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A wealth of evidence has led to the conclusion that virtually all cases of cervical
cancer are attributable to persistent infection by a subset of human papillomavirus (HPV) types, especially HPV type 16 (HPV-16) and HPV-18. These HPV
types also cause a proportion of other cancers, including vulvar, vaginal, anal,
penile, and oropharyngeal cancers. Although cervical cancer screening, primarily with the Papanicolaou (Pap) smear, has reduced the incidence of this cancer
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
approaches to reduce the incidence of this disease. The first is the development
cause of death from cancer in women worldwide, because the developing world
has lacked the resources for widespread, high-quality screening. In addition to
2008;113(7 suppl):198093.
Address for reprints: Douglas R. Lowy, MD, Laboratory of Cellular Oncology, Center for Cancer
Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4106, MSC
4263, Bethesda, MD 20892; Fax: (301) 480-5322;
E-mail: lowyd@mail.nih.gov
Received February 19, 2008; accepted March 5,
2008.
*This article is a US Government work and, as
such, is in the public domain in the United States
of America.
sensitivity of HPV testing, suggest that such testing could permit increased
may be incorporated as part of an economically viable screen-and-treat
approach in the developing world. The manner in which vaccination and
screening programs are integrated will need to be considered carefully so that
they are efficient in reducing the overall incidence of cervical cancer. Cancer
Published 2008 by the American Cancer Society.*
KEYWORDS: cervical intraepithelial lesion, developing world, human papillomavirus assays, Papanicolaou smear, screen-and-treat approach, virus-like particle
vaccines.
widespread Pap smear implementation led to reductions in the incidence of cervical cancer in communities with the resources for high-quality screening
programs. However, the incidence of this cancer has
remained high in the developing world, which lacks
the resources for widespread screening programs as
practiced in nations with greater resources. A second
achievement was the recognition, from observations
initiated in the 1970s that reached their fruition in
the 1980s and early 1990s, that human papillomaviruses (HPVs) were linked etiologically to cervical
cancer. This major advance in our understanding of
the etiology and pathogenesis of cervical cancer also
led to 2 important clinical advances: a preventive HPV
vaccine for the primary prevention of cervical cancer
and HPV assays to improve secondary prevention
(screening programs). The availability of these etiology-based interventions for the primary and secondary
prevention of cervical cancer has provided an opportunity for even greater and more efficient reductions in
the incidence of this cancer in settings with established secondary screening programs and may offer
the possibility of bringing cost-effective cervical cancer
prevention strategies to the developing world. There is
an urgent need for such interventions, because cervical cancer remains the second most common cause of
death from cancer among women worldwide, accounting for >250,000 deaths each year.1
This review is divided into 3 parts. First, we summarize the current understanding of cervical cancer
pathogenesis; then, we consider the use of vaccination and other approaches aimed at the primary prevention of cervical cancer. Finally, we discuss
strategies for secondary prevention in vaccinated and
unvaccinated populations.
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and HPV-11) cause most cases of genital warts (condyloma acuminatum), but many other low-risk types
may cause virtually no pathology. The high-risk types
are related phylogenetically,5 and HPV-associated
carcinomas arise as the result of long-term, persistent infection with high-risk types. HPV DNA is
found almost universally in primary cervical tumors
(regardless of histology) and their metastases. The
HPV types associated with cervical cancer are similar
throughout the world, although minor regional differences in frequency have been noted.6 HPV-16 is
the type identified most frequently in all regions,
accounting for approximately 50% of all cervical cancers. In most regions, HPV-18 is the next most common type and typically is found in from 15% to 20%
of squamous cell cancers and in a greater proportion
of adenocarcinomas. HPVs also are implicated in the
development of a variable proportion of vulvar, vaginal, anal, penile, and oropharyngeal cancers, with
HPV-16 accounting for the vast majority of the HPVassociated tumors at these sites.1 Worldwide, cervical
cancer represents approximately 80% of the cancers
attributable to genital-mucosal HPV infection. However, in countries with effective cervical cancer
screening programs, the noncervical cancers, which
tend not to be subject to widespread screening,
represent a higher proportion of these cancers.
Genital HPV infection is believed to be the most
common sexually transmitted infection.7 Young
women are at particularly high risk of acquiring HPV
soon after initiating sexual activity. Women in their
early 20s have point prevalence rates on cross-sectional screening that range from 20% to 40%, with a
roughly equal distribution between high-risk and
low-risk HPVs.8 The cumulative incidence depends
on the frequency of sampling. One longitudinal study
with semiannual visits demonstrated that sexually
active women ages 15 to 19 years had a 3-year cumulative incidence >40%.9 The cumulative lifetime
risk of infection cannot be estimated accurately but
is most likely 75% for 1 or more genital HPV infections. The great majority of these infections are selflimited or controlled by the immune system, and the
prevalence of HPV infection among women aged
>30 years is substantially lower than among women
soon after the average age of first sexual intercourse,10 although age-specific prevalence at older
ages varies for unclear reasons. Clearance of infection is believed to be immune-mediated and largely
type-specific, as evidenced by the association
between degree of immunosuppression and rates of
infection among immunocompromised individuals,
altered immune profiles of women with persistent
infections, and the independent clearance of specific
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HPV types among women with 2 HPV infections.11,12 Neutralizing antibodies that develop in
response to infection are type-restricted, with limited
evidence of cross-reaction observed for some closely
related HPV types.13,14
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Primary Prevention
Introduction
Until very recently, cervical cancer prevention has
involved mainly secondary prevention, specifically,
screening based on the Pap test. However, the recognition that virtually all cases of cervical cancer are attributable to HPV infection implies that primary
prevention of a high proportion of the infections that
lead to cervical cancer could represent a powerful complementary approach to reducing the incidence of this
cancer and other cancers attributable to HPV infection.
The current high incidence of genital HPV infection suggests that traditional approaches to reduce
infection rates have had limited efficacy. One reason
is that condoms, as used by most individuals, afford
limited protection against HPV, in contrast to their
relatively high protection against pregnancy and efficacy against several other sexually transmitted infections.3739 There is evidence that circumcision for
men may reduce the incidence of infection among
sexual partners.40,41 Nevertheless, the incidence of
HPV infection among circumcised men and their
partners remains high. Reducing the number of sexual partners also could reduce incidence, although
the high frequency of HPV exposure among sexually
experienced individuals and the apparent high transmissibility of infection suggests that other approaches to primary prevention are needed.
HPV vaccination: Theoretical considerations
In this regard, approaches that are directed more
specifically toward preventing HPV infection could
have a more substantial impact on infection rates
and subsequent cancer. Theoretically, the long interval between infection and cancer development
implies that a therapeutic vaccine could have high
utility. However, it has proven easier to develop effective preventive vaccines, as indicated by the finding
that most approved vaccines against other infections
are preventive rather than therapeutic. Furthermore,
preventive vaccination historically has been identified as a cost-effective approach that can reduce dramatically the incidence of many infections.42
Preventive vaccines may be composed of virions
(virus particles) that have been inactivated chemi-
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Vaccine efficacy
Published clinical efficacy trials of the 2 vaccines
have been performed in women ages 15 to 26 years
(Table 1). In controlled trials, both vaccines demonstrated a high level of protection against incident
persistent infection and disease caused by the HPV
types in the respective vaccine (vaccine types), and
both had a good safety record. In fully vaccinated
women, according to a protocol analysis in which
women who were positive for a given HPV type at
enrollment or during the vaccination period were
excluded from analysis for that type, protection was
close to 100% against incident endpoints involving
vaccine types. For the Merck vaccine, in their interim
analysis of phase 3 trials, such protection was
demonstrated for HPV-16 and HPV-18associated
cases of moderate- and high-grade CIN and moderate- and high-grade vulvar and vaginal dysplasia as
well as for external genital warts associated with any
of the 4 vaccine types.53,54 The majority of the genital
warts, as expected, were associated with HPV-6 and
HPV-11. A similar degree of protection against incident persistent infection or high-grade CIN attributable to HPV-16 or HPV-18 infection was
demonstrated for the GSK vaccine in fully vaccinated
women.55 The interim analysis of the GSK phase 3
trials was conducted as a modified intention to treat
(MITT) protocol in which women who were positive
for a given HPV type at enrollment were excluded
from analysis for that type, but they were not
excluded if they became positive during the vaccination period.51 The MITT analysis produced somewhat
lower protection rates, which may reflect decreased
protection during the vaccination period rather than
an actual reduction in vaccine potency. Phase 2 trials
have demonstrated that prophylactic protection from
the vaccines lasts at least 5 years.55,56 To our knowledge to date, the women in the phase 3 trials, which,
of necessity, started after the phase 2 trials, have
been followed for a shorter period.
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TABLE 1
Prophylactic Efficacy of Virus-like Particle Vaccines Against Vaccine Targeted Human Papillomavirus Types
Outcome (ATP or MITT)
CIN-21
MITT
MITT
ATP
ATP
CIN-11
MITT
MITT
ATP
Persistent HPV DNA
ATP, 12 mo
MITT, 12 mo{
MITT, 12 mo
ATP, 4 mo
MITT, 4 mo
External genital warts
ATP
Test Vaccine
Reference
Controls
Vaccinees
GSK*
GSK
Mercky
Merck
Harper 200655
Paavonen 200751
Garland 200752
FUTURE II Study Group 58
5/470
21/7838
44/2258
42/5260
0/481
2/7788
0/2241
1/5305
100 (27-100)
90 (53-99)
GSK
GSK
Merck
Harper 200655
Paavonen 200751
Garland 200752
8/470
28/7838
65/2258
0/481
3/7788
0/2241
100 (42-100)
89 (59-99)
100 (94-100)
GSK
GSK
GSK
Merck
Merck
Harper 200655
Harper 200655
Paavonen 200751
Villa 200656
Villa 200656
9/385
16/470
46/3437
45/233
48/254
0/414
1/481
11/3386
2/235
4/256
100 (61-100)
94 (78-99)
76 (48-90)
96 (83-100)
94 (83-98)
Merck
Garland 200752
48/2279
0/2261
100 (92-100)
98 (86-100)
ATP indicates according to protocol (fully vaccinated women who were negative for a given vaccine type at enrollment and throughout the vaccination period); MITT, modified intention to treat (women who
were negative for a given vaccine type at enrollment); CI, confidence interval; FUTURE, Females United to Unilaterally Reduce Endo/Ectocervical Disease; CIN, cervical intraepithelial neoplasia; HPV, human
papillomavirus; GSK, GlaxoSmithKline.
*GSK vaccine: bivalent HPV types 16 and 18.
y
Merck vaccine: quadrivalent HPV types 6, 11, 16, and 18.
{With regard to MITT, the number of months indicates the time between positive HPV tests required for the infection to be defined as persistent.
Despite their efficacy in preventing incident infection and disease, the vaccines do not appear to influence the rate of clearance of prevalent HPV-16 or
HPV-18 infections and/or CIN.57,58 This observation is
consistent with preclinical animal papillomavirus studies in which the VLP vaccine did not induce regression of established lesions.59 Therefore, it is not
surprising that, when the Merck vaccine was been analyzed by an intention to treat protocol, which
includes a mixture of prevalent and incident infections, because women who were positive for a given
HPV type at enrollment were not excluded from analysis for that type, its level of protection was much lower
than when only incident infections were counted.52,58
In addition to protecting against incident infection and disease caused by the vaccine types, limited
cross-protection against other HPVs has been
observed, as published in the GSK phase 2 and phase
3 trials51,55 and as reported at meetings for the Merck
vaccine. In the published studies, cross-protection
has been limited to those HPV types that are related
most closely to HPV-16 and HPV-18. These results
indicate that protection is type-restricted rather than
strictly type-specific. The cross-protection apparently
increases the overall level of protection against highgrade CIN associated with any HPV type, but
approximately 25% of such lesions may not be prevented by the vaccine. In vitro assays indicate that
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that they also would be protected. Two relevant considerations were the widespread recognition that it
would be extremely difficult to perform efficacy trials
in young adolescents and data from the US and
many other countries indicating that young adolescents should be the main target group for the vaccine. That is because the vaccine should be most
cost-effective (ie, prevent the most cases of highgrade CIN and cancer for a given public expenditure)
if it is given before women become sexually active;
and US behavioral surveys indicate that approximately 25% of young women aged 15 years have
been sexually active, with this proportion increasing
to approximately 70% of young women aged 18 years.
The European Union approved the Merck vaccine for young men ages 9 to 15 years in addition to
young women ages 9 to 26 years based on their acceptance of immunologic bridging studies of young
men ages 9 to 15 year, which produced results that
were virtually identical to the results produced
among young women ages 9 to 15 years. The FDA
presumably will consider approval for vaccination of
men only after efficacy has been demonstrated in
them, perhaps because it was demonstrated that an
experimental herpes simplex virus subunit vaccine
conferred partial protection in women, but none in
men.60 This sex-specific response raised the possibility that prophylactic vaccination against mucosal
genital infections may have reduced efficacy among
men. Efficacy trials of the HPV vaccine in men have
been initiated.
In the US, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease
Control and Prevention makes national recommendations for approved vaccines, although implementation is at the state and local level. The ACIP
recommended routine vaccination of girls aged 11
and 12 years as the main target group for the vaccine
with catch-up vaccination for girls and women ages
13 to 26 years, and they recommended vaccination
of girls ages 9 and 10 years at the discretion of the
medical personnel involved. However, the recommendation for catch-up vaccination for women aged
19 years has not been embraced universally.61
The ACIP also recommended that the federal government purchase vaccine through its Vaccine for Children (VFC) program, which now can provide the HPV
vaccine for girls aged 18 years who come from poor
families. This aspect of vaccine implementation may
be particularly important for public health, because
women from this socioeconomic background tend to
have less access to screening when they are older and,
thus, are at greater risk of developing cervical cancer.62
Traditional vaccines that are part of the VFC program
FIGURE 2. Model, from Finnish women, of the proportion of annual incident HPV16-associated cervical cancer cases prevented with different ages
at vaccination, if coverage is 70% of females only and is initiated in 2008.
Reprinted by permission from Macmillan Publisher Ltd: British Journal of
Cancer, 2007;96:514518, Copyright 2007.
1987
Secondary Prevention
Introduction
Despite the high efficacy of the vaccine against the
high-risk HPV types that cause the greatest morbidity
and mortality, cervical cancer screening will continue
to play a critical role in the control of cervical cancer.75 It will take at least 2 decades for a prophylactic
HPV vaccine program targeting a cohort of adolescent girls to reduce substantially their incidence of
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cancer and its related mortality occur in lowresource settings,1 it is desirable to adapt new technologies for these underserved populations. Cost,
infrastructure, and acceptability must be addressed
to achieve widespread use. In low-resource regions,
screening is most effective if women are reached at
the ages of peak risk of treatable precancerous conditions attributable to persistent infection (1015 years
after the population median age of sexual debut) and
before the average age at which most frankly invasive
cancers occur.77,97 It has been demonstrated that
simple visual inspection with acetic acid reduces cervical cancer incidence in low-resource settings.98
Although this technique saves lives, it does not
appear to be sensitive or specific enough to be considered the optimal, long-term approach.
It is appealing intuitively, if feasible, to use secondary prevention methods for cervical cancer based
directly on HPV detection. Candidate HPV-based
tests are being developed currently into rapid, robust, easy-to-use, and inexpensive formats.99 In lowresource regions, screening might target women a
total of once or twice in the age range of peak risk of
treatable, high-grade CIN and earliest cancer.97 Onevisit screen-and-treat strategies would minimize loss
to follow-up that frequently reduces the effectiveness
of screening programs. Two limitations of screenand-treat strategies still remain. It will be difficult to
fully rule out lesions that require advanced care.100
Also, full success of this innovative strategy awaits
development of improved safe, inexpensive, and
effective outpatient treatment for HPV-positive
women.101,102
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Conclusions
The justifiable excitement over primary prevention by
vaccination should be coordinated with screening
efforts. Further understanding of HPV as a uniquely
powerful human carcinogen also remains an important
research goal. In the postvaccination era, screening
must continue but will need to be changed to preserve
the cost-effectiveness of the total program. The challenge will be to screen women in high-resource regions
appropriately while applying the latest advances
rationally and equitably to low-resource regions.
14.
15.
16.
17.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:
3030-3044.
de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur
Hausen H. Classification of papillomaviruses. Virology.
2004;324:17-27.
Chan S-Y, Ho L, Ong C-K, et al. Molecular variants of
human papillomavirus-16 from 4 continents suggest pandemic spread of the virus and its coevolution with
humankind. J Virol. 1992;66:2057-2066.
Munoz N, Bosch FX, Castellsague X, et al. Against which
human papillomavirus types shall we vaccinate and
screen? The international perspective. Int J Cancer.
2004;111:278-285.
Schiffman M, Herrero R, Desalle R, et al. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology. 2005;337:76-84.
Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and highgrade cervical lesions: a meta-analysis update. Int J Cancer. 2007;121:621-632.
Baseman JG, Koutsky LA. The epidemiology of human
papillomavirus infections. J Clin Virol. 2005;32(suppl 1):
S16-S24.
Herrero R, Castle PE, Schiffman M, et al. Epidemiologic
profile of type-specific human papillomavirus infection
and cervical neoplasia in Guanacaste, Costa Rica. J Infect
Dis. 2005;191:1796-1807.
Woodman CB, Collins S, Winter H, et al. Natural history
of cervical human papillomavirus infection in young
women: a longitudinal cohort study. Lancet. 2001;357:
1831-1836.
Franceschi S, Herrero R, Clifford GM, et al. Variations in
the age-specific curves of human papillomavirus prevalence
in women worldwide. Int J Cancer. 2006;119:2677-2684.
Palefsky JM, Holly EA. Chapter 6: immunosuppression
and coinfection with HIV. J Natl Cancer Inst Monogr.
2003;(31):41-46.
Plummer M, Schiffman M, Castle PE, Maucort-Boulch D,
Wheeler CM. A 2-year prospective study of human papillomavirus persistence among women with a cytological
diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J
Infect Dis. 2007;195:1582-1589.
Pastrana DV, Buck CB, Pang YY, et al. Reactivity of human
sera in a sensitive, high-throughput pseudovirus-based
papillomavirus neutralization assay for HPV16 and
HPV18. Virology. 2004;321:205-216.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
1991
1992
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
CANCER Supplement
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
1993
103. Schiffman M. Integration of human papillomavirus vaccination, cytology, and human papillomavirus testing. Cancer. 2007;111:145-153.
104. Kovacic MB, Castle PE, Herrero R, et al. Relationships of
human papillomavirus type, qualitative viral load, and age
with cytologic abnormality. Cancer Res. 2006;66: 10112-10119.
105. Jeronimo J, Schiffman M. Colposcopy at a crossroads. Am
J Obstet Gynecol. 2006;195:349-353.
106. Gage JC, Hanson VW, Abbey K, et al. Number of cervical
biopsies and sensitivity of colposcopy. Obstet Gynecol.
2006;108:264-272.
107. Jeronimo J, Massad LS, Castle PE, Wacholder S, Schiffman
M. Interobserver agreement in the evaluation of digitized
cervical images. Obstet Gynecol. 2007;110:833-840.
108. Jeronimo J, Massad LS, Schiffman M. Visual appearance
of the uterine cervix: correlation with human papillomavirus detection and type [serial online]. Am J Obstet Gynecol. 2007;197:47.e1-e8.