Study Does Not Support
HPV Vaccine in Older Women
By Janis C. Kelly, Medscape.com
Findings from a natural-history study of
human papillomavirus (HPV) have led the
investigators to conclude that the
"potential benefit" of HPV vaccination in
older women (≥42 years) is "low."
The research team, led by Ana Cecilia
Rodríguez, MD, from the Proyecto
Epidemiológico Guanacaste, Fundación
INCIENSA, in San José, Costa Rica, found
that the rate of new HPV infections declines
with age and that new infections usually do
not progress to grade 2 or 3 cervical
intraepithelial neoplasia (CIN) in older
women.
The investigators found that infections at
baseline were more likely to persist in
older than in younger women (P < .01 for a
comparison of 8 groups). Furthermore, most
of the grade 2 or worse CIN disease that was
detected during follow-up (66 of 85 cases)
was associated with infections already
present at baseline.
The 7-year study of Costa Rican women — the
largest ever to examine age, HPV
persistence, and cervical cancer precursors
— was published online February 15 in the
Journal of the National Cancer Institute.
This is a great paper.
"This is a great paper, the longest
follow-up study to date available on women
in a broad age range," said Silvia
Franceschi, MD, who was approached by
Medscape Oncology for independent comment.
Dr. Franceschi, who is coordinator of the
epidemiology and biology cluster at the
International Agency for Research on Cancer
in Lyon, France, noted that there seems to
be very little to gain by vaccinating women
older than 25 years or so.
"The 'dangerous' or persistent infections
may be already there and will not be
eliminated by the current HPV vaccines," she
added. "The pharmaceutical industry's claim
that vaccine should be given to older women
because HPV infections are more dangerous
after a certain age has been proven not to
be true."
More Than 9000 Women, 7-Year Follow-Up in
HPV Study
The researchers screened more than 9000
women, 18 to 97 years, in Costa Rica. Those
with CIN 2 disease or worse at enrollment
were treated and not followed any further.
Among the remaining participants, those at
low risk for CIN 2 or worse were rescreened
at 5 to 7 years (passively followed),
whereas higher-risk participants and subsets
of low-risk women and initially sexually
nonactive women were rescreened annually or
semiannually (actively followed) for up to 7
years.
As noted above, most women diagnosed with
CIN 2 or worse during the study period were
already infected with a carcinogenic HPV
strain (prevalent infection) at the time of
initial testing.
Regardless of the woman's age, most newly
detected HPV resolved and did not lead to
CIN 2 or worse during the study period.
Total cumulative CIN 2+ associated with
newly appearing infections ranged from 2.1%
to 6.2% over the first 3 years of follow-up.
Age-related changes in immunity have also
been a concern, and the data showed that
women older than 34 years were not at
greater risk than younger women for
progression to CIN3+ after 3 years. Newly
detected infections led to a CIN3+ diagnosis
in 0 of 17 women 34 years or older and in 5
of 41 (12.2%) women younger than 34 years.
Furthermore, rates of newly detected HPV
infections declined sharply with age, from
35.9% in women 18 to 25 years to 13.5% in
women 42 years and older in the actively
followed group.
Among infections present at first
examination, persistent infections were more
common among women 42 years or older than
among younger women.
The researchers conclude that cervical
cancer risk is determined by the previous
overt duration of carcinogenic HPV
infections, not by genital warts caused by
HPV 6 or HPV 11, and not by age. New
infections, which are the only type that can
be prevented by currently available HPV
vaccination, carry little near-term cancer
risk at any age, and most of them resolve
within 2 to 3 years, say the investigators.
Vaccinating girls before they become
sexually active reduces the chance that a
new carcinogenic HPV infection will persist
for the 25 to 30 years required to cause
invasive cervical cancer, write the
researchers. However, they remind clinicians
that most HPV infections are benign. "[A]
focus on HPV persistence, and avoidance of
overreaction to HPV infections that are
likely to resolve spontaneously, is
essential for a rational introduction of HPV
testing into cervical cancer screening
programs."
By Age 30, Most Women Already Have HPV
"The HPV vaccines that are available now are
prophylactic," Dr. Rodríguez told Medscape
Oncology. "They can only prevent getting
infected; they do not treat infections that
are already present. In a given population
with an average age at first sexual
intercourse of around 15 to 17 years, to
vaccinate women after the age of 30 is not
cost-efficient."
"By age 30, most women would have been
infected with the HPV types covered by the
vaccines, and women are not getting that
many new infections; therefore, the residual
benefit provided by the vaccine is very
small," she added.
We were surprised by the distinct
persistence pattern observed for the group
of prevalent infections among women 42+
years of age.
"We were surprised by the distinct
persistence pattern observed for the group
of prevalent infections among women 42+
years of age. For all other prevalent
infections and for all incident infections,
regardless of the woman's age, the chance of
persistence was very similar," Dr. Rodríguez
said. Persistence for 6 or more years of
carcinogenic HPV infections detected by
polymerase chain reaction (PCR) at baseline
was 5.1% in women 18 to 25 years of age,
14.4% in women 26 to 33 years of age, 12.2%
in women 34 to 41 years of age, and 18.2% in
women 42 years or older. This was the key
element that supported the authors'
conclusion that previous infection duration,
not a woman's age, determines subsequent
risk.
This raises the question of whether there
might be possible residual benefit of
vaccination at older ages to prevent
reacquisition of HPV types that were
apparently cleared when the woman was
younger. "Thus far, there is some evidence
that reappearance of previously cleared
infections is a very rare event and that
those that reappear do not carry high risk
for CIN 2+, but this requires confirmation,"
Dr. Rodríguez said.
HPV Screening Interval Should Probably Be
2.5 Years or Longer
This study offers some guidance on HPV
screening. Dr. Rodríguez told Medscape
Oncology that HPV screening data must be
interpreted according to the frequency of
screening, rather than the woman's age.
A single HPV-positive finding in a screening
program must be not cause for alarm at any
age.
"A single HPV-positive finding in a
screening program must be not cause for
alarm at any age," Dr. Franceschi said. "An
HPV-positive test should just be repeated
after approximately 12 months, and only
persistent infections should be investigated
in depth. If histologically proven, they are
treated. PCR assays should not be used in
screening programs, because they detect too
many harmless infections."
The ideal HPV screening interval has yet to
be determined, but Dr. Rodríguez said that
previous analyses from the study suggested
that HPV screens should at least 2.5 years
apart, and could be longer.
The most important study limitation, note
the authors, is that the conclusion that
newly detected HPV infections typically do
not progress to CIN 2 or worse at any age
might not hold beyond the 7 years of
follow-up. Dr. Rodríguez said that the
researchers plan to revisit the cohort
approximately 20 years after the initial
screening visit.
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