Ganciclovir

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Abstract
The antiviral nucleoside analogue ganciclovir has demonstrated in vitro activity against human cytomegalovirus and effectively treats infection caused by this organism in various immunocompromised patient groups. The drug prolongs time to progression in patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus retinitis although life-long maintenance therapy is required. Direct comparisons between ganciclovir and foscarnet in this indication are few; nevertheless, the 2 drugs appear to have equal therapeutic efficacy in treating cytomegalovirus retinitis although results from 1 study in this indication suggest that foscarnet has an advantage in terms of patient survival. AIDS-related gastrointestinal and, to a lesser extent, pulmonary cytomegalovirus infection also respond to treatment with ganciclovir; maintenance therapy does not appear to be required in these latter 2 indications. Ganciclovir is also useful against cytomegalovirus infection in organ transplant recipients. The drug is most effective when given prophylactically or as early treatment for asymptomatic infection in bone marrow transplant recipients; treatment of established infection is less ef-fective in this patient group. However, established infection in solid organ transplant recipients appears to respond to treatment with ganciclovir. The most common adverse event during ganciclovir therapy is haematological toxicity but this appears to be readily reversible on discontinuation of the drug. In addition, coadministration of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage CSF (GM-CSF) has been shown to prevent ganciclovir-associated neutropenia. Thus, ganciclovir is a valuable treatment for cytomegalovirus infection in patients with AIDS and in organ transplant recipients. Further studies comparing ganciclovir and foscarnet — ideally incorporating the use of G-CSF or GM-CSF to prevent ganciclovir-associated neutropenia and assessing survival as I end-point — should further clarify the relative role of ganciclovir as treatment or prophylaxis for cytomegalovirus infection. Ganciclovir has demonstrated good in vitro activity against human cytomegalovirus and is considerably more potent than aciclovir (acyclovir) against this or-ganism. The combination of ganciclovir and foscarnet synergistically inhibited replication of human cytomegalovirus in vitro. The presence of ganciclovir reduced the in vitro activity of zidovudine against human immunodeficiency virus in 2 studies but enhanced it in another. Ganciclovir has demonstrated in vivo efficacy in animal models including disseminated and pulmonary murine cytomegalovirus infection and murine cyto-megalovirus encephalitis. Cytomegalovirus strains resistant to ganciclovir appear to have point mutations in a gene encoding a kinase that phosphorylates ganciclovir and another encoding a viral DNA polymerase. The true incidence of resistance to ganciclovir is still unclear; however, the clinical impact of resistance has been minimal to date. Intravenous administration of 1 to 5 mg/kg doses of ganciclovir produces linearly increasing peak plasma concentrations; no evidence of accumulation has been observed in patients with normal renal function. Intravitreal administration of ganciclovir produces high concentrations in vitreal fluid with minimal, if any, systemic absorption. The bioavailability of orally administered ganciclovir was approximately 6% after administration of 10 mg/kg, or 1000mg doses. Concentrations of ganciclovir in cerebrospinal fluid were lower than those reported in serum after intravenous administration. Ganciclovir has a steady-state volume of distribution of approximately 32 to 44.5 L/1.73m2. Almost 100% of an intravenously administered dose of ganciclovir is excreted in the urine of patients with normal renal function. The drug has an elimination half-life of between 2 and 4 hours after intravenous administration of 1 to 5 mg/kg doses. Clearance decreases linearly with decreasing creatinine clearance in patients with renal dysfunction. Ganciclovir is effectively cleared by haemodialysis. Symptomatic cytomegalovirus infection occurs predominantly in immunocompromised patients; thus, most studies evaluating the efficacy of ganciclovir against cytomegalovirus infection have been conducted in this patient group. Many noncomparative trials suggest that intravenous ganciclovir is an effective treatment for acquired immune deficiency syndrome (AIDS)-related cytomegalovirus retinitis. Rapid progression of retinitis has been observed when ganciclovir therapy is deferred in patients whose retinitis is not an immediate threat to sight. Combination therapy with ganciclovir and either foscarnet or (to a lesser extent) cytomegalovirus immune globulin appears to be effective, especially in patients refractory to ganciclovir monotherapy. Few direct comparisons of ganciclovir and foscarnet have been conducted. Although the 2 drugs appear to be similar in terms of efficacy against cytomegalovirus retinitis, the Studies of Ocular Complications of AIDS (SOCA) research group and AIDS clinical trials group (ACTG) trial revealed a survival advantage in foscarnet versus ganciclovir recipients in this indication. Intravitreal injection of ganciclovir has been shown to be as effective as intravenous administration for treatment of AIDS-related cytomegalovirus retinitis and has proven useful in patients unable to tolerate systemic administration. Preliminary studies of sustained-release intraocular formulations designed to improve patient acceptability have provided favourable results as have trials evaluating the use of oral ganciclovir maintenance therapy in patients with cytomegalovirus retinitis. Limited data suggest that ganciclovir may be an effective treatment for AIDS-related gastrointestinal cytomegalovirus infection and, to a lesser extent, AIDS-related cytomegalovirus pneumonia. A number of studies have shown ganciclovir to be a useful treatment for established cytomegalovirus infection in adult organ transplant recipients. Results from a small number of studies in paediatric transplant recipients are also favourable. The drug has been studied as prophylaxis, early treatment of asymptomatic infection and treatment for established symptomatic infection. Although more studies are required to confirm initial findings, it appears that bone marrow transplant recipients benefit most from prophylaxis or early treatment; results from studies evaluating the treatment of established cytomegalovirus infection in this patient group are less favourable. However, treatment of established infection is effective in solid organ transplant recipients. Results from a single pilot study suggest that 3 months’ maintenance therapy with ganciclovir after 2 weeks’ induction therapy improves outcome in infants with congenital cytomegalovirus infection compared with 2 weeks’ therapy alone. Neutropenia and thrombocytopenia are the most common adverse events in patients receiving ganciclovir, occurring, respectively, in 38 and 20% of patients who received ganciclovir during the compassionate use programme. Haematological adverse events during ganciclovir therapy are usually reversible on withdrawal of the drug. Preliminary studies suggest that concomitant administration of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage CSF (GM-CSF) can prevent ganciclovir-associated neutropenia and confirmatory results are awaited with interest. Less common adverse events reported during ganciclovir therapy include central nervous system symptoms, abnormal liver function values, fever and rash. The toxicity profiles of ganciclovir and zidovudine overlap and reduction of the zidovudine dosage is sometimes required in patients receiving the 2 drugs concomitantly. Concurrent administration of ganciclovir with other drugs that inhibit replication in rapidly dividing cell populations is not recommended. The recommended dosage regimen for ganciclovir as treatment for patients with cytomegalovirus retinitis and normal renal function is 5 mg/kg (as a constant intravenous infusion over 1 hour) every 12 hours for 14 to 21 days. If required, maintenance doses of 5 mg/kg/day (as a constant intravenous infusion over 1 hour) 7 days/week, or 6 mg/kg/day (similarly administered) 5 days/week, can be given following the initial induction regimen. The same dosages with a shorter (7 to 14 days) induction regimen are recommended for the prevention of cytomegalovirus disease in transplant recipients. The drug should be infused over a 1-hour period. Subcutaneous or intramuscular administration is not recommended. Dosage reductions according to creatinine clearance are recommended in patients with renal impairment. Intravitreal ganciclovir is generally given at a dose of 200 to 400μg once or twice weekly during induction therapy, weekly maintenance doses are then given. Extreme caution is warranted before ganciclovir is used in children, because the safety of the drug in this population has not been established.