Mechanism of Action: Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses. Ganciclovir has been shown to be active against cytomegalovirus (CMV) and herpes simplex virus (HSV) in human clinical studies.

To achieve anti-CMV activity, ganciclovir is phosphorylated first to the monophosphate form by a CMV-encoded (UL97 gene) protein kinase homologue, then to the di- and triphosphate forms by cellular kinases. Ganciclovir triphosphate concentrations may be 100-fold greater in CMV-infected than in uninfected cells, indicating preferential phosphorylation in infected cells. Ganciclovir triphosphate, once formed, persists for days in the CMV-infected cell. Ganciclovir triphosphate is believed to inhibit viral DNA synthesis by (1) competitive inhibition of viral DNA polymerases; and (2) incorporation into viral DNA, resulting in eventual termination of viral DNA elongation.

Antiviral Activity: The median concentration of ganciclovir that inhibits CMV replication (IC50) in vitro (laboratory strains or clinical isolates) has ranged from 0.02 to 3.48 mcg/mL. Ganciclovir inhibits mammalian cell proliferation (CIC50) in vitro at higher concentrations ranging from 30 to 725 mcg/mL. Bone marrow-derived colony-forming cells are more sensitive (CIC50 0.028 to 0.7 mcg/mL). The relationship of in vitro sensitivity of CMV to ganciclovir and clinical response has not been established.

Clinical Antiviral Effect of Ganciclovir Capsules:In trials comparing ganciclovir IV with ganciclovir capsules for the maintenance treatment of CMV retinitis in patients with AIDS, serial urine cultures and other available cultures (semen, biopsy specimens, blood and others) showed that a small proportion of patients remained culture-positive during maintenance therapy with no statistically significant differences in CMV isolation rates between treatment groups.

A study of ganciclovir capsules (1000 mg q8h) for prevention of CMV disease in individuals with advanced HIV infection (ICM 1654) evaluated antiviral activity as measured by CMV isolation in culture; most cultures were from urine. At baseline, 40% (176/436) and 44% (92/210) of ganciclovir and placebo recipients, respectively, had positive cultures (urine or blood). After 2 months on treatment, 10% vs 44% of ganciclovir vs placebo recipients had positive cultures.

Viral Resistance: The current working definition of CMV resistance to ganciclovir in in vitro assays is IC50 > 3 mcg/mL (12 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. In a controlled study of oral ganciclovir for prevention of AIDS-associated CMV disease, 364 individuals had one or more cultures performed after at least 90 days of ganciclovir treatment. Of these, 113 had at least one positive culture. The last available isolate from each subject was tested for reduced sensitivity, and 2 of 40 were found to be resistant to ganciclovir. These resistant isolates were associated with subsequent treatment failure for retinitis.

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy. The principal mechanism of resistance to ganciclovir in CMV is the decreased ability to form the active triphosphate moiety; resistant viruses have been described that contain mutations in the UL97 gene of CMV that controls phosphorylation of ganciclovir. Mutations in the viral DNA polymerase have also been reported to confer viral resistance to ganciclovir.