Background Information

For more information, see the monograph:

Genital and Orofacial Herpes Simplex Virus Infections - Clinical Implications of Latency

• All herpesviruses persist for the lifetime of the human host they infect

• Herpesviruses exist in two forms:
  - an active, replicative form in which whole progeny (daughter) viruses are made
  - a latent or dormant form in which only a few virus proteins are made and the virus is metabolically inactive

• Herpesviruses usually destroy the cells they infect. However, during an initial infection, the virus will also establish latency within a living cell

• Herpes simplex virus (HSV) replication in the oral or genital mucosa results in infection of the sensory nerve endings. Virus is then transported up the nerve to the neuronal cell nuclei in the sensory ganglia. Latency is established after a brief period of virus replication. Latent virus does not replicate, therefore, drugs designed to stop virus replication will not exert an effect on latent virus

Molecular Basis of Latency
Virus genome

• Virus replication involves the expression of three classes of genes, immediate early (alpha), early (beta) and late (gamma). Replication begins when one of the alpha genes interacts with a cellular transcription factor to induce five alpha genes. These genes induce beta genes, and eventually gamma genes are expressed

• During the maintenance stage of latency, virus a gene expression is blocked

• The only virus expression found in sensory neurones are ribonucleic acids (RNAs) referred to as latency-associated transcripts (LATs). The understanding of how LATs work is incomplete and there are two theories:
  - LATs are thought to suppress the expression of one of the alpha genes, alpha0, to maintain the HSV genome in a transcriptionally inert, latent state
  - Two proteins, Open Reading Frame-P (ORF-P) and Open Reading Frame-O (ORF-O), are antisense to gamma1 34.5, which is essential for virus multiplication. Proteins encoded in ORF-P, ORF-O and possibly other ORFs from the same region, are transcribed during latency, bind alone or in combination with cellular proteins to virus DNA, and block transcription of alpha genes.

Role of Host Response in Maintaining Latency

• The role of the host immune response, in maintaining latency is unclear

• How the virus avoids detection by host immunity during latency is also unclear.
  
  

For more information, see the monographs:

	The Medical Importance of Genital HSV infection
	Genital and Orofacial Herpes Simplex Virus Infections - Clinical Implications of Latency

Natural History

• There are two types of HSV: HSV-1 and HSV-2. HSV-1 is the most common cause of orolabial herpes (cold sores), while HSV-2 is the most common cause of genital herpes

• Genital HSV infection is transmitted through contact with infectious virus on oral, genital or mucosal surfaces and can be transmitted in the absence of symptoms (asymptomatic virus shedding)

• After initial infection with HSV, the virus undergoes a period of latency. The person with HSV infection usually experiences clinical recurrences or asymptomatic virus reactivation episodes throughout their life

• A primary episode of genital HSV-2 infection (i.e. infection in an individual with no HSV-1 or -2 antibodies) can have painful and distressing symptoms for more than 2 weeks. The manifestations typically include genital lesions, pain, itching, dysuria, vaginal or urethral discharge and systemic symptoms

• Clinical symptoms and manifestations of recurrent genital herpes are generally less severe, more localized and of a shorter duration than symptoms of primary infection

• Limited evidence suggests that recurrences decrease in severity and frequency over time, but this can take many years

• The chronic nature of genital HSV infection, combined with its lack of predictability, means that many patients suffer persistent psychosexual or psychosocial distress

• Primary episodes of genital HSV-1 and HSV-2 infection are indistinguishable. However, the recurrence rate of genital HSV-1 infection is lower than for genital HSV-2 infection. This difference has implications for counselling and treatment

• Atypical manifestations of genital HSV infection are common and physicians should consider genital HSV infection in any patient presenting with lesions below the waist

• Atypical manifestations of genital HSV-2 infections can lead to recurring symptoms being misdiagnosed as, for example, cystitis, candidiasis or neuralgia.

Asymptomatic virus shedding

• HSV can be shed in the absence of signs or symptoms of infection (asymptomatic virus shedding)

• Asymptomatic HSV shedding can take place from multiple sites and is more common with HSV-2 infection than with HSV-1 infection

• Asymptomatic shedding occurs in two forms:
  - HSV reactivation on an inapparent mucosal site such as the cervix or perianal area
  - Virus shedding from unrecognized, small, asymptomatic lesions, e.g. fissures, on genital surfaces

• Asymptomatic HSV shedding is common, appears to occur in nearly all HSV-2 seropositive individuals, and accounts for 1/3 of the total days with reactivation of genital HSV infection

• Asymptomatic virus shedding is detected in men and women although it occurs at a higher rate in women. It is most common immediately prior to, or following, clinical recurrences of HSV infection

• Epidemiological studies suggest that most HSV-2 transmission to sexual partners and neonates occurs during episodes of asymptomatic virus shedding.

Unrecognized infections

• Genital herpes is under-diagnosed. The key contributors to this lack of recognition are:
  - high proportion of asymptomatic and unrecognized infection:
  - wide range of symptoms and clinical presentations

• It is estimated that 80% of all HSV-2 infections are unrecognized:
  - 60% of symptomatic HSV-2 infections are undiagnosed
  - 20% of HSV-2 infections are truly asymptomatic

• Most individuals (2/3) who are seropositive for HSV-2 have no history of clinical recurrences. However, when educated about clinical symptoms and what lesions look like and can feel like, the majority can recognize subsequent herpes outbreaks.

Diagnosis

• Prompt and accurate diagnosis allows:
  - effective treatment to alleviate symptoms
  - a potential impact on neonatal herpes by identifying those most at risk of acquiring HSV infection late in pregnancy
  - identification of those at greater risk of acquisition of HIV infection

• For any individual, it should be determined whether or not testing is of potential value for their management. Once it has been decided testing will be conducted, pre- and post-test counselling is a requirement

• There is a need to consider the populations in whom diagnostic testing should be performed and the resource implications of using tests

• Diagnostic tests will have greatest utility for selected patient populations: those patients with atypical but troublesome symptoms, among those presenting with symptoms suggestive of genital herpes in order to confirm a diagnosis of genital herpes, for pregnant women and for STD clinic attendees

• Every patient with genital herpes, including those with classic symptoms, should receive a laboratory-confirmed diagnosis, regardless of whether or not it is the first episode. For definitive diagnosis, when a patient presents with a lesion, a swab should be taken and a direct detection test used (e.g. virus culture, Polymerase Chain Reaction [PCR], EIA).

Direct detection tests for HSV infection

• Direct detection tests detect virus or its components in swabs from a lesion or scrapings or infected secretions

• Direct detection tests include virus culture, immunofluorescence assay, immunoperoxidase assay, PCR, enzyme immunoassay (EIA), immunostaining tests (immunoperoxidase assay [IPA]; immunoflourescence assay [IFA])

• The sensitivities of these tests vary (PCR>culture>EIA>IPA or IFA). In general, the most sensitive and specific test should be used but availability and cost (PCR>culture>EIA>IPA or IFA) influence the choice of test

• In a presentation of genital herpes, the virus should be typed because this gives important prognostic information

• Physicians should recognize that a swab may give a false-negative for HSV in the late stages of a recurrent genital herpes episode and so one negative test result does not rule out genital HSV infection

• If a patient's first test is negative, the patient should be invited to return for another direct test as soon as possible when they next have symptoms in case it leads to a diagnosis of genital HSV infection (unless negative serological testing at the appropriate time rules out HSV infection)

• Serial swabs may be useful for monitoring an immunocompromised patient.

Serological tests for HSV infection

• The advent of type-specific serological tests for HSV has the potential to benefit patient management. Serological tests that are not type-specific have limited value for diagnosis

• Serological tests allow diagnosis of HSV infection when direct detection methods are impractical (e.g. when lesions have healed) or when evidence of seroconversion is being sought (e.g. in pregnancy)

• Serological tests for HSV only indicate past infection, they cannot identify the site of infection or prove that a genital lesion is due to HSV infection

• Serological testing may also be useful in the patient who has chronic recurrent genitourinary symptoms for which there is no apparent aetiology, and also where there is a concern about transmission in discordant couples

• Type-specific serological testing alone will not differentiate genital HSV infection and facial HSV infection

• It is unlikely that widespread screening to detect unrecognized or asymptomatic infection will be accepted by policy makers because of the likelihood of false-positives and the lack of an intervention proven to slow (or stop) the spread of HSV infection. If screening for HSV-2 infection in the general population were to be conducted, it will require tests of very high sensitivity and specificity.

Epidemiology

• Genital herpes persists in the population because it is caused by a virus that:
  - establishes latency
  - can recur either clinically or in the absence of symptoms
  - cannot be eradicated by antiviral treatment

• The seroprevalence of HSV-2 varies worldwide. In the USA, approximately one-fifth of the general population is HSV-2 seropositive. In serological studies conducted in general populations (i.e. not STD clinic attendees or other specific higher risk groups) and reported at the 6th Annual Meeting of the IHMF, the HSV-2 seroprevalence was:
  - 4.3% in UK
  - 12.5% in Germany
  - 3.9-6.0% in Italy

• HSV serological surveys are ongoing in a number of other countries

• The prevalence of genital HSV-1 infection also varies

• Seroprevalence of HSV-2 is influenced by:
  - socioeconomic status
  - sexual history
  - number of past sexual partners
  - ethnic origin of sexual partners
  - patterns of sexual behaviour

• Assessment of these risk factors for a given individual when testing is being considered can increase diagnostic certainty

• The prevalence of genital herpes is increasing worldwide. In the USA, the seroprevalence of HSV-2 has increased by 30% since the late 1970s. Growth in the prevalence of genital herpes has also been reported in other countries, including Zaire and the UK

• While the incidence of genital herpes is increasing, that of STDs is decreasing (e.g. gonorrhoea in the USA; syphilis in the UK)

• Seroprevalence of HSV-2 infection in higher risk groups can be high (e.g. up to 50% among women attending STD clinics in the USA, UK or Australia; 60-90% in female commercial sex workers worldwide; in the USA, up to 90% in men who have sex with men).

Factors contributing to the spread of genital herpes

• Several factors contribute to the worldwide increase in the spread of genital herpes:
  - HSV infection establishes a latent infection that can recur clinically or asymptomatically
  - no treatment available to eradicate infection
  - under-recognition of genital herpes
  - asymptomatic virus shedding

• Early exposure to HSV-1 is decreasing in many areas of the world and this has led to a growing incidence of first episode genital HSV-1 infection. The incidence in the USA varies between 10-30%. In the UK and Japan, it is as high as 50% of all initial genital herpes infections.

Transmission
Populations at risk

• Transmission is more likely from partners who are unaware that they are infected (i.e. they have unrecognized or asymptomatic genital HSV infection)

• Herpes is more easily transmitted from men to women

• The risk of herpes transmission to the newborn is greatest when the mother is experiencing a primary infection in the third trimester.

Management strategies to prevent transmission

• Condoms may be partially effective for preventing acquisition of HSV, although this has not be formally proven

• Suppressive anti-herpes therapy reduces asymptomatic shedding of HSV and clinical recurrences. Its effect on transmission is not yet known but is being evaluated with valaciclovir

• No effective HSV-2 vaccine is currently available. Newer vaccines are under development.

Economic Impact of Genital Herpes
The costs of genital herpes (estimated range from US$77-332 million) fall in the middle of the range of common STDs. However, the estimates of the burden of STDs often do not include indirect costs (e.g. lost productivity) or intangible costs (e.g. pain and effects on lifestyle). Therefore, the true burden of this widespread infection is likely to be underestimated.

For more information, see the monographs:

	The Medical Importance of Genital HSV infection
	Genital and Orofacial Herpes Simplex Virus Infections - Clinical Implications of Latency

• The social stigma associated with genital herpes and the general lack of information among the general public combine to adversely impact on quality of life

Barriers to Education

• Patient distress at the time of a diagnosis of genital herpes can hamper education and counselling messages.

Pre-test Counselling

• Pre-test counselling aims to determine whether a test is likely to be positive and how a diagnosis of HSV infection will benefit management of the patient

• It should include:
  - information about the proposed test and interpretation of results
  - an explanation of the natural history of genital herpes and its consequences
  - an offer of resources for coping with a positive test result

• During pre-test counselling, the willingness of a patient to know the result of a test, [if positive] the likely psychological impact, the likelihood of behavioural change, and the effects on relationships should all be determined.

Post-test Counselling
If the result is positive

• Tailor education to the patient needs

• Educate in stages - do not overwhelm with information too early

• Encourage patient to tell partner

• Provide information on what test results mean
  - explain difference between result for direct test (e.g. culture) and for serological test

• Provide written information on the natural history of genital herpes, asymptomatic shedding, transmission risk, risk reduction (can include websites: www.herpesweb.net, www.ashastd.org; www.herpesalliance.org)

• Discuss antiviral therapy options

• Provide follow-up session for questions

• Provide further support and information. Patient can be:
  - directed to a practice nurse or other healthcare professional (e.g. counsellor)
  - put in touch with a local support group
  - referred to an STD clinic where further counselling and information is available.

If the result is negative

• Explain meaning of negative test result (and possible need for re-testing)

• Combine STD/HIV education with risk reduction messages

• Recommend condoms to reduce the risk of HSV infection

Resources

American Social Health Association (ASHA) - Genital Herpes Support Group (www.ashastd.org)

HerpesWeb (www.herpesweb.net)

International Herpes Alliance (www.herpesalliance.org).

• All patients diagnosed with genital herpes are candidates for oral antiviral therapy, which can reduce the duration, severity and number of recurrent outbreaks of genital herpes. Not every patient will require treatment and not every attack needs to be treated

• Aciclovir, valaciclovir and famciclovir are effective therapies for HSV infection but differ in their dosages and dosing frequencies

• There are two main approaches for the management of genital herpes with antivirals:
  - episodic oral antiviral therapy, where therapy is initiated by the patient on early symptoms of a recurrence
  - suppressive oral antiviral therapy, where the patient takes antiviral therapy every day to suppress recurrences. Suppressive therapy is particularly useful where the disease has a severe impact on quality of life and recurrences are frequent, severe or debilitating

• Antivirals for herpes have very good safety profiles

• Decisions as to whether or not to take suppressive or episodic therapy depends both on the number of recurrences and impact genital herpes has on the patient's life.

Cost-effectiveness of Antiviral Therapy in Adult Genital Herpes

• Suppressive therapy for genital HSV infection is a more cost-effective treatment option than episodic therapy for people with frequent recurrences

• While episodic therapy relieves the signs and symptoms of outbreaks, it is unlikely to provide psychosexual benefits for patients between recurrences. Thus, preventing outbreaks with suppressive therapy has potentially much greater impact than episodic treatment.

Impact of Treatment on the Herpes Epidemic

• A mathematical model has explored the effects of more widespread use of episodic therapy on the prevalence of HSV infection and on the development of HSV resistance. Three conclusions can be drawn from the model with regard to an impact on the herpes epidemic:
  - chronic suppressive therapy is likely to be more beneficial than episodic treatment because it reduces both symptomatic and asymptomatic infectious episodes
  - genital herpes treatments should be aimed at suppressing the frequency of HSV reactivation
  - therapeutic HSV vaccines, if they could be shown to reduce recurrence rate, might be very useful in controlling the epidemic

• Increased use of episodic therapy in genital herpes, according to the model, would only transiently increase the likelihood of resistant virus appearing, thereafter prevalence would fall.

For more information, see the monographs:

	The Medical Importance of Genital HSV infection
	Progress with Diagnostic Tests and Vaccines for Alpha-Herpesviruses

• Genital HSV-2 infection has been implicated as a co-factor in the acquisition, transmission, and progression of HIV-related disease

• Symptomatic HSV-2 infection may render a person more susceptible to acquiring HIV

• Symptomatic genital HSV infection in the person who is HIV-positive is likely to be a major risk factor in the transmission of HIV. Since HIV virions are present in genital HSV lesions, symptomatic genital HSV infection may facilitate the transmission of HIV

• In an HIV-discordant partnership, if either partner is infected with an STD, the risk of HIV transmission or acquisition is generally estimated to be increased by a factor of 2-8

• HSV-2 is a significant cause of morbidity in the person with HIV infection

• HSV-2 reactivates more frequently in the HIV-seropositive person, which also facilitates the spread of HSV-2 infection

• HSV-2 reactivation in an individual with HIV infection is associated with increased HIV-1 viraemia and potentially therefore, the progression of HIV-related disease.

Cost Implications of the STD-HIV Interaction

• In an intervention study in Tanzania, the savings achieved by the prevention of HIV infection offset the cost of treating genito-urinary ulcers. The cost of the intervention compares favourably with other highly effective public health interventions (e.g. childhood vaccinations)

• Anti-herpes therapy should be incorporated into future studies of the role of STD prevention on HIV acquisition and transmission.

• HSV infection has severe consequences for the newborn and family, with the potential for death or physical or mental handicap for the child, psychological and social implications for the parents, and cost burdens for the healthcare provider and family

• For infants infected with HSV, the disease is classified as one of three types:
  - skin, eye and mouth (SEM) infection
  - central nervous system (CNS) disease
  - disseminated infection

• SEM disease is rarely fatal whereas many infants with encephalitis or disseminated infection die without treatment and morbidity is high

• Intravenous aciclovir can reduce the morbidity and mortality of neonatal herpes

• The USA annual cost of neonatal herpes has been estimated to range from US$101-150 million.

Risk Factors for HSV Transmission to the Neonate

• HSV is mainly transmitted from mother to child during delivery when the infant has direct contact with infected maternal genital secretions

• The risk of transmission to the neonate is greater if the mother acquires primary genital HSV infection during the third trimester of pregnancy, particularly if she has lesions at the time of delivery

• Recurrent episodes of genital herpes in the pregnant woman at delivery carry a reduced risk of neonatal disease compared with a primary episode.

Management of Genital HSV Infection during Pregnancy
First-episode genital herpes

• Routine aciclovir use during pregnancy is not recommended. However, disseminated or presumed maternal primary HSV infection should be treated with aciclovir

• Because of the risk of HSV transmission to the neonate, if a woman presents with a first episode in the third trimester, every effort should be made to characterize it serologically (e.g. primary versus non-primary). In women with a primary HSV infection after 34 weeks, delivery by elective Caesarean section should be considered.

Recurrent maternal herpes

• Anti-herpes prophylaxis in late pregnancy for women with a history of genital herpes recurrences is not currently recommended. This recommendation should be reviewed as results of ongoing studies become available.

Management of HSV Infection at Delivery

• In the past, Caesarean section has been used widely but controlled trials to determine its true value as a management policy are required. Caesarean section and other management options should be discussed with the patient. The mode of delivery may be based on clinical findings at the time of delivery; the presence of obvious herpetic lesions is only a relative indication for Caesarean section

• Invasive monitoring of the infant (e.g. use of fetal scalp electrodes) should only be used for defined obstetrical indications.

Management of the Infant with Possible HSV Infection
Diagnosis

• The high risk of death or neurological damage with delayed, or no treatment, of neonatal HSV infection requires that diagnosis be pursued promptly if the infection is suspected

• At the same time that diagnostic tests are ordered, empiric treatment with intravenous aciclovir must be initiated. It is not sufficient to rely solely on the presence of skin lesions for diagnosis as neonatal HSV infection can be present in their absence. Therefore, diagnostic testing is required whenever neonatal HSV infection is suspected

• Material should be collected from all of the following sites and submitted to the laboratory for virus culture and/or PCR detection of HSV:
  - skin or mucosal lesions
  - conjunctiva
  - mouth and throat
  - rectum
  - urine
  - cerebrospinal fluid (CSF)

• Evidence of disseminated or CNS infection should be sought by performing liver function tests, complete cell blood count (CBC) CSF analysis and, if there are any respiratory abnormalities, a chest X-ray. Whenever possible, PCR analysis of the CSF for HSV DNA should be used to diagnose suspected neonatal herpes; a finding of HSV DNA in the CSF is evidence of disseminated or CNS infection.

Treatment

• Intravenous aciclovir (20 mg/kg every 8 hours) is recommended for suspected or proven neonatal HSV infection. Early therapy, which may improve long-term neurological outcome, is vital and treatment should be started at the time diagnostic tests are ordered

• The duration of the intravenous aciclovir treatment depends on whether or not neonatal herpes is localized. If the disease is limited to the skin, eyes or mouth (i.e. normal CSF), the treatment should be for 14 days. For other forms of neonatal HSV infection (i.e. abnormal CSF), administration for 21 days is recommended. If a CSF analysis is not available, the longer treatment period should be used

• Under no circumstances should oral or topical therapy be used to treat neonatal HSV infection.

Cost-effectiveness of antiviral therapy in pregnancy

• Economic modelling suggests that antiviral therapy is cost-effective in the prevention of neonatal herpes. However, the number of studies evaluating antiviral therapy in pregnancy is small and the safety of antiviral therapy has not been fully assessed in this setting.

For more information, see the monographs:

	The Medical Importance of Genital HSV infection
	Genital and Orofacial Herpes Simplex Virus Infections - Clinical Implications of Latency

See also- Letter to The Lancet (Whitley R. Lancet 1998;352:651) and the article L Corey, HH Handsfield. Genital herpes and public health: addressing a global problem. JAMA 2000;283:791-794.

• The prevalence of HSV-2 infection is increasing in many countries and brings with it an emotional, medical and economic burden. HSV-2 is easily transmitted and is implicated in the acquisition and spread of HIV infection

• The International Herpes Management Forum (IHMF) and local Herpes Management Forums (HMFs) are developing public health recommendations

• These educational initiatives should be of benefit in other regions where genital herpes is recognized as a public health problem.

Elements of the IHMF Public Health Strategy in Development

• The public health significance of genital herpes is underappreciated. Healthcare policy-makers, physicians and the wider public do not recognize the burden that genital herpes places on society and the individual

• To address this lack of awareness, more information is required on the epidemiology of genital herpes. This will help to:
  - communicate how widespread the infection is
  - target prevention efforts

• Importantly, the socioeconomic costs of genital herpes and the cost-effectiveness of interventions must be quantified as this can guide healthcare policy

• Primary care practitioners and/or public health specialists, not just specialists in sexual health, could become closely involved in identifying and educating people about STDs, particularly HSV

• Nationally approved educational procedures, which give information about HSV infection, symptoms and available therapies, are needed in countries where the problem of genital HSV infection is recognized

• More effective mechanisms for the communication of public health messages are needed. Mass media influences social behaviour and can therefore have a role in raising awareness about genital herpes. However, the effectiveness of this and other interventions should be evaluated formally to ensure the best use of resources

• Measurable outcomes would be a decrease in the incidence of newly acquired HSV infections (both genital and neonatal) or a rise in prescriptions

• Public awareness has become a key issue. People must be informed of their HSV serostatus and be sexually responsible to impact on the epidemic of genital herpes

• The role of governments, at national and global levels, needs definition. A recognized infrastructure for genital herpes awareness, perhaps within sexually transmitted disease awareness programmes, needs to be put in place.

For more information, see the monograph:

Genital and Orofacial Herpes Simplex Virus Infections - Clinical Implications of Latency

Epidemiology of Orofacial HSV-1 Infection

• Orofacial HSV-1 infection is usually acquired during early childhood or adolescence

• Risk factors include the following:
  - geographic location
  - socioeconomic status
  - age.

Primary Orofacial HSV infection

• Primary HSV-1 infection occurs by virus inoculation of the oral mucosa. Infection may be asymptomatic, unnoticed, unrecognised or present as symptomatic disease

• Gingivostomatitis is the most common symptomatic presentation in small children and infants. In adolescents, gingivostomatitis is rare and symptomatic disease may present as pharyngitis or a mononucleosis-like syndrome

• Gingivostomatitis typically presents as lesions on the tongue, lips, gums and buccal mucosa, as well as the hard and soft palate. It is often associated with fever, lethargy, loss of appetite and fractiousness. Children with gingivostomatitis may be unable to swallow because of the associated pain and may become dehydrated

• During and immediately after primary infection, HSV-1 ascends through sensory nerve axons to establish latent infection in the ganglia of the trigeminal, facial and/or vagus nerves

Therapy

• Palliative treatments include analgesics, antipyretics and antiseptic mouthwash

• Oral aciclovir (suspension) has been shown to be effective in children with acute primary gingivostomatitis.

Recurrent Orofacial Herpes

• HSV reactivates periodically from its latent state in sensory ganglia to cause symptomatic or asymptomatic orofacial herpes outbreaks. Symptomatic episodes on or around the lips may be referred to as herpes labialis (H. labialis) or coldsores

• Much of the population (20-40%) experience recurrent orofacial HSV outbreaks. The condition is severe in only about 1% of people but for most sufferers, it can be associated with significant discomfort and is cosmetically disfiguring

• For immunocompromised patients, HSV-1 lesions at orofacial or buccal sites may be life threatening as there is a risk of the virus disseminating to other organs

• Reactivation may be caused by a number of physiological, psychosocial or environmentally derived 'trigger factors'

• Reported triggers of recurrent orofacial HSV outbreaks include the following:
  - common cold or 'flu
  - oral trauma
  - surgical treatment
  - ultraviolet light
  - emotional stress
  - menstruation

• The classic presentation of an orofacial HSV outbreak is prodromal pain followed within a few hours by one or more erythematous maculo-papular lesions. These develop into vesicles (blisters) which collapse to form ulcers that eventually crust over. Healing is considered complete when the crust is lost and the skin re-epithelialises. The duration of an orofacial HSV episode is about 8-10 days

• Prodromal symptoms, reflecting virus replication in sensory nerve endings, include tingling, pain and itching

• Recurrent HSV outbreaks tend to be on the lips or face rather than intra-oral. Recurrent gingivostomatitis is rare

• Asymptomatic HSV shedding occurs in 8% of healthy patients, but in up to 40% of patients who have had oral surgery or who are immunocompromised.

Therapy

• Antiviral agents for recurrent orofacial HSV infection can be used as:
  - prodromal therapy
  - pre-emptive therapy
  - suppressive (continuous) therapy

• The maximum benefit of antiviral therapy for acute treatment of an evolving orofacial herpes outbreak is gained from early initiation so that HSV replication ceases promptly, reducing the risk and/or extent of tissue damage

• Prodromal therapy is treatment applied sufficiently early in response to a signal of virus reactivation to terminate HSV replication and prevent skin or mucosal damage, the formation of vesicles and the subsequent stages of healing (e.g. ulcer, scab):
  - aciclovir cream can hasten lesion healing. Some studies demonstrate that aciclovir can 'abort' the development of vesicular lesions typical of an orofacial herpes outbreak
  - penciclovir cream can speed lesion healing and reduce the overall duration of the episode
  - oral aciclovir reduces the healing time and the duration of pain of recurrent HSV episodes

• Topical or oral antiviral therapy should be started as soon as the patient feels the characteristic tingling sensation of an orofacial herpes episode.

• Pre-emptive therapy aims to prevent HSV reactivation and subsequent lesion development in settings where the patient knowingly will be exposed to a trigger factor for an orofacial herpes outbreak. It is also termed short-term prophylaxis or short-term suppression. It may be suitable for patients whose recurrences are triggered by stressful situations (e.g. wedding or new relationship) or environmental factors (e.g. mountain sports enthusiasts exposed to increased ultraviolet radiation at high altitudes):
  - aciclovir cream, applied a few days before vacation, has been shown to be modestly effective in preventing facial herpes episodes in skiers
  - oral aciclovir beginning 12-24 hours prior to exposure can prevent ultraviolet light-induced facial herpes recurrences
  - in the treatment of experimental ultraviolet radiation-induced orofacial herpes, oral famciclovir beginning 48 hours after exposure has been shown to increase the speed of healing. Studies to determine the optimal famciclovir dose are required.

• Suppressive therapy is recommended for patients who experience frequent and/or severe recurrences, e.g. recurrent outbreaks triggered by emotional stress, or who are immunocompromised and therefore at risk of complications due to orofacial HSV reactivation:
  - oral aciclovir is effective in suppressing orofacial herpes episodes in immunocompetent adults
  - in patients who are immunocompromised, oral aciclovir can prevent orolabial HSV outbreaks.

Prevention strategies for HSV-1 infection

• Strategies for prevention of HSV-1 infection include:
  - medical and dental personnel should wear protective latex gloves
  - patients with orofacial herpes should be advised to avoid contact with others (e.g. kissing) when lesions are present
  - oral-genital sex should be avoided when orofacial herpes lesions are present.

Eczema Herpeticum

• This potentially serious complication of HSV-1 infection manifests as painful cutaneous lesions with occasional dissemination to visceral organs primarily in children with eczema

• Parents of a child with atopic eczema should be advised to take care if the child experiences recurrences of orofacial herpes and be taught to recognize the signs of eczema herpeticum

• In addition to intensive circulatory support and antibiotics, oral aciclovir therapy is warranted.

Erythema Multiforme

• The role of HSV in the pathogenesis of erythema multiforme is unknown, but it is frequently preceded by an orofacial herpes outbreak

Therapy

• Treatment with oral aciclovir at the first sign of an outbreak of orofacial herpes is recommended

• Suppressive oral aciclovir therapy has been shown to be effective in preventing recurrences of erythema multiforme

• Supportive care should include analgesics and appropriate rehydration.

Herpetic Whitlow

• This is an occupational hazard of medical and dental workers who are exposed to HSV-infected oral secretions that are inoculated through minor abrasions on the hands, particularly the fingers

• Another source of herpetic whitlow is through autoinoculation from mouth to hand during an active orofacial HSV episode

Therapy

• Oral aciclovir has shown efficacy in the treatment of herpetic whitlow

• In one study, eight patients with recurrent disease had all attacks aborted by oral aciclovir given during the prodrome