Herpes simplex

The herpes simplex virus (HSV) (also known as Cold Sore, Night Fever, or Fever Blister) 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 with present technology. An infection on the lips is commonly known as a "cold sore" or "fever blister," though this should not be confused with a canker sore, which appears inside the mouth and is not caused by the herpes simplex virus.

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 (but isn't) a less serious infection. HSV-2 is associated with the infection of the genitals, although 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.

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)
Image from patient.
 * 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 usually occur on lips especially near the vermilion border. 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. Vesicles may also appear on the fingers, an infection called whitlow.

Genital infection (Generally HSV 2)

 * 1) Prodromal symptoms
 * 2) Sore appears
 * 3) 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.

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 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
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. Preliminary studies indicate 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. Allergic reactions can also trigger an outbreak, chronic herpes genitalis may be caused by a chronic undiagnosed low-level food allergy for example.

Transmission
Herpes is contracted through direct skin contact (not necessarily in the genital area) with an infected person, and less frequently by indirect contact, in particular by sharing lip balm. 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, it was found 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. Oral sex performed by someone with oral lesions, or other symptoms, should be avoided, to avoid transmission of HSV1 to the partner's genitals.

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. 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 research. 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 ; and on an individual scale because some blisters may not be covered by the condom.

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 vaccines
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.

Medications
There are several prescription antiviral medications for controlling herpes outbreaks, including acyclovir (Zovirax), valacyclovir (Valtrex), famcyclovir (Famvir), and pencyclovir. Acyclovir was the original and prototypical member of this class and generic brands are now available at a greatly reduced cost. Valacyclovir and famcyclovir are prodrugs of acyclovir and pencyclovir respectively, with improved oral bioavailability. Valacyclovir has approximately 55% oral bioavailability, versus 20% for generic acyclovir. Famvir has approximately 75% oral bioavailability, versus 5% for generic pencyclovir. Both acyclovir and pencyclovir 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. Pencyclovir's primary advantage over acyclovir 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 acyclovir. 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.

Acyclovir is the recommended antiviral for suppressive therapy to prevent transmission of herpes simplex to the neonate. The use of valacyclovir and famcyclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. There is evidence in mice that treatment with famcyclovir, rather than acyclovir, 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 acyclovir drops to zero a few months post-infection.

Availability of generic drugs

 * Acyclovir is no longer under US patent protection, available in generic form
 * Valacyclovir (GlaxoSmithKline) protected under protection expiring June 2009
 * Famcyclovir (Novartis) protected under protection expiring Sept 2010
 * Pencyclovir (GlaxoSmithKline) protected under protection expiring Sept 2010
 * Docosanol (Avanir) protected under protection expiring April 2014

Research drugs

 * BAY 57-1293, a helicase-primase inhibitor researched by Bayer AG scientist Gerald Kleymman's team in Wuppertal, Germany.


 * 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.


 * Roscovitine is an inhibitor of cellular cyclin-dependent kinase and seems to prevent transcription of viral genomes. Roscovitine has entered clinical trials for HIV infection.

Lysine
Lysine 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.

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 (Fanconi's Syndrome) after taking lysine 3000 mg daily for approximately 5 years.

Other natural compounds
Carrageenans, 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 skottsbergii seaweed inhinited the replication avtivity of HSV-1 and HSV-2 in infected mouse astrocyte nerve cells and vero cells.

Lactoferrin, 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 (i.e., the EC50) also acted in synergy with aciclovir; the concentration required to achieve EC50 for each substance was reduced "two- to seven-fold."

Resveratrol, a compound in red wine, has been shown by researchers to prevent HSV replication in vitro 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 benefits.

Unproven
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.

Cimetidine, a common component of heartburn medication, 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 clearence 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. Due to the tendency of aciclovir to precipitate in renal tubules, combining these drugs should only occur under the supervision of a physician.

Other
The evidence for the effectiveness of zinc and Vitamin C supplementation is poor. Other supplements with anecdotal evidence of benefits include monolaurin, vitamin A, vitamin B12, garlic, and echinacea. 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.

Unsubstantiated claims
There are many unsubstantiated claims of cures for HSV. None of these have been approved by the FDA and very little study has been done to prove these claims. Any cure claiming to eradicate the virus by preventing the virus from retreating to the neural ganglia is an unproven claim. The virus only travels into the neural ganglia once, at the time of primary infection. Once the virus is established in the nucleus of the neuron, it is there for life. All recurrences involve a unidirectional flow of newly replicated viral particles from within the neuron to the site of shedding. There are currently no treatments which are proven to act against latent infection.

Similarly, there are many claims made by proponents of "hyper-oxygenation" therapies, namely H2O2 and DMSO, that oxygen "kills", HSV infected cells or discourages subsequent outbreaks. Although this is true in basis of fact, it is misleading. Oxygen in these forms becomes a free radical when absorbed in the body, in simple terms, it is destructive to all cellular structures, healthy or infected. This lack of a targeted delivery mechanism combined with the lack of an ability to target only infected cells implies that it is impossible for these therapies to have any benefit without causing much more damage to otherwise healthy cells.

Latent Infection and Biology
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 cell nucleus, where a loop of dsDNA is maintained. During inactive, or latent, periods of the infection, a subset of the Herpes genome termed LAT or Latency Associated Transcript is active and may be involved in maintenance of latency.

Long-term effects
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 the 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.

Currently, there is no viable cure for herpes. 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.

Psychological and social effects
Discovering that a person has genital herpes can have a dramatic effect on that person'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. One study surveyed people about their first episode of genital herpes. Findings showed proportions of people who experienced All of these proportions reduced over time.
 * depression 82%
 * 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 masturbation
 * increased depression

In order to improve the well-being of people with herpes, a number of support groups exist, both physically and with a presence on the Internet.

Disclosure to new partners
People with genital herpes are often hesitant to divulge that they have the virus to other people, especially new or potential sexual partners. Results from one study show that people are less likely to inform what they consider to be casual partners. In addition, the perception of the likely reaction is taken into account before making a decision about whether to inform a new partner. An event such as a couple moving in together was found to be the point when some people disclosed their status.

The study showed people informed 62% of regular partners and 22% of casual partners, and was unrelated to the gender of the person. Strategies used when telling partners included keeping the issue "low key," choosing a relaxed environment and suggestions of the couple being tested jointly for a range of sexually transmitted infections. The ratio of positive reactions to negative reactions to disclosure was 22:4.

Doctors at some hospitals and health clinics actually advise men not to tell their partners unless the woman is pregnant, reasoning that the psychological effects of herpes far outweigh the physical effects in adults. This advice is still controversial, especially as genital herpes affects women significantly worse than it does men.

Myths
Some common myths and misconceptions about herpes (usually meaning "genital") are:
 * that it is fatal (only true for newborns, where it is rare, or if it infects the brain, which is again uncommon),
 * that it only affects the genital areas (it can affect any part of the body),
 * that condoms are completely effective in preventing the spread of this disease,
 * that it is transmittable only in the presence of symptoms,
 * that it can make you sterile,
 * that pap smears detect herpes,
 * and that only promiscuous people get it (it is so common that anyone having sex is at risk).

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 someobody with active lesions should be avoided.

Other herpes viruses
There are eight members of the herpes virus family that are known to cause human disease, including not only the Herpes Simplex viruses (HSV-1 and HSV-2), but also the varicella-zoster virus (VZV, or HSV-3) which causes both shingles and chickenpox, Epstein-Barr virus (EBV, or HSV-4), cytomegalovirus (CMV, or HSV-5), human B cell lymphatic virus (HSV-6), roseola poorly characterised virus (HSV-7), and the Kaposi's sarcoma-associated herpesvirus (KSHV, or HSV-8).