Questions surrounding Gardasil

iVillage Member
Registered: 06-05-2008
Questions surrounding Gardasil
3
Wed, 08-20-2008 - 11:19pm

From today's New England Journal of Medicine:
http://content.nejm.org/cgi/content/full/359/8/861

Despite great expectations and promising results of clinical trials,
we still lack sufficient evidence of an effective vaccine against
cervical cancer. Several strains of human papillomavirus (HPV) can
cause cervical cancer, and two vaccines directed against the currently
most important oncogenic strains (i.e., the HPV-16 and HPV-18
serotypes) have been developed. That is the good news. The bad news is
that the overall effect of the vaccines on cervical cancer remains
unknown. As Kim and Goldie1 point out in this issue of the Journal,
the real impact of HPV vaccination on cervical cancer will not be
observable for decades.

Although it was licensed for use in the United States in June 2006,
the first phase 3 trials of the HPV vaccine with clinically relevant
end points — cervical intraepithelial neoplasia grades 2 and 3 (CIN
2/3) — were not reported until May 2007, first in the Journal2 and 1
month later in the Lancet.3,4 The vaccine was highly successful in
reducing the incidence of precancerous cervical lesions caused by
HPV-16 and HPV-18, but a number of critical questions remained
unanswered.5,6 For instance, will the vaccine ultimately prevent not
only cervical lesions, but also cervical cancer and death? How long
will protection conferred by the vaccine last? Since most HPV
infections are easily cleared by the immune system, how will
vaccination affect natural immunity against HPV, and with what
implications? How will the vaccine affect preadolescent girls, given
that the only trials conducted in this cohort have been on the immune
response? The studies with clinical end points (i.e., CIN 2/3)
involved 16- to 24-year-old women. How will vaccination affect
screening practices? Since the vaccines protect against only two of
the oncogenic strains of HPV, women must continue to be screened for
cervical lesions. Vaccinated women may feel protected from cervical
cancer and may be less likely than unvaccinated women to pursue
screening. How will the vaccine affect other oncogenic strains of HPV?
If HPV-16 and HPV-18 are effectively suppressed, will there be
selective pressure on the remaining strains of HPV? Other strains may
emerge as significant oncogenic serotypes.

Resolving the first essential questions will require decades of
observation of large numbers of women. The last question may be
answered sooner. Published reports of trials show an increasing trend
of precancerous cervical lesions caused by HPV serotypes other than
HPV-16 and HPV-18.2,4,6 The results were not statistically
significant, however, possibly because there were too few clinically
relevant end points in the observation periods reported. If
randomized, controlled trials involving vaccinated and unvaccinated
women continue for a few more years, we will most likely be able to
tell whether this is a true trend. If so, there is reason for serious
concern.

By the summer of 2007, there were definitely promising results with
regard to the effectiveness of the HPV vaccine in the prevention of
precancerous lesions (i.e., CIN 2/3) caused by the HPV-16 and HPV-18
serotypes. However, serious questions regarding the overall
effectiveness of the vaccine in the protection against cervical cancer
remained to be answered, and more long-term studies were called for
before large-scale vaccination programs could be recommended.5,6
Unfortunately, no longer-term results from such studies have been
published since then.

In the meantime, there has been pressure on policymakers worldwide to
introduce the HPV vaccine in national or statewide vaccination
programs. How can policymakers make rational choices about the
introduction of medical interventions that might do good in the
future, but for which evidence is insufficient, especially since we
will not know for many years whether the intervention will work or —
in the worst case — do harm? One way to provide decision support is to
develop mathematical models of the natural history of the disease in
question, introduce various intervention strategies, and use
cost-effectiveness analysis to estimate the costs and health benefits
associated with each clinical intervention. The results are typically
expressed in terms of the amount we will have to pay for the extra
health benefit of the treatment — that is, in dollars per life-year or
quality-adjusted life-year (QALY) saved. Cost-effectiveness analyses
are tools for decision making under conditions of uncertainty. These
analyses do not in themselves provide evidence that medical
interventions are effective. In this issue of the Journal, Kim and
Goldie present a model of HPV vaccination, and they use a
cost-effectiveness analysis to make projections of the possible health
and economic implications of the use of the vaccine.1

To evaluate the quality of a cost-effectiveness analysis, it is
essential to appraise the model's input variables, the uncertainties,
and the choices the researchers have made. To set up such an analysis
of a preventive medical intervention — in this case, a vaccine given
to healthy 12-year-old girls — that might have an effect on the
incidence of cervical cancer decades from now is extremely complex.
The analysis has to model the natural history of HPV infection in this
cohort of girls over their lifetime, the effect of the vaccine over
all those years (whether it is the same effect or one that is waning),
the effect on other HPV strains, the effect of the vaccine on the
natural immunity against HPV infections, the sexual behavior of the
girls and women and their partners, and finally, women's
cervical-cancer screening practices.

The model presented by Kim and Goldie is well done and ambitious, and
it includes most of these factors. They conclude that under certain
assumptions, vaccinating 12-year-old girls is associated with an
incremental cost-effectiveness ratio of $43,600 per QALY gained,
whereas adding a catch-up program for older girls and women is not
cost-effective. However, their base-case assumptions are quite
optimistic. They presume lifelong protection of the vaccine (i.e., no
need for a booster dose), that the vaccine has the same effect on
preadolescent girls as on older women, that no replacement with other
oncogenic strains of HPV takes place, that vaccinated women continue
to attend screening programs, and that natural immunity against HPV is
unaffected. Whether these assumptions are reasonable is exactly what
needs to be tested in trials and follow-up studies. If the authors'
baseline assumptions are not correct, vaccination becomes less
favorable and even less effective than screening alone. For example,
as shown in the article, if the protection of the vaccine wanes after
10 years, vaccination is much less cost-effective and screening is
more effective than catch-up programs.

With so many essential questions still unanswered, there is good
reason to be cautious about introducing large-scale vaccination
programs. Instead, we should concentrate on finding more solid answers
through research rather than base consequential and costly decisions
on yet unproven assumptions.

No potential conflict of interest relevant to this article was reported.

Source Information

From the Journal of the Norwegian Medical Association, Oslo.

References

Kim JJ, Goldie SJ. Health and economic implications of HPV vaccination
in the United States. N Engl J Med 2008;359:821-832.
The FUTURE II Study Group. Quadrivalent vaccine against human
papillomavirus to prevent high-grade cervical lesions. N Engl J Med
2007;356:1915-1927.
Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic
adjuvanted bivalent L1 virus-like-particle vaccine against infection
with human papillomavirus types 16 and 18 in young women: an interim
analysis of a phase III double-blind, randomised controlled trial.
Lancet 2007;369:2161-2170.

Ault KA. Effect of prophylactic human papillomavirus L1
virus-like-particle vaccine on risk of cervical intraepithelial
neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined
analysis of four randomised clinical trials. Lancet
2007;369:1861-1868.
Baden LR, Curfman GD, Morrissey S, Drazen JM. Human papillomavirus
vaccine -- opportunity and challenge. N Engl J Med 2007;356:1990-1991.

Sawaya GF, Smith-McCune K. HPV vaccination -- more answers, more
questions. N Engl J Med 2007;356:1991-1993.

This article has been cited by other articles:

(2008). HPV Vaccination: Is It Cost-Effective?. JWatch Women's Health
2008: 1-1

iVillage Member
Registered: 12-14-2005
Thu, 08-21-2008 - 11:16am

"However, their base-case assumptions are quite optimistic. They presume lifelong protection of the vaccine (i.e., no need for a booster dose), that the vaccine has the same effect on
preadolescent girls as on older women, that no replacement with other oncogenic strains of HPV takes place, that vaccinated women continue to attend screening programs, and that natural immunity against HPV is unaffected. Whether these assumptions are reasonable is exactly what needs to be tested in trials and follow-up studies. If the authors' baseline assumptions are not correct, vaccination becomes less favorable and even less effective than screening alone. "

Now that was a semi-refreshing read ;)

1) Acknowledgment that the vaccine might not confer life-long protection. (Remember the just one shot measles campaign for life long immunity)

2) The vaccine might not have the same affect on different cohorts

3) That natural immunity can be affected by vaccination

3) That often strains will mutate to continue their survival

About time!






iVillage Member
Registered: 06-05-2008
Thu, 08-21-2008 - 12:37pm
This was on the evening news last night. And not too long ago, CBS evening news did a not so nice story on vaccines. Is the tide starting to turn alittle in our favor? Just maybe? I sure hope!
iVillage Member
Registered: 12-14-2005
Thu, 08-21-2008 - 12:41pm

Only if they start to talk about all those issues wrt. to all the other vaccines NOT just HPV.

Though I have to say - if you visit playgroup and EC boards on IV that it would appear more people are seeking to delay, selective vaccinate or not vaccinate at all.

There is certainly a more heightening awareness but where that will lead I think it's too early to predict. :-\