Predictors of virologic response in combination therapy with interferon (IFN) alfa 2B plus ribavirin of recurrent hepatitis C after liver transplantation (LT)

321

191

Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation. It was shown previously that greater pretransplantation HCV titers are associated with relatively poor patient and graft survival. The tolerability and efficacy of antiviral therapy in patients with decompensated liver disease are not known. We conducted a pilot study to determine the likely tolerability and efficacy of pretransplantation antiviral therapy with interferon alfa-2b, with or without ribavirin. HCV RNApositive patients at or near the top of their respective waiting lists were randomly assigned to one of three treatment regimens until the time of liver transplantation: (1) group A, interferon alfa-2b, 1 ؋ 10 6 U/d; (2) group B, interferon alfa-2b, 3 ؋ 10 6 U three times weekly; or (3) group C, interferon alfa-2b, 1 ؋ 10 6 U/d, plus ribavirin, 400 mg twice daily. Less than half the patients screened met entry criteria, with thrombocytopenia and leukopenia the most common reasons for exclusion. Fifteen patients were administered antiviral therapy; three patients in group A and six patients each in groups B and C. Loss of detectable HCV RNA was seen in 33% of patients, whereas 55% had a decrease in viral titers on therapy. Twenty-three adverse events occurred, including 20 serious adverse events. Thrombocytopenia was the most common adverse event. Two infectious complications occurred; one of these had a fatal outcome. We conclude that although pretransplantation antiviral therapy may reduce HCV titers in a minority of patients who meet treatment initiation criteria, adverse events associated with therapy are frequent and often severe in patients with Child's class B and C cirrhosis. C hronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States. 1 Although patients undergoing liver transplantation for HCV have been reported to have similar overall patient and graft survival to most other indications, 2-6 recurrence of HCV is a substantial source of morbidity, mortality, and graft loss. 2,4,7-10 To date, meaningful data regarding posttransplantation follow-up in HCV-infected recipients are only available for a mean of 3 to 5 years. [2][3][4][5][6] In the nontransplantation setting, it is estimated that the mean time from infection to the development of cirrhosis is 20 years. 11,12 In liver transplant recipients, the course of HCV-induced liver injury is accelerated, with HCV recurrence apparent histologically in approximately 50% of HCVinfected transplant recipients and HCV-associated allograft failure leading to death or graft loss in approximately 10% of transplant recipients by the fifth postoperative year. 2,3,7,10,[13][14][15][16][17] Greater pretransplantation levels of viremia have been associated with attenuated patient and allograft survival among HCV-infected liver transplant recipients. 7 The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplant Database report...

Section: Discussionmentioning

confidence: 99%

A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus–infected patients awaiting liver transplantation

Crippin

McCashland

Terrault

et al. 2002

321

191

“…Although the number and size of studies are small, studies that reported the efficacy of nonpegylated interferon alfa have ribavirin combination therapy in the treatment of posttransplantation HCV infection suggest that the overall efficacy of these agents is broadly similar to that in the nontransplantation setting, with end-of-treatment virological response rates varying between 15% and 50%. [15][16][17][18][19][20] Reversal of fibrosing cholestatic posttransplantation HCV infection, although reported,21,20 appears to be unusual. 22 We designed a protocol to determine the efficacy and tolerability of posttransplantation interferon and ribavirin therapy initiated on histological documentation of recurrence of HCV infection.…”

mentioning

confidence: 99%

Treatment of posttransplantation recurrence of hepatitis C with interferon and ribavirin: Lessons on tolerability and efficacy

Menon

Poterucha

Elamin

et al. 2002

110

Recurrence of hepatitis C virus (HCV) infection after orthotopic liver transplantation is a major cause of graft failure. The aim of our study was to determine the safety, efficacy, and tolerability of combination therapy with interferon and ribavirin in the treatment of recurrent hepatitis after liver transplantation. Twenty-six patients (18 men) with histologically established HCV recurrence after liver transplantation for cirrhosis secondary to chronic HCV infection were treated with a combination of interferon alfa-2b (3 million units three times weekly) and ribavirin (800 to 1,000 mg/d). Dosage modifications were according to a standard protocol incorporating laboratory values and clinical side effects. Fifty percent of patients completed 1 year or more of therapy. On an intention-totreat basis, nine patients (35%) showed an end-of-treatment virological response. Six of these nine patients completed greater than 6 additional months of follow-up, and all have had sustained virological responses. A histological response (decrease in histological activity index 2 2) was seen in 75% of virological responders and 67% of nonresponders. Adverse events requiring dose modification or cessation of therapy occurred in 66% of patients. Adjuvant therapies used to support hemoglobin levels included erythropoietin and red blood cell transfusions. There were no independent pretreatment predictors of a virological response, perhaps because of the small sample size. Combination therapy with interferon and ribavirin may be beneficial in patients with recurrent HCV after liver transplantation. The majority of patients require dose modifications because of side effects. Histological response is common in virological nonresponders. Unfortunately, the plethora of robust data in the nontransplantation setting is not available in transplant recipients. Although the number and size of studies are small, studies that reported the efficacy of nonpegylated interferon alfa have ribavirin combination therapy in the treatment of posttransplantation HCV infection suggest that the overall efficacy of these agents is broadly similar to that in the nontransplantation setting, with end-of-treatment virological response rates varying between 15% and 50%. [15][16][17][18][19][20] Reversal of fibrosing cholestatic posttransplantation HCV infection, although reported,21,20 appears to be unusual. 22 We designed a protocol to determine the efficacy and tolerability of posttransplantation interferon and ribavirin therapy initiated on histological documentation of recurrence of HCV infection. Methods Study PopulationAll patients who underwent transplantation for end-stage liver disease secondary t o H C V infection were eligible for combination antiviral therapy with interferon and ribavirin.

“…Although the number and size of studies are small, reports of the efficacy of standard IFN-alfa and ribavirin combination therapy in the treatment of post-LT HCV infection suggest that the overall efficacy and tolerability of these agents is less than that in the nontransplantation setting. [28][29][30][31][32][33] IFN and ribavirin combination therapy in the nontransplantation setting has produced a greater than twofold increase in both end-of-treatment and sustained virological response rates compared with standard IFN monotherapy. 34,35 Results among liver transplant recipients have been diverse.…”

Section: Combination Therapy With Nonpegylated Interferon and Ribavirinmentioning

confidence: 99%

Pre-emptive treatment of recurrent hepatitis C infection

Charlton

2002

A pproximately 3 million individuals are infected with hepatitis C virus (HCV) in the United States, where HCV infection causes 20% of acute and 70% of chronic hepatitis. 1,2 Currently, more than 30% of liver transplant recipients are HCV infected, making endstage liver disease associated with HCV infection the most common indication for liver transplantation (LT) in the United States. 3 In contrast to the other leading indications for LT, such as alcoholic liver disease, cholestatic liver disease, and cryptogenic cirrhosis, recurrence of HCV infection, measured by detection of HCV RNA by polymerase chain reaction, is nearly universal. 4-10 Although patients undergoing LT for HCV have been reported to have overall patient and graft survival broadly similar to those for most other indications, 5,8,[11][12][13] recurrence of HCV is a substantial source of morbidity, mortality, and graft loss. 5,11,[14][15][16][17] Furthermore, a recent analysis of the United Network for Organ Sharing (UNOS) database found that mediumterm patient and graft survival may be worse for HCVinfected transplant recipients than those for other indications for LT. 18 To date, meaningful data regarding post-LT follow-up in HCV-infected transplant recipients are available only for means of 3 to 5 years. 5,8,[11][12][13] As the duration of post-LT follow-up of HCV-infected transplant recipients lengthens, the impact of HCV recurrence on long-term patient and graft survival is likely to increase. In the nontransplantation setting, it is estimated that the mean time from infection to the development of cirrhosis is 20 years. 19,20 Conversely, HCV recurrence results in allograft failure in approximately 10% of transplant recipients by the fifth postoperative year. 5,6,8,14,17,[21][22][23][24] In the setting of an increasingly acute shortage of cadaveric donor organs, the need to optimize outcomes after LT for hepatitis C has become one of the most pressing issues facing the transplantation community. Data concerning the timing, efficacy, and safety of antiviral therapy for the amelioration of the post-LT recurrence of HCV infection are scant.Transplant recipients with greater pre-LT HCV RNA titers experience mortality and graft loss rates approximately 30% greater than for transplant recipients with lower pre-LT HCV RNA titers. 14 In light of this observation, a pilot study of the tolerability and efficacy of pre-LT antiviral therapy was conducted. This study found that although antiviral response was similar to that of other cirrhotic patients, most UNOS status 2b HCV-infected patients did not meet treatment-initiation criteria, and serious adverse effects occurred commonly. 25 Who, When, and How to Treat Post-LT HCV Infection: The Case for Preemptive TreatmentTo date, there have been no well-controlled large clinical trials to determine the optimal management approach to treating recurrent HCV infection after LT. Most available studies are small and largely not similar because of differences in the definition of recurrent hepatitis C; timing of...