Herpes simplex

Herpes simplex
Classification and external resources

Herpes labialis of the lower lip. Note the blisters in a group marked by an arrow.
ICD-10 A60., B00., G05.1, P35.2
ICD-9 054.0, 054.1, 054.2, 054.3, 771.2
DiseasesDB 5841 33021
eMedicine med/1006
MeSH D006561

Herpes simplex (Ancient Greek: ἕρπης - herpes, lit. "creeping") is a viral disease caused by both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever blisters, infects the face and mouth. Oral herpes is the most common form of infection. Genital herpes, known simply as herpes, is the second most common form of herpes. Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are all caused by herpes simplex viruses.

Herpes viruses cycle between periods of active disease—presenting as blisters containing infectious virus particles—that last 2–21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. After initial infection, the viruses move to sensory nerves, where they become latent and reside as life-long. Causes of recurrence are uncertain, though some potential triggers have been identified. Over time, episodes of active disease reduce in frequency and severity.

Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual. Transmission may also occur through skin-to-skin contact during periods of asymptomatic shedding. Barrier protection methods are the most reliable method of preventing transmission of herpes, but they merely reduce rather than eliminate risk. Oral herpes is easily diagnosed if the patient presents with visible sores or ulcers. Early stages of orofacial herpes and genital herpes are harder to diagnose; laboratory testing is usually required.

A cure for herpes has not yet been developed. Once infected, the virus remains in the body for life. However, after several years, some people will become perpetually asymptomatic and will no longer experience outbreaks, though they may still be contagious to others. Treatments with antivirals can reduce viral shedding and alleviate the severity of symptomatic episodes. Vaccines are in clinical trials but have not demonstrated effectiveness. It should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster, which is caused by varicella zoster virus. The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin.

Contents

Classification

Herpes simplex is divided into two types HSV type 1 and HSV type 2.[1] HSV1 primarily causes mouth, throat, face, eye, and central nervous system infections well HSV2 primarily causes anogenital infections.[1] However each may cause infections in all areas.[1]

Signs and Symptoms

HSV infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow). More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). Patients with immature or suppressed immune systems, such as newborns, transplant recipients, or AIDS patients are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of bipolar disorder,[2] and Alzheimer's disease,[3] although this is often dependent on the genetics of the infected person.

In all cases HSV is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion.[4] As a result of primary infection, the body produces antibodies to the particular type of HSV involved, preventing a subsequent infection of that type at a different site. In HSV-1 infected individuals, seroconversion after an oral infection will prevent additional HSV-1 infections such as whitlow, genital herpes, and keratitis. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted. Most indications are that an HSV-2 infection contracted prior to HSV-1 seroconversion will also immunize that person against HSV-1 infection.

Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes.[5]

Condition Description Illustration
Herpetic gingivostomatitis Herpetic gingivostomatitis is often the initial presentation during the first herpes infection. It is of greater severity than herpes labialis which is often the subsequent presentations. Around 90% of the U.S. population is affected with this disease.[6]
Herpesgingiva.JPG
Herpes labialis Infection occurs when the virus comes into contact with oral mucosa or abraded skin.
Cold sore.jpg
Herpes genitalis When symptomatic, the typical manifestation of a primary HSV-1 or HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores.
SOA-Herpes-genitalis-female.jpg
Herpetic whitlow Herpes whitlow is a painful infection that typically affects the fingers or thumbs. Occasionally infection occurs on the toes or on the nail cuticle.
Herpeticwhitolow.JPG
Herpes gladiatorum Individuals that participate in contact sports such as wrestling, rugby, and soccer sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler’s herpes, or mat herpes, which presents as skin ulceration on the face, ears, and neck. Symptoms include fever, headache, sore throat and swollen glands. It occasionally affects the eyes or eyelids.
Herpetic keratoconjunctivitis Primary infection typically presents as swelling of the conjunctiva and eye-lids (blepharoconjunctivitis), accompanied by small white itchy lesions on the surface of the cornea.
Herpesviral encephalitis A herpetic infection of the brain that is thought to be caused by the retrograde transmission of virus from a peripheral site on the face following HSV-1 reactivation, along the trigeminal nerve axon, to the brain. HSV is the most common cause of viral encephalitis. When infecting the brain, the virus shows a preference for the temporal lobe.[7].
Hsv encephalitis.jpg
Herpesviral meningitis HSV-2 is the most common cause of Mollaret's meningitis, a type of recurrent viral meningitis.
Neonatal herpes simplex Neonatal HSV infection is a rare but serious condition, usually caused by vertical transmission of HSV (type 1 or 2) from mother to newborn.
During immunodeficiency In patients with a weakened immune system, herpes simplex can cause unusual lesions in the skin. One of the most striking is the appearance of clean linear erosions in skin creases, with the appearance of a knife cut.[8]
Herpetic sycosis Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicle.[9]:369
Eczema herpeticum Infection with herpesvirus in patients with chronic atopic dermatitis may result in spread of herpes simples throughout the eczematous areas.[9]:373
Herpes esophagitis Symptoms may include painful swallowing (odynophagia) and difficulty swallowing (dysphagia). It is often associated with impaired immune function (e.g. HIV/AIDS, immunosuppression in solid organ transplants).
Herpes esophagitis.JPG

Bell's palsy

Although the exact cause of Bell's palsy, a type of facial paralysis, is unknown it may be related to reactivation of herpes simplex virus type 1.[10] This theory has been contested, however since HSV is detected in large numbers of individuals who never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy compared to those without.[11] Regardless antivirals have been found to not improve outcomes.[12]

Alzheimer's disease

HSV-1 has been proposed as a possible cause of Alzheimer's disease.[13][14] In the presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's disease.[15][16] Without the presence of the gene allele, HSV type 1 does not appear to cause any neurological damage and thus increase the risk of Alzheimer’s.[17] Herpes simplex virus type 1 DNA is localized within the beta-amyloid plaques that characterize Alzheimer's disease.[18] It suggests that this virus is a major cause of the plaques and hence probably a significant aetiological factor in Alzheimer's disease.

Pathophysiology

Herpes is contracted through direct contact with an active lesion or body fluid of an infected person.[19] Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. The only way to contract Herpes simplex virus 2 is through direct skin-to-skin contact with an infected individual. To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.

HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases.[20] Virus enters into susceptible cells via entry receptors[21] such as nectin-1, HVEM and 3-O sulfated heparan sulfate[22]. Infected people that show no visible symptoms may still shed and transmit virus through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission.[20] Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding.[23] There are indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with one to twelve annual recurrences to those who have no recurrences.[20]

Antibodies that develop following an initial infection with a type of HSV prevents reinfection with the same virus type—a person with a history of orofacial infection caused by HSV-1 cannot contract herpes whitlow or a genital infection caused by HSV-1. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV infection from a seropositive male partner.[24] If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection.

Diagnosis

Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis.[25] Adults with non-typical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.[25]

Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical symptoms.[25] Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis.[25] Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include: culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.[25]

Until recently, serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice[25]. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, the new Immunodot glycoprotein G-specific (IgG) HSV test is more that 98% specific at discriminating HSV-1 from HSV-2. [26] It is the opinion of some modern medical professionals that the new IgG test should always be clinically preferred to the old IgM test, however not all doctors appear to be informed of the availability of the newer, reliable IgG tests. [27]

Prevention

Barrier protection, such as a condom, can reduce the risk of herpes transmission.

As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men.[28] On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is approximately 8-10%.[24][29] 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.[29] Suppressive antiviral therapy reduces these risks by 50%.[30] Antivirals also help prevent the development of symptomatic HSV in infection scenarios—meaning the infected partner will be seropositive but symptom free—by about 50%. Condom use also reduces the transmission risk by 50%.[31][32][33] Condom use is much more effective at preventing male to female transmission than vice-versa.[31] 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.

However, asymptomatic carriers of the HSV-2 virus are still contagious. In many infections, the first symptom a person will have of their own infection is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.

Barrier methods

Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30% lower risk of HSV-2 acquisition compared with those who never use condoms[34] The virus cannot pass through a latex condom, but a condom's effectiveness is limited because it does not prevent skin contact or bodily fluid contact with the scrotum, anus, buttocks, upper thighs or area immediately surrounding the penis, all of which are susceptible to infection with and transmission of the virus. Preventing contact with these areas during sex, in addition to wearing a condom, should theoretically provide enhanced protection against herpes. Wearing clothing or undergarments such as boxer shorts that cover these susceptible areas but still allow access to the genitals through a small opening (such as a fly) should help prevent transmission and infection.

The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa) during oral sex. When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir, in conjunction with a condom, further decreases the chances of transmission to the uninfected partner.[4] Topical microbicides which contain chemicals that directly inactivate the virus and block viral entry are being investigated.[4]

Vaccine

Vaccines for HSV are undergoing trials. Once developed, they may be used to help with prevention or minimize initial infections as well as treatment for existing infections.[35]

One vaccine under trial is Herpevac, a vaccine against HSV-2. The National Institutes of Health (NIH) in the United States is conducting phase III trials of Herpevac.[36] 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.[36] During initial trials, the vaccine did not exhibit any evidence of preventing HSV-2 in males.[36] 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-2 infection at the time they got the vaccine.[36][36]

A laboratory at Harvard Medical School has developed dl5-29 (now known as ACAM-529), a replication-defective mutant virus that has proved successful both in preventing HSV-2/HSV-1 infections, and in combating the virus in already infected hosts, in animal models. It has been shown that the replication-defective vaccine induces strong HSV-2-specific antibody and T-cell responses; protects against challenge with a wild-type HSV-2 virus; greatly reduces the severity of recurrent disease; provides cross-protection against HSV-1, and renders the virus unable to revert to a virulent state or to become latent.[37] His vaccine is now being researched and developed by Accambis, and is due to be applied as an Investigational New Drug in 2009.[38]

Antivirals

Antivirals may reduce asymptomatic shedding; it is believed asymptomatic genital HSV-2 viral shedding occurs on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy.[20]

Pregnancy

The risk of transmission from mother to baby is highest if the mother becomes infected at around the time of delivery (30% to 60%),[39][40] but the risk falls to 3% if it is a recurrent infection, and is less than 1% if there are no visible lesions.[41] To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1 seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. A seronegative mother that contracts HSV at this time has up to a 57% chance of conveying the infection to her baby during childbirth, since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child, whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant.[42][43] Women that are seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g., fetal scalp electrodes, forceps, and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal.[4] The use of antiviral treatments, such as acyclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.[4]

Acyclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy. The use of valaciclovir and famciclovir, while potentially improving compliance have less well determined safety in pregnancy.

Treatment

There is no method to eradicate herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks. Analgesics such as ibuprofen and acetaminophen can reduce pain and fever. Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine or tetracaine can also relieve itching and pain.[44][45][46]

Antiviral

The antiviral medication acyclovir

There are several antivirals that are effective for treating herpes including:acyclovir, valacyclovir, famciclovir, and penciclovir. Acyclovir was the first discovered and is now available in generic.

Evidence supports the use of acyclovir and valacyclovir in the treatment of herpes labialis[47] as well as herpes infections in people with cancer.[48] The evidence to support the use of acyclovir in primary herpetic gingivostomatitis is less strong.[49]

Topical

A number of topical antivirals are effective for herpes labialis including acyclovir, penciclovir, and docosanol.[47][50] Docosanol can be purchased over the counter in Canada and the USA.

Alternative medicine

Certain dietary supplements and alternative remedies are claimed to be beneficial in the treatment of herpes. There is however insufficient evidence to support use of many of these compounds including echinacea, eleuthero, L-lysine, zinc, bee products and aloe vera.[51]

A single study indicates possible benefit from 1072 nm wavelength light.[52]

Treatment strategies still in trial

Researchers at the University of Florida have made a hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead which targets the mRNA of the UL20 gene greatly reduced the level of HSV-1 ocular infection in rabbits and reduced the viral yield in vivo.[53] The gene-targeting approach uses a specially designed RNA enzyme to inhibit strains of the herpes simplex virus. The enzyme disables a gene responsible for producing a protein involved in the maturation and release of viral particles in an infected cell. The technique appears to be effective in experiments with mice and rabbits, but further research is required before it can be attempted in people who are infected with herpes.[54]

Another possibility to eradicate the HSV-1 variant is being pursued by a team at Duke University. By figuring out how to switch all copies of the virus in the host from latency to their active stage at the same time, rather than the way the virus copies normally stagger their activity stage, leaving some dormant somewhere at all times, it is thought that conventional anti-viral drugs can kill the entire virus population completely, since they can no longer hide in the nerve cells. One class of drugs called antagomir could serve this purpose. These are chemically engineered oligonucleotides or short segments of RNA, that can be made to mirror their target genetic material, namely herpes microRNAs. They could be engineered to attach and thus 'silence' the microRNA, thus rendering the virus incapable to keep latent in their host.[55] Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.[56]

Additionally, another solution may be found with regards to curing the infection. A cross anti-viral drug called bavituximab has already proved successful in effectively treating mice and guinea pigs infected with various enveloped viruses. Herpes viruses fall within this category, and it is thought that the virus might be eradicated from the body using this drug.[57] The drug works by binding onto infected cells, including cancer cells, and signaling to the immune system to come and destroy the problem cells. This is a novel technique in medicine and is eagerly anticipated. It is believed that cross-protection against latent viruses such as herpes simplex, Epstein-Barr, etc., will make an important contribution to improving public health.[58]

Vironova AB, which is a privately held Swedish biotech company, created an antiviral approach to stop viral growth by inhibiting viral structures from forming, e.g. the capsid. Correct assembly of structural proteins is essential for the virus to survive the extracellular environment and to become infectious, and is thus a suitable drug target. Vironova AB is dedicated to the development of antiviral therapeutics and virus diagnostics products to combat and prevent the spread of viral diseases.[59]

Prognosis

Following active infection, herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerve's cell body. HSV latency is static—no virus is produced—and is controlled by a number of viral genes, including Latency Associated Transcript (LAT).[60]

Many HSV-infected people experience recurrence within the first year of infection.[4] Prodrome precedes development of lesions. Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop, lesions are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection.[4] Subsequent outbreaks tend to be periodic or episodic, occurring on average four to five times a year when not using antiviral therapy.

The causes of reactivation are uncertain, but several potential triggers have been documented. A recent study (2009) showed that a protein VP16 plays a key role in reactivation of the dormant virus.[61] Changes in the immune system during menstruation may play a role in HSV-1 reactivation.[62][63] Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to infection is the likely source of the historic terms cold sore and fever blister.

Other identified triggers include: local injury to the face, lips, eyes, or mouth, trauma, surgery, radiotherapy, and exposure to wind, ultraviolet light, or sunlight.[64][65][66][67][68]

The frequency and severity of recurrent outbreaks vary greatly between patients. Some individuals' outbreaks can be quite debilitating with large, painful lesions persisting for several weeks, while others will experience only minor itching or burning for a few days. There is some evidence that genetics plays a role in the frequency of cold sore outbreaks. An area of human chromosome 21 that includes 6 genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals will experience fewer outbreaks and outbreak symptoms will often become less severe. After several years, some people will become perpetually asymptomatic and will no longer experience outbreaks, though they may still be contagious to others. Immuno-compromised individuals may experience episodes that are longer, more frequent, and more severe. Antiviral medication has been proven to shorten the frequency and duration of outbreaks.[69] Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs. HSV-2 infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons,[70] particularly during an outbreak with active lesions.[71]

Epidemiology

Worldwide rates of HSV infection are between 65% and 90%.[1] HSV1 is more common than HSV2 with rates of both increasing as people age.[1] Rates of infection are determined by the presence of antibodies against either viral species.[72]

In the US 17.2% of the population is HSV-2 seropositive with only 14.5% of the seropositive population aware that they are infected.[73]

History

Herpes has been known for at least 2,000 years. It is said that Emperor Tiberius banned kissing in Rome for a time due to so many people having cold sores. In the 16th century Romeo and Juliet, it is mentioned that there are blisters "o'er ladies' lips." In 18th century it was so common among prostitutes that it was called "a vocational disease of women."[74]

The term Herpes Simplex appeared in Richard Boulton's A System of Rational and Practical Chirurgery in 1713, where the terms Herpes miliaris and Herpes exedens also appeared.

Herpes was not found to be a virus until the 1940s.[74]

Herpes antiviral therapy began in the early 1960s with the experimental use of medication that interfered with viral replication called deoxyribonucleic acid (DNA) inhibitors. The original use was against normally fatal or disabilitating illness such as adult encephalitis,[75] keratitis,[76] in immunocompromised (transplant) patients,[77] or disseminated herpes zoster.[78] The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C,[79] later marketed under the name cytosar or cytorabine. The usage expanded to include topical treatment of herpes simplex,[80] zoster, and varicella.[81] Some trials combined different antivirals with differing results.[75] The introduction of 9-β-D-arabinofuranosyladenine, AKA ara-A or vidarabine, considerably less toxic than Ara-C, in the mid 1970s, heralded the way for the beginning of regular neonatal antiviral treatment. Vidarabine was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed for use by the U.S. Food and Drug Administration (FDA) in 1977. Other experimental antivirals of that period included: Heparin [82], trifluorothymidine (TFT)[83], Ribivarin,[84] interferon,[85] Virazole,[86] and 5-methoxymethyl-2'-deoxyuridine (MMUdR).[87] The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA acyclovir, in the late 1970s[88] raised antiviral treatment another notch and led to vidarabine vs. acyclovir trials in the late 1980s.[89] The lower toxicity and ease of administration over vidarabine has led to acyclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998.[90] Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, something that did not occur when compared with increased dosages of vidarabine.[90] On the other side of the equation, acyclovir seems to inhibit antibody response and newborns on acyclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine.[90]

Society and culture

Some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Feelings can include depression, fear of rejection, feelings of isolation, fear of being found out, self-destructive feelings, and fear of masturbation.[91] These feelings usually lessen over time. Much of the hysteria and stigma surrounding herpes stems from a media campaign beginning in the late 1970s and peaking in the early 1980s. There were multiple articles worded in fear-mongering and anxiety-provoking terminology, such as the now ubiquitous "attacks," "outbreaks," "victims," and "sufferers." At one point the term "herpetic" even entered the popular lexicon. The articles were published by Reader's Digest, U.S. News, and Time magazine, among others. A made-for-TV movie was named Intimate Agony. The peak was when Time magazine had 'Herpes: The New Scarlet Letter' on the cover in August 1982, forever stigmatizing the word in the public mind.[74] The scientific reality is that most people are asymptomatic, the virus causes no real health problems for a vast majority of people, and a vast majority (around 90%) of the Earth's population carries HSV-1, 2, or both.[92][93] Herpes support groups have been formed in the United States and the UK, providing information about herpes and running message forums and dating websites for "sufferers."[94]

People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners whom they consider casual.[95] A perceived reaction is sometimes taken into account before making a decision about whether to inform new partners and at what point in the relationship. Many people do not immediately make their condition known to new partners, but wait until a later point in the relationship. Other people disclose herpes status at the beginning. Still others choose only to date other people who already have herpes. The premise of informing was constructed in conjunction with the emotional media coverage of the 1970s-1980s. Those infected prior to the mid- to late-1970s had never heard of informing the uninfected, or felt any need to inform. People who are not infected generally agree it is a responsible thing to do from a health perspective, since individuals who are not infected prefer to continue that way. With more knowledge about a partner, an individual can make an informed decision about a health issue.

See also

References

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  2. ↑ Dickerson FB, Boronow JJ, Stallings C, et al. (March 2004). "Infection with herpes simplex virus type 1 is associated with cognitive deficits in bipolar disorder". Biol. Psychiatry 55 (6): 588–93. doi:10.1016/j.biopsych.2003.10.008. PMID 15013827. 
  3. ↑ Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (January 1997). "Herpes simplex virus type 1 in brain and risk of Alzheimer's disease". Lancet 349 (9047): 241–4. doi:10.1016/S0140-6736(96)10149-5. PMID 9014911. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Gupta R, Warren T, Wald A (December 2007). "Genital herpes". Lancet 370 (9605): 2127–37. doi:10.1016/S0140-6736(07)61908-4. PMID 18156035. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)61908-4. 
  5. ↑ Handsfield HH (2000). "Public Health Strategies to Prevent Genital Herpes: Where Do We Stand?". Curr Infect Dis Rep 2 (1): 25–30. doi:10.1007/s11908-000-0084-y. PMID 11095834. 
  6. ↑ "PRIMARY INFECTION OR PRIMARY HERPETIC GINGIVOSTOMATITIS (PHG )". http://www.dent.ucla.edu/pic/visitors/herpes/page1.html#primar. 
  7. ↑ "Herpes Encephalitis: eMedicine Radiology". http://emedicine.medscape.com/article/341142-overview. 
  8. ↑ Jocelyn A. Lieb, Stacey Brisman, Sara Herman, Jennifer MacGregor, Marc E. Grossman (2008). "Linear erosive Herpes Simplex Virus infection in immunocompromised patients: the “Knife-Cut Sign”". Clin Infect Dis 47 (11): 1440–1441. doi:10.1086/592976. PMID 18937574. 
  9. ↑ 9.0 9.1 James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
  10. ↑ Tankéré F, Bernat I (September 2009). "[Bell's palsy: from viral aetiology to diagnostic reality]" (in French). Rev Med Interne 30 (9): 769–75. doi:10.1016/j.revmed.2008.12.006. PMID 19195745. 
  11. ↑ Linder T, Bossart W, Bodmer D (January 2005). "Bell's palsy and Herpes simplex virus: fact or mystery?". Otol. Neurotol. 26 (1): 109–13. doi:10.1097/00129492-200501000-00020. PMID 15699730. 
  12. ↑ Lockhart P, Daly F, Pitkethly M, Comerford N, Sullivan F (2009). "Antiviral treatment for Bell's palsy (idiopathic facial paralysis)". Cochrane Database Syst Rev (4): CD001869. doi:10.1002/14651858.CD001869.pub4. PMID 19821283. 
  13. ↑ Itzhaki RF, Wozniak MA (May 2008). "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within". J. Alzheimers Dis. 13 (4): 393–405. PMID 18487848. 
  14. ↑ Holmes C, Cotterell D (December 2009). "Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment". CNS Drugs 23 (12): 993–1002. doi:10.2165/11310910-000000000-00000. PMID 19958038. 
  15. ↑ Dobson CB, Itzhaki RF (1999). "Herpes simplex virus type 1 and Alzheimer's disease". Neurobiol. Aging 20 (4): 457–65. doi:10.1016/S0197-4580(99)00055-X. PMID 10604441. http://linkinghub.elsevier.com/retrieve/pii/S0197-4580(99)00055-X. 
  16. ↑ This research identifies HSVs as the pathogen most clearly linked to the 2001Pyles RB (November 2001). "The association of herpes simplex virus and Alzheimer's disease: a potential synthesis of genetic and environmental factors" (PDF). Herpes 8 (3): 64–8. PMID 11867022. http://www.ihmf.com/journal/download/83pyles(64)vol864.pdf. 
  17. ↑ Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (January 1997). "Herpes simplex virus type 1 in brain and risk of Alzheimer's disease". Lancet 349 (9047): 241–4. doi:10.1016/S0140-6736(96)10149-5. PMID 9014911. 
  18. ↑ Wozniak MA, Mee AP, Itzhaki RF (January 2009). "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques". J Pathol. 217 (1): 131–8. doi:10.1002/path.2449. PMID 18973185. http://www3.interscience.wiley.com/journal/121411445/abstract. 
  19. ↑ "AHMF: Preventing Sexual Transmission of Genital herpes". http://www.ahmf.com.au/health_professionals/guidelines/preventing_gh_transmission.htm. Retrieved 2008-02-24. 
  20. ↑ 20.0 20.1 20.2 20.3 Leone P (2005). "Reducing the risk of transmitting genital herpes: advances in understanding and therapy". Curr Med Res Opin 21 (10): 1577–82. doi:10.1185/030079905X61901. PMID 16238897. 
  21. ↑ Akhtar, Jihan; Shukla, Deepak. "Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry". FEBS Journal 2009 (276). http://www3.interscience.wiley.com/cgi-bin/fulltext/122668866/PDFSTART. 
  22. ↑ Shukla, Deepak; Liu, Jian; Blaiklock, Peter; Shworak, Nicholas W.; Bai, Xiaomei; Esko, Jeffrey D.; Cohen, Gary H.; Eisenberg, Roselyn et al. (1999). "A Novel Role for 3-O-Sulfated Heparan Sulfate in Herpes Simplex Virus 1 Entry". Cell 99 (1): 13–22. doi:10.1016/S0092-8674(00)80058-6. PMID 10520990. http://www.cell.com/retrieve/pii/S0092867400800586. 
  23. ↑ Kim H, Meier A, Huang M, Kuntz S, Selke S, Celum C, Corey L, Wald A (2006). "Oral herpes simplex virus type 2 reactivation in HIV-positive and -negative men.". J Infect Dis 194 (4): 420–7. doi:10.1086/505879. PMID 16845624. 
  24. ↑ 24.0 24.1 Mertz, G.J. (1993). "Epidemiology of genital herpes infections.". Infect Dis Clin North Am 7 (4): 825–39. PMID 8106731. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 Fatahzadeh M, Schwartz RA (2007). "Human herpes simplex virus infections: epidemiology, pathogenesis, symptomatology, diagnosis, and management". J. Am. Acad. Dermatol. 57 (5): 737–63; quiz 764–6. doi:10.1016/j.jaad.2007.06.027. PMID 17939933. 
  26. ↑ Ashley RL, et. al. (1988). "Comparison of wester blod (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus type 1 and type 2 in human era". J. Clin. Microbiol. 26 (4): 662–667. PMID 2835389. PMC 266403. http://jcm.asm.org/cgi/content/abstract/26/4/662?ijkey=e6b5d2fe810a92d0353f5a1649d94014839a0663&keytype2=tf_ipsecsha. 
  27. ↑ Warren, Terri (2009). The Good News About The Bad News. New Harbinger Publications. p. 209. ISBN 1572246189. http://books.google.com/?id=PoRB5qQXW70C&printsec=frontcover&dq=%22good+news+about+the+bad+news%22&q. 
  28. ↑ Carla K. Johnson (August 23, 2006). "Percentage of people with herpes drops". Associated Press. http://www.newsobserver.com/150/story/477928.html. 
  29. ↑ 29.0 29.1 Kulhanjian JA, Soroush V, Au DS, et al. (April 2, 1992). "Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy". N. Engl. J. Med. 326 (14): 916–20. PMID 1311799. http://content.nejm.org/cgi/content/abstract/326/14/916. 
  30. ↑ Corey L, Wald A, Patel R, et al. (January 2004). "Once-daily valacyclovir to reduce the risk of transmission of genital herpes" (PDF). N Engl J Med. 350 (1): 11–20. doi:10.1056/NEJMoa035144. PMID 14702423. http://content.nejm.org/cgi/reprint/350/1/11.pdf. 
  31. ↑ 31.0 31.1 Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, Tyring S, Douglas JM Jr, Corey L. (2001). "Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women". JAMA 285 (24): 3100–3106. doi:10.1001/jama.285.24.3100. PMID 11427138. http://jama.ama-assn.org/cgi/content/full/285/24/3100. 
  32. ↑ Casper C, Wald A. (2002). "Condom use and the prevention of genital herpes acquisition," (PDF). Herpes 9 (1): 10–14. PMID 11916494. http://www.ihmf.org/journal/download/91casper(10)vol910.pdf. 
  33. ↑ Wald A, Langenberg AG, Krantz E, et al. (November 2005). "The relationship between condom use and herpes simplex virus acquisition". Ann Intern Med. 143 (10): 707–13. PMID 16287791. http://www.annals.org/cgi/reprint/143/10/707. 
  34. ↑ Emily T. Martin, MPH; Elizabeth Krantz, MS; Sami L. Gottlieb, MD, MSPH; Amalia S. Magaret, PhD; Andria Langenberg, MD; Lawrence Stanberry, MD, PhD; Mary Kamb, MD, MPH; Anna Wald, MD, MPH (2009). "A Pooled Analysis of the Effect of Condoms in Preventing HSV-2 Acquisition". Archives of Internal Medicine 169 (13): 1233–1240. doi:10.1001/archinternmed.2009.177. PMID 19597073. PMC 2860381. http://archinte.ama-assn.org/cgi/content/abstract/169/13/1233. 
  35. ↑ Seppa, Nathan (2005-01-05). "One-Two Punch: Vaccine fights herpes with antibodies, T cells". Science News. p. 5. http://www.sciencenews.org/articles/20050101/fob6.asp. Retrieved 2007-03-29. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 "Herpevac Trial for Women". http://www.niaid.nih.gov/dmid/stds/herpevac/. Retrieved 2008-02-25. 
  37. ↑ http://www.acambis.com/default.asp-id=2052.htm
  38. ↑ "FOCUS | March 7, 2008 | LICENSING: Herpes Vaccine Developed at HMS Licensed for Preclinical Trials". http://focus.hms.harvard.edu/2008/030708/licensing.shtml. 
  39. ↑ Brown ZA, Selke S, Zeh J et al.. The acquisition of herpes simplex virus during pregnancy. N Engl J Med. 1997;337:509–515.
  40. ↑ Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L (2003). "Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant". JAMA 289 (2): 203–209. doi:10.1001/jama.289.2.203. PMID 12517231. 
  41. ↑ Brown ZA, Benedetti J, Ashley R et al. (1991). "Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor". N Engl J Med 324: 1247. 
  42. ↑ Whitley RJ, Kimberlin DW, Roizman B (1998). "Herpes simplex viruses". Clin Infect Dis 26 (3): 541–53. doi:10.1086/514600. PMID 9524821. http://www.journals.uchicago.edu/doi/pdf/10.1086/514600. 
  43. ↑ Brown ZA, Benedetti J, Ashley R, et al. (May 1991). "Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor". N. Engl. J. Med. 324 (18): 1247–52. PMID 1849612. 
  44. ↑ "Local anesthetic creams". BMJ 297 (6661): 1468. December 1988. PMID 3147021. 
  45. ↑ Kaminester LH, Pariser RJ, Pariser DM, et al. (December 1999). "A double-blind, placebo-controlled study of topical tetracaine in the treatment of herpes labialis". J. Am. Acad. Dermatol. 41 (6): 996–1001. doi:10.1016/S0190-9622(99)70260-4. PMID 10570387. 
  46. ↑ Leung DT, Sacks SL (October 2003). "Current treatment options to prevent perinatal transmission of herpes simplex virus". Expert Opin Pharmacother 4 (10): 1809–19. doi:10.1517/14656566.4.10.1809. PMID 14521490. 
  47. ↑ 47.0 47.1 Chon T, Nguyen L, Elliott TC (July 2007). "Clinical inquiries. What are the best treatments for herpes labialis?". J Fam Pract 56 (7): 576–8. PMID 17605952. 
  48. ↑ Glenny AM, Fernandez Mauleffinch LM, Pavitt S, Walsh T (2009). "Interventions for the prevention and treatment of herpes simplex virus in patients being treated for cancer". Cochrane Database Syst Rev (1): CD006706. doi:10.1002/14651858.CD006706.pub2. PMID 19160295. 
  49. ↑ Nasser M, Fedorowicz Z, Khoshnevisan MH, Shahiri Tabarestani M (2008). "Acyclovir for treating primary herpetic gingivostomatitis". Cochrane Database Syst Rev (4): CD006700. doi:10.1002/14651858.CD006700.pub2. PMID 18843726. 
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  52. ↑ Hargate G (September 2006). "A randomised double-blind study comparing the effect of 1072-nm light against placebo for the treatment of herpes labialis". Clin. Exp. Dermatol. 31 (5): 638–41. doi:10.1111/j.1365-2230.2006.02191.x. PMID 16780494. 
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  66. ↑ Rooney JF, Straus SE, Mannix ML, et al. (1992). "UV light-induced reactivation of herpes simplex virus type 2 and prevention by acyclovir". J. Infect. Dis. 166 (3): 500–6. PMID 1323616. 
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  68. ↑ Ichihashi M, Nagai H, Matsunaga K (2004). "Sunlight is an important causative factor of recurrent herpes simplex". Cutis 74 (5 Suppl): 14–8. PMID 15603217. 
  69. ↑ Martinez V, Caumes E, Chosidow O (2008). "Treatment to prevent recurrent genital herpes". Curr Opin Infect Dis 21 (1): 42–48. doi:10.1097/QCO.0b013e3282f3d9d3. PMID 18192785. 
  70. ↑ Sobngwi‐Tambekou J, Taljaard D, Lissouba P, et al. (2009). "Effect of HSV‐2 Serostatus on Acquisition of HIV by Young Men: Results of a Longitudinal Study in Orange Farm, South Africa". J Infect Dis 199 (7): 958–964. doi:10.1086/597208. PMID 19220143. 
  71. ↑ Koelle DM, Corey L (2008). "Herpes Simplex: Insights on Pathogenesis and Possible Vaccines". Annu Rev Med 59: 381–395. doi:10.1146/annurev.med.59.061606.095540. PMID 18186706. 
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  73. ↑ Xu, Fujie; Fujie Xu, MD, PhD; Maya R. Sternberg, PhD; Benny J. Kottiri, PhD; Geraldine M. McQuillan, PhD; Francis K. Lee, PhD; Andre J. Nahmias, MD; Stuart M. Berman, MD, ScM; Lauri E. Markowitz, MD (2006-10-23). "Trends in Herpes Simplex Virus Type 1 and Type 2 Seroprevalence in the United States". JAMA (AMA) 296 (8): 964–73. doi:10.1001/jama.296.8.964. PMID 16926356. http://jama.ama-assn.org/cgi/content/full/296/8/964. 
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  76. ↑ Kaufman HE, Howard GM (August 1962). "Therapy of experimental herpes simplex keratitis". Invest Ophthalmol 1: 561–4. PMID 14454441. http://www.iovs.org/cgi/pmidlookup?view=long&pmid=14454441. 
  77. ↑ Ch'ien LT, Whitley RJ, Alford CA, Galasso GJ (June 1976). "Adenine arabinoside for therapy of herpes zoster in immunosuppressed patients: preliminary results of a collaborative study". J. Infect. Dis. 133 Suppl: A184–91. PMID 180198. 
  78. ↑ McKelvey EM, Kwaan HC (November 1969). "Cytosine arabinoside therapy for disseminated herpes zoster in a patient with IgG pyroglobulinemia". Blood 34 (5): 706–11. PMID 5352659. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=5352659. 
  79. ↑ Fiala M, Chow A, Guze LB (April 1972). "Susceptibility of herpesviruses to cytosine arabinoside: standardization of susceptibility test procedure and relative resistance of herpes simplex type 2 strains". Antimicrob. Agents Chemother. 1 (4): 354–7. PMID 4364937. PMC 444221. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=4364937. 
  80. ↑ Allen LB, Hintz OJ, Wolf SM, et al. (June 1976). "Effect of 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate on genital lesions and encephalitis induced by Herpesvirus hominis type 2 in female mice". J. Infect. Dis. 133 Suppl: A178–83. PMID 6598. 
  81. ↑ Juel-Jensen BE (March 1970). "Varicella and cytosine arabinoside". Lancet 1 (7646): 572. doi:10.1016/S0140-6736(70)90815-9. PMID 4190397. 
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  83. ↑ Allen LB, Sidwell RW (September 1972). "Target-organ treatment of neurotropic virus diseases: efficacy as a chemotherapy tool and comparison of activity of adenine arabinoside, cytosine arabinoside, idoxuridine, and trifluorothymidine". Antimicrob. Agents Chemother. 2 (3): 229–33. PMID 4790562. PMC 444296. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=4790562. 
  84. ↑ Allen LB, Wolf SM, Hintz CJ, Huffman JH, Sidwell RW (March 1977). "Effect of ribavirin on Type 2 Herpesvirus hominis (HVH/2) in vitro and in vivo". Ann. N. Y. Acad. Sci. 284: 247–53. doi:10.1111/j.1749-6632.1977.tb21957.x. PMID 212976. 
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  94. ↑ Lists of support groups and events:
  95. ↑ Green J, Ferrier S, Kocsis A, Shadrick J, Ukoumunne OC, Murphy S, Hetherton J. (2003). "Determinants of disclosure of genital herpes to partners.". Sex. Transm. Infect. 79 (1): 42–44. doi:10.1136/sti.79.1.42. PMID 12576613. PMC 1744583. http://sti.bmj.com/cgi/content/full/79/1/42. 

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