2 HPV vaccines, 7 questions that you need answered
The availability of two vaccines against human papillomavirus raises numerous questions about fine points of cervical cancer prevention
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The trials also had different protocols for referral to colposcopy, which would affect disease detection. And the length of follow-up differs between trials.3,9
Dr. Lonky: Can we draw any conclusions about efficacy?
Dr. Smith-McCune: Yes. The trials defined outcomes in several populations of participants. In addition to the overall population (called the “intention-to-treat population” in the Gardasil trials and the “total vaccinated cohort” in the Cervarix trials), the trials defined a subpopulation of women naïve to oncogenic HPV types to gain information about the likely impact of vaccinating girls before the onset of sexual activity. The definitions of these “naïve” populations were slightly different, mainly in the number of HPV types tested, so again, some caution needs to be exercised in making comparisons.
End-of-trial data in the naïve population show a 43% reduction in CIN 3 lesions for Gardasil and 87% for Cervarix (for CIN 3 or worse). By inference, we can tell the sexually naïve patient that vaccination with either vaccine will provide significant protection against CIN 3 lesions, likely to result in significant protection against cervical cancer over time.
We can gather some estimates of efficacy in sexually non-naïve women by looking at results from all trial participants. Gardasil reduced overall CIN 3 lesions by 16% overall; Cervarix reduced CIN 3 or worse by 33%. When counseling an individual patient, if she has had a similarly low number of lifetime sexual partners (e.g., the median number in the Gardasil trials was 2), these results provide an estimate of her likely protection against CIN 3 with vaccination.
Common excisional treatments for cervical dysplasia are known to be associated with adverse perinatal outcomes.17 The ability to reduce the need for these treatments is an important outcome of vaccination. In the HPV-naïve populations, vaccination reduced definitive cervical therapies or excisions by 42% (Gardasil) and 69% (Cervarix). These figures are useful in counseling virginal patients about the long-term benefits of vaccination.
For sexually active patients 26 years and younger, HPV vaccination significantly reduced definitive cervical therapy or excisions by 23% (Gardasil) and 25% (Cervarix). Again, these figures are most applicable for counseling patients who have had relatively few lifetime sexual partners. So the exact extent of protection is likely to vary by the patient’s total number of lifetime sexual partners.
I expect that we will see more data on the effects of vaccination stratified by the number of lifetime sexual partners, because that information would be very useful in counseling individual sexually active women.
Dr. Harper: Both vaccines reduce the rate of abnormal Pap tests by 10% regardless of HPV type in that population of women.9,18
4. Are the two vaccines safe?
Dr. Lonky: What about safety of the vaccines? What do we know?
Dr. Felix: The safety profiles seen in clinical trials of both vaccines are very similar and consist almost entirely of nonserious adverse events.2,9 In the United States, a greater number of Gardasil doses has been administered, owing to its earlier development. As of January 1, 2010, more than 28 million doses had been distributed, and numerous major events had been recorded in the Vaccine Adverse Event Reporting System (VAERS). Of 15,829 adverse events reported, only 8% were considered serious by the CDC. CDC investigation, by expert panels, of all serious adverse events found no evidence linking Gardasil to any of them, including Guillain-Barré syndrome, blood clots, and death.19
Dr. Huh: A few other points to consider:
- The reporting rate for Gardasil is triple that for all other vaccines combined
- Because VAERS is a passive reporting system, under-reporting is distinctly possible
- Post-licensure safety surveillance is still underway
- Both products have pregnancy registries.
Dr. Harper: The current postmarketing commitment between Merck and the FDA is to recognize a rate of serious adverse events that exceeds 2 cases in every 10,000 women in a cohort of 44,000 women who have received all three doses of Gardasil. Although autoimmune neurologic sequelae have occurred after Gardasil administration, regulatory authorities are not required to evaluate these reactions, such as Guillain-Barré syndrome, because the frequency is lower than the agreed-upon threshold. Nevertheless, adverse events could be life threatening to some girls.
Any risk of death—even if it is lower than the agreed-upon threshold—should be presented to women as a possible risk of vaccination with Gardasil. In the United States, the same women could choose a lifetime of Pap screening and be afforded the same protection against cervical cancer as they would get from vaccination.
5. Is quadrivalent better than bivalent?
Dr. Lonky: Why would a clinician choose a bivalent vaccine when the quadrivalent vaccine protects not only against carcinogenic types 16 and 18, but also against HPV-associated genital warts?
