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Aciclovir, an antiviral medication, is primarily used to treat infections caused by the herpes simplex virus, chickenpox, and shingles. It can be taken orally, applied as a cream, or injected. Common side effects include nausea and diarrhea, while serious risks involve kidney problems and low platelets. Aciclovir is considered safe during pregnancy and breastfeeding. As a nucleoside analogue mimicking guanosine, it works by inhibiting viral DNA production. Patented by Burroughs Wellcome in 1974, it’s on the WHO’s List of Essential Medicines and widely available as a generic medication.

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Medical use

Aciclovir acts by inhibiting viral DNA replication and is used for the treatment of herpes simplex virus (HSV) and varicella zoster virus infections, including:212223

It has not been found to be effective against Epstein–Barr virus and its associated infectious mononucleosis.25 Aciclovir risks causing resistance to antiviral agents, and in 1% to 10% of cases can cause unpleasant side effects.26

Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles.27 In those with herpes of the eye, aciclovir may be more effective and safer than idoxuridine.28 It is unclear if aciclovir eye drops are more effective than brivudine eye drops.29

Intravenous aciclovir is effective in treating severe medical conditions caused by different species of the herpes virus family, including severe localized infections of the herpes virus, severe genital herpes, chickenpox and herpesviral encephalitis. It is also effective in systemic or traumatic herpes infections, eczema herpeticum, and herpesviral meningitis. Reviews of research dating from the 1980s show there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak.30 Research shows effectiveness of topical aciclovir in both the early and late stages of the outbreak as well as improving methodologically and in terms of statistical certainty from previous studies.31 Aciclovir trials show that this agent has no role in preventing HIV transmission, but it can help slow HIV disease progression in people not taking anti-retroviral therapy (ART). This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir and cotrimoxazole, in people with HIV.32

Pregnancy

The CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.33 For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.34

Studies in mice, rabbits, and rats (with doses more than 10 times the equivalent of that used in humans) given during organogenesis have failed to demonstrate birth defects.35 Studies in rats in which they were given the equivalent to 63 times the standard steady-state human concentrations of the drug36 on day 10 of gestation showed head and tail anomalies.37

Aciclovir is recommended by the CDC for treatment of varicella during pregnancy, especially during the second and third trimesters.38

Aciclovir is excreted in breast milk, therefore it is recommended that caution should be used in breast-feeding women. It has been shown in limited test studies that the nursing infant is exposed to approximately 0.3 mg/kg/day following oral administration of aciclovir to the mother. If nursing mothers have herpetic lesions near or on the breast, breast-feeding should be avoided.3940

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,41 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.424344

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.454647

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.48 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.49

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.50

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.51

Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.52

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.53

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.54

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).55 ACV-TP is a very potent inhibitor of viral DNA replication. ACV-TP competitively inhibits and inactivates the viral DNA polymerase.56 Its monophosphate form also incorporates into the viral DNA, resulting in chain termination.575859

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.6061

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:6263

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.64 Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%.65 The elimination half-life (t1/2) of aciclovir depends according to age group; neonates have a t1/2 of 4 hours, children 1–12 years have a t1/2 of 2–3 hours whereas adults have a t1/2 of 3 hours.66

Chemistry

Details of the synthesis of aciclovir were first published by scientists from the University at Buffalo.67

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.68 This synthesis and other methods for preparing the compound have been reviewed.69

History

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity.70 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.717273 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.74 Later, Schaeffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion.75 A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979.76 Vince later invented abacavir, an nRTI drug for HIV patients.77 Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir.78

A related prodrug form, valaciclovir came into medical use in 1995. It is converted to aciclovir in the body after absorption.79

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).8081

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.82

Notes

Further reading

References

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