Herpes simplex

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Genital herpes is a chronic, life-long viral infection. Two types of HSV have been identified as causing genital herpes: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and at least 50 million people in the United States are infected with this type of genital herpes.^[1] Nationwide, 16.2%, or about one out of six, people 14 to 49 years of age have genital HSV-2 infection. Over the past decade, the percentage of Americans with genital herpes infection has remained stable. Genital HSV-2 infection is more common in women (approximately one out of five women 14 to 49 years of age) than in men (about one out of nine men 14 to 49 years of age). Transmission from an infected male to his female partner is more likely than from an infected female to her male partner.^[2]

Although many people infected with HSV develop labial or genital lesions, many more are either not diagnosed or display no physical symptoms. Individuals with no symptoms are described as being asymptomatic or as having subclinical herpes.^[3] Since asymptomatic individuals are often are unaware of their infection, they are considered at high risk for spreading HSV. Many studies have been performed around the world to estimate the numbers of individuals infected with HSV-1 and HSV-2 by determining if they have developed antibodies against either viral species.^[4] This information provides population prevalence of HSV viral infections in individuals with or without active disease.

Large differences in HSV-1 seroprevalence are observed across Europe. HSV-1 seroprevalence is high in Bulgaria (83.9%) and the Czech Republic (80.6%), but lower in Belgium (67.4%), the Netherlands (56.7%), and Finland (52.4%).^[7] The typical age at which HSV-1 infection is acquired ranges from 5–9 years in Eastern European countries like Bulgaria and the Czech Republic to over 25 years of age in Northern European countries such as Finland, the Netherlands, Germany, and England and Wales. Young adults in Northern European countries are less likely to be infected with HSV-1. However, European women are more likely to be HSV-1 seropositive than men.^[7]

HSV-2 seropositivity is widely distributed in Europeans older than 12, although there are large differences in the percentage of the population that had been exposed to HSV-2. Bulgaria has a high (23.9%) HSV-2 seroprevalence relative to other European countries: Germany (13.9%), Finland (13.4%), Belgium (11.1%),the Netherlands (8.8%), the Czech Republic (6.0%) and England and Wales (4.2%).^[7] Women are more likely to be seropositive than men, and likely acquire the virus at an earlier age. In each country of Europe, HSV-2 seropositivity becomes more common from adolescence onward and increases in the population with age, with a decline in the older age groups in some countries.^[7]

United States

In healthy adults, HSV-2 infection occurs more frequently in the USA than in Europe, and appears to be increasing; in individuals over 12 years old, HSV-2 seroprevalence has increased from 16.4% in 1976 to 21.8% from in 1994 and is still rising.^[8] Thus, the current incidence of genital herpes caused by HSV-2 in the U.S. is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year.^[9] African Americans appear to be more susceptible to HSV-2, although the presence of active genital symptoms are more likely to be observed in Caucasian Americans. The largest increase in HSV-2 acquisition during the past few years has been observed in white adolescents. People with many lifetime sexual partners and those who are sexually active from a young age are also at a higher risk for the transmission of HSV-2 in the U.S.^{[10][11][12][13]} Women are at a higher risk than men for acquiring HSV-2 infection, and the chance of being infected increases with age.^[9]

African Americans and immigrants from developing countries typically have an HSV-1 seroprevalance in their adolescent population that is two or three times higher than that of Caucasian Americans, possibly reflecting differences in their socioeconomic backgrounds. ^[9] Many white Americans enter sexual activity, marriage and child bearing years seronegative for HSV-1. The absence of antibodies from a prior oral HSV-1 infection leaves these individuals susceptible to primary HSV-1 genital infections. This brings with it a risk of vertical transmission to the neonate if the mother contracts a primary infection during the third trimester of pregnancy. A seronegative mother has up to a 57% chance of conveying an HSV infection to her baby during childbirth whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant.^[14] Women that are seropositive for only one type of HSV fall somewhere in between but are still only half as likely to transmit HSV as the seronegative mother. Genital infection caused by HSV-1, in the U.S. is now thought to be about 50%^{[15] [16]}and contributes to a rate of 6 to 20 cases of neonatal herpes per 100,000 live births in the U.S. depending on region and demographics. ^[17][18]

Canada

Following a study in Ontario, up to 55% of Canadians age of 15 to 16, and 89% of individuals in their early forties are estimated have antibodies to HSV-1. Teenagers are less likely to be seropositive for HSV-2; antibodies against this virus are only found in 0-3.8% of 15-16 year old adolescents. However, 21% of individuals in their early forties have antibodies against HSV-2 reflecting the sexually transmitted nature of this virus. When standardising for age, HSV-2 seroprevalence in Ontario, for individuals between the ages of 15 to 44, was 9.1%. This is much lower than estimated levels of HSV-2 seroprevalence in people of a similar age range in the United States.^[19] HSV-2 seroprevalence in pregnant women, between the ages of 15-44, in British Columbia is similar, with 57% having antibodies for HSV-1 and 13% having antibodies for HSV-2.^[4]

Sub-Saharan Africa

HSV-2 in more common in some countries, such as those of Sub-Saharan Africa, than in Europe or the North America. Up to 82% of women, and 53% of men in Sub-Saharan Africa are seropositive for HSV-2 (see table), representing the highest levels of HSV-2 infection in the world, although exact levels vary from country to country in this continent.^[20] In most African countries, HSV-2 prevalence increases with age. However, age-associated decreases in HSV-2 seroprevalence has been observed for women in Uganda and Zambia, an in men in Ethiopia, Benin, and Uganda.^[4]

Northern Africa

Genital herpes appears less common in Northern Africa compared to Sub-Saharan Africa, with only 26% of middle-aged women having antibodies for HSV-2 in Morocco.^[5] Woman are more likely to be infected with HSV-2 once they are over the age of 40.^[5] Children in Egypt are often infected with HSV from a young age; HSV-1 or HSV-2 antibodies are estimated in 54% in children under the age of 5 years and 77% in children over 10 years of age.^[21] Algerian children are also likely to acquire HSV-1 infection at a young age (under 6) and 81.25% of the population has antibodies to HSV-1 by the age of 15.^[22]

HSV-2 seroprevalency is high in Central and South America, relative to rates in Europe and North America with levels estimated between 20-60%.^[4][20] During the mid 1980s, HSV-2 prevalence was 33% in 25–29 years old women and 45% in those aged 40 and over in Costa Rica, and, in the early 1990s, was approximately 45% among women over 60 in Mexico.^[4] The highest HSV-2 prevalence (60%) in Central or South America has been found Colombian middle-aged women although similar HSV-2 prevalence (54%) has been observed in younger women in Haiti.^[4] HSV-2 infects about 30% in women more than 30 years old from Colombia, Costa Rica, Mexico, and Panama and steadily increases to 52% in an age-associated manner in those aged 50–59. HSV-2 antibodies were found in more than 41% of women of childbearing age in Brazil.^[4] However, no increase in seroprevalence was associated with age in women over 40 years old in this country – HSV-2 prevalence was estimated at 50% among women aged 40–49 years, 33% among women 50–59, and 42% among women over 60. Women in Brazil are more likely to acquire an HSV-2 infection if their male partners had history of anal sex and had many sexual partners in his lifetime.^[5] In Peru, HSV-2 prevalence is also high among women in their 30s but is lower in men.^[4]

Eastern and South East Asia

HSV-2 seroprevalence in developing Asian countries is comparable (10-30%) to that observed in North America and Northern Europe.^[20] HSV-1 seroprevalence in some Asian countries is low, relative to other countries worldwide, with only 51% women in Thailand and between 50-60% in Japan possessing antibodies against this virus.^[5][4] However, estimates of HSV-2 infectivity, in Thailand, is higher than observed in other Eastern Asian countries – total HSV-2 seroprevalence is approximately 37% in this country.^[5] HSV-2 seroprevalence is low in women in the Philippines (9%), although commencing activity while young is associated with an increase risk of acquiring HSV-2 infection; woman starting sexual activity by the time they reach 17 are seven times more likely to be HSV-2 seropositive that those starting sexual activity when over 21.^[23] In South Korea, incidence of HSV-2 infection in those under the age of 20 is low at only 2.7% in men and 3.0% in women.^[6] Seroprevalence levels increase in older South Koreans, however, such that the population over 20 that has antibodies against HSV-2 is 21.7% of men and 28% of women, with increasing HSV-2 prevalence becoming significant once individuals reached their 30’s.^[6]

Southern Asia

In India, 33.3% of individual are seropositive for just HSV-1 and 16.6% are seropositive for only HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. Indian men are more likely to be infected with HSV-2 than women, and increasing seroprevalence of this virus is associated with an increasing age.^[24]

Middle East

High levels of HSV-2 (42%) and HSV-1 (97%) were found amongst pregnant women in the city of Erzurum in Eastern Anatolia Region, Turkey.^[4] In Istanbul, a city in the Marmara Region in North West Turkey, however, lower HSV-2 seroprevalence was observed; HSV-2 antibodies were found in 4.8% of sexually active adults, and HSV-1 antibodies were found in 85.3%.^[25] Only 5% of pregnant women were infected with HSV-2, and 98% were infected with HSV-1. Prevalence of these viruses was higher in sex workers of Istanbul, reaching levels of 99% and 60% for HSV-1 and HSV-2 prevalence respectively.^[25] The prevalence of HSV-2 in Jordan is 52.8% for men and 41.5% for women.^[26] HSV-1 seroprevalence is 59.8% in the population of Israel and increases with age in both genders. An estimated 9.2% of Israelian adults are infected with HSV-2. Infection of either HSV-1 or HSV-2 is higher in females; HSV-2 seroprevalence reaches 20.5% in females in their 40s. These values are similar to levels in HSV infection in Europe.^[27] Antibodies for HSV-1 or HSV-2 are also more likely to be found individuals born outside of Israel, and individuals residing in Jerusalem and Southern Israel. People from jewish origin, living in Israel, are less likely to possess antibodies against herpes.^[27] HSV-1 causes 66.3% of genital herpes in individuals living in Tel Aviv, Israel.^[28] Genital herpes infection from HSV-2 is predicted to be low in Syria although HSV-1 levels are high. HSV-1 infections is common (95%) among healthy Syrians over the age of 30, whilst HSV-2 prevalence is low in healthy individuals (0.15%), and persons infected with other sexually transmitted diseases (9.5%). High risk groups for acquiring HSV-2, in Syria, include prostitutes and bar girls that have 34% and 20% seroprevalence respectively.^[29]

In Australia, the seroprevalence of HSV-1 is 76%, with differences associated with age, gender and Indigenous status.^[30] An estimated 12% of Australian adults are seropositive for HSV-2, with higher prevalence in women (16%) than in men (8%).^[30] Larger cities have higher HSV-2 seroprevalence (13%) than rural populations (9%) in this country. Higher prevalence is found in Indigenous Australians (18%) than non-Indigenous Australians (12%) but is lower than HSV-2 prevalence observed in the United States.^[30] As in the U.S., HSV-1 is increasingly identified as the cause of genital herpes in Australians; HSV-1 was identified in the anogenital area of only 3% of the population in 1980, but had risen to 41% in 2001.^[31] This was most common in females and persons under 25.^[31]

The number of genital herpes infections appears to be rising in New Zealand with three times more cases in 1993 compared to 1977.^[32] In this country, HSV-2 affects 60% more women than men of similar age.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Lakshmi Gopalakrishnan, M.B.B.S.

HSV asymptomatic shedding occurs at some time in most individuals infected with herpes.

• Asymptomatic shedding can occur more than a week before or after a symptomatic recurrence in 50% of cases. However, it is believed to occur on 2.9% of days while on antiviral therapy, versus 10.8% of days without, and is estimated to account for one-third of the total days of viral shedding.^[1]

• Asymptomatic shedding is more frequent within the first 12 months after acquiring HSV, and concurrent infection with HIV also increases the frequency and duration of asymptomatic shedding.^[2]

• There are some indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified. No significant differences are observed between the frequency of asymptomatic shedding in people with 1 to 12 annual recurrences versus those with no recurrences.^[1]

Aciclovir, famciclovir, and valaciclovir appear equally effective for episodic treatment of genital herpes and also aid in the suppression of symptomatic and asymptomatic viral shedding. Antiviral therapy has shown to reduce asymptomatic HSV shedding by about 80% to 90% in clinical trials. Although the threshold for infection from asymptomatic shedding has not been established, small studies have shown that valaciclovir appears to suppress asymptomatic shedding better than famciclovir. Acyclovir (400 mg twice daily) has been shown to suppress asymptomatic shedding at least as well as valaciclovir (1000 mg daily).^{[3][4][5][6][7][8]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Lakshmi Gopalakrishnan, M.B.B.S.

Genital herpes can cause recurrent painful genital sores in many adults, and herpes infection can be severe in patients with suppressed immune systems. It is important that women avoid contracting herpes during pregnancy because a newly acquired infection during late pregnancy poses an increased risk of transmission to the baby. If a woman has active genital herpes at delivery, a cesarean delivery is usually indicated. Patients infected with herpes are more susceptible to HIV infection; hence, herpes may indirectly play a role in the spread of HIV.

• Following active infection, herpes viruses become quiescent to 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 cell nucleus of a nerve’s cell body.

• HSV latency is static, during which no virus is produced and is controlled by a number of viral genes including Latency Associated Transcript (LAT).^[1]

The causes of reactivation from latency are uncertain but several potential triggers have been documented.

• Physical or psychological stress can trigger an outbreak of herpes.^[2]

• Local injury to the face, lips, eyes or mouth, trauma, surgery, wind, radiotherapy, ultraviolet light or sunlight are well established triggers.^{[3][4][5][6][7]}

• Some studies suggest changes in the immune system during menstruation may play a role in HSV-1 reactivation.^[8][9]

• In addition, concurrent infections such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks, hence the historic terms “cold sore” and “fever blister.”

• The frequency and severity of recurrent outbreaks may vary greatly depending upon the individual.

• Outbreaks may occur at the original site of the infection or in close proximity to nerve endings that reach out from the infected ganglia.

• In the case of a genital infection, sores can appear near the base of the spine, the buttocks, back of the thighs, or they may appear at the original site of infection.

• Immunocompromised individuals may experience episodes that are longer, more frequent, and more severe.

• Saline bathing, vaseline, analgesia, 5% lidocaine ointment may be generally advised.

• Antiviral medication has been proven to shorten the duration and/or frequency of the outbreaks.^[10]

• You can read more in detail about the episodic and suppressive antiviral treatment for the management of HSV recurrence here.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Usama Talib, BSc, MD [3]

Herpes simplex infection can be symptomatic or asymptomatic. If left untreated herpes simplex can become recurrent. Neonatal herpes infection is a rapidly progressive disease resulting in CNS disease and disseminated disease. Clinical presentation of herpes initially include vesicular skin rash. Early diagnosis and treatment with acyclovir prevents the progression of disease. If left untreated the infection can rarely progress to involve the CNS and other organ systems. Involvement of CNS presents with irritability, confusion and respiratory difficulty. Disseminated disease may result in rare cases. CNS disease can have residual neurological deficits. Other complications include pneumonia, esophagitis, encephalitis, premature birth, spontaneous abortion and death of the infant. Babies can have developmental delay and death.^[1]The prognosis is good for herpes skin infections in immunocompetent individuals. The use of acyclovir has reduced mortality in CNS and disseminated disease but the overall prognosis is poor in immunocompromized and infants.^[2][3]

If left untreated herpes simplex can become recurrent. Neonatal herpes infection is a rapidly progressive disease resulting in CNS disease and disseminated disease. Clinical presentation of herpes initially include vesicular skin rash. Early diagnosis and treatment with acyclovir prevents the progression of disease. If left untreated the infection can rarely progress to involve the CNS and other organ systems. Involvement of CNS presents with irritability, confusion and respiratory difficulty. Disseminated disease may result in rare cases. CNS disease can have residual neurological deficits. Babies can have developmental delay and death.^[1][4]

Individuals with HIV or other immunocompromized patients are at a higher risk of complications of HIV. The complications of herpes simplex infection include: ^[5][6][7][8]

• Recurrent painful genital sores

• Severe infection in immunocompromized

• Psychological distress

• Prematurity

• Spontaneous abortion

• Developmental delay

• Laryngitis

• Genital HSV can be fatal infections in babies

• Increased susceptibility to HIV infections

• Pneumonia

• Esophagitis

• Encephalitis

• Meningoencephalitis

• Hepatitis

• Damaged adrenals

• The prognosis is good for herpes skin infections in immunocompetent individuals.
• The use of acyclovir has reduced mortality in CNS and disseminated disease but the overall prognosis is poor in immunocompromized and infants.^[2][9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Primary orofacial herpes is readily identified by clinical examination in persons without a previous history of lesions, and with reported contact with an individual with known HSV-1 infection. The appearance and distribution of sores, in these individuals, typically presents as multiple, round, and superficial oral ulcers, accompanied by acute gingivitis.^[1] Adults with non-typical presentation are more difficult to diagnose. However, prodromal symptoms that occur before the appearance of herpetic lesions helps to differentiate HSV symptoms from the similar symptoms of, for example, allergic stomatitis. Occasionally, when lesions do not appear inside the mouth, primary orofacial herpes is mistaken for a bacterial infection known as impetigo. Common mouth ulcers (aphthous ulcer), also resemble intraoral herpes, but do not present a vesicular stage.^[1]

Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical signs and symptoms.^[1] To confuse diagnosis, several other conditions resemble genital herpes, including lichen planus, atopic dermatitis, or urethritis.^[1] Laboratory testing is, therefore, often used to confirm genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, polymerase chain reaction (PCR) to test for presence of viral DNA. A Tzanck test (or smear) can also be performed, although this cannot differentiate between herpes simplex or varicella (chicken pox) (the primary infection of varicella zoster virus (VZV or shingles). Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.^[1] Serological tests for antibodies to HSV are rarely useful to diagnosis but are important in epidemiological studies. Serologic assays cannot differentiate between antibodies generated in response to a genital versus 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. For these reasons and the diagnostic delay; serology is not routinely used in clinical practice.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3], Lakshmi Gopalakrishnan, M.B.B.S.

Antiviral therapy is the mainstay of management for genital herpes. Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat either first clinical and recurrent episodes, or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that three antiviral medications (Acyclovir, Valacyclovir, and Famciclovir) provide clinical benefit for genital herpes.^{[1][2][3][4][5][6][7][8][9]} Topical therapy with antiviral drugs offers minimal clinical benefit; its use is discouraged.

Currently, there is no treatment that can eradicate any of the herpes viruses from the body. Supportive treatment includes non-prescription analgesics and topical anesthetic treatment (such as Prilocaine, Lidocaine, or Tetracaine) for itching and pain.^[10][11] Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is an integral part of clinical management.

• Docosanol prevents herpes simplex virus from fusing to cell membranes, thus barring the entry of the virus into the skin.
• It was approved for use after clinical trials by the FDA in July 2000.^[12]
• It was the first over-the-counter antiviral drug approved for sale in the United States and Canada

• Tromantadine is available as a gel that inhibits entry and spreading of the virus by altering the surface composition of skin cells and inhibiting release of viral genetic material.

• It is a topical analgesic barrier treatment, which forms a “shield” at the area of application to prevent a sore from increasing in size and decreases viral spreading during the healing process.

Cimetidine commonly used in heartburn, has been shown to lessen the severity of herpes zoster outbreaks in several different instances, and offered some relief from herpes simplex.

• Vaseline or any other type of fat prevents water or saliva from reaching the cold sore. Since water helps in perpetuation of the cold sore, preventing water exposure will hasten the healing process.^[13][14][15] This is an off-label use of the drug. It and Probenecid have been shown to reduce the renal clearance of aciclovir.^[16] These compounds also reduce the rate, but not the extent, at which Valacyclovir is converted into Acyclovir.

• Low doses of Aspirin (125 mg daily) have shown to be beneficial in patients with recurrent HSV infections. However, there is a lack of sufficient supporting evidence.

• It reduces the level of the inflammatory mediators Prostaglandins ^[17]
• 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.^[18]

• The sex partners of patients who have genital herpes can benefit from evaluation and counseling.
• Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions.
• Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection.

• Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical.
• HSV shedding is increased in HIV-infected persons. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs.^[19]
• Clinical manifestations of genital herpes might worsen during immune reconstitution after initiation of antiretroviral therapy.
• Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive persons. ^[20][21]
• The extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. HSV type-specific serologies can be offered to HIV-positive persons during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection.

• Acyclovir, Valacyclovir, and Famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of genital herpes. For severe HSV disease, initiating therapy with acyclovir 5–10 mg/kg IV every 8 hours might be necessary.

• If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing (184). Such persons should be managed in consultation with an HIV specialist, and alternate therapy should be administered.

• All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet, 40 mg/kg IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. IntravenousCidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days.

• Clinical management of antiviral resistance remains challenging among HIV-infected patients, and other preventative approaches might be necessary. However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy with outbreaks.^[22]

• Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes.^[23] *The risk for transmission to the neonate from an infected mother is high (30%–50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy.^[24]

• However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial. *Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. *Because the risk for herpes is high in infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with an infectious disease specialist.

• Women without known genital herpes should be counseled to abstain from intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to abstain from receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes.

• Some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy and that such testing should be offered to uninfected women whose sex partner has HSV infection.

• However, the effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women by infected partners has not been studied.

• All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions.* Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Although cesarean section does not completely eliminate the risk for HSV transmission to the infant, women with recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to prevent neonatal HSV infection.

• The safety of systemic Acyclovir, Valacyclovir, and Famciclovir therapy in pregnant women has not been definitively established. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester^[25]findings that provide assurance to women who have had prenatal exposure to acyclovir. However, data regarding prenatal exposure to Valacyclovir and Famciclovir are too limited to provide useful information on pregnancy outcomes. *Acyclovir can be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection.

• Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term^[26][27]); the effect of antiviral therapy late in pregnancy on the incidence of neonatal herpes is not known.

• No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes.

• Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious disease specialist.
• Surveillance cultures of mucosal surfaces to detect HSV infection might be considered before the development of clinical signs of neonatal herpes. In addition, administration of acyclovir might be considered for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants. All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir.
• The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

The National Institutes of Health (NIH) in the United States is currently in the midst of phase III trials for a vaccine against HSV-2, called Herpevac.^[1] 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.^[1] During initial trials, the vaccine did not exhibit any evidence of the prevention of HSV-2 in males.^[1] 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.^[1] Because about 20% of people in the United States have HSV-2 infection, this further reduces the population for whom this vaccine might be appropriate.^[1]

• The most effective way to avoid the transmission of sexually transmitted diseases, including genital herpes, is to abstain from sexual contact, or to be in a long-term and mutually monogamous relationship with a partner who has been tested and is known to be uninfected.

• Genital ulcer diseases can occur in both male and female genital areas that are covered or protected by a latex condom, as well as in areas that are not covered. Correct and consistent use of latex condoms can reduce the risk of genital herpes.

• People with herpes should abstain from sexual activity with uninfected partners when lesions or other symptoms of herpes are present. It is important to know that even if a person does not have any symptoms he or she can still infect sex partners.

• Sex partners of infected persons should be advised that they may become infected and they should use condoms to reduce the risk of infection.

• Sex partners can seek testing to determine if they are infected with HSV. A positive HSV-2 blood test most likely indicates a genital herpes infection.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Usama Talib, BSc, MD [3]

Herpes simplex infection can be symptomatic or asymptomatic. If left untreated herpes simplex can become recurrent. Neonatal herpes infection is a rapidly progressive disease resulting in CNS disease and disseminated disease. Clinical presentation of herpes initially include vesicular skin rash. Early diagnosis and treatment with acyclovir prevents the progression of disease. If left untreated the infection can rarely progress to involve the CNS and other organ systems. Involvement of CNS presents with irritability, confusion and respiratory difficulty. Disseminated disease may result in rare cases. CNS disease can have residual neurological deficits. Other complications include pneumonia, esophagitis, encephalitis, premature birth, spontaneous abortion and death of the infant. Babies can have developmental delay and death.^[1]The prognosis is good for herpes skin infections in immunocompetent individuals. The use of acyclovir has reduced mortality in CNS and disseminated disease but the overall prognosis is poor in immunocompromized and infants.^[2][3]

If left untreated herpes simplex can become recurrent. Neonatal herpes infection is a rapidly progressive disease resulting in CNS disease and disseminated disease. Clinical presentation of herpes initially include vesicular skin rash. Early diagnosis and treatment with acyclovir prevents the progression of disease. If left untreated the infection can rarely progress to involve the CNS and other organ systems. Involvement of CNS presents with irritability, confusion and respiratory difficulty. Disseminated disease may result in rare cases. CNS disease can have residual neurological deficits. Babies can have developmental delay and death.^[1][4]

Individuals with HIV or other immunocompromized patients are at a higher risk of complications of HIV. The complications of herpes simplex infection include: ^[5][6][7][8]

• Recurrent painful genital sores

• Severe infection in immunocompromized

• Psychological distress

• Prematurity

• Spontaneous abortion

• Developmental delay

• Laryngitis

• Genital HSV can be fatal infections in babies

• Increased susceptibility to HIV infections

• Pneumonia

• Esophagitis

• Encephalitis

• Meningoencephalitis

• Hepatitis

• Damaged adrenals

• The prognosis is good for herpes skin infections in immunocompetent individuals.
• The use of acyclovir has reduced mortality in CNS and disseminated disease but the overall prognosis is poor in immunocompromized and infants.^[2][9]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Lakshmi Gopalakrishnan, M.B.B.S.

Counseling of infected persons and their sex partners is critical to the management of genital herpes.

• The goals of counseling include 1) helping patients cope with the infection and 2) preventing sexual and perinatal transmission.
• Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides.
• Multiple resources, including websites (http://www.ashastd.org) and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling.

Since there is currently no cure for herpes, some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Though these feelings lessen over time, they can include depression, fear of rejection, feelings of isolation, fear of being found out, self-destructive feelings, and fear of masturbation.^[1] In order to improve the well-being of people with herpes, support groups have been formed in the United States and the UK, providing supporting communities and information about herpes of message forums and dating websites.^{[2][3][4][5][6]}

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 that they consider ‘casual’.^[7] 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 choose not to disclose their herpes status when they first begin dating someone, but wait until it later becomes clear that they are moving towards a sexual relationship. Other people disclose their herpes status upfront. Still others choose only to date other people who already have herpes.

• Persons who have genital herpes should be educated concerning the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission.

• Persons experiencing a first episode of genital herpes should be advised that suppressive therapy is available and effective in preventing symptomatic recurrent episodes and that episodic therapy often is useful in shortening the duration of recurrent episodes.

• All persons with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.

• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.

• All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.

• The risk for HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person. Episodic therapy does not reduce the risk for transmission and its use should be discouraged for this purpose among persons whose partners might be at risk for HSV-2 acquisition.

• Infected persons should be informed that male latex condoms, when used consistently and correctly, might reduce the risk for genital herpes transmission.^[8][9][10]

• Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of the asymptomatic partners of persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists.
• The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy and those who will care for their newborn infant about their infection. Pregnant women who are not known to be infected with HSV-2 should be advised to abstain from intercourse with men who have genital herpes during the third trimester of pregnancy. Similarly, pregnant women who are not known to be infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (e.g., oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).
• Asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection. In addition, such persons should be educated about the clinical manifestations of genital herpes.
• When exposed to HIV, HSV-2 seropositive persons are at increased risk for HIV acquisition. Patients should be informed that suppressive antiviral therapy does not reduce the increased risk for HIV acquisition associated with HSV-2 infection.^[11][12]

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