Resistance to ganciclovir increases with duration of use. The more common mutation, in UL97, results in decreased levels of the triphosphorylated (ie, active) form of ganciclovir. The less common UL54 mutation in DNA polymerase results in higher levels of resistance and potential cross-resistance with cidofovir and foscarnet. Antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically.
The most common adverse effect of intravenous ganciclovir treatment is myelosuppression, which although reversible may be dose-limiting. Other potential adverse effects are nausea, diarrhea, fever, rash, headache, insomnia, and peripheral neuropathy. Central nervous system toxicity (confusion, seizures, psychiatric disturbance) and hepatotoxicity have been rarely reported. Intravitreal ganciclovir has been associated with vitreous hemorrhage and retinal detachment. Ganciclovir is mutagenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical significance of these preclinical data is unclear.
Levels of ganciclovir may rise in patients concurrently taking probenecid or trimethoprim. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.
Valganciclovir is an l-valyl ester prodrug of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly hydrolyzed to ganciclovir by esterases in the intestinal wall and liver.
Valganciclovir has a bioavailability of 60% and should be taken with food. The AUC0–24h resulting from oral valganciclovir (900 mg once daily) is similar to that after 5 mg/kg once daily of intravenous ganciclovir and approximately 1.65 times that of oral ganciclovir. The major route of elimination is renal, through glomerular filtration and active tubular secretion. Plasma concentrations of valganciclovir are reduced ~50% by hemodialysis.
Valganciclovir is as effective as intravenous ganciclovir for the treatment of CMV retinitis and is also indicated for the prevention of CMV disease in high-risk solid organ and bone marrow transplant recipients. Adverse effects, drug interactions, and resistance patterns are the same as those associated with ganciclovir.
Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation. Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2.
Foscarnet is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Cerebrospinal fluid concentrations are 43–67% of steady-state serum concentrations. Although the mean plasma half-life is 3–7 hours, up to 30% of foscarnet may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown. Clearance of foscarnet is primarily renal and is directly proportional to creatinine clearance. Serum drug concentrations are reduced ~50% by hemodialysis.