Aciclovir is a guanine analogue antiviral drug primarily used for the treatment of herpes simplex virus infection. It is one of the most commonly-used antiviral drugs, and is marketed under trade names such as Zovirax and Zovir (GSK).
Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Pharmacologist Gertrude B. Elion was awarded the 1988 Nobel Prize in Medicine partly for the development of aciclovir.
Mechanism of action - Aciclovir differs from previous nucleoside analogues in that it contains only a partial nucleoside structure – the sugar ring is replaced by an open-chain structure.
Therefore, aciclovir can be considered a prodrug – it is administered in an inactive (or less active form) and is metabolised into a more active species after administration.
Microbiology - Aciclovir is active against most species in the herpesvirus family. In descending order of activity:
Activity is predominately active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.
To date, resistance to aciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.
Pharmacokinetics - Aciclovir is poorly water soluble and has poor oral bioavailability (10–20%), hence intravenous administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. Aciclovir has a high distribution rate, only 30% is protein-bound in plasma. The elimination half-life of aciclovir is approximately 3 hours. It is renally excreted, partly by glomerular filtration and partly by tubular secretion.
Indications - Aciclovir is indicated for the treatment of HSV and VZV infections, including:[3]
It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak. Likewise oral therapy for episodes is inappropriate for most non-immunocompromised patients, whilst there is evidence for oral prophylactic role in preventing recurrences.
Dosage forms - Aciclovir is commonly marketed as tablets (200 mg and 400 mg), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%). Cream preparations are used primarily for labial herpes simplex. The intravenous injection is used when high concentrations of aciclovir are required. The ophthalmic ointment preparation is only used for herpes simplex keratitis.
Systemic therapy - Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhoea and/or headache. In high doses, hallucinations have been reported. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore throat, constipation, abdominal pain, rash and/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.[3]
Additional common adverse effects, when aciclovir is administered IV, include encephalopathy (1% of patients) and injection site reactions. The injection formulation is alkaline (pH 11), and extravasation may cause local tissue pain and irritation.[3] Renal impairment has been reported when aciclovir is given in large, fast doses intravenously, due to the crystallisation of aciclovir in the kidneys.
Topical therapy - Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin and/or transient stinging/burning sensations. Infrequent adverse effects include erythema and/or itch.[3]
When applied to the eye, aciclovir is commonly associated (≥1% of patients) with transient mild stinging. Infrequently (0.1–1% of patients), ophthalmic aciclovir is associated with superficial punctate keratitis and/or allergic reactions.[3]
Toxicity - Since aciclovir can be incorporated also into the cellular DNA, it is a chromosome mutagen, therefore, its use should be avoided during pregnancy. However it has not been shown to cause any teratogenic nor carcinogenic effects. The acute toxicity (LD50) of aciclovir when given orally is greater than 1 mg/kg, due to the low oral bioavailability. Single cases have been reported, where extremely high (up to 80 mg/kg) doses have been accidentally given intravenously without causing any major adverse effects.
There have been rare reports of Probenecid, cimetidine, theophylline and mycophenolate mofetil linked to increases in the aciclovir mean half-life and area under the plasma concentration-time curve. According to one case report, co-administration of intravenous aciclovir and lithium caused a four-fold increase in lithium serum concentrations. In these cases an adjustment of the aciclovir dosage is not thought to be necessary given the large therapeutic range of aciclovir.
