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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 70th Annual Clinical and Scientific Conference of the Society of Obstetricians and Gynecologists of Canada (SOGC)

Niagara Falls, Ontario / June 10-13, 2014

Niagara Falls, Ontario - Human papilloma virus (HPV) vaccines have been widely accepted as a primary prevention strategy in children and adolescents prior to their sexual debut before they are exposed to HPV. Less well accepted is the need for primary prevention in older individuals who may have already been exposed to HPV but who risk continued exposure as long as they are sexually active. It has now been established that efficacy following vaccination with the quadrivalent vaccine remains robust in mid-life women. The same vaccine has also been shown to significantly protect mid-life women who have already been exposed to or who have been treated for HPV-related disease from recurrence. Since family physicians are the gatekeepers of primary prevention, it falls to them to initiate discussion about HPV vaccination in patients who stand to benefit from the vaccine and recommend it where appropriate. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec                                                                                   

As the gatekeepers of primary prevention, family physicians are in an excellent position to advocate for the sexual health of their mid-life female patients. This includes prevention of sexually transmitted diseases (STDs), the human papilloma virus (HPV) infection being paramount among them. According to the Centers for Disease Control and Prevention (CDC), HPV infection is the most common of all STDs and nearly all sexually active men and women will be exposed to some type of HPV during their lifetime. Consistent condom use attenuates the risk of HPV exposure but it does not completely eliminate it, a fact that sexually active females may not know.

Clinical trial programs with the quadrivalent and the bivalent HPV vaccines have shown remarkable efficacy of both vaccines against HPV vaccine type-related disease including genital warts and cervical, vulvar and vaginal precancerous lesions and cancer with the quadrivalent vaccine, and cervical cancer and precancerous lesions with the bivalent vaccine. The quadrivalent vaccine containing HPV types 6, 11, 16 and 18 is being widely used in school-based vaccination programs for females between 9 and 26 years of age but it is also approved for use in women up to 45 years of age.

The bivalent vaccine containing HPV types 16 and 18 has similarly been approved for females between 10 and 25 years of age and on up to 45 years of age. The first question primary care providers (PCPs) themselves may need to know the answer to is: Can the vaccine still offer protection against HPV infection in older, sexually-active women? Muñoz et al. (Lancet 2009;373:1949-57) were the first to report that the quadrivalent vaccine was more than 90% effective against disease or infection related to HPV types 6, 11, 16 and 18 in women between 24 and 45 years of age with no history of genital warts or cervical disease at baseline (per-protocol analysis).

More realistically, in a sexually-active population, what about older women who have very likely been exposed to HPV in the past? After reviewing all available literature on oncogenic HPV infection and the risk of developing cervical cancer in women over 25 years of age, Castellsague et al. (Gynecologic Oncology 2009;115:S15-23) concluded that HPV vaccination is “likely to be beneficial” due to the continuing risk of acquiring new HPV infections and of developing cervical intraepithelial neoplasia (CIN) and invasive cancer as long as women remain sexually active.

This holds true even for women who have already been exposed to oncogenic HPV types 16 and 18. In a reanalysis of the phase III PATRICIA study (Int J Cancer 2012;131:106-16), Szarewski et al. reported that vaccine efficacy (VE) was 69% in women who had no evidence of HPV type 16/18 infection (DNA negative) at baseline but who had serological evidence of previous HPV types 16/18 exposure, noted Dr. Laurie Elit, Professor of Obstetrics and Gynecology, McMaster University and division head, gynecologic oncology, Hamilton Health Sciences Centre, Hamilton. In women who were HPV type 16/18 DNA negative at baseline, regardless of their HPV types 16/18 serological status, the same reanalysis showed that VE was about 92%. In women who were DNA positive for one vaccine type or the other, the vaccine was again efficacious against the other vaccine type.

The only group in which the bivalent vaccine offered virtually no protection against CIN2+ disease was women who were infected with both HPV types 16 and 18 at the time of vaccination, as Dr. Elit observed. Similar findings were reported by Olsson et al. for the quadrivalent vaccine (Hum Vaccin 2009;5:696-704). In a subset of women in the pivotal quadrivalent vaccine program, over 2600 subjects were HPV seropositive but DNA negative for 1 or more vaccine types at enrollment.

At an average follow-up of 40 months, no subject who received the quadrivalent vaccine developed disease related to vaccine HPV type to which they were seropositive at enrolment—suggesting that immune response to the quadrivalent vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types over time, as the authors noted. What about women who’ve undergone a colposcopy and have been treated for HPV-related disease?

Evidence again supports the benefit of giving the vaccine to women with prior HPV-related disease. During the quadrivalent vaccine program, 2054 participants received cervical surgery (587 vaccine recipients and 763 placebo patients) or were diagnosed with genital warts or vulvar or vaginal intraepithelial neoplasia. In this group, as reported by Joura et al. (BMJ 2012:344:e1401), the incidence of any subsequent HPV-related disease was reduced by over 46% in vaccine recipients compared with placebo controls.

Vaccination was also associated with a significant 65% reduction in the risk of any subsequent high-grade disease of the cervix and fewer than half of vaccine recipients were subsequently diagnosed with genital warts or vulvar or vaginal intraepithelial neoplasia. Kang et al. (Gynecologic Oncology 2013;130:264-8) also reported that not receiving the quadrivalent vaccine after undergoing loop electrosurgical excision in patients between 20 and 45 years of age was associated with a 7.2% likelihood of recurrent CIN2-3 disease during follow-up compared with a 2.5% risk of disease recurrence for women who chose to be vaccinated.

“Vaccinating the patient who is either sexually active or who has been in colposcopy or who has had treatment for CIN2 or higher lesions is beneficial,” Dr. Elit concluded.

Widespread Uptake

Widespread uptake of the quadrivalent vaccine in school-aged girls across the country is expected to have a major impact on screening for cervical lesions. “This is a very efficacious vaccine,” Dr. Eduardo Franco, Professor of Oncology, Epidemiology and Biostatistics, McGill University, Montreal, said. “And eventually the prevalence of cervical lesions will decrease.” This has already been reported by Australian investigators, as Dr. Franco pointed out during a symposium here this week. Brotherton et al. (Lancet 2011;377:2085-92) for example, recorded a decrease in the incidence in high-grade  adenocarcinoma-in-situ in girls under the age of 18 within 3 years of implementing a population-wide HPV vaccination program. Dr. Franco noted that Canada is already starting to observe the same phenomenon.

In the meantime, Canadian experts are leaning towards current US recommendations in terms of extending the interval between PAP testing and co-testing for high-risk HPV types in certain age groups. Joint US guidelines (Am J Clin Pathol 2012;137:516-42) now recommend:

• Cervical cancer screening begin at age 21 years.
• Screening with cytology alone every 3 years for women between 21 and 29 years of age.
• Preferential screening with cytology and HPV co-testing every 5 years in women between 30 and 65 years of age although screening with cytology alone every 3 years is acceptable in this age group as well.

“We need to be clear that we are the gate keepers for prevention,” Dr. Marc Steben, family practitioner, National Institute of Public Health of Quebec, Quebec City, emphasized. Currently, the need for primary prevention is largely unmet in adult patients—partially because patients themselves don’t know what they need in terms of primary prevention; they don’t ask questions, and don’t feel that they are in an at-risk population, as Dr. Steben suggested.

This means that physicians themselves have to initiate messaging about primary prevention in their sexually active patients, he added. A comprehensive message about HPV vaccination and its benefits in an adult population is part of that primary prevention initiative, Dr. Steben said, as is making sure that those who need screening for HPV infection receive it.

“If you tell patients that you yourself immunize against HPV and show that you support the message not only in words but in deeds, women still take their physician’s recommendations seriously,” Dr. Steben told delegates.  “And most office visits represent an opportunity to initiate vaccination, starting today.”

Final Thoughts

Primary care providers are not only family physicians and general practitioners, for many women, obstetricians and gynecologists (OB/GYNs) provide much of that primary care. Many OB/GYNs do not provide vaccination themselves in their office but as part of their Royal College mandate, Dr. Elit suggested that OB/GYNs can provide patients with the resources they need to avail themselves of the vaccine and at the very least, a prescription for it so that patients can have the script filled by a practitioner who does provide vaccination services. She also agreed with Dr. Steben that if “we believe the vaccine is effective, we need to advocate for it.”  

Based on a symposium during SOGC 2014: "Stop HPV: Steps Toward Optimal Prevention of HPV", Thursday, June 12, 2014 (12:30-1:30), Scotiabank, Convention Centre, in Niagara Falls.

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