Background
Human
papillomavirus (HPV) is the most prevalent sexually
transmitted infection
in the world, occurring at some point in up to 75% of
sexually active women (Groopman 1999). Although HPV infection
is
widespread, few people even know they are infected because
they seldom
have noticeable symptoms. For example, males with virus
infecting the cells of the urethra rarely have a discharge
or visible
lesions on the penis. Even less well known is that nearly
all cervical cancers (99.7%) are directly linked to previous
infection with one or more of the oncogenic (cancer-inducing)
types of HPV (Judson 1992; Walboomers et al 1999). While
women, and men as well, usually are infected shortly
after they become sexually active in their teens, 20s or
30s,
progression to cervical cancer generally takes place
over a period of
10 to 20 years. Unfortunately, some early lesions can
become cancerous over a shorter time interval — within
a year or two.
It is estimated that for every 1 million women infected,
10% (about 100,000) will develop precancerous changes
in their
cervical tissue (dysplasia). Of these, about 8% (8,000
women) will develop early cancer limited to the outer
layers of the
cervical cells (carcinoma in situ [CIS]) and roughly 1,600
will develop invasive cancer unless the precancerous lesions
and CIS are detected and treated. In addition to cervical
disease, there is increasing evidence that people with
HPV who engage
in anal intercourse may be at high risk for precancerous
anal lesions as well as squamous cell cancer. For example,
among
homosexual men, about 60% of those who are seronegative
for HIV carry the HPV virus, while nearly 95% of seropositive
men
have HPV (Moscicke et al 1999). Moreover, they have been
found to carry the same types of genital papilloma viruses
(e.g.,
types 16 and 18) that cause cervical cancer. Finally, women
with active infection can transfer the virus to their newborn
(vertical transmission) during delivery, which can result
in papilloma virus infection in the neonate and possible
subsequent
laryngeal papillomatosis (Cason, Rice and Best 1998).
Currently there is no treatment for HPV infection; therefore,
once infected a person is most likely infected for life.
In most cases an active infection is controlled by the
immune
system and with time becomes dormant; however, it is not
possible to predict whether or when the virus will become
active again.
For example, one recent study followed more than 600 female
university students who were tested every 6 months (Groopman
1999). Over the course of 3 years, new HPV infections occurred
in more than 40% of the women. Most infections lasted about
8 months and then subsided. After 2 years, however, about
10% of the women still carried active virus in the vagina
and cervix.
In this study the persistent infections were most commonly
with the virulent, cancer-linked types.The VirusPapilloma
viruses were first recognized many years ago as the cause
of warts
on the hands and feet or condyloma accuminata on the pubic
area (penis and urethra in males or vulva and vagina in
females). For years, warts were considered mainly a nuisance
or ugly,
rather than a forerunner of cancer. Indeed warts on fingers
and toes usually are not dangerous, but virus types that
target the face can make skin cancer more likely. Still
others that
grow largely in the mouth, producing pea-sized lumps, can
develop into fatal squamous cell cancers (Terai et al 1999).
The papilloma virus is relatively small — just two
strands of DNA contained in a round shell, or envelope,
that looks
like a golf ball when enlarged under an electron microscope.
Because HPV cannot be cultured and a reliable serologic
test was not available until recently, it has been difficult
to
collect accurate information about the incidence and course
of HPV infections. For example, prior to the 1990s the
only way cervical infection with HPV could be detected
was by examining
cells from Pap smears microscopically or by looking at
the cervix through a colposcope (a special instrument that
magnifies
the cervix so that abnormal changes can be seen more easily).
Now, using DNA testing, which is available on a research
basis, nearly a hundred types of papilloma virus have been
identified.
It is still not known, however, why certain HPV types target
skin on the hands or feet while others attack the lining
cells of the mouth, and still others the genitalia of both
males
and females (Terai et al 1999).
A link between HPV infections and cervical cancers was
first demonstrated in the early 1980s. DNA testing has
identified
nearly 20 papilloma types that primarily infect the cervix,
vulva and vagina in women; the penis in men; and the urethra
and anus in both sexes. Of these, only four are most often
found within cervical cancer cells, with type 16 accounting
for about half the cases in the United States and Europe.
In Latin America, by contrast, types 39 and 59 are the
most prevalent
types, while in West Africa, type 45 is common (Groopman
1999; Stewart et al 1996). And, as mentioned previously,
HPV is present
in virtually all cases of cervical cancer (Walboomers et
al 1999).How HPV Induces CancerCervical cancer is probably
one
of the best known examples of how infection with a virus
can lead to cancer. In humans and animals, cell division
is regulated
largely by two proteins — one called Rb and the other
p53. Recently it has been found that two genes in HPV,
the so-called
E6 and E7 genes, produce proteins that can attach themselves
to Rb and p53 and block their effect on regulating cell
division (Massimi and Banks 1997). When this happens, the
infected
cells reproduce without any control. While the virus serves
only
as the initiating event, over time some of the wildly growing
cells develop permanent changes in their genetic structure
that cannot be repaired. Once this happens, some may eventually
turn into cancer cells.
In the early stages, virus-infected cervical cells may
show only small changes in size and shape when examined
microscopically.
With time, however, not only do the cells expand and become
more distorted, but their neat arrangement in rows or columns
on the surface of the cervix is destroyed. These changes
are consistent with those of cervical dysplasia, or cervical
intraepithelial
neoplasia (CIN) of varying degrees of severity, as seen
by the pathologist when examining a biopsy specimen of
cervical
tissue. Left untreated, in some women these premalignant
cells will slowly replace the normal cells on the surface
of the
cervix and carcinoma in situ will develop. Finally, when
the cells begin to grow through the normal surface layer
into the
muscle and deeper tissues, full-blown cancer is present.
Risk
Factors for Cervical Cancer
Epidemiologic
studies have identified a number of factors that play a
significant
role in the
development of CIN, a precursor to cervical cancer
(Palank 1998). The type
and pattern of sexual activity, especially in teenagers,
is a major factor in determining whether a person becomes
infected
with HPV. As a result of relaxed attitudes about sexuality
among adolescents in many cultures, the number of sexual
partners that teenagers have before age 20 can be quite
large, and each
of their partners also may have had multiple partners.
As a consequence, this pattern of sexual activity increases
their
risk of exposure to STDs, especially HPV.
RISK
FACTORS |
|
Sexual
activity (< 20 years) |
|
Multiple
sexual partners |
|
Exposure
to STD |
|
Mother
or sister with cervical cancer |
|
Smoking |
|
Immunosuppression |
|
HIV/AIDS |
|
Chronic
corticosteroid use (asthma and lupus) |
Another risk factor is having a blood relative (mother
or sister) with cervical cancer. Magnusson, Sparen
and Gyllensten
(1999) compared the incidence of dysplasia and CIS in relatives
of women with disease and in age-matched controls. They
found a significant familial clustering among biological,
but not adoptive, relatives. For biological mothers compared
to control cases, the relative risk was 1.8 whereas for
adoptive mothers the relative risk was not significantly
different from controls (1.1). For biological full sisters,
the relative risk was even higher (1.9) versus 1.1 for
nonbiological sisters. These data provide strong epidemiological
evidence for a genetic link to the development of cervical
cancer and its precursors.
Suppression of the immune system due to HIV infection also
is an important risk factor because it makes the cells lining
the lower genital tract (vulva, vagina and cervix) more easily
infected by the cancer-inducing types of HPV (Stentella et
al 1998). Other less common conditions that cause immunosuppression
include those requiring chronic corticosteroid treatment,
such as asthma or lupus (McDonald 1999). Women also increase
their risk for CIN by engaging in other behaviors known to
suppress the immune system. These include the use of recreational
drugs, alcohol and cigarettes. The latter is particularly
important because while a decrease in smoking among men has
occurred, the number of women who smoke has increased dramatically
in recent years—especially in teenage girls (McDonald
1999). Nicotine and the byproducts of smoking are thought
to increase a woman’s relative risk for cervical cancer
because they concentrate in the cervical mucus and decrease
the immune capability of Langerhan’s cells to protect
cervical tissue from invading oncogenic factors, such as
HPV infection (Ylitalo et al 1999).
In addition, there is substantial evidence that HIV-positive
women are at increased risk of developing cervical cancer
as well (Judson 1992). In two studies, both from high HIV
prevalence areas, a statistically significant association
between HIV and CIN was reported. Because the number of adolescents,
as well as adults, with HIV is rising in most countries where
cervical cancer is largely untreated, it can be expected
that cervical cancer rates will continue to increase, especially
in areas where STDs and HIV/AIDS rates are high.
Finally, in many developing countries, women who have abnormal
Pap smears frequently do not receive treatment at an early
stage when cervical cancer could be prevented because:
* there are long delays in reading and reporting the results;
* it is difficult to locate the patient once the report becomes
available;
* the cost of treatment is not affordable for many women,
even when simple outpatient procedures are used; and
* there is a lack of equipment as well as service providers
trained to use and maintain it.
As a consequence, even in countries where Pap smears are
available, many women may not get the treatment they need
in a timely manner.
Preventing Cervical Cancer
As mentioned
above, HPV is the most prevalent sexually transmitted infection
in the world.
And, unlike other STDs such as gonorrhea or HIV/AIDS, use
of condoms and other safe-sex practices may not be nearly
as effective in preventing infection. This is because the
papilloma virus lives in the skin (squamous) cells covering
the pubic area (vulva and shaft of the penis) as well as
the interior cells lining the vagina and cervix in women,
and urethra and anus in both sexes. Condoms do not cover
the entire shaft of the penis nor do they block contact
with pubic skin. Therefore, during intercourse, even with
a condom,
skin cells containing HPV can come in contact with a woman’s
vulva or vagina, enabling the virus ultimately to reach the
cervix. In addition, the friction of sexual intercourse is
believed to cause tiny, microscopic tears in the vaginal
wall, making transmission far more likely. Moreover, even
dead cells shed during intercourse can contain the virus
and remain infective for days (Roden, Lowy and Schiller 1997).
Primary Prevention
The most
effective way to prevent cervical and other genital cancers
would be a vaccine. Individuals would
need to be
immunized at an early age before they are sexually
active. The benefits of such a vaccine would be particularly
significant in developing countries, where women’s healthcare services
are minimal. Designing a vaccine, however, will not be easy
because people’s immune response appears to be
specific to the type of HPV. For example, a person
protected against
type 16 would still be at risk of infection with other
cancer-inducing types, such as 18 or 33. There also
appear to be subtypes
or variants within type 16, and perhaps with other
types as well. Finally, as mentioned above, the types
of HPV
associated with cervical disease vary by geographical
area. With the
increase in international travel, the various carcinogenic
types soon will be spread throughout the world. Therefore,
a vaccine with a mixture of several types would have
to be created (Groopman 1999; Stewart et al 1996).
Despite these problems, safety testing of at least two
vaccines that could protect women from cancer-linked papilloma
viruses
is underway. Estimates are, however, that it will be several
years before either would be available, and many more years
before they would be affordable in developing countries.
Finally, there also are attempts to produce a therapeutic
vaccine, one which would boost the immune system of someone
who is already infected and cause the cancer to regress
or even disappear. These vaccines are targeted to inactivate
the E6 and E7 proteins, those viral proteins that block
the
action of the cell growth regulating proteins (Rb and p53)
(Massimi and Banks1997).
Until such time that a protective vaccine is widely
available, primary prevention must focus on continuing
to change
sexual practices and other behaviors that increase
a person’s
risk of becoming infected. Just as with the fight against
HIV/AIDS, risk reduction counseling related to the
risk factors listed above (Table 1) must be incorporated
into
all levels
of the healthcare system, especially those dealing
with young people. The messages must include alerting
teenagers
that
practices designed to minimize the risk of STD or HIV/AIDS
exposure (i.e., the use of male or female condoms)
may not be as effective for HPV prevention. A recent
case-control
study, however, has shown that male condom use, which
significantly
decreases the amount of infectious virus deposited
in the vagina during sexual intercourse, offers substantial
protection
(Wen et al 1999).
In addition, vigorous efforts to discourage adolescents,
especially young girls, from starting smoking and initiating
sexual activity must be widely and continuously disseminated.
Secondary Prevention
Although at present prevention of HPV infection is difficult,
for women already infected the immediate need is:
* to identify those with early, easily treatable precancerous
lesions; and
* to cost-effectively treat them before the lesions progress
to cancer.
Since 1989, JHPIEGO has been exploring the feasibility of
several low-cost alternatives for cervical cancer detection.
Prominent among these is unmagnified (naked eye) visual inspection
using a dilute solution of acetic acid (VIA). In March 1999,
researchers from JHPIEGO and the University of Zimbabwe reported
in The Lancet that the sensitivity (77%) and specificity
(64%) of VIA are comparable to those of good quality Pap
smears. This large-scale study, which involved more than
10,000 women attending primary healthcare clinics in Zimbabwe,
confirmed the findings of similar studies in South Africa
and India (Sankaranarayanan et al 1998). A second major finding
from the Zimbabwe study was that nurse-midwives, who did
all the VIA tests, quickly learned to competently perform
them. This finding is important because the vast majority
of developing country women who need to be tested live in
areas where there are no doctors and where Pap smears may
never be available. Furthermore, unlike Pap smears that require
several days to a week to get the results back, with VIA
the results are available immediately. As a consequence,
these nurse-midwives were able to quickly and easily identify
women with no disease, those with abnormal findings suitable
for immediate treatment and those with very large lesions
or advanced disease requiring referral.
With the establishment of VIA as an acceptable alternative
to Pap smears (Kitchener and Symonds 1999), it is now possible
to offer VIA with outpatient treatment of precancerous lesions
at the same visit. For example, cryotherapy, which involves
freezing the cervix with a liquid coolant such as carbon
dioxide to destroy the abnormal cervical tissue, is highly
effective. And cryotherapy has been used extensively throughout
the world for more than 20 years (Cox 1999; Mitchell et al
1998; Olatunbosun, Okonofua and Ayangade 1992). Cryotherapy
is also one of the easiest methods to learn and can be performed
by nurses and other healthcare workers. In light of these
promising epidemiologic studies and the availability of a
simple, low-cost outpatient method of treatment, the opportunity
to markedly reduce the incidence of cervical cancer globally
is at hand. As the first step (Phase 1) in this process,
JHPIEGO is conducting several safety, acceptability, feasibility
and program effectiveness (SAFE) demonstration projects in
separate regions of the world. These SAFE projects are needed
to:
* show that nurses and midwives can competently perform both
VIA and cryotherapy in low-resource settings,
* demonstrate that nurses and midwives can confidently treat
or refer women with abnormal (precancerous) lesions, and
* document the acceptability and feasibility of cervical
cancer testing that is directly linked to immediate treatment.
We anticipate the results of these studies
will show that well-trained nurses and midwives can quickly
and easily identify
patients who are appropriate for immediate treatment with
cryotherapy or refer those requiring more aggressive treatment
(or those with advanced disease). We also expect to learn
that a test, treat or referral program is a safe, acceptable
and feasibleapproach for preventing cervical cancer in low-resource
settings. Finally, we anticipate identifying ways in which
large-scale Cervical Cancer Prevention (CECAP) programs can
be implemented nationally through a combination of individual
and community education, participation by local nongovernmental
organizations and women’s groups, and sponsorship by
indigenous service organizations and clubs.
This practical approach to preventing cervical cancer has
the potential to reduce disease progression and death in
a majority of women who currently do not have access to Pap
smears and physician-staffed services. Also, it has the potential
to reduce referrals of women with early lesions to higher
levels of the healthcare system as well as increase the chance
of detecting invasive cancer at an earlier stage when it
can be treated successfully. Finally, once a precancerous
lesion is treated, a woman’s risk of developing an
infection with other HPV types may be reduced for several
years, while those women found to be normal may not need
retesting for 5 or more years (Lonky et al 1997; Lonky et
al 1999).
Summary
Human
papillomavirus is the most prevalent STD in the world,
occurring at some point in up to 75% of
sexually active women. Nearly all cervical cancers are
directly linked to previous infection with one or more
of the oncogenic
types of HPV. Other risk factors for cervical cancer
include sexual activity at a young age, multiple sexual
partners,
immunosuppression and HIV infection. Lacking an appropriate
vaccine for HPV, primary prevention of cervical cancer
must focus on condom use and changing sexual practices
as well
as other behaviors that increase a person’s risk of
becoming infected with HPV.
For women already infected with HPV, the immediate need
is to identify those with early, easily treatable precancerous
lesions and to treat these women cost-effectively before
the lesions progress to cancer. Visual inspection using
a
dilute solution of acetic acid (VIA) has been established
as an acceptable alternative to Pap smears. Therefore,
it is now possible to offer VIA with cryotherapy, an
outpatient treatment that uses a liquid coolant to destroy
abnormal
cervical tissue. Cryotherapy is highly effective and
has been used extensively throughout the world for more
than
20 years. Once a precancerous lesion is treated, a woman’s
risk of developing an infection with other HPV types may
be reduced for several years, while those women found to
be normal may not need retesting for 5 or more years.
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