Ganciclovir

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Abstract
Ganciclovir is a nucleoside guanosine analogue which incorporates ganciclovir triphosphate (the active moiety) into DNA during elongation, thereby inhibiting viral replication. Comparative studies of pre-emptive and prophylactic ganciclovir therapies in bone marrow transplant (BMT) recipients have shown similar rates of cytomeg-alovirus (CMV) infection, disease and patient mortality. Long term prophylaxis with either oral, or sequential intravenous/oral, ganciclovir has shown efficacy in renal allograft recipients, including high risk patients or those receiving antilymphocyte antibody therapy. A preliminary study indicates that ganciclovir is more efficacious than aciclovir in paediatric patients. Both oral and intravenous prophylactic ganciclovir regimens have shown efficacy compared with no antiviral treatment in lung transplant recipients; initial reports have shown similar efficacy between pre-emptive and prophylactic ganciclovir. Oral ganciclovir monotherapy is as efficacious as sequential intravenous/oral ganciclovir therapy in liver transplant recipients. Pre-emptive treatment was equally as effective as long term ganciclovir prophylaxis in high risk patients. Ganciclovir prophylaxis for 4 weeks appears ineffective in heart allograft recipients treated with antithymocyte globulin. Long term sequential intravenous/oral ganciclovir therapy has shown greater efficacy in preventing CMV disease than sequential ganciclovir/aciclovir therapy in these patients. Initial reports indicate that pre-emptive therapy may be beneficial in this patient group, although this remains to be determined. Ganciclovir in therapeutic dosage regimens generally has acceptable tolerability with adverse effects usually of a haematological or neurological nature. Neutropenia, thrombocytopenia and anaemia are the primary dose-limiting toxicities associated with ganciclovir therapy. Overall, neutropenia occurs less frequently with administration of oral ganciclovir than with intravenous ganciclovir. Monitoring of renal function is recommended as serum creatinine levels may rise during ganciclovir therapy. In addition, ganciclovir prophylaxis appears more cost effective than the majority of other currently available therapies for CMV, with oral ganciclovir more cost effective than intravenous ganciclovir. In conclusion, it is unlikely that a single strategy will be able to be applied to all transplant patients for the prevention of CMV disease. An optimal strategy will probably be a risk-adapted approach. Prophylactic treatment with ganciclovir appears the best strategy to implement in high risk patients; oral ganciclovir formulations may be best employed where lower toxicity is required. Pre-emptive treatment with ganciclovir appears most efficacious in patients identified as lower risk or, in the case of BMT recipients, where lower toxicity may be desirable. Ganciclovir remains an important therapeutic option for the prevention and treatment of CMV disease in transplant recipients. Ganciclovir, a nucleoside guanosine analogue, inhibits viral replication through incorporation of the active moiety ganciclovir triphosphate into the growing chain of viral DNA. In vitro, median ganciclovir concentrations of between 0.1 and 1.6 mg/L are sufficient to inhibit cytomegalovirus (CMV) replication by 50% (IC50). Synergistic activity against CMV has been demonstrated in vitro and in vivo with ganciclovir in combination with a variety of antivirais and immunosuppressants. Ganciclovir-resistant CMV isolates have been both selected in vitro and recovered in vivo from immunocompromised patients treated with antiviral agents and are associated with UL97 and UL54 mutations. Resistance to ganciclovir has been reported in 5.2 and 2.1% of allograft recipients in 2 retrospective analyses. Resistance was associated with a greater total dose of ganciclovir, a higher CMV viral load, a greater number of pneumonitis episodes and a longer period of time prior to detection in lung transplant patients. Resistance to ganciclovir occurred more frequently in donor seropositive/recipient seronegative (D+/R-) patients than in seropositive recipients, and in kidney and pancreas, or pancreas alone allograft recipients than in kidney or liver transplant recipients. In addition, ganciclovir-resistant isolates have been identified in bone marrow transplant (BMT) recipients who had been treated with intravenous ganciclovir after receiving aciclovir prophylaxis. Both oral and intravenous ganciclovir demonstrate linear pharmacokinetics. Mean maximum plasma ganciclovir concentrations of ⁈0.8 mg/L and mean area under the plasma concentration-time curve values of ⁈10.9 mg/L · h were seen following oral administration of ganciclovir 1000mg. The estimated oral bioavailability of ganciclovir is ⁈7% in both adult and paediatric patients. Steady-state drug trough concentrations following administration of oral ganciclovir (1000mg 3 times daily) were at least within the IC50 range. Ganciclovir shows minimal binding to plasma proteins. Both oral and intravenous ganciclovir are principally excreted via the kidneys with a terminal elimination half-life of ⁈6.0 to 9.7 hours. Renal dysfunction reduces elimination of ganciclovir and dosage reductions are required in these patients. Allogeneic bone marrow transplantation: Intravenous ganciclovir 5 mg/kg prophylaxis administered 5 times weekly was more efficacious than a 3-times-weekly regimen, with significantly lower rates of CMV infection, CMV disease and CMV-related mortality. Similar rates of CMV infection, disease and patient mortality have been observed with prophylactic (all patients) and pre-emptive (initiated on detection of asymptomatic CMV infection) treatments in comparative studies. The use of intravenous aciclovir prior to transplantation did not affect these outcomes. Pre-emptive therapy with intravenous ganciclovir (5 mg/kg twice daily) has shown equivalent efficacy to that with intravenous foscarnet (60 to 90 mg/kg twice daily) with respect to the incidence of CMV disease and CMV-related patient mortality in randomised comparisons. D+ and/or R+ patients treated pre-emptively had similar CMV infection and mortality outcomes to D-/R- patients receiving no antiviral treatment, although rates of CMV disease were higher. Kidney transplantation: Long term (3-month) prophylaxis with either oral (1500 to 3000mg daily), or sequential intravenous/oral ganciclovir (5 mg/kg/day, then 3000 mg/day) has shown greater efficacy against CMV infection than long term oral aciclovir 2400mg daily, short term intravenous ganciclovir or no antiviral prophylaxis in nonblind comparative studies. Rates of CMV disease were lower in patients who received prolonged ganciclovir prophylaxis than in patients who did not, even in the subgroups which received antilymphocyte antibody (ALA) therapy. Similarly, rates of acute rejection were lower, although this may be attributable to differences in baseline immunosuppression. Prolonged oral ganciclovir was more effective than no antiviral prophylaxis over a range of dosages in donor and/or recipient seropositive patients; higher dosages in patients receiving ALA therapy were also effective. Monoclonal antibody immunosuppression resulted in significantly higher rates of CMV infection in those receiving intravenous ganciclovir therapy, although no differences in tissue-invasive CMV disease or 12-month survival were seen. Combination oral ganciclovir/aciclovir prophylaxis was more effective than intravenous immunoglobulin/aciclovir at preventing CMV disease in a retrospective analysis. Higher rates of CMV disease were observed in paediatric patients receiving aciclovir 1500 than ganciclovir 1800 mg/day in a small retrospective trial. Results of a nonblind study of pre-emptive therapy suggest similar efficacy between oral aciclovir 1200mg daily and oral ganciclovir 1000mg daily, although tissue-invasive CMV disease was only confirmed in patients receiving antirejection therapy. Identified risk factors for recurrent episodes of CMV were having diabetes mellitus, use of acute rejection treatment, receiving a cadaver organ and receiving a simultaneous kidney-pancreas transplant. A greater number of D+/R-patients than those with other serologies experienced episodes of CMV recurrence. Lung transplantation: Long term oral (1000mg 3 times daily) and intravenous ganciclovir (5 mg/kg twice daily) prophylactic regimens have shown significant reductions in the incidence of CMV disease compared with no antiviral treatment. Patients receiving once daily ganciclovir prophylaxis had lower rates of 12-month mortality than patients receiving ganciclovir 3 times weekly, although this was not attributable to a reduction in CMV-related disease. A preliminary study demonstrated equivalent efficacy between pre-emptive treatment and prophylaxis in D-/R+ and D+/R- patients. An initial investigation employing deferred treatment reported a lower incidence of CMV disease, and no CMV disease in seropositive patients, compared with a group receiving no antiviral prophylaxis. Liver transplantation: Prolonged administration of oral ganciclovir (1000mg 3 times daily) was effective in significantly reducing CMV infection and disease in a double-blind, placebo-controlled study. A preliminary retrospective report indicated that prolonged oral ganciclovir prophylaxis was significantly more efficacious than oral aciclovir (800mg twice daily) in D+/R+ and D-/R+ patients, but not in D+/R- patients. Similar rates of CMV infection and disease were observed in patients receiving prophylaxis with either sequential intravenous ganciclovir/oral aciclovir, or oral ganciclovir monotherapy followed by oral aciclovir. Pre-emptive treatment was equally as efficacious as long term ganciclovir prophylaxis in D+/R- patients. Fewer patients (including high risk patients) subsequently developed CMV infection and disease following pre-emptive treatment with oral ganciclovir than after placebo in a double-blind, placebo-controlled trial. Similar rates of CMV infection and disease were observed in patients receiving pre-emptive treatment with either oral or intravenous ganciclovir in a nonblind comparison. Heart transplantation: Prophylaxis with intravenous ganciclovir 5 mg/kg twice daily for 4 weeks showed no benefit on CMV morbidity and mortality in high risk patients receiving antithymocyte globulin (ATG) compared with patients receiving no antiviral prophylaxis. Long term sequential intravenous/oral ganciclovir has shown greater efficacy in preventing CMV disease than sequential intravenous ganciclovir/oral aciclovir, and similar efficacy to intravenous CMVIg/oral aciclovir prophylaxis. Data regarding the use of pre-emptive treatment in heart transplantation are still limited. Preliminary data suggest that preemptive treatment may reduce the incidence of CMV disease compared with patients receiving ganciclovir prophylaxis. Adverse effects associated with ganciclovir therapy are generally of a haematological nature. Dosage reduction is most commonly indicated for neutropenia, thrombocytopenia and anaemia. BMT recipients are especially susceptible to neutropenia; neutropenia usually occurs early in treatment and is generally reversible. Prolonged administration of intravenous ganciclovir in BMT recipients is associated with an increase in opportunistic infections. No significant differences in the incidences of thrombocytopenia and leucopenia or impaired renal function were observed between patients receiving intravenous ganciclovir and those receiving intravenous foscarnet. Severe neutropenia was observed significantly less often in patients treated with foscarnet than in those receiving ganciclovir. Elevated serum creatinine levels have been observed in patients receiving intravenous ganciclovir in controlled clinical trials; renal function monitoring is recommended. Neurological adverse effects (e.g. headache, confusion) have also been reported in transplant patients. Ganciclovir is available for use in the prevention and treatment of CMV disease in bone marrow and solid organ transplant recipients. The recommended dosage regimen for prophylaxis with oral ganciclovir for patients with normal renal function is 1000mg 3 times daily with food. Intravenous ganciclovir (5 mg/kg) should be administered every 12 hours for 7 to 14 days, followed by either 5 mg/kg once daily 7 days per week or 6 mg/kg once daily 5 days per week. Dosages of ganciclovir should be adjusted according to renal dysfunction and tolerability and the drug is contraindicated in patients with an absolute neutrophil count of 3/μl. Caution is also advised in patients receiving concomitant therapy with cyclosporin, amphotericin B or other nephrotoxic drugs. Overall, prophylaxis with ganciclovir (both intravenous and oral) or oral valaciclovir is cost effective compared with other currently available therapies for the prevention of CMV infection and disease in solid organ transplant recipients. Furthermore, prophylaxis with oral ganciclovir appears more cost effective than prophylaxis with intravenous ganciclovir.