Aciclovir

Adverse effects

Systemic therapy

Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include nausea, vomiting, diarrhea, encephalopathy (with IV use only), injection site reactions (with IV use only) and 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, hair loss, rash and weakness. Rare adverse effects (<0.1% of patients) include coma, seizures, neutropenia, leukopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, thrombotic thrombocytopenic purpura, anaphylaxis, and Cotard's syndrome.

Intravenous aciclovir may cause reversible nephrotoxicity in up to 5% to 10% of patients because of precipitation of aciclovir crystals in the kidney. Aciclovir crystalline nephropathy is more common when aciclovir is given as a rapid infusion and in patients with dehydration and preexisting renal impairment. Adequate hydration, a slower rate of infusion, and dosing based on renal function may reduce this risk.

The aciclovir metabolite 9-Carboxymethoxymethylguanine (9-CMMG) has been shown to play a role in neurological adverse events, particularly in older people and those with reduced renal function.

Topical therapy

Aciclovir topical cream is commonly associated (≥1% of patients) with dry or flaking skin or transient stinging/burning sensations. Infrequent adverse effects include erythema or itch. 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 or allergic reactions.

Drug interactions

Ketoconazole: In-vitro replication studies have found a synergistic, dose-dependent antiviral activity against HSV-1 and HSV-2 when given with aciclovir. However, this effect has not been clinically established and more studies need to be done to evaluate the true potential of this synergy.

Probenecid: Reports of increased half-life of aciclovir, as well as decreased urinary excretion and renal clearance have been shown in studies where probenecid is given simultaneously with aciclovir.

Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.

Zidovudine: Although administered often with aciclovir in HIV patients, neurotoxicity has been reported in at least one patient who presented with extreme drowsiness and lethargy 30–60 days after receiving IV aciclovir; symptoms resolved when aciclovir was discontinued.

Detection in biological fluids

Aciclovir may be quantitated in plasma or serum to monitor for drug accumulation in patients with renal dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.

Mechanism of action

Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP, also known as aciclo-GTP). ACV-TP is a very potent inhibitor of viral DNA replication. ACV-TP competitively inhibits and inactivates the viral DNA polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination.

Resistance

Resistance to aciclovir is rare in people with healthy immune systems but is more common (up to 10%) in people with immunodeficiencies on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase or DNA polymerase, altering substrate sensitivity.

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:

• Herpes simplex virus type I (HSV-1)
• Herpes simplex virus type II (HSV-2)
• Varicella zoster virus
• Epstein–Barr virus
• Human cytomegalovirus – least activity

Pharmacokinetics

Aciclovir is poorly water-soluble and has poor oral bioavailability (15–30%), hence intravenous administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. According to the Biopharmaceutical Classification System, aciclovir is a Class III drug, i.e., soluble with low intestinal permeability. Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%. The elimination half-life (t_1/2) of aciclovir depends according to age group; neonates have a t_1/2 of 4 hours, children 1–12 years have a t_1/2 of 2–3 hours whereas adults have a t_1/2 of 3 hours.

Chemistry

Details of the synthesis of aciclovir were first published by scientists from the University at Buffalo.

In the first step shown, 2,6-dichloropurine was alkylated with 1-benzoyloxy-2-chloromethoxyethane. The chlorine group at the 6-position of the heterocyclic ring is more reactive than the chlorine at the 2-position, hence it can be selectively replaced by an amino group, which was then converted to an amide using nitrous acid. Finally, the remaining chlorine was replaced by the amino group of aciclovir using ammonia in methanol. This synthesis and other methods for preparing the compound have been reviewed.

History

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Since the discovery in the mid-1970s, it has been used as an effective drug for the treatment of infections caused by most known species of the herpesvirus family, including herpes simplex and varicella zoster viruses. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of aciclovir. It was codiscovered by Howard Schaeffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity. Later, Schaeffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion. A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979. Vince later invented abacavir, an nRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir.

A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption.

In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older).

Veterinary use

Aciclovir is not commonly used in veterinary medicine: there is no evidence of its efficacy for most herpesviruses. In horses the oral bioavailability is just 3% and intravenous use is required to treat equine herpes virus 1. In cats the drug is poorly absorbed and produces toxicity and feline herpes virus 1 is resistant to it.

Society and culture

Names

It was originally marketed as Zovirax; patents expired in the 1990s and since then it has been generic and is marketed under many brand names worldwide.