Acyclovir

Acyclovir (aciclovir) is a guanosine analogue active against herpes simplex virus 1 and 2 and varicella zoster virus, with weaker activity against Epstein-Barr virus. It is the usual drug for herpes simplex encephalitis and neonatal herpes, and for zoster in immunocompromised patients. Oral bioavailability is low, so valaciclovir is often preferred. Intravenous use carries a risk of crystal nephropathy.

Class. Nucleoside analogue antiviral.

Mechanism. Phosphorylated by viral thymidine kinase and then host kinases to acyclovir triphosphate, which inhibits viral DNA polymerase and terminates the DNA chain. Resistance arises through thymidine kinase deficiency.

Pharmacokinetics. Oral bioavailability 10 to 20%, half life 2.5 to 3 hours, wide distribution including cerebrospinal fluid (about 50% of plasma), renal excretion of 60 to 90% unchanged.

Genital herpes.

• First episode: 400 mg orally three times daily (or 200 mg five times daily) for 7 to 10 days.
• Recurrent episode: 400 mg three times daily for 3 to 5 days, started at the first sign.
• Suppression: 400 mg twice daily; 400 mg twice daily in HIV infection.

Herpes zoster. 800 mg orally five times daily for 7 days, started within 72 hours of the rash; for zoster ophthalmicus, the same for 7 to 10 days.

Varicella. Adults and adolescents 800 mg five times daily for 5 days; children 20 mg/kg four times daily (maximum 800 mg) for 5 days.

Herpes simplex encephalitis. 10 mg/kg intravenously every 8 hours for 14 to 21 days.

Immunocompromised mucocutaneous disease or zoster. 5 to 10 mg/kg intravenously every 8 hours for 7 to 10 days.

Neonatal herpes. 20 mg/kg intravenously every 8 hours for 14 days (skin, eye, mouth) or 21 days (central nervous system or disseminated).

Maximum: oral 4 g daily; intravenous 30 mg/kg daily. Loading dose: none. Titration: by kidney function.

Contraindications. Hypersensitivity to acyclovir or valaciclovir.

Serious adverse effects. Crystal nephropathy and acute kidney injury (rapid intravenous infusion, dehydration), encephalopathy, hallucinations and seizures (particularly in renal impairment), thrombotic microangiopathy at high doses in advanced HIV or transplantation, and phlebitis.

Common adverse effects. Nausea, vomiting, headache, diarrhoea and, with intravenous use, local inflammation.

Interactions. Probenecid and cimetidine raise levels; mycophenolate levels rise; nephrotoxic drugs add to kidney injury; theophylline levels rise.

Common prescribing errors. Intravenous bolus, poor hydration, full dose in kidney failure, and dosing on actual weight in obesity (use ideal or adjusted weight).

Special groups.

• Pregnancy: used when indicated; no increase in major malformation.
• Breastfeeding: compatible.
• Children: weight-based dosing; neonates need specialist dosing.
• Older adults: reduced clearance; adjust for kidney function.
• Kidney impairment (oral): CrCl 10 to 25 mL/min: zoster dose 800 mg three times daily; under 10: 800 mg twice daily; herpes simplex under 10: 200 mg twice daily.
• Kidney impairment (intravenous): CrCl 25 to 50: every 12 hours; 10 to 25: every 24 hours; under 10: halve the dose every 24 hours.
• Liver impairment: no adjustment.

Formulations. Tablets 200 mg, 400 mg and 800 mg; dispersible tablets; oral suspension 200 mg/5 mL; intravenous powder 250 mg and 500 mg; cream 5%.

Administration. Oral doses with or without food and ample fluid. Intravenous dose in 100 mL of 0.9% sodium chloride over at least 1 hour, with hydration.

Baseline. Creatinine and weight; cerebrospinal fluid herpes simplex PCR in suspected encephalitis (treatment is not delayed for results).

Monitoring. Creatinine every 2 to 3 days on intravenous therapy; urine output; neurological state.

Stopping thresholds. Reduce dose and interval for rising creatinine; stop for severe neurotoxicity or crystalluria with kidney injury.

Referral and escalation. Urgent admission for suspected encephalitis, neonatal herpes, disseminated infection or ophthalmic zoster.