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Herpes
Herpes
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Herpes simplex (Template:Lang-grc, lit. "creeping") is a viral disease caused by both herpes simplex virus 1 (HSV-1) and herpes simplex virus 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, infects the face and mouth. Oral herpes is the most common form of infection. Genital herpes, commonly 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 reside as life-long, latent viruses. 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. Twenty percent of the U.S. population has antibodies to HSV-2, although not all of them have a history of genital lesions.^[1]

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. Vaccines are in clinical trials but have not demonstrated effectiveness. Treatments can reduce viral reproduction and shedding, prevent the virus from entering the skin, and alleviate the severity of symptomatic episodes.

Herpes simplex should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster, which is a viral disease caused by varicella zoster virus. There is also a possibility of confusion with hand, foot and mouth disease due to apparition of lesions on the skin.

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.

There is a single report of a systemic infection with HSV-2, where a healthy 28-year old woman with a healthy immune system died 12 days after contracting the virus.^[4]

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.^[5] 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.^[6]

Condition	Description	Illustration
Herpes labialis	Infection occurs when the virus comes into contact with oral mucosa or abraded skin.
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.
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.
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].
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

Association with neuronal disorders

Bell's palsy

In a mouse model, a type of facial paralysis called Bell's palsy has been linked to the presence and reactivation of latent HSV-1 inside the sensory nerves of the face (geniculate ganglia).^[10]^[11] This is supported by findings that show the presence of HSV-1 DNA in saliva at a higher frequency in patients with Bell's palsy relative to those without the condition.^[12]

However, since HSV can also be detected in these ganglia in large numbers of individuals that have never experienced facial paralysis, and high titers of antibodies for HSV are not found in HSV-infected individuals with Bell's palsy relative to those without, this theory has been contested.^[13] In other studies, HSV-1 DNA was not detected in the cerebrospinal fluid of Bell's palsy sufferers, raising questions whether HSV-1 is the causative agent in this type of facial paralysis.^[14]^[15] The potential effect of HSV-1 in the etiology of Bell's palsy has prompted the use of antiviral medication to treat the condition. The benefits of acyclovir and valacyclovir have been studied.^[16] But the effect appears small, if at all detectable.

Alzheimer's disease

Scientists discovered a link between HSV-1 and Alzheimer's disease in 1979.^[17] 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.^[18]^[19] 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.^[20]

A study published in The Journal of Pathology,^[21] has shown a striking localization of herpes simplex virus type 1 DNA within the beta-amyloid plaques that characterize Alzheimer's disease. It suggests that this virus is a major cause of the plaques and hence probably a significant aetiological factor in Alzheimer's disease.

Mechanism

Herpes is contracted through direct contact with an active lesion or body fluid of an infected person.^[22] 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.^{[citation needed]} 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.^[23] 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.^[23] 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.^[24] 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.^[23]

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.^[25] 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.^[26] 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.^[26]

Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical symptoms.^[26] Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection,lichen planus, atopic dermatitis, and urethritis.^[26] 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.^[26]

Serological tests for antibodies to HSV are rarely useful to diagnosis and not routinely used in clinical practice^[26], but are important in epidemiological studies. Serologic assays cannot differentiate between antibodies generated in response to a genital versus or an oral HSV infection, and as such cannot confirm the site of infection. Absence of antibody to HSV-2 does not exclude genital infection, because of the increasing incidence of genital infections caused by HSV-1.

Prevention

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

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^[27] 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.^[5] Topical microbicides which contain chemicals that directly inactivate the virus and block viral entry are being investigated.^[5] 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.^[28]

As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men.^[29] 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%.^[25]^[30] 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.^[30] Suppressive antiviral therapy reduces these risks by 50%.^[31] 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%.^[32]^[33]^[34] Condom use is much more effective at preventing male to female transmission than vice-versa.^[32] The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk.^{[citation needed]} 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.^{[citation needed]}

The risk of transmission from mother to baby is highest if the mother becomes infected at around the time of delivery (transmission risk 30 to 60%),^[35]^[36] but the risk falls to 3% if it is a recurrent infection, and is less than 1% if there are no visible lesions.^[37] 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. HSV-1 being transmitted by oral sex as HSV-2 is not very common but there is always the risk ^[38]^[39] 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.^[5] 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.^[5]

HSV-2 infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons,^[40] particularly during an outbreak with active lesions.^[41]

Treatment

There is no cure that can eradicate herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks. Antiviral drugs also 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.^[23] Non-prescription analgesics can reduce pain and fever during initial outbreaks. Topical anesthetic treatments such as prilocaine, lidocaine or tetracaine can also relieve itching and pain.^[42]^[43]

Antiviral medication

Antiviral medications used against herpes viruses 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 enzyme thymidine kinase to convert the drug sequentially from its prodrug form to monophosphate (with one phosphate group), diphosphate (with two phosphate groups), and finally to the triphosphate (with three phosphate groups) form which interferes with viral DNA replication.^[44]

There are several prescription antiviral medications for controlling herpes simplex outbreaks, such as acyclovir (Zovirax®), valacyclovir (Valtrex®), famciclovir (Famvir®), and penciclovir (Denavir®). Acyclovir was the original, and prototypical, member of this drug class; it is now available in generic brands at a greatly reduced cost. Valaciclovir and famciclovir—prodrugs of acyclovir and penciclovir, respectively—have improved solubility in water and better bioavailability when taken orally.^[44] Acyclovir is the recommended antiviral for suppressive therapy for use during the last months of pregnancy to prevent transmission of herpes simplex to the neonate in cases of maternal recurrent herpes. Benzocaine is a substance in most nonprescription drug medications that can treat cold sores and reduce the severity of the symptoms.^[45] The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context.

Several studies in humans and mice provide evidence that early treatment with famciclovir soon after the first infection with herpes can significantly lower the chance of future outbreaks of herpes. Early use of famciclovir has been shown to reduce the amount of latent virus in the neural ganglia.^[46]^[47]^[48] A review of human subjects treated for five days with famciclovir 250 mg three times daily during their first herpes episode found that only 4.2 percent experienced a recurrence within six months after the first outbreak, a fivefold decrease compared to the 19 percent recurrence in acyclovir-treated patients.^[49] Despite these promising results, early famciclovir treatment for herpes in this or similar dosage regimes has yet to find mainstream adoption. As a result, some doctors and patients have opted for off-label use. One suggested regime is famciclovir at 10–20 mg/kg per day for 5–10 days, with treatment to commence as soon as possible after the first herpes infection (not the first symptoms or outbreak), and the most effective time for initiating treatment to be five days or less after the first herpes infection. However, the window of opportunity for this treatment is only a few months after first infection with the virus, following this the potential effect on latency drops to zero.^[50]

Antiviral medications are also available as topical creams for treating recurrent outbreaks on the lips, although their effectiveness is disputed.^[51] Penciclovir cream has a 7-17 hour longer cellular half-life than aciclovir cream, increasing its effectiveness relative to aciclovir when topically applied.^[52]

Topical treatments

Docosanol, used in many cosmetics as an emollient and barrier ingredient, is also available as an over-the-counter (OTC) drug formula for the treatment of oral herpes simplex outbreaks. It was thought to prevent HSV from fusing to cell membranes, but this has not been proven and it is known that docosanol also enters the cytoplasm of cells. The OTC drug formulation of docosanol is marketed by Avanir Pharmaceuticals under the name Abreva. Abreva was approved for use after clinical trials by the FDA in July 2000.^[53] Abreva was the first over-the-counter antiviral drug approved for sale in the United States and Canada. Research leading to the licensing of Abreva showed that the OTC formula shortened recovery time to a moderate degree. Avanir Pharmaceuticals and GlaxoSmithKline Consumer Healthcare were the subject of a U.S. nationwide class-action suit in March, 2007 due to the misleading claim that it cut recovery times in half.^[54]

There is some limited research that has shown that tea tree oil may have topical anti-viral activity, especially with the Herpes virus^[55]

Other drugs

Cimetidine, a common component of heartburn medication, and probenecid have been shown to reduce the renal clearance of acyclovir.^[56] These compounds also reduce the rate, but not the extent, at which valaciclovir is converted into aciclovir.

Limited evidence suggests that low dose aspirin (125 mg daily) might be beneficial in patients with recurrent HSV infections. Aspirin (acetylsalicylic acid) is an non-steroidal anti-inflammatory drug which reduces the level of prostaglandins—naturally occurring lipid compounds—that are essential in creating inflammation.^[57] A recent study in animals showed inhibition of thermal (heat) stress induced viral shedding of HSV-1 in the eye by aspirin, and a possible benefit in reducing the frequency of recurrences.^[58]

Another treatment is the use of petroleum jelly.^{[citation needed]} Healing of cold sores is sped by barring water or saliva from reaching the sore.

Alternative treatments

Certain dietary adjustments, dietary supplements, and alternative remedies are claimed to be beneficial in the treatment of herpes, either alone, or in conjunction with prescribed antiviral therapy. There is insufficient scientific and clinical evidence to support the effective use of many of these compounds to treat herpes in humans.^[59]

Lysine supplementation has been used for the prophylaxis and treatment of herpes simplex. Lysine shows greater effect against HSV-1 but may not be active against all virus variants. Dosage is critical with less than 1 gram (1000 mg) per day ineffective and more than 8 grams (8000 mg) gaining no additional benefit. Lysine is most effective if corn based products (which contain high amounts of Arginine) such as popcorn are avoided during an outbreak. Lysine treatment is somewhat body mass sensitive with higher dosage required for effective treatment as body mass increases. It should be taken as 3 or more doses in a 24 hour period and should be started when first outbreak symptoms, such as skin numbness or itching, are detected.^[60]^[61]^[62]

Aloe vera, available as a cream or gel, makes an affected area heal faster and may prevent recurrences.^[63]

Lemon balm (Melissa officinalis) has antiviral activity against HSV-2 in cell culture and may reduce HSV symptoms in herpes infected people.^[64]^[65]^[65]

Carrageenans—linear sulphated polysaccharides extracted from red seaweeds—have been shown to have antiviral effects in HSV-infected cells and in mice.^[66]^[67]

There is conflicting evidence on a possible benefit from extracts from the plant echinacea in treating oral^[68], but not genital, herpes.^[69]

Resveratrol, a compound naturally produced by plants and a component of red wine, prevents HSV replication in cultured cells and reduces cutaneous HSV lesion formation in mice. It is not considered potent enough to be an effective treatment on its own.^[70]^[71]

Extracts from garlic have shown antiviral activity against HSV in cell culture experiments, although the extremely high concentrations of the extracts required to produce an antiviral effect was also toxic to the cells.^[72]

The plant Prunella vulgaris, commonly known as selfheal, also prevents expression of both type 1 and type 2 herpes in cultured cells.^[73]

Lactoferrin, a component of whey protein, has been shown to have a synergistic effect with aciclovir against HSV in vitro.^[74]

Some dietary supplements have been suggested to positively treat herpes. These include vitamin C, vitamin A, vitamin E, and zinc.^[75]^[76]

Butylated hydroxytoluene (BHT), commonly available as a food preservative, has been shown in cell culture and animal studies to inactivate herpes virus.^[77]^[78] However, BHT has not been clinically tested and approved to treat herpes infections in humans.

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).^[79]

Many HSV-infected people experience recurrence within the first year of infection.^[5] 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.^[5] 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.^[80] Changes in the immune system during menstruation may play a role in HSV-1 reactivation.^[81]^[82] 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.^[83]^[84]^[85]^[86]^[87]

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.^[88] 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.

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."^[89]

Herpes was not found to be a virus until the 1940s.^[89]

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,^[90] keratitis,^[91] in immunocompromised (transplant) patients,^[92] or disseminated herpes zoster.^[93] The original compounds used were 5-iodo-2'-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C,^[94] later marketed under the name cytosar or cytorabine. The usage expanded to include topical treatment of herpes simplex,^[95] zoster, and varicella.^[96] Some trials combined different antivirals with differing results.^[90] 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 ^[97], trifluorothymidine (TFT)^[98], Ribivarin,^[99] interferon,^[100] Virazole,^[101] and 5-methoxymethyl-2'-deoxyuridine (MMUdR).^[102] The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA acyclovir, in the late 1970s^[103] raised antiviral treatment another notch and led to vidarabine vs. acyclovir trials in the late 1980s.^[104] 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.^[105] 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.^[105] 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.^[105]

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.^[106] 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.^[89] 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 of the Earth's population carries HSV-1, 2, or both.^{[citation needed]} 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."^[107]

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.^[108] 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.

Research

The National Institutes of Health (NIH) in the United States is conducting phase III trials of Herpevac, a vaccine against HSV-2.^[109] 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.^[109] During initial trials, the vaccine did not exhibit any evidence of preventing HSV-2 in males.^[109] 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.^[109] Because about 20% of persons in the United States have HSV-2 infection, this further reduces the population for whom this vaccine might be appropriate.^[109]

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.^[110] 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.^[111]

More importantly, a breakthrough was made by Harvard Medical School's Higgins Professor of Microbiology, Professor David Knipe. His laboratory developed dl5-29, 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. Specifically, Knipe's lab has already 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.^[112] His vaccine is now being researched and developed by Accambis, and is due to be applied as an Investigational New Drug in 2009.^[113]

Another possibility to eradicate the HSV-1 variant is being pursued by Professor Bryan Cullen and his 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.^[114] Professor Cullen believes a drug could be developed to block the microRNA whose job it is to suppress HSV-1 into latency.^[115]

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.^[116] 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.^[117]

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.^[118]

Currently, a vaccine designed to prevent infection is being researched and developed by BioVex. Clinical trials are being conducted at the Chelsea & Westminster Hospital in London. It is thought that the vaccine should be ready in about 2015, if indeed the trials prove successful.^[119]

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^ Ch'ien LT, Whitley RJ, Alford CA, Galasso GJ (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ McKelvey EM, Kwaan HC (1969). "Cytosine arabinoside therapy for disseminated herpes zoster in a patient with IgG pyroglobulinemia". Blood. 34 (5): 706–11. PMID 5352659. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Fiala M, Chow A, Guze LB (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. PMC 444221. PMID 4364937. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Allen LB, Hintz OJ, Wolf SM; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Juel-Jensen BE (1970). "Varicella and cytosine arabinoside". Lancet. 1 (7646): 572. doi:10.1016/S0140-6736(70)90815-9. PMID 4190397. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Nahmias AJ, Kibrick S (1964). "Inhibitory effect of heparin on herpes simplex virus". J. Bacteriol. 87 (5): 1060–6. PMC 277146. PMID 4289440. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Allen LB, Sidwell RW (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. PMC 444296. PMID 4790562. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Allen LB, Wolf SM, Hintz CJ, Huffman JH, Sidwell RW (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Allen LB, Cochran KW (1972). "Target-organ treatment of neurotropic virus disease with interferon inducers". Infect. Immun. 6 (5): 819–23. PMC 422616. PMID 4404669. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK (1972). "Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide". Science (journal). 177 (50): 705–6. PMID 4340949. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Babiuk LA, Meldrum B, Gupta VS, Rouse BT (1975). "Comparison of the antiviral effects of 5-methoxymethyl-deoxyuridine with 5-iododeoxyuridine, cytosine arabinoside, and adenine arabinoside". Antimicrob. Agents Chemother. 8 (6): 643–50. PMC 429441. PMID 1239978. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ O'Meara A, Deasy PF, Hillary IB, Bridgen WD (1979). "Acyclovir for treatment of mucocutaneous herpes infection in a child with leukaemia". Lancet. 2 (8153): 1196. doi:10.1016/S0140-6736(79)92428-0. PMID 91931. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Whitley R, Arvin A, Prober C; et al. (1991). "A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious Diseases Collaborative Antiviral Study Group". N. Engl. J. Med. 324 (7): 444–9. PMID 1988829. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c Kimberlin DW, Lin CY, Jacobs RF; et al. (2001). "Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections". Pediatrics. 108 (2): 230–8. doi:10.1542/peds.108.2.230. PMID 11483782. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Vezina C, Steben M. (2001). "Genital Herpes: Psychosexual Impacts and Counselling" (PDF). The Canadian Journal of CME (June): 125–34.
^
Lists of support groups and events:
^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b ^c ^d ^e "Herpevac Trial for Women". Retrieved 2008-02-25. Cite error: The named reference "titleHerpevac Trial for Women" was defined multiple times with different content (see the help page).
^ "Molecular Therapy - Abstract of article: 801. RNA Gene Therapy Targeting Herpes Simplex Virus".
^ "Potential new herpes therapy studied".
^ http://www.acambis.com/default.asp-id=2052.htm
^ http://focus.hms.harvard.edu/2008/030708/licensing.shtml
^ http://www.reuters.com/article/healthNews/idUSN0229815620080702?pageNumber=2&virtualBrandChannel=0
^ http://www.time.com/time/health/article/0,8599,1819739,00.html
^ http://herpesisnormal.com/
^ "Release", Reuters
^ http://www.vironova.com/webpage.aspx?id=149
^ http://www.timesonline.co.uk/tol/news/uk/health/article7049246.ece

External links

General

Images

Links to genital herpes pictures (Hardin MD/University of Iowa)
Herpes photo library at Dermnet
Pictures of Orofacial Herpes (Coldsores) (Skinsight)
Clinical Pictures of Genital Herpes (Skinsight)
Atlas of Ophthalmology (UoIowa), annotations under "herpes simplex"
Herpes Pictures in Men and Women

Other

[Harrison's-1] Harrison's Principles of Internal Medicine, 16th Ed., Ch. 163, Herpes simplex viruses, Lawrence Corey

[Dickerson2004_Mar_15-2] Dickerson FB, Boronow JJ, Stallings C; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Itzhaki1997_Jan_25-3] Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Southern_Medical_Journal_Jan_1983-4] Whorton CM, Thomas DM, Denham SW (1983). "Fatal systemic herpes simplex virus type 2 infection in a healthy young woman". Southern Medial Journal. 76(1): 81–3. PMID 6297097. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[pmid18156035-5] ^ ^a ^b ^c ^d ^e ^f ^g Gupta R, Warren T, Wald A (2007). "Genital herpes". Lancet. 370 (9605): 2127–37. doi:10.1016/S0140-6736(07)61908-4. PMID 18156035. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Brown1997_Aug_21-6] Brown ZA, Selke S, Zeh J; et al. (1997). "The acquisition of herpes simplex virus during pregnancy". N Engl J Med. 337 (8): 509–15. doi:10.1056/NEJM199708213370801. PMID 9262493. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[7] ttp://emedicine.medscape.com/article/341142-overview eMedicine

[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: 1440–1441. doi:10.1086/592976.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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[19] This research identifies HSVs as the pathogen most clearly linked to the 2001Pyles RB (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. {{cite journal}}: Unknown parameter |month= ignored (help)

[Itzhaki1997-20] Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Itzhaki2008-21] Wozniak MA, Mee AP, Itzhaki RF (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[titleAHMF:_Preventing_Sexual_Transmission_of_Genital_Herpes-22] "AHMF: Preventing Sexual Transmission of Genital herpes". Retrieved 2008-02-24.

[pmid16238897-23] 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.

[24] 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Mertz1993-25] Mertz, G.J. (1993). "Epidemiology of genital herpes infections". Infect Dis Clin North Am. 7 (4): 825–39. PMID 8106731. Cite error: The named reference "Mertz1993" was defined multiple times with different content (see the help page).

[pmid17939933-26] ^ ^a ^b ^c ^d ^e ^f 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.

[Martin-27] 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[28] Seppa, Nathan (2005-01-05). "One-Two Punch: Vaccine fights herpes with antibodies, T cells". Science News. p. 5. Retrieved 2007-03-29.

[29] Carla K. Johnson (August 23, 2006). "Percentage of people with herpes drops". Associated Press.

[Kulhanjian1992-30] 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[Corey2004-31] Corey L, Wald A, Patel R; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Wald-32] 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[Casper-33] Casper C, Wald A. (2002). "Condom use and the prevention of genital herpes acquisition," (PDF). Herpes. 9 (1): 10–14. PMID 11916494.

[Wald2005-34] Wald A, Langenberg AG, Krantz E; et al. (2005). "The relationship between condom use and herpes simplex virus acquisition". Ann Intern Med. 143 (10): 707–13. PMID 16287791. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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[pmid3147021-42] "Local anesthetic creams". BMJ. 297 (6661): 1468. 1988. PMID 3147021.

[pmid10570387-43] Kaminester LH, Pariser RJ, Pariser DM; et al. (1999). "A double-blind, placebo-controlled study of topical tetracaine in the treatment of herpes labialis". J. Am. Acad. Derm. 41 (6): 996–1001. doi:10.1016/S0190-9622(99)70260-4. PMID 10570387. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

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[46] The effects of antiviral therapy on the distribution of herpes simplex virus type 1 to ganglionic neurons and its consequences during, immediately following and several months after treatment"[1]"

[47] Famciclovir and Valaciclovir Differ in the Prevention of Herpes Simplex Virus Type 1 Latency in Mice: a Quantitative Study"[2]"

[48] Persistence of Infectious Herpes Simplex Virus Type 2 in the Nervous System in Mice after Antiviral Chemotherapy"[3]"

[49] Observation May Indicate A Possible Clinical Effect On Latency"[4]"

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[pmid9134943-52] Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R (1997). "Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group". JAMA. 277 (17): 1374–9. doi:10.1001/jama.277.17.1374. PMID 9134943.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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[55] Bishop, C.D. (1995). "Anti-viral Activity of the Essential Oil of Melaleuca alternifolia". Journal of Essential Oil Research: 641–644.

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[Zacharopoulos-66] Zacharopoulos VR, Phillips DM. (1997). "Vaginal formulations of carrageenan protect mice from herpes simplex virus infection". Clin. Diagn. Lab. Immunol. 4 (4): 465–468. PMID 9220165.

[Carlucci-67] Carlucci MJ, Scolaro LA, Damonte EB. (1999). "Inhibitory action of natural carrageenans on Herpes simplex virus infection of mouse astrocytes". Chemotherapy. 45 (6): 429–436. doi:10.1159/000007236. PMID 10567773.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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v t e Sexually transmitted infections (STI)
Bacterial	Chancroid (Haemophilus ducreyi) Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) Donovanosis (Klebsiella granulomatis) Gonorrhea (Neisseria gonorrhoeae) Mycoplasma hominis infection (Mycoplasma hominis) Syphilis (Treponema pallidum) Ureaplasma infection (Ureaplasma urealyticum)
Protozoal	Trichomoniasis (Trichomonas vaginalis)
Parasitic	Crab louse Scabies
Viral	AIDS (HIV-1/HIV-2) Cancer cervical vulvar penile anal Human papillomavirus (HPV) Genital warts (condyloma) Hepatitis B (Hepatitis B virus) Herpes simplex HSV-1 & HSV-2 Molluscum contagiosum (MCV) Zika fever (Zika virus)
General inflammation	female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU)