Herpesvirus Antivirals

Herpesvirus antivirals are guanosine analogues and related agents that inhibit viral DNA polymerase. They control herpes simplex, varicella zoster and cytomegalovirus infection but do not clear latent virus, so recurrence follows when treatment stops. Their benefit depends on early use, within 72 hours of the first lesion for most skin disease.

Mechanism.

• Aciclovir, valaciclovir and famciclovir are phosphorylated first by viral thymidine kinase, so they act selectively in infected cells and are inactive against cytomegalovirus.
• Ganciclovir and valganciclovir are activated by the cytomegalovirus UL97 kinase.
• Foscarnet binds the polymerase directly and needs no activation. Cidofovir needs only host kinases.
• Letermovir blocks the cytomegalovirus terminase complex. Maribavir inhibits the UL97 kinase.

Pharmacokinetics. Aciclovir has oral bioavailability of about 20%. Valaciclovir is its prodrug and gives 3 to 5 times higher exposure. Famciclovir is converted to penciclovir. All are cleared by the kidney.

• Aciclovir: oral and intravenous; the choice for encephalitis and neonatal disease.
• Valaciclovir: twice or three times daily dosing; same indications as oral aciclovir.
• Famciclovir: herpes zoster and genital herpes; twice or three times daily.
• Ganciclovir (intravenous) and valganciclovir (oral): cytomegalovirus disease and prophylaxis; marrow toxic.
• Foscarnet and cidofovir: cytomegalovirus or aciclovir-resistant herpes simplex; nephrotoxic.
• Letermovir: prophylaxis in transplant recipients. Maribavir: cytomegalovirus refractory to other agents.

Aciclovir (adult).

• Herpes simplex encephalitis: 10 mg/kg intravenously every 8 hours for 14 to 21 days. Neonatal herpes: 20 mg/kg every 8 hours for 14 to 21 days.
• Genital herpes first episode: 400 mg orally three times daily for 7 to 10 days. Suppression: 400 mg twice daily.
• Herpes zoster or adult chickenpox: 800 mg orally five times daily for 7 days. Severe disease or immunocompromise: 10 mg/kg intravenously every 8 hours.
• Child chickenpox: 20 mg/kg four times daily (maximum 800 mg) for 5 days.

Valaciclovir. Genital herpes first episode 500 mg to 1 g twice daily for 7 to 10 days; recurrent 500 mg twice daily for 3 days; suppression 500 mg daily. Herpes zoster 1 g three times daily for 7 days.

Famciclovir. Herpes zoster 500 mg three times daily for 7 days; genital herpes first episode 250 mg three times daily for 5 days.

Cytomegalovirus.

• Valganciclovir 900 mg twice daily for induction (21 days), then 900 mg daily; prophylaxis 900 mg daily. Ganciclovir 5 mg/kg intravenously every 12 hours for 14 to 21 days, then 5 mg/kg daily.
• Foscarnet 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 2 to 3 weeks with saline pre-hydration, for ganciclovir resistance or marrow failure.

Renal adjustment. Intravenous aciclovir: creatinine clearance 25 to 50 mL/min every 12 hours; 10 to 25 mL/min every 24 hours; under 10 mL/min half the dose every 24 hours. Valaciclovir 1 g three times daily becomes twice daily at 30 to 49 mL/min and once daily at 10 to 29 mL/min. Valganciclovir induction falls to 450 mg twice daily at 40 to 59 mL/min.

Region. In East Africa, herpes zoster, severe genital herpes and cytomegalovirus retinitis occur mainly with advanced HIV disease. Ganciclovir and foscarnet supply is limited, so ophthalmology and infectious diseases input is needed early.

Contraindications. Hypersensitivity. Valganciclovir with neutrophils under 0.5 x 10^9/L or platelets under 25 x 10^9/L.

Serious adverse effects. Aciclovir: crystal nephropathy with rapid infusion or dehydration, and confusion or seizures in renal failure. Ganciclovir: neutropenia, anaemia, thrombocytopenia, and gonadal toxicity. Foscarnet: nephrotoxicity, hypocalcaemia, hypomagnesaemia, seizures. Cidofovir: proximal tubular injury; given with probenecid and hydration.

Monitoring. Creatinine and hydration with aciclovir. Full blood count twice weekly during ganciclovir or valganciclovir induction, then weekly. Foscarnet: electrolytes, calcium, magnesium and creatinine at least twice weekly.

Interactions. Ganciclovir with zidovudine (additive marrow toxicity) and mycophenolate. Foscarnet and cidofovir with other nephrotoxic drugs. Probenecid raises aciclovir levels.

Special groups.

• Pregnancy: aciclovir and valaciclovir are used; suppression from 36 weeks lowers genital lesions at delivery. Ganciclovir is avoided unless sight or life is threatened.
• Breastfeeding: aciclovir and valaciclovir are compatible.
• Children: weight-based dosing; neonates need the 20 mg/kg regimen.
• Older adults: neurotoxicity risk, so reduce for renal function.

Referral and escalation. Refer suspected encephalitis, ocular herpes, cytomegalovirus disease, and lesions failing 7 to 10 days of aciclovir (consider resistance).