Laurel Davis

INTERFERON-?? AND RIBAVIRIN FOR THE TREATMENT OF RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION1

BACKGROUND Initial studies utilizing interferon-alpha and ribavirin for the treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation showed promising results. Here we report our single-center experience using this combination therapy. METHODS Liver transplant recipients with recurrent HCV (elevated serum aminotransferases, positive serum HCV RNA, and biopsy-proven hepatitis without rejection) received interferon-alpha (1.5-3 million units subcutaneously three times a week) and ribavirin (400-1000 mg p.o. daily) for 12 months or more. Serum aminotransferases, HCV RNA, and severity of hepatitis were followed. RESULTS Thirty-two patients have been treated for at least 3 months, including 13 who have been on 12 or more months of therapy. Three died from allograft failure due to recurrent HCV. Dose reductions of interferon-alpha and/or ribavirin occurred in 22 patients. Thirteen had their medications permanently discontinued for severe adverse effects. Twenty-six patients (81%) had a biochemical response (BR; normalization of serum aminotransferases) after 3 months. End-of-treatment and sustained BR were 77% and 71%, respectively. Mean viral loads decreased 68-77%; however, only three patients became serum HCV RNA negative. After 12 months of therapy, no histological improvement was observed in 11 patients who were biopsied. Patients who received mycophenolate mofetil or daclizumab had a less likelihood of achieving a BR. CONCLUSIONS A significant number of patients did not tolerate interferon-alpha or ribavirin. Although BR was excellent and mean viral loads decreased significantly, virological clearance was poor and no histological improvement was noted. A more efficacious treatment with less adverse effects for recurrent HCV after liver transplantation is needed.

Nonresponders of interferon/ribavirin treatment for recurrent hepatitis C following liver transplantation

BACKGROUND Treatment of recurrent hepatitis C (HCV) following liver transplant currently includes alpha-interferon with ribavirin. OBJECTIVE The aim of this study is to evaluate nonresponder protocols for patients failing current treatment for recurrent hepatitis C following liver transplantation. METHODS From February 1998 through November 2002, 67 patients, all serum RNA-positive for hepatitis C with histological evidence of recurrent hepatitis C, underwent treatment with alpha-interferon and ribavirin. For patients who failed initial treatment, patients were begun on either amantadine along with interferon/ribavirin or peginterferon with ribavirin. RESULTS Of the initial 67 patients, there was a complete viral clearance in only 14.9% (10/67). Of the 57 remaining patients not clearing the virus, 30 (52.6%) were taken off treatment due to adverse events associated with bone marrow or hemoglobin suppression. In the amantadine group (n = 12), three (25%) had to discontinue due to CNS side effects of slurred speech, dizziness, and increased depression. In the amantadine group, no patients cleared the virus but there was a one log drop in viral load (1.6 x 10(6) vs 0.9 x 10(6); P =.4). In the peginterferon group, there were three (20%) patients with complete viral clearance during treatment with similar drops to amantadine. There was also seen a biochemical response by month 3 with peginterferon, which was not seen with amantadine. CONCLUSIONS Peginterferon with ribavirin appears to be superior to amantadine with interferon/ribavirin when used in nonresponders for hepatitis C viral clearance.

Renal sparing effects of mycophenolate when used in long-term liver transplant receipients

LONG-TERM, chronic use of calcineurin inhibitors (tacrolimus and cyclosporine) is known to lead to nephrotoxicity and renal failure. Mycophenolate mofetil (MMF) is metabolized to mycophenolic acid, which acts as an immunosuppressive agent by blocking de novo purine synthesis in both Tand B-cell lymphocytes. Infectious complications with the use of MMF have been questioned due to the perceived implication of increased immunosuppression. A multivariate analysis of risk of infection in liver transplant recipients receiving MMF was preformed to determine the incidence of bacterial, viral, and fungal infections. The cohort consisted of more than 150 consecutive liver transplant recipients, and an increase in risk of developing infection after liver transplantation was not demonstrated. Mycophenolate has been used in multiple roles in transplantation. One role for which MMF had been evaluated is steroid-free immunosuppression. For patients with renal impairment, MMF has been useful in limiting calcineurin dosing to help increase or maintain renal function. Creatinine clearance has been shown to increase from 38.16 ( 5.60) to 47.01 ( 6.76) mL/min (P .005). Monotherapy with MMF has also been reported for limiting calcineurin-induced nephrotoxicity. The aim of this review was to determine if a mycophenolate-based immunosuppressive regimen that limits calcineurin inhibitors can prevent further renal dysfunction in the long-term, stable liver transplant recipient.