Antivirals for Herpes Simplex and Varicella-zoster Infection

The antiviral compounds of the 1950s were very toxic and it was not until the discovery of acyclovir in the 1970s that it was possible to strongly inhibit viral replication without toxicity to uninfected cells.¹ Aciclovir works on the virus specific enzyme thymidine kinase. The epidemic of AIDS in the 1980s accelerated development of antivirals.

Eight human herpes viruses have been identified and about 100 in other animal species. They share the ability to establish latency during the primary infection. Reactivation of the dormant infection can then be triggered by factors such as changing immune status, stress, sunlight etc. See varicella zoster, herpes simplex, genital herpes.

• Aciclovir - strongly inhibits viral replication without eradicating the herpes viruses. It is used systemically for varicella-zoster infection. It can be used systemically and topically for herpes simplex infections. Eye ointment can be used for HSV eye infection and in combination with systemic treatment for ophthalmic VZV.
• Valaciclovir - is an ester of acyclovir and licensed for genital herpes and VZV. It is also licensed for prevention of cytomegalovirus infection after organ transplantation.
• Famciclovir - is a prodrug of peniciclovir. It is available topically for cold sores and is licensed for genital herpes and VZV infection.
• Idoxuridine - can be used topically for HSV infections.
• Inosine pranobex - can be used orally for HSV infections but efficacy is in doubt.

Effective use of these drugs is best achieved after accurate diagnosis with:

• An understanding of the nature of the infection (Latency, lifelong etc) and possible complications.
• Recognition of the type and site of the infection.
• Consideration of the context of the infection (immune competence, age etc).

This can be appreciated by considering different clinical scenarios.

Varicella

Most people contracting varicella will not need antiviral treatment. However it is important to recognise groups of patients who will benefit from antiviral treatment. Some patients will need referral for intravenous acyclovir:

• High risk patients who are immunocompromised (haematological malignancy, HIV with CD4<200 cells/mm³, organ transplant, high dose immunosuppressive treatment).
• Systemic disease (for example affecting heart, lungs).
• Patients on high dose steroids (children on more than 2 mg/kg/day for more than 14 days, or in adults on 40 mg/day for more than a week).
• New lesions appearing after 8 days.

• Patients with a chronic medical condition (Lung or heart disease for example).
• Patients over 12 years of age to reduce the complication rate.
• When the patient is a secondary case in a household.
• Pregnant patients, although use is not licensed. There is no evidence of teratogenicity.

Valaciclovir and famciclovir are probably indicated but evidence of efficacy is lacking.

Varicella contacts

For close face to face contact of greater than 4 hours duration² the exposure is significant. In such cases of significant exposure oral acyclovir at the dose above should be offered when:

• There is no specific history of previous varicella exposure and/or serological testing confirms exposure (if available within 2 days) and
• It is 5-7 days after exposure
• Patient is high risk (immunocompromised or pregnant) or transmission on to high risk contact (e.g. parent of immunocompromised child) is possible.

Note: high risk and under 96 hours after exposure, give specific varicella zoster immunization (VZIG).

Herpes zoster

Treat with 7 days of oral antivirals (valaciclovir, famciclovir or acyclovir) if at risk of post herpetic neuralgia. Those at risk are:

• Suffering with severe acute pain.
• Over 50 years old.
• Have significant prodromal symptoms.

Although it is suggested that treatment beyond 72 hours of onset is not indicated, most agree this should be stretched for those at risk of post herpetic neuralgia. Better methods of identifying patients at risk of post herpetic neuralgia have been called for.³ For ophthalmic zoster treat and refer, again even if beyond 72 hours of onset.

Primary genital herpes

Holistic management involving explanation and information is essential.^4,5
Diagnosis will be suggested by history, risk factors, symptoms and on examination genital vesicles or ulcers (with fever, pain, stiff neck, extensive lesions). Swabs should be taken and treatment given immediately with aciclovir (400 mg tds 5-10 days), valaciclovir (500 mg bd 5-10 days) or famciclovir (250 mg tds 5-10 days).
Note: topical therapy is of no proven value.

Recurrent genital herpes

Treatment with oral antivirals is appropriate:

• Episodically for infrequent but severe or lengthy attacks (aciclovir 400 mg, tds 5 days or valaciclovir 500 mg bd 5 days or famciclovir 250 mg tds 5 days).
• Continuously for frequent or severe attacks (acyclovir 400 mg bd, valaciclovir 500 mg once daily, famciclovir 250 mg bd). This is indicated to suppress attacks.

Ensure good fluid intake. Caution in pregnancy, with breast feeding, in renal impairment and hepatic impairment.

Gastrointestinal side effects and rashes are amongst the most common. Photosensitivity, hepatitis, neurological reactions and renal failure have been reported.

Indications for referral are:
High risk varicella patients for intravenous therapy (as above):

• Ophthalmic zoster
• Primary HSV infection if toxic, immunocompromised or pregnant.⁶
• Diagnostic or management difficulties with recurrent genital herpes.