Combined therapy with interferon and low-dose ribavirin in posttransplantation recurrent hepatitis C: A pragmatic study

Abstract

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical endtreatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by longterm ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological R ecurrent hepatitis C is a major clinical problem after liver transplantation because it affects 50% to 80% of patients at 5 years. [1][2][3][4] Although most patients experience a benign course with mild histological lesions, evolution to severe hepatitis is well documented, reported in as many as 20% of cases. 2,5 In addition, a rapidly progressive form of fibrosing cholestatic hepatitis has been associated with hepatitis C virus (HCV) recurrence, 6 similar to that observed for hepatitis B virus.Based on this clinical evidence, antivirals have been used in an attempt to favorably modify the natural history of recurrent hepatitis C disease. In this respect, preliminary reports of treatment with combination therapy (interferon [IFN] alfa plus ribavirin) have been promising, but long-term follow-up data are not yet available. 7 Moreover, it is not clear how many patients with histologically proven recurrent hepatitis C can be treated with combination therapy because of the presence of contraindications and comorbidities.We report our experience in a cohort of 50 consecutive liver transplant recipients...

Treatment of recurrent hepatitis C

“…56 In nontransplantation registration studies for interferon and ribavirin, hemolysis necessitated dose reduction in 7% and dose withdrawal in less than 1%. 30 Unfortunately, hemolysis is more severe in liver 15,23,[32][33][34][35][36][37][38][39]57 and kidney transplant recipients, 58,59 necessitating dose reduction in 40% to 66% and dose withdrawal in 10% to 33%. This reflects rapid accumulation of ribavirin after liver transplantation because of reduced renal clearance secondary to calcineurin-inhibitor nephrotoxicity and HCV-related glomerulonephritis.…”

“…4). [31][32][33][34][35][36][37][38][39] Unfortunately, between 20% and 50% 37 of patients were unable to complete treatment because of drug-related serious adverse events. …”

“…However, 10% to 20% of liver transplant recipients administered interferon-␣ cease treatment because of severe neutropenia and thrombocytopenia. [32][33][34][35][36][37][38][39] Transplant recipients are more susceptible because of coexisting hypersplenism, viral infections (cytomegalovirus, human herpes virus 6) and myelosuppressive drugs (ganciclovir, cotrimoxazole, mycophenolate mofetil [MMF]).…”

The clinical and immunologic impact of using interferon and ribavirin in the immunosuppressed host

“…To prevent morbidity and mortality associated with recurrent hepatitis C, many centers have used interferon alfa (IFN-␣) and/or ribavirin (RVN) as either antiviral prophylaxis or treatment of established hepatitis C or hepatitis B. Regimens have ranged from monotherapies with RVN, [8][9][10][11][12][13][14] standard IFN-␣ , 9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] or pegylated IFN [30][31][32] to combination therapies with a standard IFN-␣ and RVN 27,29,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] or pegylated IFN-␣ and RVN. 53 H...…”

Treatment of hepatitis C virus infection in the allograft

“…With few exceptions, most studies have been nonrandomized. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Side effects are common, and dose reduction and withdrawals are seen in up to half of the patients. Furthermore, many patients require support to maintain hemoglobin and white cell count.…”