http://www.gsk.com/press_archive/sb/1997/press_19970710b.htm





LANDMARK CLINICAL TRIAL WILL DETERMINE IF TREATING PATIENTS'

FIRST GENITAL HERPES OUTBREAK WITH FAMVIR WILL

ELIMINATE FUTURE OUTBREAKS

Compelling Pre-clinical Data Prompts Large Worldwide Study

LONDON, 10 July 1997 - At the 8th European Congress of Clinical
Microbiology and Infectious Diseases held recently in
Luasanne,Switzerland, new evidence from animal studies was presented
which suggested that the antiviral drug famciclovir Famvir could help
prevent recurrences of genital herpes.

The research, carried out in mice and published by Dr Hugh Field and
colleagues at Cambridge University Veterinary School, showed that
famciclovir, manufactured by SmithKline Beecham, given during the
initial acute phase of the infection, markedly reduced the ability of
herpes simplex virus (HSV) to establish latent infection in the
ganglia.

Observational data suggested that Dr Field's findings may have
clinical implications. A retrospective study by Dr Paul Woolley and
colleagues at Withington Hospital, Manchester, of 116 first-episode
genital herpes patients treated with either famciclovir or aciclovir
showed that only 6.8% of the famciclovir patients had suffered a
recurrence of their disease between one and six months after
treatment, compared to 16.9% of those given aciclovir.

Dr Woolley, of the department of genitourinary medicine at Withington
Hospital and editor of the British Journal of Sexual Medicine, said:
"These results suggest that, when treated with Famvir, mice are less
likely to re-activate HSV. If these results are replicated in clinical
trials, we may be looking at a whole new treatment approach which
would alter the natural history of the condition and transform the
lives of individuals with genital herpes.

Indeed, a worldwide clinical trial has recently begun to further
examine the effects of famciclovir on latency in first-episode genital
herpes. "We know that antivirals are effective in reducing the
symptoms of genital herpes, but no drug has been shown to stop
subsequent genital herpes outbreaks when taken during the first
outbreak," said Robin Saltzman, MD, group director of antiviral
clinical research and development at SmithKline Beecham USA. "Based on
the promising pre-clinical

data of Famvir and a lot of enthusiasm in the medical community, we
initiated this trial to truly enable us to further define its clinical
potential."

Famciclovir, which is also indicated for the treatment of acute herpes
zoster (shingles), has been shown to be very well tolerated by
patients. In clinical trials there was no difference in the number of
side effects reported by patients treated with famciclovir compared
with those receiving matching placebo.

Genital herpes is the most common cause of genital ulceration in
developed countries and the number of people infected is increasing
rapidly worldwide. The exact number of infected individuals is not
known but in the United States, the country for which the most
reliable statistics are available, one in four adults has the genital
herpes virus. Between 10% and 30% of women attending ante-natal
clinics in most developed countries have genital herpes. For more
detailed information about genital herpes please see the attached
backgrounder.

SmithKline Beecham - one of the world's leading healthcare companies -
discovers, develops, manufactures and markets pharmaceuticals,
vaccines, over-the-counter medicines and health-related consumer
products, and provides healthcare services including clinical
laboratory testing, disease management and pharmaceutical benefit
management. For company information, visit SmithKline Beecham on the
World Wide Web at http://www.sb.com

Background Information:

Introduction

Genital herpes is the most common cause of genital ulceration in
developed countries (1). The exact number of people with genital
herpes is unknown but between 10% and 30% of women attending
ante-natal clinics in most developed countries are infected (2). In
the United States, the country for which there are the most reliable
statistics, one in every four adults has genital herpes (3).

The number of infected individuals is growing rapidly. In North
America figures from sexually transmitted disease clinics suggest
there are between 500,000 and 1,000,000 new cases of genital herpes a
year (4). However, as many people with genital herpes are treated by
other specialists or by their family doctor the true increase in the
numbers of infected individuals may be much higher.

What is genital herpes?

Herpes is the result of infection with the herpes simplex virus (HSV).
This is a common viral infection which often causes sores or blemishes
on the skin, especially on the face or in the genital area. Herpes
simplex infection on the face is most common, with "cold sores"
typically appearing on the lips or mouth. Herpes simplex infection
below the waist is known as genital herpes. It can cause sores of a
similar appearance but its symptoms can be quite varied.

There are two strains of herpes simplex virus, HSV-1 and HSV-2.
Although each strain can cause both facial and genital herpes, HSV-1
is the most common cause of facial herpes and HSV-2 is largely
responsible of genital herpes. However, in recent years the number of
cases of genital herpes caused by HSV-1 have grown.

The symptoms of genital herpes

Genital herpes can produce a wide range of symptoms. The most obvious
are blister-like sores that can appear in various locations: the
penis, scrotum, labia, vagina, upper thigh, buttocks, or around the
anus. These eventually crust over into a scab before healing.

However, more than 60% of people with genital herpes have no symptoms
at all (5) or have symptoms so mild that they do not realise they have
the infection. Such symptoms can include a red patch of skin, a small
slit or fissure in the genital skin, a tiny sore that can be confused
with a pimple or irritation around the anus that can be mistaken for
haemorrhoids. In some cases genital herpes can resemble vaginal yeast
infections in women. It can also cause small sores in the urethra that
make urination painful.

The "first episode"

Herpes symptoms are usually most severe and last longest when an
individual is first infected with the virus. This is known as the
"first episode." First episodes are more severe because it is the
first time that the body's immune system is faced with the herpes
simplex virus. First episodes can last three to four weeks, can
involve a second or even third outbreak of sores and are often
accompanied by 'flu-like symptoms, including fever, swollen glands and
fatigue.

Recurrences

Like most viruses, the herpes simplex virus remains in the body for
the lifetime of the infected individual. The first episode ends when
the body's immune system succeeds in destroying most of the virus.
However, some of the virus evades attack by entering the nerve
pathways. Hidden from the immune systems, the virus then travels up
the nerve pathways and hibernates in the nerve roots (ganglia) which
lie next to the spinal cord.

Once the virus is safely established in the nerve root it enters an
inactive or "latent" phase. This can last for weeks, months or even
years but every so often the virus reactivates and sets off again down
the nerve pathway to cause another outbreak of symptoms. The immune
system, now alert to the invader, quickly destroys most of this
reactivated virus but some of it escapes back into the nerve pathways
and the cycle repeats itself.

In many cases it is easy to tell when HSV is active because it causes
symptoms. But HSV can also reactivate without causing any noticable
symptoms. Reactivation can be measured by tests which look for "viral
shedding" - the presence of virus particles on the skin or mucous
membranes. Research shows that viral shedding occurs when herpes
symptoms are present but also sometimes when they are not. This known
as "asymptomatic shedding." Studies indicate that asymptomatic
shedding occurs on 2% of days in those infected with HSV-2 and on 0.7%
of days in individuals with HSV-1 (6).

Sometimes the only clue that HSV is active again in an infected
individual is the "prodrome." This is a highly individual sensation
which can involve an itching or tingling in the genital area,
backache, shooting pains through the legs or other sensations. The
prodrome often serves as a warning that sores or other symptoms are
about to come but not always. Either way the sensations of a prodrome
mean the virus is in its active state.

Transmission

The herpes simplex virus can spread through skin-to-skin contact,
especially when the site of contact is a soft, mucosal tissue such as
that of the genitals or mouth, any time the virus is in its active
phase. If a person has a herpes sore on the lips they can spread the
infection to someone else by kissing. Infection can also be
transmitted from the lips to the genitals during oral sex. This
probably explains why more than a third of new cases of genital herpes
are caused by HSV-1 (7)

However, herpes can be transmitted if the virus is active even if
there are no noticable symptoms. Asymptomatic shedding can occur in or
around the mouth and in various genital sites, such as the vagina,
penis and anus. Therefore, if HSV is active, oral, vaginal or anal
intercourse can result in transmission, even if no symptoms are
present.

Pregnancy

Herpes infections in newborns are rare (1 in 2000-5000 live births
reported in the USA, 1 in 9000 in Australia and 1 in 30,000 in the UK)
However, when it does occur neonatal herpes is an extremely serious
disease with high mortality and morbidy. Babies are infected at the
time of delivery if they come into contact with HSV in the birth
canal. Babies at greatest risk are those whose mothers experience a
first episode of genital herpes during third trimester of pregnancy.
Mothers who experience a recurrent episode during pregnancy are at
much lower risk of transmitting the infection to their baby. (8)

Risk factors

The major risk factor for genital herpes is sexual intercourse. The
more partners an individual has the greater the risk. Studies in
Vancouver, British Columbia, show that 20% of women who have ever had
sex have genital herpes. Once they have had six or more sexual
partners, about 40% of women have genital herpes. Having more than 10
partners gives women a risk of almost 60% for genital herpes (9).
Researchers attribute the steep rise in the number of individuals with
genital herpes to changes in sexual practices. People now have a
greater number of sexual partners and begin to have sex earlier (10).

Diagnosis

Even if sores are present it is sometimes difficult to distinguish
genital herpes from other infectious and non-infectious conditions.
Therefore laboratory analysis of samples swabbed from the sores is
often necessary. The standard laboratory test is a viral culture. Here
the cells taken from the suspected herpes sore are placed in a sample
of normal cells. If HSV is present it will grow throughout the sample
over a period of several days.

A faster laboratory procedure is an antigen test and some laboratories
now use a new test known as the polymerase chain reaction test (PCR).
PCR is much more sensitive than the culture test but it is also much
more expensive. A blood test can be used to diagnose HSV infection in
individuals who have no symptoms.

Treatment

Antiviral drugs are the mainstay of treatment for genital herpes.
These drugs cannot remove the virus from the body and therefore cure
genital herpes but they do help relieve the pain and discomfort and
speed the healing of the sores.

The first, aciclovir, was introduced as an oral medication for genital
herpes in 1985 and is still in widespread use. Today, there are two
new oral antivirals for genital herpes: famciclovir (Famvir), a new
antiviral manufactured by SmithKline Beecham, and valaciclovir
(Valtrex), a new formulation of aciclovir manufactured by Glaxo
Wellcome. All three work by disrupting the process by which HSV
replicates itself in infected cells. This helps the body's own immune
system to control the infection.

Antiviral drugs can ease the symptoms and shorten the duration of the
first episode and subsequent recurrences of genital herpes.
Individuals who suffer frequent recurrences can also take the drug on
a daily basis as suppressive therapy. This normally results in a
dramatic reduction in frequency of recurrences and in milder symptoms
when they do occur. Side effects are rare ocurring at a similar rate
to placebo.

Aciclovir is also available as an ointment. However, it is poorly
absorbed through the skin and has not been shown to be effective in
genital herpes.

The psychosocial impact of genital herpes

Genital herpes rarely affects the overall physical health of an
infected individual. However, for many people the emotional
consequences of having genital herpes are considerable. A diagnosis of
genital herpes frequently results in feelings of shock, anger and
depression. Infected individuals worry about rejection by friends and
lovers and fear transmitting the virus to sexual partners.

Safer sex

Abstaining from sexual intercourse and oral sex while symptoms,
including those of the prodrome, are present reduces the risk of
transmission. However, it cannot completely prevent transmission as
viral shedding can still occur in the absence of symptoms. The use of
male or female condoms for penetrative sex between recurrences helps
reduce the risk posed by asymptomatic shedding. But as condoms do not
cover all sites of possible viral shedding they cannot provide 100%
protection. Barrier methods can reduce the risk posed by asymptomatic
shedding during oral sex but these are not popular with most
individuals. For example, men can wear an unlubricated condom when
oral sex is being performed on them, while a barrier, such as a piece
of heavy-duty household plastic food wrap, can be used by women to
cover their genitals.

Self-help for genital herpes

The following self-help strategies can relieve the pain and discomfort
of genital herpes, help prevent bacterial infection of the sores and
speed healing:

Take frequent warm baths or showers. Although a few individuals find
water on their herpes sores intolerable, the majority find water very
helpful.
After a bath or shower blow the genital area dry with a hair-dryer set
to air-only, low or cool.
If urination is very painful, try urinating in a bath of cool or warm
water. Alternatively, pouring a glass of warm water over the genital
area can also help.
Wear cotton underwear and avoid tights
Cafe Herpe - genital herpes on the Internet

Detailed information about herpes simplex virus, genital herpes and
its treatment is now available on the Internet. SmithKline Beecham's
genital herpes web site, Cafe Herpe, is at
http://www.genitalherpes.com