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ANRV334-ME59-16 ARI 7 December 2007 13:29
Appropriate Use of Cervical
Cancer Vaccine
Gregory D. Zimet,1Marcia L. Shew,1
and Jessica A. Kahn2
1Department of Pediatrics, Section of Adolescent Medicine, Indiana University School
of Medicine, Indianapolis, Indiana 46202; email: gzimet@iupui.edu; mshew@iupui.edu
2Division of Adolescent Medicine, Cincinnati Children’s Hospital Medical Center,
Cincinnati, Ohio 45229; email: Jessica.Kahn@cchmc.org
Annu. Rev. Med. 2008. 59:223–36
The Annual Review of Medicine is online at
http://med.annualreviews.org
This article’s doi:
10.1146/annurev.med.59.092806.131644
Copyright c
2008 by Annual Reviews.
All rights reserved
0066-4219/08/0218-0223$20.00
Key Words
human papillomavirus, HPV, vaccination, immunization,
adolescent
Abstract
Human papillomavirus (HPV) is a necessary, though not sufficient,
cause of cervical cancer. Two vaccines have been developed that pre-
vent two HPV types associated with 70% of cervical cancers. One of
the vaccines (a quadrivalent vaccine) also prevents two HPV types as-
sociated with 90% of genital warts. Both HPV vaccines have shown
very good efficacy and safety. This review summarizes the guide-
lines for use of the quadrivalent vaccine published by the Advisory
Committee on Immunization Practices, presents data on vaccine
efficacy and safety, and gives an overview of the findings of cost-
effectiveness studies. In addition, we summarize the research on the
attitudes of parents and health care providers toward HPV vaccine
and critically evaluate controversial and challenging issues surround-
ing HPV vaccination, including concerns about sexual disinhibition
and potential obstacles to vaccine distribution and uptake.
223
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HPV: human
papillomavirus
STI: sexually
transmitted infection
ACIP: Advisory
Committee on
Immunization
Practices
INTRODUCTION
More than 100 types of human papillomavirus
(HPV) have been identified, with >40 specif-
ically infecting the anogenital areas (1). Gen-
ital HPV infections are transmitted primar-
ily through sexual contact; prevalence rates
peak among young persons after the initia-
tion of sexual activity and decline after age
30 (2, 3). HPV infection is a highly prevalent
sexually transmitted infection (STI) (4–6). In a
large cross-sectional nationally representative
sample of women in the United States, HPV
prevalence rates among women who had en-
gaged in sexual intercourse were 39.6% for
those aged 14–19 years and 49.3% for those
aged 20–24 years (6). Cumulative prevalence
rates as high as 82% have been found in ado-
lescent populations (7). Low-risk HPV types,
such as types 6 and 11, cause genital warts,
low-grade cervical dysplastic lesions, and
respiratory papillomatosis. High-risk HPV
types, such as types 16, 18, 31, and 45, are re-
sponsible for cervical and other genital tract
cancers and for both low- and high-grade dys-
plastic (precursor) lesions (8). It is estimated
that ∼90% of genital warts are caused by HPV
types 6 and 11 (9), and that 70% of cervical
cancers are caused by HPV types 16 and 18 (8).
Most genital HPV infections are asymp-
tomatic and transient (10). In some women,
HPV infection may cause abnormal cervi-
cal cytology on Papanicolaou (Pap) tests,
including atypical squamous cells of unde-
termined significance, low-grade squamous
intraepithelial lesion, or high-grade squa-
mous intraepithelial lesion. Abnormal cytol-
ogy may indicate cervical dysplasia, a his-
tologic diagnosis. Mild cervical dysplasia
often regresses, but severe cervical dysplasia
usually progresses to cervical cancer. Lon-
gitudinal studies have established that per-
sistence of high-risk, or cancer-associated,
HPV types is necessary for progression to
severe cervical dysplasia and cervical can-
cer. Persistence of high-risk HPV is a nec-
essary, but not sufficient, cause of cervi-
cal cancer. Other factors that contribute to
cervical carcinogenesis are viral characteris-
tics, sexual behaviors (e.g., condom nonuse
and multiple sexual partners), chlamydial in-
fections, immunosuppression, and smoking
(11).
Cervical cancer is the second most com-
monly diagnosed cancer among women
worldwide, accounting for >250,000 deaths
per year. Approximately 80% of deaths due to
cervical cancer occur in less developed regions
of the world because Pap screening programs
do not exist in those regions (12). Because of
the well-organized Pap screening program in
the United States, cervical cancer incidence
and mortality are relatively low compared to
those of other cancers; however, cervical can-
cer still causes ∼3700 deaths per year in the
United States (13). In 2000, it was estimated
that the lifetime financial burden of HPV dis-
ease in the United States was $3.9 billion and
that 90% of this amount was spent on follow-
up of abnormal Pap tests and treatment of pre-
cancerous lesions (14).
Two vaccines have been developed to pre-
vent HPV infection. One vaccine, approved
by the U.S. Food and Drug Administration
(FDA) in June 2006, prevents HPV types 6,
11, 16, and 18, protecting against the types
most frequently associated with both cervical
cancers and genital warts (15). A second vac-
cine, not yet licensed but currently under re-
view by the FDA, prevents HPV types 16 and
18 (16). Both vaccines show sustained efficacy
of at least five years with good safety profiles
(17–19).
Here we review the guidelines for HPV
vaccine administration published by the Ad-
visory Committee on Immunization Practices
(ACIP), address vaccine efficacy and safety
data, discuss the findings of cost-effectiveness
studies, summarize the literature on parental
and physicians’ knowledge about HPV and
attitudes about HPV vaccination, and dis-
cuss different immunization strategies and
issues.
224 Zimet ·Shew ·Kahn
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ANRV334-ME59-16 ARI 7 December 2007 13:29
ACIP GUIDELINES FOR
QUADRIVALENT VACCINE
ADMINISTRATION
The ACIP recommends routine vaccination
with the quadrivalent HPV vaccine of all
11- to 12-year-old girls, catch-up vaccina-
tion of all 13- to 26-year-old young women
not previously vaccinated, and vaccination of
9- to 10-year-old girls at the provider’s dis-
cretion (20). The vaccine is targeted toward
11- to 12-year-old girls because vaccination
is most effective in preventing type-specific
HPV infection if given prior to sexual initia-
tion. However, the ACIP notes that vaccina-
tion may still provide protection among sexu-
ally active young women, as demonstrated in
clinical trials (17, 21). Pap testing and HPV
DNA testing are not recommended prior to
vaccination.
The dosing schedule that was evaluated
in clinical trials and is recommended by the
ACIP is 0, 2, and 6 months. However, recog-
nizing that this ideal schedule may not always
be followed, the ACIP offers the following ad-
ditional recommendations:
1. The first and second doses must be sep-
arated by at least 4 weeks.
2. The second and third doses must be sep-
arated by at least 12 weeks.
3. If the dosing schedule has been inter-
rupted at any point, the vaccine series
should not be restarted, but the required
dose should be administered as soon as
possible.
The HPV vaccine can be administered
during the same visit as other age-appropriate
vaccines, such as the meningococcal conjugate
vaccine (MCV4) and the tetanus, diphtheria,
and pertussis booster (Tdap).
According to the ACIP, lactating women
can receive the vaccine, as can young women
who are immunocompromised. Although the
quadrivalent vaccine has not been associated
with any pregnancy-related adverse events,
currently there are insufficient data on the
potential effects of the vaccine on pregnant
women to advance the recommendation.
Finally, the ACIP emphasizes the impor-
tance of continued cervical cancer screening
in vaccinated women, because (a) 30% of cer-
vical cancers are caused by types not con-
tained in the vaccine, (b) the vaccine may
not be 100% effective, and (c) the vaccine
has no therapeutic value for those already in-
fected (20). Additional details regarding the
ACIP guidelines can be found in Reference
20.
VACCINE EFFICACY AND
SAFETY
Clinical trials have demonstrated that HPV
vaccines are effective and safe, but for both
ethical and scientific reasons, surrogate end
points were viral persistence, genital dyspla-
sia, and genital warts as opposed to cervical
cancer. The quadrivalent vaccine has demon-
strated efficacy not only in participants who
followed exact clinical protocols, but also in
trial populations with less strenuously defined
criteria. In the per-protocol population, the
vaccine demonstrated 100% efficacy in pre-
venting warts and/or vulvar or vaginal dys-
plastic lesions and 98% efficacy in prevent-
ing high-grade cervical lesions (18–22). In
the intention-to-treat population analysis (de-
fined as including those with infection or
disease associated with vaccine types before
vaccination and/or protocol violations), the
quadrivalent vaccine was 44% effective in pre-
venting high-grade cervical lesions and 73%
percent effective in reducing warts as well as
vulvar and vaginal lesions (21, 22).
Similarly, the bivalent vaccine demon-
strated 100% efficacy in preventing persistent
infection in cervical samples and cervical
intraepithelial neoplasia (CIN) lesions asso-
ciated with vaccine types in the according-
to-protocol analysis. In the intention-to-treat
analysis (defined as receiving at least one
dose of the vaccine and testing negative for
high-risk HPV types or no abnormalities
on Pap testing at a screening visit that was
within 90 days of enrollment), the vaccine
was 94% efficacious in preventing persistent
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ANRV334-ME59-16 ARI 7 December 2007 13:29
infection at 12 months and 96% efficacious
in preventing abnormal cytology (17, 19).
Additional studies continue to demon-
strate high efficacy, particularly among
women not previously infected with types 16
and 18 (21, 22). Both vaccines have been well
tolerated without serious vaccine-related side
effects. No therapeutic effects have been ob-
served in women who have existing HPV
infection or HPV-related disease caused by
vaccine-specific types (20). Research on the
quadrivalent vaccine in young men indicates
that it stimulates a strong immunogenic re-
sponse and has no significant short-term
safety issues (23). Vaccine efficacy in men has
not yet been demonstrated, but studies are un-
der way to evaluate the efficacy of the vaccine
in preventing warts as well as penile, perineal,
and perianal cancers.
Studies of HPV vaccine safety, immuno-
genicity, and efficacy in certain populations
are ongoing. Follow-up studies of women vac-
cinated with bivalent or quadrivalent vaccine
report sustained efficacy of both vaccines for
at least five years (17, 18). In addition, a mod-
eling study suggests that antibody levels may
remain above those stimulated by natural in-
fection for 12 years or more (24). Finally,
a study of women 60 months postvaccina-
tion found that an additional dose of the vac-
cine induced a strong anamnestic response
typical of vaccines with long-lasting efficacy
(25). The immunogenicity and clinical effi-
cacy of HPV vaccination in individuals with
chronic disease, particularly those who are
immunosuppressed, are still unclear. How-
ever, previous work has shown that other vi-
ral vaccines (e.g., hepatitis A and B) gener-
ate an effective, though attenuated, immune
response in those who are immunocompro-
mised (26, 27). In addition, individuals in-
fected with human immunodeficiency virus
(HIV) generate an immune response to nat-
ural HPV infection (28, 29). Future clinical
trials will generate more definitive data con-
cerning the immunogenicity and clinical ef-
ficacy of HPV vaccines in immunocompro-
mised individuals. The quadrivalent vaccine
also appears to be safe in pregnant women:
clinical trials have demonstrated no increase
in spontaneous loss rate or fetal malforma-
tions as compared to placebo groups, and the
vaccine has been classified as Category B in
terms of risk in pregnancy (20). Longer-term
and larger studies that examine the safety of
HPV vaccines in pregnancy are in progress.
Given the current status of clinical trial data,
the ACIP does not recommend vaccination in
women known to be pregnant.
COST-EFFECTIVENESS
Several cost-effectiveness studies on HPV
vaccination have been carried out, using
different methodologies and assumptions
(30–35). All of these studies suggest that
vaccinating 12-year-old girls against HPV can
be cost-effective. One of these studies found
that the most effective strategy for reduc-
tion of cancer morbidity and mortality was
vaccination of girls, followed by annual cer-
vical screening starting at age 18 (30). An-
other study determined that the ideal ap-
proach would be vaccination of girls at age 12,
followed by cytologic screening every three
years starting at age 25 (31). The potential
effects of vaccinating males, however, were
not considered in either of these papers. Taira
et al. (32) found that vaccination of both fe-
males and males would not be cost-effective,
but Elbasha et al. (33) found that it would.
The divergent findings are likely attributable
to differences in modeling assumptions; for
example, Elbasha et al. included HPV types
6, 11, 16, and 18 in their model, whereas
Taira et al. considered only the two oncogenic
types.
All of these studies, which used very dif-
ferent approaches to analysis, found the vac-
cination of 12-year-old girls against HPV
to be a cost-effective strategy. These stud-
ies did not consider costs such as lost
productivity due to cancer-related illness
and death. Inclusion of such factors would
only improve the cost-effectiveness of HPV
vaccination.
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KNOWLEDGE AND ATTITUDES
OF PARENTS AND HEALTH
CARE PROVIDERS
The research published to date on knowl-
edge about HPV and attitudes about HPV
vaccination relies on data collected prior to
the licensure and availability of HPV vaccine.
These studies, therefore, were carried out be-
fore information about HPV and HPV vac-
cine was widely disseminated to the public and
professionals by pharmaceutical companies,
the media, and professional organizations. It
is likely that knowledge about HPV has in-
creased and that attitudes about vaccination
have changed somewhat since these studies
were implemented.
Parents
In 2006, Zimet et al. (36) reviewed ten pub-
lished reports on parental attitudes about
HPV/STI vaccination. These studies, which
included both qualitative and quantitative
methodologies, all found that parents ex-
pressed moderate to strong interest in vac-
cinating their preadolescent and adolescent
children against STI. All but two of the stud-
ies were carried out in the United States,
and Zimet et al. recommended that fu-
ture research include parents from other re-
gions of the world, particularly developing
countries.
The same review examined research on
knowledge about HPV and HPV-related con-
ditions (36). Across multiple studies, women
demonstrated a poor understanding of HPV,
often reporting no knowledge of the virus or
unawareness of the associations of HPV with
Pap testing and with cervical cancer. At the
same time, other research has indicated that
women are very interested in learning more
about HPV infection; many state that infor-
mation about HPV should be provided to
young women prior to the initiation of sex-
ual activity (37, 38).
Results of studies published since the re-
view by Zimet et al. have been largely con-
sistent with previous findings (see Table 1)
(39–44). With one exception (39), these stud-
ies found the majority of parent partici-
pants willing to have their children vacci-
nated against HPV. Brabin et al. (41) focused
on British parents’ attitudes about adolescent
self-consent for vaccination and found that
nearly half of parents agreed that HPV vac-
cine should be provided to adolescents at sex-
ual health clinics without parental consent.
Across all studies, opposition to HPV vaccine
was associated with concern about vaccina-
tion leading to sexual disinhibition, viewing
one’s child as being at low risk for infec-
tion, and worries about vaccine safety. Al-
though these recent studies were carried out
in several countries (e.g., United Kingdom,
Netherlands, Finland), only one study exam-
ined attitudes of parents in a developing coun-
try, Vietnam (44). Results from the Vietnam
study are comparable to those reported in
other research, with parents strongly support-
ive of HPV vaccination for their children.
Further research on HPV vaccine acceptabil-
ity in developing countries is needed.
Health Care Providers
Providers’ attitudes and knowledge about
HPV and HPV vaccination are likely to in-
fluence their immunization practices. Zimet
et al. (36) reviewed four studies that examined
attitudes of nurse practitioners, obstetrician/
gynecologists, family practice physicians,
and pediatricians toward recommending
HPV/STI vaccines for their adolescent pa-
tients. Across health care provider types, these
studies found relatively strong endorsement
of HPV vaccination. However, all health care
provider groups expressed greater reluctance
to vaccinate younger adolescents compared to
older ones. Studies that assessed knowledge
about HPV found that both pediatricians and
family practice physicians lacked awareness of
several aspects of HPV infections (45–47).
A more recent large-scale study of pe-
diatricians found strong support for HPV
vaccination of older adolescents but sub-
stantially less support for recommending the
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Table 1 HPV vaccine acceptability among parents: studies from 2006 and 2007
Year
(Reference) Region Participants Method
Outcome
measures Main findings
2006 (39) United Kingdom Parents of
8–10-year-old
children
participated in
6 focus groups
of 4–5 parents
each
Focus groups Parental knowledge
about HPV and
attitudes about
HPV vaccination
for their children
Parents had little awareness of HPV.
Parents were confused about the degree
of protection against cervical cancer
offered by a 16/18 bivalent vaccine.
Parents expressed some concerns about
possible side effects of vaccination and
about a vaccine designed to prevent a
sexually transmitted infection.
Overall, parents were more comfortable
with vaccinating adolescent than
preadolescent children.
2007 (40) California,
United States
522 parents with
at least one
daughter 18
years old or
younger
Random-digit-
dial phone
survey
Parental attitudes
about vaccinating
a daughter against
HPV prior to her
thirteenth
birthday and
sixteenth birthday,
respectively
75% of parents said they would likely
vaccinate a daughter prior to age 13.
Attitudes about HPV vaccination varied
with ethnicity, race, education,
religious service attendance, and
political leaning.
Parents in favor of vaccination
emphasized the importance of
protecting children from harm due to
HPV infection.
Parents opposed to vaccination
expressed concerns about vaccine
safety and sexual disinhibition.
2007 (41) Manchester,
United
Kingdom
305 parents of
11–12-year-old
children
Semi-qualitative
study
Parental attitudes
about provision of
HPV vaccine
without parental
consent
13.8% of parents strongly agreed and
33.8% agreed that HPV vaccine
should be provided to adolescents
without parental consent.
Parents in favor of adolescent
self-consent emphasized issues of
autonomy and competence.
Parents opposed referred to parental
rights and emphasized the importance
of parental involvement and guidance.
2007 (42) The Netherlands 356 parents of
10–12-year-old
children
Phone interview Parental knowledge
about HPV and
attitudes about
HPV vaccination
for their children
29.5% of parents had heard of HPV and
only 14.3% knew of its relationship to
cervical cancer.
87.9% said they would have their child
vaccinated.
23% thought that their child should be
involved in the HPV vaccination
decision-making process.
2007 (43) Finland 727 parents of
15-year-old
children
Mailed
questionnaire
Parental knowledge
about HPV and
attitudes about
HPV vaccination
for their children
79% of parents had heard of HPV.
86% were interested in vaccinating their
child against HPV.
Parental opposition to vaccination was
associated with lower knowledge about
HPV, perception that their adolescent
was at low risk for infection, and
concerns about vaccine safety and
sexual disinhibition.
2007 (44) Da Nang,
Vietnam
181 mothers of
10–18-year-old
daughters
Questionnaire Parental attitudes
about HPV
vaccination for
their children
91% of parents said they were likely or
very likely to vaccinate their daughters.
90% did not believe that HPV
vaccination would lead to earlier
initiation of intercourse.
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ANRV334-ME59-16 ARI 7 December 2007 13:29
vaccine for 10- to 12-year-old girls (48). In this
same study, pediatricians demonstrated great
variability in their knowledge about HPV.
Nearly all respondents knew that HPV caused
genital warts, but >30% did not know that
HPV causes virtually all cervical cancers. A
qualitative interview study with 31 pediatri-
cians working in diverse clinical settings found
strong interest in HPV vaccination and sup-
port for universal age-based recommenda-
tions (49). However, respondents noted that
cultural and religious factors may influence
parental attitudes about HPV vaccine and
some felt that these issues may be difficult
for them to address with parents. Participants
were mixed in their views about school-entry
mandates for HPV vaccine, with about one
third expressing support for mandates, one
third opposing them, and one third unsure.
The studies of providers, like the parent
studies, were carried out prior to licensure
of the quadrivalent vaccine. Since the vac-
cine was licensed, a great deal of informa-
tion has been provided to health care pro-
fessionals regarding HPV infection and the
ACIP recommendation for universal vaccina-
tion of all 11- to 12-year-old girls. Multiple
studies indicate that providers look to pro-
fessional organizations for guidance with re-
gard to new vaccines (46, 50, 51). It is likely,
therefore, that attitudes about HPV vaccina-
tion have shifted toward greater acceptance
of vaccinating younger adolescents. Now that
HPV vaccine is available, it will be important
to study the actual HPV vaccination practices
of health care providers.
CONTROVERSIES
Even before the quadrivalent HPV vaccine
was licensed, some media reports focused
on presumed controversies surrounding HPV
vaccination (52). However, the scientific re-
search described in the previous section sug-
gests that for most parents, this vaccine is not,
in fact, controversial. In most studies, the large
majority of parents have expressed an interest
in preventing cervical cancer in their daugh-
ters through vaccination. Research indicates
that for the relatively small group of parents
with doubts about HPV vaccination, opposi-
tion arises from concerns about sexual disin-
hibition and about implied consent for sexual
initiation.
Sexual Disinhibition
The issue of sexual disinhibition as it relates
to HPV vaccination has been addressed in
several articles (36, 53–55). The question is
whether HPV vaccination will give 11- to
12-year-old girls a false sense of protection
against STIs, leading them to initiate sexual
behavior at an earlier age or not use condoms
when sexually active. Now that HPV vaccine
is licensed and available, carefully designed
studies may be able to answer this question
directly. To date, it has been addressed only
indirectly.
The notion of risk compensation or risk
homeostasis has supporters and detractors
(56, 57), but it is not clear to what extent it ap-
plies to HPV vaccination. A basic assumption
underlying the compensation or disinhibition
argument is that worries about HPV infection
have motivated young women to delay initia-
tion of coitus. However, research has repeat-
edly demonstrated that most young women
do not know about HPV, so concerns about
HPV could not have had an inhibitory influ-
ence on them. In addition, to the extent that
fear of STI does delay the initiation of sexual
intercourse, fear of non-vaccine-preventable
infections such as HIV, chlamydia, gonorrhea,
and genital herpes would remain inhibitory.
Several other areas of research provide fur-
ther indirect evidence that HPV vaccination is
not likely to result in disinhibition. Studies on
school-based sex education and condom dis-
tribution programs and on provision of emer-
gency contraception have found no evidence
that these programs have led to earlier ini-
tiation of sexual intercourse or engagement
in riskier sexual behaviors (58, 59). Another
study reviewed research on sexual risk reduc-
tion interventions and employed a variety of
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ANRV334-ME59-16 ARI 7 December 2007 13:29
mathematical modeling strategies in order to
assess the likelihood of sexual risk compen-
sation and the potential effects on HIV/STI
risk (60). A small degree of risk compensation
was found, but not nearly enough to negate
the salutary effects of risk-reduction behav-
iors (e.g., increased condom use).
Issues of risk compensation or disinhibi-
tion have also been studied with respect to
the introduction of highly active antiretroviral
treatment (HAART) for persons with AIDS.
Two related questions have been raised:
1. Do HAART-related reductions in vi-
ral load lead HIV-infected individuals
to engage in more unprotected sexual
behavior?
2. By altering the perception of AIDS from
a fatal disease to a chronic, manageable
illness, has HAART led HIV-negative
but at-risk populations to engage in
riskier sexual behavior?
Some of the research examining these is-
sues has produced evidence of risk compen-
sation related to HAART or low viral load
(61), but most research indicates no associa-
tion of HAART with increases in risky sexual
behaviors (62, 63). In addition, even when the
possibility of disinhibition is discussed, there
is no suggestion that HAART should be with-
held owing to these concerns. Rather, inter-
ventions are proposed that would emphasize
the importance of maintaining safer sexual be-
haviors to minimize transmission of HIV, to
decrease the probability of exposure to resis-
tant viral strains, and to protect against other
STI (64). Implementing this same approach
makes sense with respect to HPV vaccination.
Recipients of the vaccine and/or their parents
should receive anticipatory guidance empha-
sizing the importance of safe sexual behav-
ior and the ongoing need for regular cervical
screening.
Implied Permission to Have Sex
Related to the disinhibition issue is the con-
cern that a parent who has an adolescent
or preadolescent daughter vaccinated against
HPV is conveying approval of sexual behav-
ior. This concern has received some media
coverage (65), but several arguments sug-
gest that worries about implied permission to
have sex are misguided (55). From a practical
viewpoint, like any preventive vaccine, HPV
vaccine will be maximally effective if adminis-
tered prior to exposure to the virus. The tar-
geting of 11- to 12-year-olds for vaccination,
therefore, makes a great deal of sense because
very few girls in this age range have engaged in
sexual behaviors (66). In addition, age-based
immunization programs have proven to be
more effective at maximizing vaccine coverage
than risk-based approaches, partly because it
is difficult to determine who is at risk. An
additional justification for targeting younger
adolescent girls for HPV vaccination is that
studies indicate a stronger immunogenic re-
sponse in younger compared to older adoles-
cents (23). Finally, it may not be necessary to
describe HPV vaccine as an STI vaccine to an
11- or 12-year-old. The modes of transmis-
sion of infections targeted by other vaccines
are not typically discussed with children and
young adolescents.
HPV vaccination is a health protective
measure designed to reduce the risk of an ad-
verse outcome, cervical cancer. It is similar
in this respect to many other widely advo-
cated measures, including use of bicycle hel-
mets, brushing and flossing of teeth, tetanus
vaccination, and use of sunscreen. Research
suggests that rather than encouraging riskier
behaviors, health-protective behaviors tend
to co-occur (67). That is, for instance, per-
sons who use seatbelts are also more likely to
have a healthier diet. Furthermore, as pointed
out by Haber et al. (55), when we have chil-
dren vaccinated against tetanus, we are not
implying that they should play with dirty,
rusty nails. Similarly, it should not be as-
sumed that in vaccinating adolescents against
HPV we are endorsing earlier involvement
in sexual activity. Rather, by vaccinating girls
and young women against HPV, we are com-
municating our desire to protect them from
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the potentially devastating effects of cervical
cancer.
VACCINE DELIVERY
CHALLENGES
Now that one HPV vaccine is available and a
second is likely to become available shortly,
we face the logistical and policy challenges
of delivering the vaccine to preadolescents
and early adolescents. One potentially signif-
icant obstacle to delivery is the cost of HPV
vaccine. Although most insurance companies
have already decided to cover the vaccine,
the extent of reimbursement is variable. The
Vaccine for Children Program is designed to
cover the cost of vaccination for uninsured and
underinsured children and certainly will help
to decrease disparities in access to HPV vac-
cine. Financial barriers are likely to pose an
even greater problem in developing countries,
where the burden of cervical cancer is much
greater than in the United States but personal
income and national wealth are limited (68).
In addition to financing issues, the logistical
challenges of any vaccine delivery and possible
cultural issues related to an STI vaccine may
hinder the introduction of HPV vaccine in the
developing world (69). A number of authors
have discussed some of the unique political,
cultural, and organizational challenges asso-
ciated with the introduction of any new im-
munization program in developing countries
(70–72).
The majority of vaccines are given to
younger children and are timed around a
well-established schedule of health care vis-
its. Vaccinating adolescents is a relatively new
phenomenon and one that poses unique chal-
lenges (73). For instance, a regular health care
visit at age 11 or 12 is not well-established
and many providers may have limited ex-
perience providing health care services to
young adolescents. In order to achieve opti-
mal coverage, alternative approaches to vac-
cination may need to be explored, including
school-based and pharmacy-based programs
(73).
One approach to minimizing health care
disparities and ensuring that the greatest
number of young women are vaccinated
would be for states to require HPV vacci-
nation at middle school entry. A number of
states have considered implementing man-
dates, with some states passing and others
defeating mandate legislation (74). The issue
of compulsory HPV vaccination also has re-
ceived a great deal of attention in the pro-
fessional literature, with arguments for and
against school entry requirements (55, 75–
77). The controversies surrounding manda-
tory HPV vaccination and the apparent rush
to pass legislation have created a degree of
backlash and shifted attention away from the
benefits of HPV vaccination to issues of gov-
ernmental coercion (55, 77). What has been
missing, but is beginning to emerge, is an
open, reasoned discussion of the pros and
cons of school-entry requirements for HPV
vaccination.
SUMMARY
Multiple large-scale research studies have
demonstrated that the bivalent and quadriva-
lent HPV vaccines are efficacious for at least
five years and safe. Ongoing surveillance stud-
ies will evaluate long-term safety, but there is
nothing inherent in either HPV vaccine to
suggest any long-term safety issues. There is
indirect evidence that the protection afforded
by HPV vaccine may last as long as 12 years
or more. In addition, all modeling studies in-
dicate that vaccination of 11- and 12-year-old
girls is a cost-effective strategy.The ACIP rec-
ommends vaccination of all 11- to 12-year-old
girls, catch-up vaccination of 13- to 26-year-
old young women, and vaccination of 9- to
10-year-old girls at the health care provider’s
discretion.
Studies carried out prior to vaccine licen-
sure indicated that most parents and health
care providers had very positive attitudes
about HPV vaccination. However, both par-
ents and providers had misconceptions about
HPV and HPV vaccine. Although many of
www.annualreviews.org •Cervical Cancer Vaccine 231
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ANRV334-ME59-16 ARI 7 December 2007 13:29
these misunderstandings may have been ad-
dressed by educational efforts undertaken
since the quadrivalent vaccine was licensed,
it will be important for ongoing research to
examine parental decisions about HPV vacci-
nation and health care providers’ immuniza-
tion practices over time. There is no evidence
that adolescents will respond to HPV vaccina-
tion with sexual disinhibition; however, direct
study of this issue can only begin now that the
vaccine is available.
Although the quadrivalent vaccine has only
been licensed since June of 2006, there are al-
ready concerns and controversies regarding
vaccine cost and delivery issues. The rapid
pursuit of legislation in a number of states
to mandate HPV vaccine for girls at middle
school entry led to a great deal of criticism and
served to distract from the potential enormous
benefits of this vaccine. Delivery of HPV vac-
cine in developing countries, where the need
for the vaccine is particularly acute, also is
likely to be very difficult. In addition to the
cost of the vaccine, unique cultural, political,
and logistical challenges will need to be stud-
ied and addressed.
FUTURE ISSUES
1. Evaluation of the long-term safety and efficacy of HPV vaccines, including among
pregnant women, males, and individuals who are immunosuppressed.
2. Identification of predictors of HPV vaccine acceptance and evaluation of brief behav-
ioral interventions designed to optimize HPV vaccine uptake.
3. Assessment of post-HPV-vaccination changes in attitudes and behavior that may be
attributable to receipt of vaccine.
4. Development and evaluation of biomedical, political, logistic, and financial strategies
for world-wide delivery of HPV vaccine, particularly in developing countries.
DISCLOSURE STATEMENT
G.D.Z. has received speaking fees from Merck and Co., Inc. and has served as a consultant
to M2 Communications and SciMed, two medical education companies. M.L.S. is a clinical
investigator for research grants and serves as a consultant for Merck and Co., Inc.
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Annual Review of
Medicine
Volume 59, 2008
Contents
The FDA Critical Path Initiative and Its Influence on New Drug
Development
Janet Woodcock and Raymond Woosley pppppppppppppppppppppppppppppppppppppppppppppppppppp1
Reversing Advanced Heart Failure by Targeting Ca2+Cycling
David M. Kaye, Masahiko Hoshijima, and Kenneth R. Chien pppppppppppppppppppppppp13
Tissue Factor and Factor VIIa as Therapeutic Targets in
Disorders of Hemostasis
Ulla Hedner and Mirella Ezban ppppppppppppppppppppppppppppppppppppppppppppppppppppppppp29
Therapy of Marfan Syndrome
Daniel P. Judge and Harry C. Dietz pppppppppppppppppppppppppppppppppppppppppppppppppppp43
Preeclampsia and Angiogenic Imbalance
Sharon Maynard, Franklin H. Epstein, and S. Ananth Karumanchi ppppppppppppppppp61
Management of Lipids in the Prevention of Cardiovascular Events
Helene Glassberg and Daniel J. Rader pppppppppppppppppppppppppppppppppppppppppppppppppp79
Genetic Susceptibility to Type 2 Diabetes and Implications for
Antidiabetic Therapy
Allan F. Moore and Jose C. Florez ppppppppppppppppppppppppppppppppppppppppppppppppppppppp95
Array-Based DNA Diagnostics: Let the Revolution Begin
Arthur L. Beaudet and John W. Belmont pppppppppppppppppppppppppppppppppppppppppppppp113
Inherited Mitochondrial Diseases of DNA Replication
William C. Copeland pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp131
Childhood Obesity: Adrift in the “Limbic Triangle”
Michele L. Mietus-Snyder and Robert H. Lustig pppppppppppppppppppppppppppppppppppppp147
Expanded Newborn Screening: Implications for Genomic Medicine
Linda L. McCabe and Edward R.B. McCabe pppppppppppppppppppppppppppppppppppppppppp163
Is Human Hibernation Possible?
Cheng Chi Lee ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp177
Advance Directives
Linda L. Emanuel ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp187
v
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Genetic Determinants of Aggressive Breast Cancer
Alejandra C. Ventura and Sofia D. Merajver pppppppppppppppppppppppppppppppppppppppppp199
A Role for JAK2 Mutations in Myeloproliferative Diseases
Kelly J. Morgan and D. Gary Gilliland pppppppppppppppppppppppppppppppppppppppppppppppp213
Appropriate Use of Cervical Cancer Vaccine
Gregory D. Zimet, Marcia L. Shew, and Jessica A. Kahn ppppppppppppppppppppppppppppp223
A Decade of Rituximab: Improving Survival Outcomes in
Non-Hodgkin’s Lymphoma
Arturo Molina ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp
237
Nanotechnology and Cancer
James R. Heath and Mark E. Davis ppppppppppppppppppppppppppppppppppppppppppppppppppp251
Cancer Epigenetics: Modifications, Screening, and Therapy
Einav Nili Gal-Yam, Yoshimasa Saito, Gerda Egger, and Peter A. Jones pppppppppppp267
T Cells and NKT Cells in the Pathogenesis of Asthma
Everett H. Meyer, Rosemarie H. DeKruyff, and Dale T. Umetsu pppppppppppppppppppp281
Complement Regulatory Genes and Hemolytic Uremic Syndromes
David Kavanagh, Anna Richards, and John Atkinson pppppppppppppppppppppppppppppppp293
Mesenchymal Stem Cells in Acute Kidney Injury
Benjamin D. Humphreys and Joseph V. Bonventre pppppppppppppppppppppppppppppppppppp311
Asthma Genetics: From Linear to Multifactorial Approaches
Stefano Guerra and Fernando D. Martinez ppppppppppppppppppppppppppppppppppppppppppp327
The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in
Human Disease
Stavros Garantziotis, John W. Hollingsworth, Aimee K. Zaas,
and David A. Schwartz ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp343
Advances in Antifungal Therapy
Carole A. Sable, Kim M. Strohmaier, and Jeffrey A. Chodakewitz pppppppppppppppppp361
Herpes Simplex: Insights on Pathogenesis and Possible Vaccines
David M. Koelle and Lawrence Corey pppppppppppppppppppppppppppppppppppppppppppppppppp381
Medical Management of Influenza Infection
Anne Moscona pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp397
Bacterial and Fungal Biofilm Infections
A. Simon Lynch and Gregory T. Robertson ppppppppppppppppppppppppppppppppppppppppppppp415
EGFR Tyrosine Kinase Inhibitors in Lung Cancer: An Evolving Story
Lecia V. Sequist and Thomas J. Lynch pppppppppppppppppppppppppppppppppppppppppppppppppp429
Adaptive Treatment Strategies in Chronic Disease
Philip W. Lavori and Ree Dawson pppppppppppppppppppppppppppppppppppppppppppppppppppppp443
vi Contents
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AR334-FM ARI 18 December 2007 17:20
Antiretroviral Drug–Based Microbicides to Prevent HIV-1 Sexual
Transmission
Per Johan Klasse, Robin Shattock, and John P. Moore ppppppppppppppppppppppppppppppppp455
The Challenge of Hepatitis C in the HIV-Infected Person
David L. Thomas pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp473
Hide-and-Seek: The Challenge of Viral Persistence in HIV-1 Infection
Luc Geeraert, Günter Kraus, and Roger J. Pomerantz ppppppppppppppppppppppppppppppp487
Advancements in the Treatment of Epilepsy
B.A. Leeman and A.J. Cole pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp503
Indexes
Cumulative Index of Contributing Authors, Volumes 55–59 pppppppppppppppppppppppp525
Cumulative Index of Chapter Titles, Volumes 55–59 ppppppppppppppppppppppppppppppppp529
Errata
An online log of corrections to Annual Review of Medicine articles may be found at
http://med.annualreviews.org/errata.shtml
Contents vii
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