Genital herpes is one of the most common sexually transmitted diseases and is the most common cause of genital ulcers in developed countries. It is caused by herpes simplex virus types 1 and 2 (HSV-1, HSV-2). The worldwide annual incidence of genital herpes is about 20 million cases. The prevalence of HSV-2 infection is 10-30% in most developed countries.

When herpes simplex virus is transmitted to the genital mucosa, it starts to replicate within the epidermal cells. This leads to cell lysis, resulting in the formation of vesicles, which then rupture to form ulcers. Not everyone exposed to herpes simplex virus develops symptomatic genital herpes. A prior HSV-1 infection, usually acquired during childhood, generally protects the individual from later genital HSV-1 infection. Symptoms and signs are also less common if this individual subsequently develops genital HSV-2 infection.

HSV also enters into the sensory nerve endings and moves along the axon to the neurons within the spinal sensory ganglia. It then either replicates within the neurons or enters a state of ‘latency’. Latent virus can reactivate either spontaneously or in response to a variety of environmental stimuli, such as ultraviolet irradiation, trauma or stress. It is then conveyed back to the epidermis along the sensory nerves, resulting either in asymptomatic shedding or in clinical recurrences. The frequency of recurrences varies considerably between individuals. In general, the more severe the primary infection, the more frequent the recurrences will be. Many patients with primary genital HSV-1 infection do not experience recurrent infections in the first year; if they do so, the recurrence rate is usually low (on average one per year in the year following diagnosis). However, most patients with primary genital HSV-2 infection have recurrences in the first year and the recurrence rate may be high (on average four recurrences in the first year). For most people, recurrences get less common over time, but about 25% of people with symptomatic HSV-2 continue to have frequent recurrences for many years.

Transmission occurs by close personal contact. This can occur during periods of symptomatic or asymptomatic shedding of the virus. The overall transmission rate for HSV-2 infection to a seronegative partner is estimated to be 5-10% per year. The risk of transmission appears to be highest when clinical lesions are present. However, transmission from asymptomatic partners is more common because the individual with symptoms is likely to abstain from sexual contact, or the partner may not wish to have sexual contact with someone with obvious lesions.

Presentation of Herpes

First-episode genital herpes

Most infected persons have subclinical infection. When symptoms and signs are present, severity is determined by the presence of prior immunity to HSV. In non-primary first episodes (patients with prior herpes simplex virus infection), symptoms are often less severe and resolve more quickly. True primary genital herpes only accounts for about 50% of patients presenting with their first symptomatic episode.

The incubation period is 2-20 days. In most patients, there is a generalized ‘flulike’ illness with fever, malaise, headache and myalgia. These systemic symptoms persist for a week and are usually more prominent in women and in those with HSV-2 infection.

Lesions first appear as vesicles and rapidly ulcerate. The number of lesions varies considerably and lesions often coalesce to form a large area devoid of epithelium. Pain is an almost universal complaint. Tender inguinal lymphadenopathy is also common. Without treatment, the lesions remain painful for 10-12 days, with resolution after 2-3 weeks.

The urethra is commonly involved. Men may present with symptoms of urethritis, whereas women often complain of internal as well as external dysuria. Vaginal discharge also affects some women and occasionally uterine and adnexal tenderness is present, suggesting upper genital tract involvement. Rarely, the cervix is involved and appears ulcerated or necrotic.

The perianal area is frequently involved, especially in women. This involvement does not necessarily indicate that the person has had receptive anal intercourse. Lesions in the anal canal may give rise to symptoms of proctitis, including severe anal pain, tenesmus, constipation and rectal discharge. Clinical features of pharyngeal infection, usually after orogenital contacts, vary from mild erythema to ulcerated pharyngitis with tender cervical lymphadenopathy.

Some patients develop extragenital lesions. The most common sites are the buttocks and the thighs. Less commonly, the fingers and the eyes are involved. These lesions can be caused by autoinoculation or in the case of the buttocks, reflect the overlap between genital and buttock sacral innervation.

Recurrent genital herpes

In recurrent disease, systemic symptoms are uncommon and the duration and severity of symptoms are much less. The lesions are fewer, usually unilateral, and normally resolve within 10 days. Complications are rare. About 50% of patients notice prodromal symptoms 1-2 days prior to appearance of genital lesions. These symptoms include genital itching and burning. Numbness and tingling in the buttocks or thighs may also occur. Some patients may experience prodromal symptoms that are not followed by lesion formation.

Complications of Herpes

Complications of genital herpes occur more frequently in women. The most common complications of genital herpes are bacterial and fungal superinfections and neurological involvement. Symptoms of meningeal involvement with photophobia and neck stiffness may be present in some patients. Less common complications include sacral autonomic radiculopathy resulting in urinary retention, perineal and buttock paraesthesias, and in men, transient erectile dysfunction.

Although rare, neonatal infection can cause severe encephalitis and death. Neonatal infection is more common if the mother acquired the infection in the third trimester, since there would not be enough time to pass on immunoglobulin G (IgG) transplacentally. An obstetrician should be consulted if a woman develops new genital ulcers in the third trimester. If it is confirmed as being a first episode, then the delivery will usually be performed under i.v. acyclovir cover and/or by Caesarian section.

Diagnosis of Herpes

See site for the differential diagnosis of genital ulceration.

The diagnosis of primary genital herpes can often be made on clinical grounds. Typical appearance of multiple and painful vesicles or ulcers is sufficient to make the diagnosis. In non-primary first-episode herpes and in recurrent genital herpes, diagnosis can sometimes be difficult, especially when manifestations are atypical. For example, genital skin fissures may occur with minor trauma or Candida vaginitis, as well as with genital herpes.

Clinical diagnosis of genital herpes should always be confirmed by laboratory methods. Laboratory confirmation will also allow distinction between HSV-1 and HSV-2, which carry different prognoses. When genital lesions are present, herpes simplex virus isolation is the main method used. The specimen is collected by de-roofing a vesicular lesion with a sterile needle and scraping the base of the lesion with a swab. Where lesions are already ulcerated, the specimen is collected by swabbing the base of the ulcer. This is then placed in a viral transport medium. Specimens that cannot be processed immediately should be refrigerated at 4°C. After inoculation, the cell culture is inspected for the characteristic cytopathic effects, which usually appear within 12-48 hours. herpes simplex virus is then confirmed with specific monoclonal antibodies that will also allow typing of the isolates as HSV-1 or HSV-2. The specificity of viral culture approaches 100% but the sensitivity depends on the stage of the lesion. About 95% of vesicular lesions and 70% of ulcerative lesions will yield HSV, but only 30% of crusted lesions. Hence, a negative culture does not rule out genital herpes.

Diagnostic methods using enzyme immunoassay (EIA) technology for the detection of herpes simplex virus antigen are available. The main advantage of this technique is the rapid processing time: results can be available within hours. Sensitivity of the antigen detection test varies between kits. The more sensitive ones are comparable to that of culture, and may perform better in late-stage lesions.

Molecular methods using the polymerase chain reaction (PCR) for herpes simplex virus have been developed more recently. Their main use has been in diagnosing herpes simplex virus encephalitis and meningitis in adults and neonates, but many laboratories are starting to use them for genital specimens. PCR is more sensitive than culture, although slightly less specific. Research studies have shown that polymerase chain reaction may be useful in determining the frequency of asymptomatic shedding and in the diagnosis of culture-negative lesions. Specimens for polymerase chain reaction can tolerate wider temperature fluctuations during transport than those required for culture, but the technique requires special containment laboratories, appropriate equipment and expert staff.

HSV serology has limited usefulness in diagnosing herpes simplex virus infection. The newer type-specific serology can be useful for diagnosing asymptomatic infection, determining the risk of transmitting genital HSV-2 to sexual partners, screening pregnant women at risk of herpes simplex virus transmission to their babies, and for epidemiological studies.

Management of Herpes

Although antiviral drugs effective against herpes simplex virus have been available for many years, the clinical management of genital herpes continues to present difficult challenges. Antiviral drugs can stop the replication of the virus but cannot eradicate latent infection. Nevertheless, current management strategies can improve the lives of most individuals diagnosed with genital herpes.

Antiviral drugs

Aciclovir is the most frequently used drug in the treatment of genital herpes. Side effects are uncommon but may include headache, nausea and rash. It is eliminated by the kidney and may require dosage adjustment in patients with renal failure. herpes simplex virus resistance to aciclovir has been described in immunosuppressed patients but rarely in immunocompetent patients.

Famciclovir and valaciclovir are newer drugs with higher bioavailability and longer intracellular half-life. They appear to offer at least equivalent efficacy to aciclovir, but with more convenient dosages. They both have a similar side effect profile to aciclovir. Patients with aciclovir-resistant herpes simplex virus will also fail to respond to treatment with famciclovir or valaciclovir and both drugs are more expensive than generic aciclovir.

First-episode genital herpes

Aciclovir 200 mg (400 mg in the immunocompromised) orally five times per day for 5 days is effective in treating first-episode genital herpes. In more severe cases, this can be extended to 10 days. Treatment decreases the duration of local and systemic symptoms, reduces viral shedding from lesions and promotes healing. These effects are most marked if treatment is initiated early in the course of the infection. Hence, treatment should be prescribed at the time of clinical diagnosis (before laboratory confirmation), unless the infection is already almost resolved. Treatment does not alter the natural course of the illness as treated patients are just as likely as untreated patients to develop subsequent recurrences. Intravenous aciclovir is indicated only in the minority of severe cases requiring hospitalization.

Poor drug penetration to the site of virus replication means that topical aciclovir is much less effective and hence not recommended.

Famciclovir 250 mg orally three times per day for 5 days and valaciclovir 500 mg orally twice daily for 5 days are also licensed for use in first-episode genital herpes.

Recurrent genital herpes

Recurrent genital herpes may be treated with a 5-day course of oral aciclovir, famciclovir (125 mg twice daily) or valaciclovir. The efficacy of this treatment depends on prompt initiation of treatment. Patients could therefore be prescribed antivirals in advance of the recurrence, so that treatment is available for the patients to initiate at the first sign of recurrence (or prodrome). Such episodic treatment reduces the duration of virus shedding and persistence of the lesions. However, the benefits are not as dramatic as for treatment of first episodes, often shortening the duration of the symptoms by only a day or so. As most recurrent episodes are mild and brief, many patients choose just to take symptomatic treatment.

Suppression of recurrences

Indications for suppressive treatment include frequent recurrences (>6 per year) and in patients with significant symptoms or psychosexual problems. Suppressive treatment should eliminate or significantly reduce the number of recurrences. There is no evidence that such suppression decreases the likelihood of subsequent recurrences after treatment is discontinued. However, many patients experience a gradual decrease in recurrence rate over time even without treatment. Hence, suppressive treatment is usually stopped after 6-12 months to re-evaluate the need for continuing it.

Suppressive treatment also reduces the frequency of asymptomatic shedding, and a 2004 study indicated that treatment with valaciclovir reduces the risk of transmission to sexual partners as a result.

The recommended dose of aciclovir in suppression is 400 mg twice daily. This may be reduced to 200 mg two or three times daily if recurrences have been completely suppressed by the higher dose. If the patient continues to experience ‘breakthrough’ recurrences, a more frequent dosing interval of 200 mg four times per day may be tried. Famciclovir 250 mg twice daily and valaciclovir 500 mg daily are also licensed for use in suppression therapy.

Supportive therapy

First-episode genital herpes should be managed with appropriate supportive measures. Measures for symptom control include pain relief (paracetamol and/or topical lidocaine), salt water baths, micturition in water baths and wearing of loose clothing. In more severe cases, admission to hospital and treatment with intravenous fluids and suprapubic catheterization (if retention) may be required. Bacterial or fungal superinfections may require treatment with antibiotics or antifungal agents. Supportive treatment for recurrent genital herpes is similar but because recurrences are generally milder, the need of such measures should be individually considered.

Counselling and education

Genital herpes is one of the first chronic recurring illnesses encountered by young adults. Its diagnosis often causes substantial anxiety in patients. In addition to guilt, some patients experience depression, psychosexual dysfunction, fear of rejection and fear of transmission. Other patients may direct anger to their sexual partners who may be asymptomatic. Counselling with accurate information about genital herpes is therefore important and may minimize the psychosocial and psychosexual complications.

Counselling starts with an accurate description of the natural history of the herpes simplex virus and its associated clinical syndrome. The concepts of latency and recurrences should be discussed. Patients should also be familiarized with asymptomatic shedding and their fears of transmission should be addressed. In female patients of childbearing age, the management of genital herpes in pregnancy should also be discussed.

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