Prophylaxis followed by preemptive therapy versus preemptive therapy for prevention of human cytomegalovirus disease in pediatric patients undergoing liver transplantation. Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver Transplantation Database. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Controlled trial of prophylactic versus therapeutic use of ganciclovir after liver transplantation in adults. Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients. Preemptive use of oral ganciclovir to prevent cytomegalovirus infection in liver transplant patients: a randomized, placebo-controlled trial. Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma.
Twenty-one pediatric liver transplant recipients were enrolled in a study comparing prophylaxis followed by preemptive therapy (10 patients) versus preemptive therapy alone (11 patients) for prevention of human cytomegalovirus (HCMV) disease. In the prophylaxis arm, patients were treated with ganciclovir for 30 days, then preemptive therapy was initiated with virologic monitoring for pp65 antigenemia. In the preemptive therapy arm, patients were treated on reaching 100,000 DNA copies/mL whole blood. An interim analysis showed that, although numbers of both infected and treated patients were comparable in the two arms, the median number of total days of antiviral therapy per patient (30 vs. 18, P<0.01) was significantly higher in the prophylaxis arm. No case of HCMV disease occurred in either arm. Therefore, the trial was interrupted and prophylaxis replaced with preemptive therapy alone. In parallel, the development of T-cell-mediated immune response was found to be comparable in both arms. The optimal prophylactic regimen to prevent cytomegalovirus (CMV) infection and disease in orthotopic liver-transplant patients remains to be established. We tested whether a combination of intravenous ganciclovir (GCV) followed by high dosages of oral acyclovir (ACV) for 4 months provided a higher degree of protection from CMV than oral ACV alone.
                One hundred sixty-seven liver-transplant recipients were randomized to receive 120 days of antiviral treatment starting at the time of transplantation consisting of either ACV 800 mg orally four times daily (n=84) or 14 days of GCV 5 mg/kg intravenously every 12 hr followed by oral ACV 800 mg four times daily (n=83). Prospective laboratory and clinical surveillance was performed to determine primary endpoints (onset of CMV infection and CMV disease) and secondary endpoints (rates of fungal and bacterial infection, allograft rejection, and survival after transplantation). One-year event rates are presented as cumulative percentages.
                During the first year after transplantation, CMV infection developed in 57% of patients treated with ACV and in 37% of patients treated with GCV + ACV (P=0.001). CMV disease developed in 23% of patients treated with ACV and in 11% of patients treated with GCV + ACV (P=0.03). In seronegative recipients of allografts from CMV-seropositive donors (D+/R-), CMV disease developed in 58% of patients treated with ACV and in 25% of patients treated with GCV + ACV (P=0.04). In the D+/R- group, 54% of patients treated with ACV and 17% of patients treated with GCV + ACV developed infection with Candida albicans (P=0.05).
                Prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous GCV followed by high-dosage oral ACV is more effective than high-dosage oral ACV alone at reducing CMV infection and disease, even for patients in the D+/R- CMV serological group. Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs. The potential of prophylactic ganciclovir for the control of cytomegalovirus (CMV) infection was evaluated in a prospective controlled trial of 65 patients after liver transplantation. A group of 33 patients received ganciclovir (10 mg/kg/day) during the third and fourth weeks after transplantation, while 32 patients were randomised to receive ganciclovir (10 mg/kg/day) only when clinical CMV disease was diagnosed. Eight patients (25%) in the latter group received ganciclovir and included the only death attributed to CMV infection in the study. Prophylactic ganciclovir was associated with a lower incidence of serologically diagnosed secondary infection and the development of the IgM anti-CMV antibody. However, the frequency of clinical infections was similar in the two groups (9/33 vs. 11/32). Liver function tests during the second month after transplantation were not significantly better in the patients receiving prophylactic ganciclovir. Leucopaenia was not seen in patients receiving prophylactic ganciclovir. Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV. Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients. The use of postdetection antiviral treatment of cytomegalovirus (CMV) as a strategy to prevent infection and disease in solid-organ transplant patients has not been evaluated by placebo-controlled trials. We carried out such a study in 69 patients who had received liver transplants and had positive results of CMV polymerase chain reaction within 8 weeks after transplantation but did not have concomitant CMV infection or disease. These patients were randomly assigned to receive placebo or oral ganciclovir for 8 weeks. CMV infection developed in 21% and disease developed in 12% of placebo recipients (P =.022), compared with 3% and 0%, respectively, among ganciclovir recipients (P =.003). Similarly, in the placebo arm, 55% and 36% of CMV-negative patients who received organs from CMV-positive donors developed CMV infection or disease, respectively (P =.02), compared with 11% and 0% of such patients in the ganciclovir arm (P <.01). Oral ganciclovir administered on CMV detection by PCR prevents CMV infection or disease after liver transplantation. The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment.
                Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver.
                Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function.
                Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis. Adjuvant oral chemotherapy was studied in 67 patients with stage II hepatocellular carcinoma who underwent curative resection between May 1988 and December 1990. Patients were stratified into two groups according to preoperative liver dysfunction: 55 had stage I disease (mild dysfunction) and 12 had stage II (moderate dysfunction). A randomized controlled study of postoperative oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) was conducted in each group. From October 1994 HCFU administration was suspended because of side-effects in nine patients with stage I liver dysfunction and in three with stage II dysfunction who had received the drug for more than 4 weeks. Cumulative survival and recurrence-free survival rates of patients with stage I disease in the treatment group were higher (P = 0.08 and P = 0.04 respectively) than those in the control group. However, in patients with stage II disease no significant difference was observed (P = 0.77 and P = 1.0 respectively). This study suggests that the potential benefits of HCFU on tumour recurrence should be weighed against the risk of adverse reactions in patients with mild liver dysfunction.
There is currently no evidence to recommend prophylactic antiviral treatment to prevent recurrence of HCV infection either in primary liver transplantation or re-transplantation. Further randomised clinical trials with adequate trial methodology and adequate duration of follow-up are necessary.