The Herpes simplex virus infection (common names: herpes, cold sores) is a common, contagious, incurable, and in some cases  sexually transmitted  disease caused by a double-stranded DNA virus. The infection can also affect the brain, in which case the consequent disease is called herpes simplex encephalitis.

There are two main kinds of herpes simplex virus: type 1 (HSV-1) and type 2 (HSV-2). Although HSV-1 is generally considered to be associated with orofacial infection, and HSV-2 with genital infection; both types can affect any region of the body. There are some differences, however, in the infectivity and severity of infection — HSV-1 infections are more easily acquired and infections are more severe in the orofacial region and similar with HSV-2 in the genital 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

1. Prodromal symptoms

2. Skin appears irritated

3. Sore or cluster of fluid-filled blisters appear

4. Lesion begins to heal, usually without scarring

These infections may appear on the lips, nose or in surrounding areas. The sores may appear to be either weeping or dry, and may resemble a pimple, insect bite, or large chickenpox lesion. Lesions typically heal after a few days to a week (or more), but this varies among individuals.

Genital infection

5. Prodromal symptoms

6. Sore appears

7. 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.

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

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.

Herpes simplex encephalitis

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 commonest 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

Neonatal HSV disease is a rare, but serious, consequence of vertical HSV transmission from mother to neonate. 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. 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 neonate.

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)

Transmission

Herpes is contracted through direct skin contact 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 gold standard in the prevention of herpes simplex infection, as demonstrated in numerous studies. The effectiveness of this method is somewhat limited on a public health scale by the limited-use of condoms in the community and on an individual scale because some blisters may not be covered by the condom. Abstinence, including from oral sex, is another effective 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:

• the use of a chapstick
• 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) are 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 approxmiately 48% effective in preventing HSV-2 seropositivity and about 78% effective in preventing symptomatic HSV-2. Assuming FDA approval, a commerical version of the vaccine is estimated to become available around 2008.

There are good 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 on going large scale efficacy trial of a similar formulation under way on humans but results are not expected to be published until 2007.

Treatments

Pharmacotherapy

There are several prescription antiviral medications for controlling herpes outbreaks, including aciclovir,  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.

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.

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.

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.