**Human Papillomavirus (HPV) and Cervical Cancer: *An Update on
Prevention Strategies* Script**

**August 9, 2005**

\[1\]DANIELS

Hello and welcome to "Human Papillomavirus (HPV) and Cervical Cancer:
*An Update on Prevention Strategies."*

I'm Kysa Daniels, your moderator for this program, which is originating
from the Centers for Disease Control and Prevention in Atlanta, Georgia.

In this Webcast, we'll be discussing genital human papillomavirus (HPV)
infection, a sexually transmitted disease. This is an extremely common
infection of growing concern to both the public and to health care
providers.

Our focus today is

\- an update on the natural history of HPV infection,

\- the association of different HPV types with various clinical
manifestations,

\- HPV transmission, and\...

\- methods for HPV and cervical cancer prevention.

Before we introduce our panelists, let's hear from CDC Director, Dr.
Julie Gerberding.

DR. JULIE GERBERDING:

Hello! I am Dr. Julie Gerberding, Director of the Centers for Disease
Control and Prevention. Thanks for joining us for this very important
webcast on Human Papilloma Virus.

Genital infection with HPV is the most common sexually transmitted
infection in the United States. About 20 million Americans are currently
infected with the virus, and about 6.2 million people become newly
infected each year.

 

Most infections cause no clinical problems and go away on their own
without treatment. But some infections lead to genital warts in men and
women, and cervical cancer in women.

 

Although a vaccine against HPV is in development, there is no curative
treatment for genital HPV infection. Treatments are available for the
abnormalities caused by HPV infection.

 

Persistent infection with certain types of HPV is a leading cause of
cervical cancer. Progression from HPV infection to invasive cancer is a
slow process, estimated to take 10-15 years or longer. Cervical cancer
is an uncommon consequence of HPV infection. Nevertheless, regular
screening for cancer with Pap tests can detect cervical abnormalities
that can be treated before they become cancerous. Screening also helps
detect cancer at an early stage where it can be cured in over 90 percent
of people.

In the past 40 years, widespread cervical cancer screening using the Pap
test and treatment of precancerous cervical abnormalities have resulted
in a dramatic decrease in the incidence and mortality due to cervical
cancer in the United States.

 

However, each year in the U.S., more than 10,000 women still develop
cervical cancer and over 3,000 women die from it. Sadly, of women in the
U.S. who develop cervical cancer, about half have never had a Pap test.

 

For this reason, CDC established an HPV and cervical cancer workgroup
that involves scientists from four of CDC\'s 12 national centers. The
workgroup helps us bring our best experts together so we can have more
impact on this important health threat.

 

This Webcast focuses on the prevention of genital HPV infection in men
and women. It summarizes key aspects of the epidemiology of HPV
infection and its transmission, and discusses the best strategies to
prevent HPV infections and its associated diseases. This knowledge can
help support the action that we must take to decrease the threat of HPV
and protect women and men from the preventable diseases it causes. Thank
you.

Thank you, Dr. Gerberding. Now it's time to introduce our guests for
today's program.

Dr. John Douglas is the Director of the Division of Sexually Transmitted
Disease Prevention of the National Center for HIV, STD, & TB Prevention
at CDC.

Dr. Mona Saraiya is a medical epidemiologist working in the Epidemiology
and Applied Research Branch of the Division of Cancer Prevention and
Control at the National Center for Chronic Disease Prevention and Health
Promotion at CDC.

And Dr. Tom Wright is Associate Professor of Pathology at the College of
Physicians and Surgeons at Columbia University. Welcome to all of you.

Before we begin, allow me to go over a few details about today's
program.

This program will be available for viewing at the program website at
www.phppo.cdc.gov/PHTN/HPV-05.

We will be offering continuing education credits for various professions
based on one hour of instruction. Credit will be available by
registering and completing an evaluation at www.phppo.cdc.gov/
phtnonline. The course number for this program is WD0075. Credit will be
available through August 2008.

If you need additional help you may call 800-41-TRAIN or 404-639-1292,
Monday through Friday, from 8 am until 4:40 pm Eastern time.

Or, you may write us at C-E at C-D-C dot G-O-V. *\[PAUSE\]*

Now, let's review the objectives for this program.

Upon successful completion, you should be able to identify high-risk and
low-risk types of genital HPV infection, and discuss the epidemiology of
genital HPV infection in the United States.

You should also be able to describe the natural history of genital HPV
infection and identify methods used to detect cervical cellular
abnormalities for the prevention of cervical cancer \....and describe
the clinical uses of the HPV DNA tests in the context of Pap test
screening and management.

Finally, you should be able to summarize appropriate patient counseling
messages for genital HPV infection, and identify methods for preventing
genital HPV infection.

At the end of the program, there will be a question and answer session,
at which time the panel will answer questions that have been previously
e-mailed.

We will not be accepting phone calls.

Dr. Douglas, let's begin with you for an introduction to genital HPV
infection.

\[3\]DOUGLAS

Thank you, Kysa.

Genital HPV infection is very common in sexually active men and women.

It's estimated that at least 50 percent of sexually active
[women]{.underline} are infected with genital HPV at some point in their
lives, and it's likely that comparable rates would be found in
[men]{.underline} \...if there were good HPV testing methods available
for men.

Papillomaviruses are a complex group of DNA tumor viruses. They are
found in many species, where they can cause benign growths, or
papillomas, and cancers. They can't be routinely grown in the lab.

This makes it hard to test experimental treatment. Papillomaviruses are
most commonly detected by the presence of DNA.

HPV types are distinguished by genetic sequences, hence their
designation as genotypes. More than 30 genotypes of HPV are sexually
transmitted and can infect the genital tract.

Genital HPV infection is a sexually transmitted infection, but it's not
transmitted like many other STDs, which are passed from partner to
partner through semen or other bodily fluids. Instead, it's transmitted
through skin-to-skin contact.

Genital HPV infections are transmitted primarily by penetrative genital
contact, usually through vaginal or anal sex. But penetration isn't the
only way HPV can be transmitted.

It can also be passed through oral-genital, manual-genital, and external
genital, genital contact, although we believe these routes of
transmission are much less efficient and thus, much less common than
sexual intercourse.

In most cases, genital HPV infection is transient, asymptomatic, and
resolves without treatment or without a person ever being aware they had
the infection.

When clinical manifestations do occur in adults, they most typically
include: genital warts, as shown on this slide, cellular abnormalities
known as intra- epithelial neoplasia, and anogenital squamous cell
cancers.

The most common clinically significant manifestation of genital HPV
infection is cervical intra-epithelial neoplasia, or CIN, which is
detected by Pap test screening.

CIN is generally classified as low-grade, or CIN1, or high-grade,
including CIN 2 or 3. High-grade abnormalities have some risk of
progression to cancer and are thus considered cancer precursors.

Finding and treating these high-grade lesions through Pap smear
screening is the backbone of cervical cancer prevention programs.

The approximately 30 types of genital HPV are divided into low-risk and
high-risk types based on their association with cervical cancer.

Low-risk types of genital HPV can cause genital warts and benign or
low-grade cervical cell changes that result in mild Pap test
abnormalities.

These abnormalities are not associated with cervical cancer.

An estimated 1.4 million people have genital warts at any one time in
the United States. That's about 1% of the sexually active population,
making genital warts one of our most common STDs.

Very rarely, genital HPV infection can also occur in the respiratory
tract where wart-like lesions cause a syndrome known as recurrent
respiratory papillomatosis, or RRP. This syndrome can occur in adults,
possibly due to oral-genital sexual contact, but is more common in young
children due to perinatal transmission. In children, estimates of the
incidence rate for RRP are imprecise, but range from 0.4 to 1.1 cases
per 100,000 children. Although data are limited, cesarean delivery does
not appear to be protective and is not recommended to prevent RRP in the
children of women with genital warts. The most common low-risk HPV types
are types 6 and 11. Other low-risk types include types 40, 42, 43, 44,
54, 61, 72, 73, and 81.

The vast majority of genital warts are caused by types 6 and 11.

While all of the low-risk types can cause low-grade Pap smear
abnormalities, .it is important to emphasize that they are rarely
associated with higher-grade cervical cell changes.

Because of this, testing for low-risk types is not recommended for
clinical management.

Infection with high-risk types of genital HPV can cause both low-grade
and high-grade cervical cell abnormalities.

In rare cases, infection with high-risk genital HPV that is not cleared
by the immune system

-- known as persistent infection

-- can cause cancers of the cervix, vulva, anus, and penis.

Common high-risk types of genital HPV are 16, 18, 31, 33, 35, 39, 45,
51, 52, 56, 58, 59, 68, and 82.

HPV 16 is found in approximately half of all women with cervical
cancers. HPV 16 is also the single most commonly identified HPV type in
CIN 2, 3.

Infection with high-risk types of genital HPV is much more common than
infection with low-risk types.

Again, it is important to emphasize that. In addition, an estimated
5%-30% of people infected with genital HPV are infected with multiple
types of the virus.

Infection with either low-risk or high-risk types of genital HPV usually
causes no clinical signs or symptoms and is transient.

As mentioned, genital HPV infections are primarily transmitted through
sexual activity.

And because people infected with genital HPV typically don't know that
they have the virus, infections are commonly shared between sex
partners.

Certain risk factors are associated with acquiring a genital HPV
infection.

These include being 25 years of age or younger, and having first sexual
intercourse at the age of 16 or younger.

The risk of acquiring a genital HPV infection increases with an
increasing number of lifetime sex partners. In addition, having sex with
a new partner may be a stronger risk factor for acquiring a genital HPV
infection than having sex with a steady partner. Finally, having sex
partners who have had multiple sex partners also increases the risk of
infection.

\[4\]DANIELS

Thank you, Dr. Douglas.

Since genital HPV infections are so common in the United States,

Dr. Saraiya, what can you tell us about the epidemiology of genital HPV
infection and cervical cancer in this country?

\[5\]SARAIYA

Well, Kysa, it's difficult to assess incidence and prevalence
information on genital HPV infection because it's not a reportable
infection in any state, although genital warts are reportable in a few
states.

The reason for this is that most genital HPV infections are brief and
symptomatic or sub clinical --- that is, they usually have no visible
clinical manifestations or clinical consequences. Given the high
prevalence of infection, case reporting would be burdensome for
providers, health departments, and laboratories while at the same time
providing no personal or public health benefit.

However, as already mentioned, infection with genital HPV is believed to
be extremely common.

CDC estimates that 15% of the population

\--or about 20 million people

\--currently have a detectable genital HPV infection, and an estimated
9.2 million sexually active adolescents and young adults 15 to 24 years
of age are infected with genital HPV.

An estimated 6.2 million new genital HPV infections occur each year.

It is important to emphasize that only a small percentage of women
infected with genital HPV develop persistent infections.

And only women who develop these persistent infections are at risk for
developing high-grade cancer precursors and cancers.

The most critical risk factor for developing cervical cancer is not
participating in a routine cervical cancer screening program.

Other risk factors that may increase the chance of developing cervical
cancer precursors and cervical cancers include:

\-- Cigarette smoking which has been consistently shown to be an
independent risk factor

\-- Less consistent, but A few well-designed studies have also shown
that long-term use of oral contraceptives and having a high number of
live births is also a risk factor.

And co-infection with Chlamydia trachomatis or *herpes simplex virus
type 2* may be considered cofactors along with HPV

Cervical cancer once claimed the lives of more American women than any
other type of cancer.

But over the last 40 years, widespread cervical cancer screening using
the Pap test and treatment of precancerous cervical abnormalities has
resulted in

a marked reduction in the incidence of and mortality due to cervical
cancer in the

United States.

Incidence of new cervical cancer cases has fallen by approximately 75%
since the introduction of Pap screening programs.

This slide here using cancer registry data shows how both new cases and
deaths from cervical cancer have dropped approximately 30 to 40 percent
over the last

25 years.

According to the American Cancer Society, there will be 10,370 new cases
of cervical cancer and 3,710 deaths from the disease in 2005.

But there are disparities in both incidence and mortality in cervical
cancer among certain racial and ethnic subgroups.

For example, using data from CDC's National Program of Cancer Registries
and

NCI's SEER Cancer Registries, we see that incidence rates for cervical
cancer among black women is about 1.5 times that in white women.

Similarly, rates for Hispanic women are 1.5 times higher than that of
non-Hispanic women and, although not shown on this slide, incidence for
certain Asian subgroups, such as Vietnamese women, are much higher than
other Asian subgroups.

In general, women born outside the United States have higher mortality
rates from cervical cancer than U.S. born women.

This map shows that even in the U.S., there are some regional
disparities.

The red areas indicate the higher mortality rates.

As you can see, the Appalachian states, states in the south, and states
bordering Mexico have higher mortality rates from cervical cancer.

At least some of these variations are explained by differences in
socioeconomic indicators such as income, education, possibly cultural
barriers, and access to screening.

Usually we think in terms of predisposing factors which contribute to
cervical cancer incidence for example,

\- HPV,

\- sexual activity at an early age,

\- multiple sexual partners, and

\- smoking), .but we've now identified that the most serious factor
contributing to cervical cancer incidence and mortality is lack of
screening.

This pie chart highlights experience with cervical cancer screening
among women who actually develop cervical cancer.

While there are a variety of factors contributing to failure of the
prevention program, such as; false negative cytology tests and
inadequate follow up, by far the largest factor is lack of screening.

Up to 60% of cervical cancer cases in the United States occur among
women who have never been screened or rarely been screened.

Even when it comes to Pap testing in the U.S., there are some women who
are less likely to have had a recent Pap. Data from a 2000 national
health interview survey shows that, overall, 83 percent of women
reported a Pap in the last 3 years ---but the data also showed
considerably lower screening rates among

\- women without health insurance,

\- recent immigrant women, and

\- women of Hispanic or Asian origin.

\[6\]DANIELS

Thank you, Dr. Saraiya.

Now, for the natural history of genital HPV infection, let's go to Dr.
Wright.

\[7\]WRIGHT

Thanks, Kysa.

As we've stated, most genital HPV infections are asymptomatic or sub
clinical, and are transient. They have no clinical consequences in
immunocompetent individuals.

The interval between first exposure and clinical signs is unclear, but
it's probably three weeks to one year for genital warts.

Most genital HPV infections clear spontaneously within 1-2 years.

HPV 16 is more likely to persist than other HPV types, but in most
cases, even with HPV 16, infection becomes undetectable within
[two]{.underline} years.

The gradual development of an effective immune response is thought to be
the likely mechanism for HPV DNA clearance.

Currently it is unclear whether those genital HPV infections that become
non-detectable using standard molecular tests have completely cleared or
whether they remain latent in basal cells with the potential for later
reactivation.

If the virus is able to remain in a nondetectable dormant state and
reactivate

many years later, it may explain why some older women in a mutually
monogamous relationship can begin to shed genital HPV.

It's also important to note that HPV is more likely to be detected in
people who are immunosuppressed,.such as those who are HIV-infected,
have had an organ transplant, or are undergoing chemotherapy.

An HPV infection that persists is required for high-grade cervical
cancer precursors and invasive cervical cancers to develop.

A persistent infection is an infection that is not cleared by the immune
system and is characterized by persistently detectable HPV DNA.

Factors associated with persistent infection include being 30 years of
age and older, having high-risk HPV types, and having a suppressed
immune system.

However, it's important to note that most women with persistent HPV
infection do not develop precancerous cervical cell changes or cervical
cancer.

\[8\]DANIELS

What do clinicians need to know about cervical cancer screening and
current recommendations, Dr. Saraiya?

\[9\]SARAIYA

Cervical cell abnormalities are frequently attributed to the transient
presence of certain HPV types. These abnormalities usually have no signs
or symptoms, and they often regress spontaneously without either
detection or treatment.

When cervical cell abnormalities are detected, it's usually by cervical
cytology ---the Pap test. Cervical cytology is used as a screening tool
to identify women who need a diagnostic biopsy. Characteristic changes
in the cells shed and scraped from the surface are predictive of
underlying changes.

Histological evaluation, on the other hand, requires a full thickness
biopsy or excision.

Biopsies are usually obtained while visualizing lesions with
colposcopy---a magnified examination of the cervix.

Biopsies are considered the "gold standard" and key to diagnosis of
cervical cell abnormalities.

Here is a slide that shows the difference between histology and
cytology.

The Pap test does not directly detect HPV. It detects - epithelial cell
changes that are frequently due to genital HPV infection.

If they are not detected, these changes may lead to cervical cancer.

There are [two]{.underline} Pap test methods - the conventional Pap test
and the newer liquid-based cytology or LBC. Each has pros and cons.

In a conventional Pap test, cells are scraped from the cervix and placed
on a slide to be examined in a laboratory.

The sensitivity of a single conventional cytology test is between 51%
and 88%, although the sensitivity increases with repeated testing as is
currently recommended.

The specificity of a single conventional cytology test is between 95%
and 98%.

False negatives in conventional Pap tests can occur for a number of
reasons:

\- samples may not contain enough cervical cells,

\- abnormal cells may be hard to see because of inflammation or mucus,

\- or a lab technician may simply not see abnormal cells.

For LBC, cells are suspended in liquid medium and then applied to a
slide in a laboratory as a thin cellular layer, eliminating most blood,
mucus, and inflammatory cells. There has been a lot of controversy about
the comparative sensitivities and specificities of the 2 approaches,
largely due to a lack of well-designed studies.

The Liquid based Pap has a higher sensitivity but lower specificity. The
evidence based on sensitivity and specificity of conventional Pap vs.
liquid-based cytology does [not]{.underline} indicate that LBC should be
the standard.

There are other factors, though, that might make LBC more attractive.
Because only a portion of the LBC sample is used in preparing the slide
for cytologic examination, residual material can be used for HPV DNA
testing when very mild cytological abnormalities are found which are
referred to as ASC-US.

Conventional cytology requires the collection of a separate sample at
the time of the cervical swab or a return visit by the patient for
collection of a new sample.

More satisfactory results have been reported with LBC, in part because
the technique reduces problems with preparation of the sample.

The disadvantage of LBC tests is that they are more expensive than
conventional cytology.

The 2001 Bethesda System is a modification of the previous one from the
1990\'s for classifying PAP test results. I'll be focusing today on
squamous cell abnormalities in the Bethesda system, which differs from
the older classification system in that it subdivides atypical squamous
cells, or ASC, that don't appear to be completely normal into
[two]{.underline} categories.

The first is atypical squamous cells of undetermined significance, or
ASC-US.

ASC--US changes are usually mild or equivocal abnormalities, and are
sometimes related to genital HPV infection.

These are quite common in the United States. Approximately 4%-5% of all
cervical cytology results are reported as ASC-US.

The second is ASC--H, or *atypical squamous cells* that cannot exclude a
high-grade squamous intraepithelial lesion, or HSIL.

ASC--H changes are more likely to be precancerous abnormalities.

A separate category is low-grade squamous intraepithelial lesion, or
LSIL, which are generally cellular changes due to a transient infection
with a

high-risk HPV type. This encompasses HPV, mild dysplasia, and CIN 1.

The last category is high-grade squamous intraepithelial lesion, or
HSIL\--generally cellular changes due to a persistent infection with a
high-risk HPV type with a higher risk for progression to cervical
cancer.

This encompasses: moderate and severe dysplasia, CIN 2, CIN 3 and CIS.

This slide shows us just how common these Pap test abnormalities are.

It is estimated that of the 50 million Pap tests that are performed
every year, approximately

\-- 2 million are ASC-US Paps, these include a small proportion that are
ASC-H,

\-- 1 million are LSIL Paps, and

\-- 300,000 HSIL Paps.

In addition to these new Bethesda Classifications, several organizations
provide guidelines for cervical cancer screening, including:

\- the age to begin screening,

\- screening intervals, and

\- special considerations.

These organizations include the American Cancer Society (ACS), the
American College of Obstetricians and Gynecologists ACOG), and the U.S.
Preventive Services Task Force (USPSTF).

These organizations have agreed on several things in the last decade, in
particular the age to start screening, and who not to screen.

However, there are some differences. They also differ in how often to
screen, and on the use of HPV testing in cervical cancer screening.

All 3 organizations suggest that cytologic screening begin within three
years of onset of sexual intercourse or age 21, whichever comes first,
and that women be screened at least every three years.

However, the ACS recommends that screening be conducted yearly with
conventional Pap tests and biennially with liquid-based cytology methods
up until age 30.

ACOG recommends yearly screening up until age 30, regardless of the Pap
test type used.

According to the ACS and ACOG, regardless of the Pap test women at or
older than age 30 who have had 3 consecutive, technically satisfactory
normal/negative cytology results may be screened every two to three
years.

Of course, women who have a history of in-utero DES exposure, are HIV
positive, or are immuno- compromised. These women may require more
frequent screening.

As to when to stop screening, the USPSTF and ACS recommends against
routinely screening women older than 65 to 70 respectively if they have
had adequate recent screening with normal Pap smears and are not
otherwise at high risk for cervical cancer.

ACOG states that it is difficult to set an upper age limit, and that it
should be determined on an individual basis, based on medical history
and risk factors for CIN.

The USPSTF, ACOG, and ACS recommend against routine Pap smear screening
in women who have had a total hysterectomy for benign disease. A
molecular test to detect HPV DNA has been approved by the FDA.

This test, known as solution hybridization, detects most of the
high-risk types and several of the more common low-risk types of HPV.

The FDA approved the high-risk HPV DNA test to be used in basically 2
ways:

\-- For management of women with ASC-US Pap tests in the context of
screening.

\-- HPV DNA testing may be added to cervical cytology for screening in
women 30 years of age and older.

This has been called adjunct screening, primary screening, or HPV with
PAP test screening.

Tom will provide more detail on this later.

As you can see in this slide, several organizations have followed with
recommendations on the use of the HPV test for both ASC-US triage and
for HPV testing with the Pap test for routine cervical cancer screening.
Although the USPSTF did not address HPV testing for management of
abnormal Pap tests, USPSTF found insufficient evidence for primary
screening.

The American Cancer Society stated that HPV testing along with the Pap
test for routine cervical cancer screening is an option.

The American College of Obstetricians and Gynecologists recommends ---
as does the American Society of Colposcopy and Cervical Pathology ---HPV
testing for both indications.

\[10\]DANIELS

Thanks, Dr. Saraiya. Dr. Wright, can you provide more detail in the role
that

HPV DNA testing plays in cervical cancer screening and management of
abnormal Pap tests?

\[11\]WRIGHT

With the recent FDA approval of HPV DNA testing as an adjunct to the Pap
test to screen for cervical cancer in women 30 years or older, this
approach is beginning to be used by some clinicians. Both the American
Cancer Society and the American College of Obstetricians and
Gynecologists consider this to be an acceptable approach to screening
women 30 years and older.

Recently ACS, NCI, and ASCCP published guidance to help in the
management of specific test results when HPV testing is used as an
adjunct:

Women who are negative by both HPV DNA testing and cytology, which
should be the majority of women, should [not]{.underline} be rescreened
before three years. This is because their risk of developing CIN is
quite low.

Women who are cytology negative but HPV DNA positive should not undergo
colposcopy.

Instead HPV DNA testing along with cervical cytology should be repeated
at 6-12 months.

Finally, women who has a LSIL or greater PAP test should be referred to
colposcopy, irrespective of their HPV result.

Use of the combination of HPV DNA testing and cervical cytology should
be discontinued at the same age, and under the same circumstances, as
discontinuance of cervical cytology screening.

However, because 5%-15% of women age 30 and older will be high-risk

HPV DNA positive, concern has been raised about the potential negative
impacts of using HPV DNA testing for screening.

These concerns are related to lack of counseling of women with respect
to their risk of cervical disease, the source of their infection, and
their infectivity.

There is also fear that HPV DNA positive women without CIN 2, 3 or
cancer will undergo unnecessarily intensive and expensive follow-up or
treatment.

It needs to be stressed that HPV DNA testing with the Pap test is not
approved as a screening method for women under age 30.

This is because there's a very high rate of transient HPV infection in
this age group.

In adolescents and young adults in their 20's, the prevalence of
high-risk HPV DNA positivity is high, while the prevalence of cancer is
relatively low.

HPV DNA testing is also not recommended for use in women who are immuno-
suppressed for any reason including infection with HIV. This is because
testing has no proven role in clinical management.

The other way in which HPV DNA testing is widely used in the United
States is to determine which women with very mild cytological
abnormalities, referred to as ASCUS, require additional workup. As
already mentioned, ASCUS results are quite common, about 5% of all Pap
tests.

The 2001 Consensus Guidelines identify [three]{.underline} approaches to
managing women with ASCUS.

These include:

\-- repeating the Pap test twice at 4-6 month intervals,

\-- performing immediate colposcopy, or

\-- testing for high-risk HPV DNA.

HPV DNA testing identifies those women with ASCUS who are at greatest
risk for having a high-grade cervical cancer precursor and who need
colposcopy.

In contrast, women with ASCUS who are HPV DNA negative can simply be
followed-up with a repeat cytology in one year.

It needs to be pointed out that HPV DNA testing is not indicated in a
number of situations. These include women or men diagnosed with external
genital warts, for women or men as a general screening test for HPV.

HPV testing is also not indicated for women with LSIL, HSIL, or ASC-H
Pap test results.

Testing is not recommended in those situations because there is no
evidence that it improves clinical management.

And for men, HPV DNA test reliability is not well defined.

\[12\]DANIELS

Dr. Wright, *how should providers counsel and educate their patients
about genital HPV infection?*

\[13\]WRIGHT

Kysa, the general U.S. population has very limited knowledge about
genital HPV infection and its relationship with cervical cancer.
Nonetheless, studies have found a high level of anxiety and concern
among women when informed that they are infected with genital HPV.

Patient counseling and education about HPV should take place

\-- when genital warts are diagnosed,

\-- at Pap screening visits,

\-- when a Pap test result is abnormal, and

\-- when a HPV test is positive.

Counseling should include:

\- general information about HPV infection,

\- how HPV infection is transmitted,

\- how to prevent HPV infection and its clinical manifestations, and.

\- partner issues.

Counseling may be assisted by the use of written materials.

The general information about genital HPV infection that patients need
to know starts with the fact that most sexually active adults will
become infected with genital HPV at some point in their lives, and the
infection usually goes away.

Patients need to know that the interval between time of infection and
onset of signs or symptoms is variable, and it is often difficult to
determine the source of infection.

They also need to know that there are two types of genital HPV.

Low-risk genital HPV types that are associated with mild Pap test
abnormalities and genital warts and high-risk types that can be
associated with high-grade cancer precursor lesions as well as cancers
of the cervix, vulva, anus, and penis.

When counseling patients, it needs to be stressed that persistent
infection over many years with a high-risk genital HPV type is necessary
but is not sufficient for the development of cervical cancer.

The vast majority of women infected with low-risk or high-risk HPV types
will not develop significant cervical cancer precursors and will never
develop cervical cancer.

As for how genital HPV infections are transmitted, patients need to know
that it's usually difficult to determine the source of infection, and
that infection is not evidence of infidelity.

Moreover, the likelihood of transmission and duration of infectivity
with or without treatment cannot be predicted in an individual patient.

Strategies to prevent genital HPV infection include:

\- abstinence from sexual activity,

\- mutual monogamy with an uninfected partner,

\- limiting the number of sex partners, and

\- using condoms.

Having said this, the most important thing sexually active women can do
to avoid getting cervical cancer is to have regular cervical cancer
screening.

With respect to partner issues, the key counseling points are:

First, patients need to know that genital HPV is commonly transmitted
between sex partners, making it likely that partners are already
infected once an HPV infection is detected.

Second, the value of disclosing a past diagnosis of genital HPV
infection to future partners is unclear, although candid discussions
about past STDs should be supported whenever possible.

And finally, sex partners of patients diagnosed with genital warts may
benefit from an examination to assess for the presence of genital warts
and other STDs.

\[14\]DANIELS

Thank you, Dr. Wright.

Dr. Douglas, *can you elaborate on preventing the transmission of
genital HPV infections?*

\[15\]DOUGLAS

Sure, Kysa.

In general, strategies to prevent transmission of sexually transmitted
infections include:

\-- reducing the duration of infectiousness by treatment,

\-- decreasing the efficiency of transmission by measures aimed at
reducing infectivity, and

\-- reducing the number of sex partners.

First, regarding treatment, currently there is no effective systemic
treatment for genital HPV infection.

Genital warts are treated with topical pharmacologic agents.

Cervical cancer precursors are treated with local measures such as
cryotherapy, electrocautery, or surgical excision.

Evidence indicates that currently available therapies for HPV-related
cervical cell abnormalities and genital warts may reduce infectiousness,
but probably don't eliminate it.

Second, the most common approach to decreasing the efficiency of
transmission of a STD is to use a physical barrier such as a condom.

However, because genital HPV infections are transmitted through
skin-to-skin contact, and because infections can occur in male and
female genital areas that are not covered by a latex condom as well as
those areas that are covered, condoms can't offer complete protection
from genital HPV infection.

Because of inadequate existing scientific studies, just how effective
condoms are in preventing genital HPV infection is unknown and thus they
cannot be relied upon as a primary strategy for prevention of these
infections.

However, condoms have been associated with lower rates of genital warts
and cervical cancer.

Third, the most effective way to avoid acquiring genital HPV infection
is to limit the number and type of sex partners.

The surest way to prevent future genital HPV infection is to abstain
from any genital contact, including non-penetrative intimate contact of
the genital area.

For those who choose to be sexually active, long-term mutual monogamy
with a single uninfected partner is likely to be the next most effective
way to prevent infection.

However, as we discussed, it is difficult to determine whether a partner
who has been sexually active in the past is currently infected with HPV
because there is no general screening test for HPV ---and most infected
people are asymptomatic and have no clinical manifestations of
infection.

For people who are sexually active who are not in a long-term mutually
monogamous relationship, reducing the number of sex partners and
choosing a partner who is less likely to be infected with genital HPV
---meaning a partner with no or few previous sex partners ---may reduce
the risk of acquiring genital HPV infection.

Finally, the most important thing sexually active women can do to avoid
getting cervical cancer is to have *regular cervical cancer screening*
with the Pap test and follow up as recommended.

\[16\]DANIELS

Dr. Douglas, *is there a vaccine for genital HPV infections?*

\[17\]DOUGLAS

Not currently, Kysa.

However, several potential HPV vaccine approaches are under
investigation.

These vaccines use viral-like particles (VLPs), which preserve native
conformation of viral proteins but are non-infectious because they lack
viral DNA.

In a recent double-blind, multi-center randomized clinical trial,
administration of an HPV type 16 VLP vaccine was highly effective in
preventing persistent HPV 16 infection and also HPV-16-related CIN.

Likewise, a study of a combined HPV 16-18 vaccine was also highly
effective in preventing persistent infections and abnormal Pap smears
caused by both types.

In the future, receiving a safe and effective HPV vaccine to help
prevent genital HPV infection as well as the HPV-associated diseases of
genital warts and cervical cancer may be an important prevention
measure.

However, because vaccines are unlikely to provide 100% protection and
because they likely will not include all types of genital HPV, an
effective HPV vaccine would [not]{.underline} replace other prevention
strategies such as reduced sexual exposure and regular Pap tests.

\[18\]DANIELS

In closing, Dr. Douglas, *what are the bottom line key messages about
genital HPV infection that clinicians should convey to their patients?*

\[19\]DOUGLAS

Well Kysa, there a number of messages that clinicians should convey to
their patients.

First, HPV infection is common in sexually active adults.

Second, most HPV infections are transient and have no signs or symptoms.

Third, persistent infection with a high-risk HPV type is necessary but
not sufficient for the development of cervical cancer.

And last, cervical cancer is by far the most important problem caused by
genital HPV infection.

The most important tool to prevent it is regular Pap test screening and
follow-up for all sexually active women.

\[20\]DANIELS

Doctors, thank you for bringing us up to date on preventing and treating
genital human papillomavirus infection and cervical cancer.

Now we'll move on to the question and answer segment of our program.

Please be reminded that these questions were submitted via email prior
to this webcast by you, our viewing audience.

*(Q & A 10 minutes not scripted)*

\[21\]DANIELS

Thank you, doctors. That ends our question and answer period.

And, thank you for your attention during this Webcast. We have attempted
to provide you with an update on prevention strategies for genital HPV
infections and cervical cancer.

We hope that this presentation will help clinicians understand,
diagnose,

and manage genital HPV infections.

I'd like to thank our panelists\...Doctors John Douglas, Mona Saraiya,
and

Tom Wright.

This brings us to the close of *"Human Papillomavirus (HPV) and Cervical
Cancer: An Update on Prevention Strategies."*

I'm Kysa Daniels and it has been my pleasure to be your moderator today.

Good-bye.

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