Herpes

The herpes simplex virus (HSV) is a virus that manifests itself in two common viral infections, each marked by painful, watery blisters in the skin or mucous membranes (such as the mouth or lips) or on the genitals. The disease is contagious, particularly during an outbreak, and is incurable. An infection on the lips is commonly known as a "cold sore" or "fever blister."

Contents
1 HSV-1 and HSV-2
2 HSV disease
2.1 Orofacial infection (Generally HSV 1)
2.2 Genital infection (Generally HSV 2)
2.3 Other skin infections
2.4 Herpes simplex encephalitis
2.5 Neonatal herpes simplex
3 Outbreak triggers
4 Prevalence
5 Transmission
6 Prevention
7 Future directions
8 Treatments
8.1 Pharmacotherapy
8.1.1 Availability of generic drugs 

Recommended reading: Stop Herpes Now, And From Coming Back.
 
HSV-1 and HSV-2
Of the eight known types of HSV, the two most common are type 1 (HSV-1) and type 2 (HSV-2). HSV-1 is more common and generally considered to be associated with orofacial infection, usually the lips. This type of infection is more easily acquired in part because of its exposed location. It is generally considered a less serious infection.

HSV-2 is associated with the infection of the genitals however both types can affect either region. HSV-2 infection is of particular concern because of the largely asymptomatic nature of the infection, and the shedding of infective virions even in asymptomatic individuals. (Koutsky et al., 1990; Wald et al., 2000)

HSV disease
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.

Orofacial infection (Generally HSV 1)
Orofacial infection [[Image:{{{Image}}}|190px|center|]]
 
ICD-10 B00.0-B00.2
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ICD-9 054.0, 054.2
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Infectious fluid-filled blister on lower lip (herpes labialis).Prodromal symptoms
Skin appears irritated
Sore or cluster of fluid-filled blisters appear
Lesion begins to heal, usually without scarring
These infections usually occur on around the lips. Rarely, will a cold sore appear inside the mouth. The sores may appear to be either weeping or dry, and may resemble a pimple, insect bite, or lesion.

Genital infection (Generally HSV 2)
Genital herpes [[Image:{{{Image}}}|190px|center|]]
 
ICD-10 A60.0
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ICD-9 054.1
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Male genital infection of HSV-2.Prodromal symptoms
Sore appears
Lesion begins to heal, usually without scarring
In men, the lesions may occur on the shaft of the penis, in the genital region, on the inner thigh, buttocks, or anus. In women, lesions may occur on or near the pubis, labia, clitoris, vulva, buttocks, or anus. This may require a very careful examination e.g. during delivery examination by use of a flashlight may be necessary.

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 or vagina, and discomfort 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 ganglia that serve the infected dermatome during non-eruptive periods, where it cannot be conventionally eliminated by the body's immune system.

Other skin infections
 
Facial infections like this are relatively rare.Other forms of herpes simplex infection are rarer, but well characterized, and are sometimes given distinctive names, such as herpes gladiatorum, a skin infection spread through wrestling and other sports involving close skin-to-skin contact. Herpetic sycosis is a herpes simplex infection of the beard area in men, which may occur after shaving through a cold sore. In rarer cases, it seems that herpetic sycosis can occur as a primary herpes simplex outbreak.

Herpes simplex encephalitis
Herpesviral encephalitis [[Image:{{{Image}}}|190px|center|]]
 
ICD-10 B00.4, G05.1
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ICD-9 054.3
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Herpes simplex encephalitis is a very serious disorder, thought to be caused by transmission of the infection from a peripheral site by nerve cells. Without treatment, it results in rapid death in around 70% of cases. Even with the best modern treatment, it is fatal in around 20% of cases, and causes serious longterm neurological damage in over half the survivors. A small population (perhaps 20%) of survivors show little long term damage. It is most common in children and middle-aged adults. Although herpes simplex is by no means the most common cause of viral encephalitis (accounting for about 10% of cases in the US), because of the high risk associated with it if it is not treated, patients presenting with encephalitis symptoms are likely to be treated against this disorder without waiting for a positive diagnosis.

Neonatal herpes simplex
Congenital herpesviral (herpes simplex) infection [[Image:{{{Image}}}|190px|center|]]
 
ICD-10 P35.2
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ICD-9 771.2
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HSV at newborn child.Neonatal HSV disease is a rare, but serious, consequence of vertical HSV transmission from mother to newborn child. Prospective active surveillance data indicates an incidence rate of 3.61 per 100,000 live births in Australia, with similar rates in the UK; but much lower than the USA. (Elliot & Rose, 2004; Jones, 2004) Preliminary studies indicates the epidemiology in Canada is closer to Europe than to America. The mortality rate from neonatal HSV disease is high (up to 25%) despite current interventions with antiviral therapies. Death results from disseminated HSV disease and/or HSV encephalitis in the newborn children.

Outbreak triggers
Many people with herpes have reported that stress, increased exposure to the sun, viral infections, facial injuries and eating foods high in arginine, such as chocolate, peanuts and walnuts, may increase the chance and severity of outbreaks. In addition, some have found that excessive usage of antibiotics can limit the immune system's ability to keep the disease within the nerve ganglia.

Prevalence
The incidence of herpes simplex in the United States rose 30% between 1976 and 1994. Data from National Health and Nutrition Examination Surveys (NHANES) indicate an HSV-2 seroprevalence of 21.9% of the United States population. This rate was higher among women (25.9%) than men (17.8%). Independent risk factors for HSV-2 seropositivity were female sex, African American or Mexican-American ethnic background, older age, less education, poverty, cocaine use, and a greater lifetime number of sexual partners. (Fleming et al., 1997)

If present trends in America continue, researchers estimate that 49 percent of women aged 15 to 39 will be infected with herpes simplex virus type 2 (HSV-2) versus 39 percent of males aged 15 to 39 by 2025. (Fisman, Lipsitch, Hook, and Goldie, Oct 2002).

HSV-1, which is generally considered to be a less serious illness, actually afflicts the majority of the United States population. At the time of puberty, 50% of Americans already test positive for HSV-1 antibodies; over 80% test positive at age 50. (source American Social Health Association)

Transmission
Herpes is contracted through direct skin contact (not necessarily in the genital area) with an infected person. The virus travels through tiny breaks in the skin or through moist areas, but symptoms may not appear for up to a month or more after infection. Transmission was thought to be most common during an active outbreak, however in the early 1980s scientists and doctors realized that the virus can be shed from the skin in the absence of symptoms. It is estimated that between 50 and 80% of new HSV-2 cases are from asymptomatic viral shedding.

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. There are some indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully supported. Sex should always be avoided in the presence of symptomic lesions.

Women are more susceptible to acquiring genital HSV-2 than men. 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. Supressive 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. (Wald et al., 2001) The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk. It is important to note that 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.

Prevention
Condoms are the recommended way to prevent transmission of herpes simplex infection, as demonstrated in numerous studies. (Wald, et al., 2001; Casper & Wald, 2002) However, this is 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 community (de Visser et al., 2003); and on an individual scale because some blisters may not be covered by the condom. Abstinence, including from kissing/oral sex, is another way to prevent contracting or spreading this disease.

When one partner has herpes simplex infection and the other doesn't, the use of valaciclovir, in conjunction with a condom, has been demonstrated to further decrease the chances of transmission to the uninfected partner, and the FDA approved this as a new indication for the drug in August 2003.

Other measures that have been suggested include:

Use of a lip protectant or lip gloss
Management of stress
Adequate sleep and nutrition
Avoidance of cross-infecting different sites on the body if HSV blisters are present

Future directions
The National Institutes of Health (NIH) in the United States is currently in the midst of phase III trials of a vaccine against HSV-2. 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.

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. (Phillips & Zacharopoulos, 1997) There is an ongoing large-scale trial of the efficacy of a similar formulation on humans results are expected to be published in 2007.

Treatments

Pharmacotherapy
There are several prescription antiviral medications for controlling herpes outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and penciclovir. Aciclovir was the original and prototypical member of this class and generic brands are now available at a greatly reduced cost. Valaciclovir and famciclovir are prodrugs of aciclovir and penciclovir respectively, with improved oral bioavailability. Valaciclovir has approximately 55% oral bioavailability, versus 20% for generic aciclovir. Famvir has approximately 75% oral bioavailability, versus 5% for generic penciclovir. Both aciclovir and penciclovir 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) versus 3 hours (HSV-1/2) for aciclovir. Famvir is currently about 33% more costly than Valtrex.

Docosanol (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.

Tromantadine is another antiviral drug effective against herpes.

Non-prescription analgesics can reduce pain and fever during initial outbreaks.

Aciclovir is the recommended antiviral for suppressive therapy to prevent transmission of herpes simplex to the neonate. The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. (Leung & Sacks, 2003)

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. (Thackray & Field, 1996)

Availability of generic drugs
Aciclovir is no longer under US patent protection, available in generic form
Valaciclovir (GlaxoSmithKline) protected under U.S. Patent 4957924 protection expiring June 2009
Famciclovir (Novartis) protected under U.S. Patent 5246937 protection expiring Sept 2010
Penciclovir (GlaxoSmithKline) protected under U.S. Patent 5075445 protection expiring Sept 2010
Docosanol (Avanir) protected under U.S. Patent 4874794 protection expiring April 2014

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