Prevention of Cytomegalovirus (CMV) disease in liver transplant patients: studies of antiviral prophylaxis and pre-emptive therapy.

INTERVENTION: High risk group and prophylaxis group are assigned to receive 900mg (two 450mg tablets) of valganciclovir (Valcyte) once daily for 3 months commenced within 72 hrs after liver transplantation and monitored regularly for CMV infection/disease. Dose will be changed based on creatinine clearance. Pre‐ Emptive group Monitored regularly for CMV infection only. If this occurs patients will be given 5 mg/kg intravenously over one hour, of ganciclovir (GCV) twice daily for 2 weeks CMV infection is determined on testing with Qualitative Polymerease chain reaction (PCR) Valganciclovir doses as per creatinine clearance: Creatinine clearance >/=60 ml/min 900mg daily Creatinine clearance 40‐59 ml/min 450mg daily Creatinine clearance 25‐39 ml/min 450mg second daily Creatinine clearance 10‐24 ml/min 450 mg twice weekly CONDITION: CMV and liver transplantation PRIMARY OUTCOME: CMV infection and disease in lower‐risk liver transplant recipients in the observational/preemptive therapy arm: ; ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. Incidence of CMV infection and disease in the high risk group treated with prophylactic valganciclovir: ; ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. Primary incidence of CMV infection and disease in both arms: ; Identification of active CMV replication in patients within either the prophylactic or pre‐emptive group will be based on: ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. SECONDARY OUTCOME: Assess the association between host factors and outcomes of CMV infection: ; ; All unexpected untoward adverse events will be recorded. ; They are defined as: ; Any untoward, undesired unplanned clinical event such as physical signs, symptoms, disease or laboratory observation including: ; Worsening of a pre‐existing condition ; Overdose whether accidental or intentional ; An event that causes discontinuation of the trial product for any reason Assess viral characteristics of infection in the two largest liver transplant units in Australia: ; ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. Determine incidence of antiviral resistance CMV in liver transplant recipients receiving valganciclovir: ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 4. Seroconversion in seronegative recipients. Determine and compare the incidence of other opportunistic viral infections, Human herpesvirus 6 (HHV‐6) and human herpesvirus 7 (HHV‐7) in the blood using a multiplex qualitative PCR Determine efficacy of valganciclovir prophylaxis, in terms of timing and duration, for prevention of CMV disease in liver transplant recipients: ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. Determine quantitative polymerase chain reaction (QPCR) results in blood in both groups of patients and determine values indicative of later CMV disease: ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. Determine the CMV genotypes (initially gB, gN genotypes) involved in CMV infection in both groups: ; ; 1. Two consecutive positive qualitative PCRs, on plasma specimens (second test done within 7 days following first positive screen) or; ; 2. Increasing viral load by greater than 0.5 log or; ; 3. Clinical or histopathological evidence of CMV disease, or ; 4. Seroconversion in seronegative recipients. INCLUSION CRITERIA: 1. Male or female > 16 years of age 2. Patients undergoing liver transplantation 3. Single or multi‐organ transplant 4. Patients meet transplant criteria 5. Chronic liver disease or fulminant hepatic failure 6. Able to give written informed consent