACI. Some concerns were raised about the duration of immunity and the subsequent need for booster vaccination. However, if we look to other subunit vaccines such as the hepatitis B vaccine, we know that patients who were vaccinated decades ago still have nearly 100% protection after 20 years.

Although the longest period of observation following vaccination with the quadrivalent vaccine is only 5.3 years, immunological responses are still holding steady and it is not inconceivable that protective antibody levels to HPV may similarly persist for decades, if not for life.

SUMMARY

CMAJ authors concluded that more research is needed before introducing a mass vaccination program against HPV. This viewpoint is not shared by other experts in the field who reviewed the same data, and who concluded that current evidence supports implementation of HPV vaccination programs for disease prevention now. Ideally, HPV programs will eventually be established so as to reach the very individuals who require protection but who are most unlikely to receive it. And while we agree that we must continue to monitor the effects of HPV vaccination over the long term, universal uptake of HPV vaccination could have an extraordinary impact on the burden of HPV-related disease, the expense of managing that disease and the psychological cost that HPV infection currently inflicts on individual patients.