PART ONE
General Cytology
Finally it is important to those countries or regions installing
screening programs to pay attention to the following points37:
1. Try to screen the largest possible number of women—
with at least one test during their lifetime.
2. Focus on the workup for those women who had a
bad diagnosis in the primary screening such as high-
degree lesions or invasive carcinomas.
3. Design the programs remembering that it will not be
possible to detect all the carcinomas.
4. Try to make the women, medical staff, politicians, and
legal authorities understand that the Pap test is not a
perfect test, and that there are advantages and disad-
vantages in its use. Because of this they should make
an effort to optimize results and even add methods to
help the prevention program achieve its targets.
Screening Programs and HPV Vaccine
HPV is a sexually transmitted infection recognized as necessary
for the development of cervical cancer, and this strong associa-
tion is currently seen as causal.11
Oncogenic types of HPV DNA
are detected in virtually all cervical cancers and recognition of
this crucial role has stimulated the investigation and develop-
ment of HPV vaccines in both prophylactic and therapeutic set-
tings. The natural history of this cancer offers two opportunities
for intervention to interrupt the course of the disease: primary
and secondary prevention. Primary prevention refers to meas-
ures to prevent infection by HPV using vaccines. Secondary
prevention, which is detection and treatment of precursor cervi-
cal cancer lesions, traditionally uses cytopathology as a screen-
ing test.
The prophylactic HPV vaccines are prepared from empty viral
capsids called virus-like particles (VLPs) composed of the capsid
proteins L1 and L2. These particles do not contain viral genetic
material and thus are unable to multiply, which means they are
non-infectious. Early studies showed that L1 protein has the
intrinsic capacity to assemble into empty capsid-like structures
whose immunogenicity is similar to that of infectious virions.38
Studies of HPV16 L1 VLP vaccine have indicated that they were
well tolerated and highly immunogenic, generating high levels
of antibodies against HPV16.39
Two studies provided convincing evidence that the pro-
phylactic vaccine is effective in preventing new and persistent
infections of the genital tract with the two types of HPV most
commonly associated with cervical cancer and its precursors.
The first published randomized, clinical trial of prophylac-
tic vaccines developed to determine whether an HPV16 L1 VLP
vaccine could prevent HPV16 infection in women reported that
the vaccine had a 100% efficacy in the vaccine group when com-
pared to the placebo group. In this study, women who received
the vaccine had the titer of HPV16 antibodies 58.7 times as high
as the titer among women with serologic evidence of natural
HPV16 infection.40
A second study on a randomized, double-blind, control-
led trial to assess the efficacy, safety, and immunogenicity of
a bivalent HPV16/18 L1 VLP vaccine showed that the vaccine
was effective in prevention of incident and persistent cervical
infections with these two virus types, and associated cytologi-
cal abnormalities and precancerous lesions. This study reported
that the vaccine efficacy was 91.6% against incident infection
and 100% against persistent infection with HPV16/18.41
So far there exist two vaccines with types HPV16 and 18,
more commonly associated with cervical cancer, which protect
against both new and persistent infections. One of the vaccines
also includes types 6 and 11, with a protector effect against geni-
tal warts.42 With this it is hoped to prevent around 70% of cervi-
cal cancer cases worldwide among women who have never been
exposed to the high-risk types of virus. Bearing in mind that
the prevalence of types 16 and 18 varies from country to coun-
try, it is believed that the vaccine that would include the seven
types of most common HPV in the world (16, 18, 45, 31, 33,
52, 58) would be able to prevent about 87% of all cases, with
small regional variations.43 However, the addition of multiple
new types of VLP in one unique vaccine could present technical
obstacles for the manufacturers.44
Although the results of studies with vaccine are promising,
some questions still need to be answered for an efficient imple-
mentation. The first of them refers to viral types other than 16
and 18 strongly associated with cervical cancer.18 Screening and
treatment services will still be required, because the vaccines
only prevent about 70% of cervical cancer cases and because it
will be years, if not decades, before we see the full benefit of
vaccination in terms of a reduction in the incidence of cervical
cancer.45 Efforts to develop multivalent vaccines that could con-
trol most HPV infections associated with cervical disease will be
necessary.
Furthermore, duration of the antibody response and protec-
tion from vaccination remains to be determined and a long-term
follow-up of vaccinated women is required before the impact
can be fully identified.18 Trial data for both vaccines suggest they
offer a minimum of 4-5 years efficacy, of close to 100%, in pre-
venting persistent infection by the vaccine genotypes.46 There are
no predictions regarding prevention of cancer among women
who have already experienced an infection. The vaccines are not
designed to treat people who have already been infected with
these genotypes. Moreover, it is not known whether effective
coverage against some genotypes could favor the emergence of
more pathogenic types.42
Some subjects are particularly relevant for programs, and serv-
ice delivery strategies still remain under study. There are several
open issues as well as the performance in Africa where chronic
malnutrition, HIV, and other infections diseases may compro-
mise the immune response, the cross-protection, vaccine com-
patibility, and the safety and efficacy in specific populations,
such as pregnant women and immunocompromised patients.
There is still a lack of data on infants and young children.47
While the development of a prophylactic HPV vaccine may
be the ultimate solution to the prevention of cervical cancer, it is
unlikely that the vaccine will be widely available in low-resource
settings within the next decade. In the meantime large numbers
of women already infected with risk types of HPV remain at risk
of developing cervical cancer.18 To prevent the disease in women
already infected or in those infected with other types of virals
not included in the vaccines, it will be necessary to maintain and
improve cervical cancer control actions, principally in develop-
ing countries where the programs are less effective.
To measure the clinical benefits and cost-effectiveness of HPV
vaccination, a computer-based model of various cancer preven-
tion policies has been developed. The most effective strategy
was one that combined vaccination and triennial conventional
cytologic screening strategies. This approach would reduce the
absolute lifetime risk of cervical cancer by 94% compared with
no intervention, in a cost-effective manner.48 HPV vaccine will
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