Herpes simplex is a viral
infection caused by one of two Herpes
Simplex Viruses (HSV), members of the Herpesviridae
family. Manifestations of herpes infections vary significantly between
individuals. Most cases of genital herpes are caused by HSV-2. It is widespread,
affecting an estimated 1 in 4 females and 1 in 5 males in the United
States. Although certain therapies can prevent
outbreaks or reduce the risk of transmission to partners, no cure is yet
There are two types of Herpes Simplex Virus: HSV Type 1 and
HSV Type 2. The ways in which herpes infections manifest themselves vary
tremendously among individuals. The following are general descriptions of the
courses outbreaks may take in the oral and genital regions.
Infectious fluid-filled blister on lower lip (herpes
Herpes is also formed on the tongue as bumps or white dots
Orofacial infection (generally
- Skin appears irritated
- Sore or cluster of fluid-filled blisters
- Lesion begins to heal, usually without scarring
It is estimated that 50% of adults in the United Kingdom are carriers of the
Herpes Simplex Virus,
many of which will never exhibit any symptoms of infection. Similarly, 50% of
Americans have HSV-1 antibodies in their blood by the time they're teenagers or
young adults and 80-90% of Americans have HSV-1 antibodies by the time they are
over age 50.
It is also possible for the virus to be transmitted across the skin in the
absence of a coldsore. Oral herpes lesions typically occur on the lips, but can
occur almost anywhere on the face. They can also occur on the fixed mucosa
inside the mouth, including the hard
palate (roof of the mouth), and gingiva
(gums). Oral herpes and cold sores can sometimes be confused with canker
sores. Only a medical physician can provide adequate
Genital infection (generally HSV-2)
- Prodromal symptoms
- Itching in affected area
- Sore appears
- Lesion begins to heal, usually without scarring.
In males, the lesions may occur on the shaft of the penis, in
the genital region, on the inner thigh, buttocks, or anus. In females, lesions
may occur on or near the pubis, labia, clitoris, vulva, buttocks, or anus. This
may require a very careful examination; for example, during delivery,
examination by use of a flashlight may be necessary. Symptoms can be confused
with that of chlamydia
so careful observation by a doctor is important.
The appearance of herpes lesions and the experience of
outbreaks in these areas varies tremendously among individuals. Herpes lesions
on/near the genitals may look like cold sores. An outbreak may look like a paper
cut, or chafing, or appear to be a yeast
infection. Symptoms of a genital outbreak may include
aches and pains in the area, discharge from the penis
and severe discomfort and burning when urinating.
Initial outbreaks are usually more severe than subsequent
ones, and generally also involve flu-like
symptoms and swollen glands
for a week or so. Subsequent outbreaks tend to be periodic or episodic,
typically occur four to five times a year, and can be triggered by stress,
illness, fatigue, menstruation,
and other changes. The virus sequesters in the nerve
that serve the infected dermatome
during non-eruptive periods, where it cannot be conventionally eliminated by the
body's immune system.
Physical or psychological stress can trigger an outbreak.
Local injury to the face, lips, eyes or mouth, as through trauma, surgery, or
sunburns are well established triggers of recurrent orolabial herpes due to
herpes simplex virus type 1 (HSV-1). Similarly, intercurrent infections, such as
upper respiratory viral infections or other febrile diseases, can cause
outbreaks, hence the historic terms "cold sore" and "fever
blister". Generalized psychological stress and anxiety are also triggers.
Controversy exists about triggers of recurrent outbreaks of
genital herpes, typically due to HSV-2. It is often stated that stress,
menstruation, diet (such as foods high in arginine,
or sexual activity may increase the chance and severity of outbreaks. However,
no scientific studies have clearly documented such triggers, and the objective
data available suggest that outbreaks are not influenced by stressful events,
anxiety, depression, or similar influences. The clinical experience of most
experts involved in clinical care is that attempts by infected persons to modify
external triggers is virtually never effective in controlling symptomatic
oubreaks of genital herpes. Similarly, neither objective data nor biological
plausibility support the notion that excessive usage of antibiotics
affect the immune system's ability to keep the disease within the nerve ganglia
(particularly as antibiotics are useless against viruses of any type) or
otherwise affect herpes recurrences, nor the occasional assertion that
"chronic" genital herpes is in any way related to low-level food
Herpes infections, whether initial or recurring, are usually
first felt as a tingling and/or itching sensation in the affected location.
These initial feelings are usually followed, depending on how severe the
infection is, by the emergence of a raised or swollen area on the skin. This
swollen area then becomes painful in general, but acutely sore when touched,
stretched or moved. Eventually the sore area will abscess, and emit a virus
laden clear fluid for several days before scabbing over. Once scabbed over the
lesion will usually heal completely within a period of a week to ten days. In
immuno-compromised individuals this cycle can be significantly protracted.
From the onset of infection/outbreak, many patients experience
headaches, fatigue (sometimes extreme), and peculiar twitching sensations in the
nerves that lead to the area of the outbreak. The fatigue associated with herpes
infections can concatenate with depression brought on by the cosmetic or
sexually compromising nature of the infection, to yield a deeply gloomy overall
mental state that some believe can contribute to increasing the length and
severity of an infection.
Herpes is contracted through direct skin
contact (not necessarily in the genital area) with an infected person, and less
frequently by indirect contact (for instance, by sharing lip balm or a virus
infested shared towel). The virus travels through tiny breaks in the skin (or
mucous membranes in the mouth and genital areas), so, healthy skin and mucous
membranes are normally an effective barrier to infection. However, in the case
of mucous membranes, even microscopic abrasions are sufficient to expose the
nerve endings into which the virus splices itself. This is why most herpes
transmission happens in mucous membranes, or in areas of the body where mucous
membranes and normal skin merge (e.g., the corners of the mouth).
Symptoms usually appear within 2 weeks. The sores usually heal
within 2 - 4 weeks. 
Transmission was thought to be most common during an active
outbreak; however, in the early 1980s, it was found that the virus can be shed
from the skin, saliva and genital secretions in the absence of symptoms.
Herpes recurs only at a site of previous infection. The
periodicity (frequency) and amplitude (severity) of recurrence varies greatly
depending on the individual and various environmental factors including stress
(both physical and mental). Often, for a given site, the infection will recur
only two or three times, with severity attenuating (decreasing) each time. The
mechanism by which the body seems to gain the upper-hand for a given recurrence
site is poorly understood by the medical community.
Self reinfection, known medically as autoinoculation, is more
likely during intensely virulent initial infection with either HSV-1 or HSV-2 in
a given infection site. The most common manifestations are herpetic whitlow, a
pustular lesion typically of a finger, and herpes of the eye (keratitis,
General hygiene principles suggest that persons with recurrent
oral or genital herpes should avoid direct contact with active lesions and
should wash their hands immediately after using the toilet or touching the area
of an oral lesion, to further limit the low risk of autoinoculation.
In cases where herpes is present in an area where the dermis
is subject to high abrasive forces (such as the often irritated shaved beard
region, or the surfaces of the penis and vagina during vigorous sexual
activity), it is quite common to spread an initial lesion to other sites, which
then become highly virulent initial infections, and so on. The medical community
has failed to make this very obvious fact clear to patients and this has
resulted in great amplification of their general misery, not to mention the much
higher likelihood that a person infected in multiple sites (whether genital, or
otherwise) will spread this disease to friends, family and sexual partners.
HSV asymptomatic shedding is believed to occur on 2.9% of days
while on antiviral therapy, versus 10.8% of days without. Shedding is known to
be more frequent within the first 12 months of acquiring HSV-2, and concurrent
infection with HIV
also increases the frequency and duration of asymptomatic shedding.
There are some indications that some individuals may have much lower patterns of
shedding, but evidence supporting this is not fully verified. Sex should always
be avoided in the presence of symptomic lesions. Oral sex performed by someone
with oral lesions or other symptoms should be avoided, to avoid transmission of
HSV-1 to the partner's genitals. Even without symptoms it is possible for
transmission to occur. Many people still believe Herpes cannot be transmitted
through oral sex. This is a dangerous myth.
Women are more susceptible to acquiring genital HSV-2 than
men; in the US, 11% of men and 23% of women carry HSV-2.
On an annual basis, without the use of antivirals or condoms, the transmission
risk from infected male to female is approximately 8-10%. This is believed to be
due to the increased exposure of mucosal tissue to potential infection sites.
Transmission risk from infected female to male is approximately 4-5% annually.
Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help
prevent the development of symptomatic HSV in infection scenarios by about 50%,
meaning the infected partner will be seropositive but symptom free. Condom use
also reduces the transmission risk by 50%. Condom use is much more effective at
preventing male to female transmission than vice-versa. 
The effects of combining antiviral and condom use is roughly additive, thus
resulting in approximately a 75% combined reduction in annual transmission risk.
These figures reflect experiences with subjects having frequently-recurring
genital herpes (>6 recurrences per year). Subjects with low recurrence rates
and those with no clinical manifestations were excluded from these studies.
For genital herpes, condoms
are a highly recommended way to limit transmission of herpes simplex infection,
as demonstrated in research. 
However, condoms are by no means completely effective. The effectiveness of this
method is somewhat limited on a public
health scale by the limited use of condoms in the
and on an individual scale because some blisters may not be covered by the
condom, or free virus in female vaginal fluid may enable infection around the
base of the penis or testicles not covered by the condom.
Condoms do not prevent the condom wearer from spreading the
infection to new sites either on himself through abrasion (if he is already
infected and suffering an outbreak), or on the female partner if she is
suffering from an outbreak and the sexual activity spreads this infection from
one site to another on her own body (see "Self Reinfection" above).
The use of condoms or dental
dams can limit the transmission of Herpes from the
genitals of one partner to the mouth of the other (or vice versa) during oral
When one partner has herpes simplex infection and the other
does not, the use of valaciclovir,
in conjunction with a condom, has been demonstrated to decrease further the
chances of transmission to the uninfected partner, and the Food
and Drug Administration (FDA) approved this as a new
indication for the drug in August 2003.
for HSV are currently undergoing trials. Once developed, they may be used to
help with prevention or minimize initial infections as well as treatment for
existing infections. 
Other measures that have been suggested include:
- Abstinence from sexual activity while HSV blisters are
- Avoidance of cross-infecting new sites on the body if HSV
blisters are present
- Gentle and well lubricated as opposed to vigorous, abrasive
- Thorough washing of the genitals after sex
- Not ejaculating inside a partner during sex (if herpes
lesions have appeared inside the urethra)
- Management of stress
- Adequate sleep and nutrition
- Use of a lip protectant or lip gloss to avoid cracks and
abrasions through which the virus may infect
- Treatment using ascorbate-Cu(II) 
Institutes of Health (NIH) in the United
States is currently in the midst of phase
III trials of a vaccine against HSV-2, called Herpevac.
The vaccine has only been shown to be effective for women who have never been
exposed to HSV-1. Overall, the vaccine is approximately 48% effective in
preventing HSV-2 seropositivity and about 78% effective in preventing
symptomatic HSV-2. Assuming FDA approval, a commercial version of the vaccine is
estimated to become available around 2008. During initial trials, the vaccine
did not exhibit any evidence in preventing HSV-2 in males. Additionally, the
vaccine only reduced the acquisition of HSV-2 and symptoms due to newly acquired
HSV-2 among women who did not have HSV-1 infection at the time they got the
vaccine. Because about 50% of persons in the United States have HSV-1 infection,
this further reduces the population for whom this vaccine might be appropriate.
Currently, there is no cure for herpes. There is no treatment
that can eradicate herpes virus from the body at reactivations of the virus.
can reduce pain and fever during initial outbreaks.
There are several prescription antiviral
medications for controlling herpes outbreaks, including aciclovir
(Famvir), and penciclovir.
was the original and prototypical member of this class and generic brands are
now available at a greatly reduced cost. Some prescription drugs to treat herpes
can cause diarrohea several times a day so patients are advised to take non
prescribed diarrohea tablets as required in these cases along with the
medication. It has been claimed that the evidence for the effectiveness of
topically applied cream for recurrent labial outbreaks is weak.
Likewise oral therapy for episodes is inappropriate for most non-immunocompromised
patients, whilst there is evidence for oral prophylactic role in preventing
Valaciclovir and famciclovir are prodrugs
of aciclovir and penciclovir respectively, with improved oral bioavailability
(55% vs 20% and 75% vs 5% respectively). These antiviral medications work by
interfering with viral replication, effectively slowing the replication rate of
the virus and providing a greater opportunity for the immune response to
intervene. All drugs in this class depend on the activity of the viral thymidine
kinase to convert the drug to a monophosphate
form and subsequently interfere with viral DNA
replication. Penciclovir's primary advantage over
aciclovir is that it has a far longer cellular half-life
– 10 hours (HSV-1)/20 hours (HSV-2) for penciclovir versus 3 hours (HSV-1/2)
is the recommended antiviral for suppressive therapy to prevent transmission of
herpes simplex to the neonate.
The use of valaciclovir
while potentially improving treatment compliance and efficacy, are still
undergoing safety evaluation in this context. 
There is evidence in mice that treatment with famciclovir, rather than aciclovir,
during an initial outbreak can help lower the incidence of future outbreaks by
reducing the amount of latent virus in the neural ganglia. This potential effect
on latency over aciclovir drops to zero a few months post-infection. 
Other drugs exhibiting anti-viral activity
(Abreva) is another treatment that may be effective. Docosanol works by
preventing the virus from fusing to cell membranes, thus barring entry into the
cell for the virus. This may keep an outbreak contained to a smaller area than
would otherwise be observed.
is an early relief cold sore/fever blister gel that works by applying the gel,
which when dry forms a "shield" to prevent the sore from increasing in
size and prevents spreading by breakage or oozing during the healing process.
is another antiviral drug effective against herpes.
a common component of heartburn medication, has been shown to lessen the
severity of herpes zoster outbreaks in several different instances, and offered
some relief from herpes simplex 
. This is an off-label
use of the drug.
It and probenecid
have been shown to reduce the renal clearance of aciclovir. 
The study showed these compounds reduce the rate, but not the extent, at which
valaciclovir is converted into aciclovir. Renal clearance of aciclovir was
reduced by approximately 24% and 33% respectively. In addition, respective
increases in the peak plasma concentration of acyclovir of 8% and 22% were
observed. The authors concluded that these effects were "not expected to
have clinical consequences regarding the safety of valaciclovir". Due to
the tendency of aciclovir to precipitate in renal tubules, combining these drugs
should only occur under the supervision of a physician.
Availability of non-generic
Availability of generic
is no longer under US patent protection, available in generic form
Drugs in development
- BILS 179 BS, BILS 45 BS, BILS 22 BS,
also inhibitors of helicase-primase enzyme, researched in Ridgefield,
Connecticut, by James Crute's team at Boehringer
Ingelheim Pharmaceuticals. 
supplementation has been proposed as a complementary therapy for the prophylaxis
and treatment of herpes simplex. Lysine supplementation is highly
dose-dependent, with beneficial effects apparent only at doses exceeding 1000 mg
per day. A small randomised
controlled trial indicated a decrease in recurrence
rates in nonimmunocompromised patients at a dose of 1248 mg of lysine
monohydrochloride, but no effect at 624 mg daily. This study did not show any
evidence of shortening the healing time compared to placebo. 
Another small randomised controlled trial indicated the benefit of 3000 mg
lysine daily for the reduction of occurrence, severity and healing time for
recurrent HSV infection. 
Tissue culture studies have shown the suppression of viral
replication when the lysine to arginine ratio in vitro favours lysine.
The therapeutic consequence of this finding is unclear, but dietary arginine may
affect the effectiveness of lysine supplementation. 
Lysine intake may be supplemented by varying the diet. Dairy
products offer the highest ratio of lysine to arginine amino-acid content.
Contrarily, nuts (and peanuts, even though they aren't true nuts), deliver a
large dose of arginine. To help forestall outbreaks, you might avoid nuts during
stressful periods, and eat cheese any time you do eat nuts. During an outbreak,
eating cheese may slow the spread of lesions, and reduce virus shedding and
self-reinfection. Eating 100g (~4oz) of Parmesan cheese supplies 3.3g of lysine,
vs. 1.3g of arginine. The same amount of almonds provides 0.7g of lysine, but
2.4g of arginine. (Cf. the Danish Food Composition Databank, http://www.foodcomp.dk/fcdb_alphlist.asp)
High doses of lysine (greater than 10 grams daily) are known
to cause gastrointestinal adverse effects. Dyspepsia
was reported in 3 of 114 subjects treated with L-lysine in one study. 
Prolonged and/or very high lysine doses may also have adverse effects on renal
function, indeed lysine is contraindicated in lysine hypersensitivity and kidney
or liver disease. (Anon., 2005) One patient, with a history of risk factors for
renal impairment, developed tubulointerstitial nephritis
Syndrome) after taking lysine 3000 mg daily for
approximately 5 years. 
linear sulphated polysaccharides
extracted from red seaweeds,
have been shown to have antiviral effects in HSV-infected cells.
- There are indications that a carrageenan
based gel may offer some protection against HSV-2 transmission by binding to
the receptors on the herpes virus thus preventing the virus from binding to
cells. Researchers have shown that a carrageenan-based gel effectively
prevented HSV-2 infection at a rate of 85% in a mouse model.
There is an ongoing large-scale trial of the efficacy of a similar
formulation on humans results are expected to be published in 2007.
- The natural carrageenans 1T1, 1C1, 1C3 isolated from Gigartina
inhibited the replication activity of HSV-1 and HSV-2 in infected mouse astrocyte
nerve cells and vero
a component of whey protein, has been shown to have a synergistic effect with
aciclovir against HSV in vitro.
The concentration of lactoferrin which achieved 50% of maximum effectiveness
observed (that is, the EC50)
also acted in synergy with aciclovir; the concentration required to achieve EC50
for each substance was reduced "two- to seven-fold."
a compound in red wine, has been shown by researchers to prevent HSV replication
by inhibiting a protein needed by the virus to replicate. Resveratrol alone was
not considered potent enough by the researchers to be an effective treatment.
A more recent in vivo
study in mice showed the efficacy of topical resveratrol cream in preventing
cutaneous HSV lesion formation.
Research on a much more potent derivative of resveratol, named stil-5, is
ongoing. There is no evidence that red wine consumption provides any similar
Limited evidence suggests that low dose aspirin
(125 mg daily) might be beneficial in patients with recurrent HSV infections. A
small study of 21 volunteers with recurrent HSV indicated a significant
reduction in duration of active HSV infections, milder symptoms, and longer
symptom-free periods as compared to a control group. 
A recent animal study found that aspirin inhibited thermal stress-induced ocular
viral shedding of HSV-1, and a possible benefit in reducing recurrences. 
Aspirin is not recommended in persons under 18 years of age with herpes simplex
due to the increased risk of Reye's
syndrome. Long term daily doses of aspirin have a side
effect of reduced blood coagulation, facilitating bruising. A single 81 mg
"daily dose" aspirin is a safer regimen given that there are no
studies of the correlation between dosage and anti-viral effects of aspirin.
The evidence for the effectiveness of zinc
C supplementation is poor. 
Other supplements with anecdotal evidence of benefits include monolaurin, vitamin
Daily multivitamin intake may be beneficial through maintenance of immune
system health. High doses of vitamin A should not be
taken in early pregnancy due to linkage with birth defects. In addition, some
anecdotal reports indicate that placing ice in contact with an emerging cold
sore for 5-10 minutes throughout the day can help shorten the duration of the
outbreak, or prevent it from developing further.
Butylated Hydroxytoluene (BHT),
commonly available as a food preservative, has been shown in in-vitro
laboratory studies to inactivate the herpes virus.
In-vivo studies in animals confirmed the anti-viral activity of BHT
against genital herpes.
However BHT has not been clinically tested and approved to treat herpes
infections in humans.
Latent infection and biology
The herpes virus is a double-stranded DNA (dsDNA)-type
virus. Herpes establishes a latent infection in cells of the nervous system.
Double-stranded DNA is incorporated into the cell physiology by infection of the
nucleus, where a loop of dsDNA is maintained. During
inactive, or latent, periods of the infection, a subset of the Herpes genome
Associated Transcript is active and may be involved in
maintenance of latency.
The long-term effects of herpes are not well known, but the
blisters may leave scars, and historically it was thought to contribute to the
risk of cervical
cancer in women. Subsequently, another virus, human
papillomavirus (HPV), has been shown to be a primary
cause of cervical cancer in women. Additionally, people with herpes are at a
higher risk of HIV
transmission because of open blisters. In newborns, however, herpes can cause
serious damage: death, neurological damage, mental retardation, and blindness.
The immune system is able to destroy active herpes virus
particles but the herpes virus has the ability to hide from the immune system in
an inactive (or latent) state. Current research suggests that this ability to
hide may be achieved via modification to cellular enzyme histone deacetylases (HDACs),
namely HDAC1 and HDAC2. 
Hypothetically, by interfering with the HDAC enzymes' effectiveness, it may be
possible to block the virus's ability to hide from the immune system, leading to
a complete elimination of the virus by the immune system. Studies on the impact
of HDAC inhibitors on viral latency are ongoing in the HIV arena.
Obstetric / Neonatal risks
Recurrent genital herpes has very significant
obstetrical/neonatal risks associated with it, and probably may merit treatment
with acyclovir as an independent problem. 
It is reasonably well-established in the last few years that
herpes simplex virus 2 (HSV-2) is the most common cause of recurrent viral meningitis
(Mollaret's meningitis). 
Psychological and social effects
Herpes can have a dramatic effect on an individual's mental
well-being and sexual behaviour.
Quality of life issues
Upon diagnosis of genital herpes, people can experience a
number of negative feelings related to the condition. Though these feelings
lessen over time, they can include:
- depression 81%
- fear of rejection 75%
- feeling of isolation 69%
- fear of being found out 55%
- self-destructive feelings 28%
The impact of genital herpes included:
- partial or complete cessation of sexual activity
- total or partial loss of interest in sex
- decreased sexual pleasure
- sex life more inhibited and less spontaneous
- anxiety related to sexual desirability
- increased depression
In order to improve the well-being of people with herpes, a
number of support groups ,
and dating sites 
have formed a presence on the Internet.
Some common misconceptions about herpes are:
- that it is fatal. Fact: This is only true for
newborns, which is rare, but it is fatal in 25% of all such cases. It can
also possibly kill an adult if it infects the brain causing encephalitis,
or infects the meninges
- that it only affects the genital areas. Fact: It
can affect any part of the body. If you touch a genital herpes sore and then
touch another part of your body, you can potentially spread the virus.
- that condoms are completely effective in preventing the
spread of this disease. Fact: They do greatly improve protection
but are imperfect, only preventing transmission 50% of the time.
- that it is only transmittable in the presence of
symptoms. Fact: There is more viral shedding during an outbreak
but it's possible to transmit any time.
- that it can make you sterile Fact: Genital
Herpes cannot make you sterile.
- that Pap
smears detect herpes Fact
PAP smears are not designed to detect herpes simplex virus infections.
Type-specific serology tests and viral cultures are used to diagnose genital
herpes and are not normally conducted during a woman's annual gynecological
- that it can not be transmitted between the genitals and
the mouth. Fact: Even the use of a condom will not prevent
transmission between genital and oral regions.
- that only promiscuous people get it. Fact: It
is so common that anyone can contract it. The more sexual partners an
individual has, however, the more likely they are to contract the disease.
There is a basis in fact that herpes could be transmitted via
an inanimate object such as a toilet seat or wet towel but the conditions
required for this kind of transmission (high heat, high moisture, and a
vulnerable exposure site) make it extremely unlikely. Although there are no
confirmed cases of this type of transmission, sharing a towel with somebody with
active lesions should be avoided. Likewise, sharing lip or mouth products
(toothbrushes, lipstick, lip balm, or similar) with somebody with active lesions
should also be avoided.