Herpes simplex virus

Herpes simplex virus Template:Taxobox begin placement virus Template:Taxobox group i entry
Family:	Herpesviridae
Subfamily:	Alphaherpesvirinae
Genus:	Simplexvirus
Species:	Herpes simplex virus 1 (HSV-1)
Species:	Herpes simplex virus 2 (HSV-2)

|} 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.

Contents

1 HSV-1 and HSV-2 2 HSV disease 2.1 Orofacial infection 2.2 Genital infection 2.3 Other skin infections 2.4 Herpes simplex encephalitis 2.5 Neonatal herpes simplex 3 Prevalence 4 Transmission 5 Prevention 5.1 Future directions 6 Treatments 6.1 Pharmacotherapy 6.1.1 Availability of generic drugs 6.1.2 Unproven 6.2 Complementary 6.2.1 Lysine 6.2.2 Other 7 Long-term effects 8 Myths 9 Other herpesviruses 10 References 11 External links

HSV-1 and HSV-2

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

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.

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. (Elliot & Rose, 2004; Jones, 2004) 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 (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 of herpes simplex infection, as demonstrated in numerous studies. (Wald, et al., 2001; Casper & Wald, 2002) 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 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 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) 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 approximately 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. (Phillips & Zacharopoulos, 1997) There is an ongoing large-scale trial of the efficacy of a similar formulation 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 (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.

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. (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 US patent 4957924 protection expiring June 2009
• Famciclovir (Novartis) protected under US patent 5246937 protection expiring Sept 2010
• Penciclovir (GlaxoSmithKline) protected under US patent 5075445 protection expiring Sept 2010
• Docosanol (Avanir) protected under US patent 4874794 protection expiring April 2014

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. (Karadi, Karpati & Romics, 1998) A recent animal study found that aspirin inhibited thermal stress-induced ocular viral shedding of HSV-1, and a possible benefit in reducing recurrences. (Gebhardt, Varnell, & Kaufman, 2004) Aspirin is not recommended in persons under 18 years of age with herpes simplex due to the increased risk of Reye's syndrome.

Complementary

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. (McCune et al., 1984) 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. (Griffith et al., 1987)

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. (Griffith et al., 1978)

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. (Griffith et al, 1987) 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. (Lo et al., 1996)

Other

Lactoferrin, a component of whey protein, has been shown to have a synergistic effect with aciclovir against HSV in vitro. (Andersen, Jenssen & Gutteberg, 2003)

The evidence for the effectiveness of zinc and Vitamin C supplementation is poor. (Anon, 2005). Other supplements with anecdotal benefits include monolaurin, vitamin B12, garlic, and echinacea. Daily multivitamin intake may be beneficial through maintenance of immune system health.

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. (Docherty et al., 1999) A more recent in vivo study in mice showed the efficacy of topical resveratrol cream in preventing cutaneous HSV lesion formation. (Docherty et al., 2004) 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.

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.

Myths

Some common myths and misconceptions about herpes are that it is fatal (only true for newborns, where it is rare, or if it infects the brain, which is again unusual), 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.

There are many hoaxes claiming cures for HSV. None of these have been approved by the FDA and all evidence suggests that none work as claimed. Any cure claiming to eradicate the virus by preventing the virus from retreating to the neural ganglia is a hoax. 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 able to act against latent infection.

Other herpesviruses

There are eight members of the herpesvirus 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), Epstein-Barr virus (EBV) and the cytomegalovirus (CMV).

References

• Anon (2005). Herpes simplex virus oral - AltMedDex Protocols. In: Klasco RK (Ed). AltMedDex System. Greenwood Village (CO): Thomson Micromedex.
• Casper C, Wald A (2002). Condom use and the prevention of genital herpes acquisition. Herpes 9 (1), 10-14. PMID 11916494
• de Visser RO, Smith AM, Rissel CE, Richters J, Grulich AE (2003). Sex in Australia: safer sex and condom use among a representative sample of adults. Aust N Z J Public Health 27 (2), 223-9. PMID 14696715
• Docherty JJ, Fu MM, Stiffler BS, Limperos RJ, Pokabla CM, DeLucia AL (1999). Resveratrol inhibition of herpes simplex virus replication. Antiviral Res 43 (3), 145-55. PMID 10551373
• Docherty JJ, Smith JS, Fu MM, Stoner T, Booth T (2004). Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res 61 (1), 19-26. PMID 14670590
• Elliott E, Rose D (2004). Australian Paediatric Surveillance Unit. Reporting of communicable disease conditions under surveillance by the APSU, 1 January to 30 September 2003. Commun Dis Intell 28 (1), 90-1. PMID 15072162
• Fleming DT, McQuillan GM, Johnson RE, Nahmias AJ, Aral SO, Lee FK, et al. (1997). Herpes simplex virus type 2 in the United States, 1976 to 1994. New Engl J Med 337 (16), 1105-11. PMID 9329932
• Gebhardt BM, Varnell ED, Kaufman HE (2004). Acetylsalicylic acid reduces viral shedding induced by thermal stress. Curr Eye Res 29 (2-3), 119-25. PMID 15512958
• Griffith RS, Norins AL, Kagan C (1978). A multicentered study of lysine therapy in Herpes simplex infection. Dermatologica 156 (5), 257-67. PMID 640102
• Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A (1987). Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica 175 (4), 183-90. PMID 3115841
• Jones CA. (2004). Vaccines to prevent neonatal herpes simplex virus infection. Expert Rev Vaccines 3 (4), 363-4. PMID 15270635
• Karadi I, Karpati S, Romics L (1998). Aspirin in the management of recurrent herpes simplex virus infection (http://www.annals.org/cgi/content/full/128/8/696-b). Ann Intern Med 128 (8), 696-7.
• Koutsky LA, Ashley RL, Holmes KK, Stevens CE, Critchlow CW, Kiviat N, et al. (1990). The frequency of unrecognized type 2 herpes simplex virus infection among women. Implications for the control of genital herpes. Sex Transm Dis 17 (2), 90-4. PMID 2163115
• Leung DT, Sacks SL (2003). Current treatment options to prevent perinatal transmission of herpes simplex virus. Expert Opin Pharmacother 4 (10), 1809-19. PMID 14521490
• Lo JC, Chertow GM, Rennke H, et al. (1996). Fanconi's syndrome and tubulointerstitial nephritis in association with l-lysine ingestion. Am J Kidney Dis 28 (4), 614-617.
• McCune MA, Perry HO, Muller SA, O'Fallon WM (1984). Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride. Cutis 34 (4), 366-73. PMID 6435961
• Phillips DM, Zacharopoulos VR (1997). Vaginal formulations of carrageenan protect mice from herpes simplex virus infection. Clin Diagn Lab Immunol 4 (4), 465-68. PMID 9220165
• Thackray AM, Field HJ (1996). Differential effects of famciclovir and valaciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J Infect Dis 173 (2), 291-9. PMID 8568288
• Wald A, Zeh J, Selke S, Warren T, Ryncarz AJ, Ashley, R, et al. (2000). Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 342 (12), 844-50. PMID 10727588
• Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, et al. (2001). Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women. JAMA 285 (24), 3100-6. PMID 11427138

External links

• Genital Herpes: Symptoms and Treatment (http://www.fact-sheets.com/health/herpes_symptoms_treatment/)
• http://racoon.com/herpes The Original Herpes Home Page. Information, support and discussion forums since 1995
• http://www.aad.org/pamphlets/herpes.html
• Herpes Primer and Information (http://www.mediprimer.com/Venereology_and_STDs/herpes/)
• Cold Sores - Natural Prevention and Remedies (http://joot.com/dave/writings/articles/sores.shtml)
• http://www.herpes.org.uk/
• http://www.herpes.com/
• http://www.genitalherpes.com/index.jsp
• http://darwin.bio.uci.edu/~faculty/wagner/movieindex.html
• http://www.virology.net/Big_Virology/BVDNAherpes.html
• http://www.herpes-coldsores-treatment-pictures.com
• E-medicine report on herpes simplex encephalitis (http://www.emedicine.com/EMERG/topic247.htm)
• The American Social Health Organization (http://www.ashastd.org)
• Center for Diseases Control Genital Herpes Fact Sheet (http://www.cdc.gov/std/Herpes/STDFact-Herpes.htm)
• Herpes Handbook (http://www.westoverheights.com/freebooktext.html)
• Anecdotal Information on HSV (http://www.diagnose-me.com/cond/C151019.html)
• Treatment Options for HSV Infections (http://www.bentham.org/cmcaia1-1/nikkels/nikkels-ms.htm)
• Authoritative information on diagnosis,testing, transmission and treatment. (http://www.herpesdiagnosis.com/index.html)
• Herpevac Trial for Women (http://www.niaid.nih.gov/dmid/stds/herpevac/default.htm)
• Acyclovir for Suppression of Shedding of HSV in the Genital Tract (http://www.natap.org/2004/HIV/092804_08.htm)
• Genital Herpes: Symptoms and Essential Oil Treatment (http://www.forces-of-nature.org/herpes/genital+herpes+cold+sore+treatments.htm)
• Genital Shedding of Herpes Simplex Virus among Men (http://www.journals.uchicago.edu/JID/journal/issues/v186nS1/020145/020145.text.html)
• General Herpes information including, causes, symptoms and treatments. (http://www.genital-herpes-simplex.com)
• Lysine Supplements in Herpes Labialis (Cold Sore) Management (http://www.dentistry.com/cecornerstones004.asp)de:Herpes

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