Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection

Abstract

We recently reported on a series of patients who experienced acute cellular rejection (ACR) during the treatment of hepatitis C virus (HCV) infection in our posttransplantation cohort. Our hypothesis is that HCV clearance improves hepatic microsomal function, which in turn results in lower trough cyclosporine (CyA) and tacrolimus (TAC) levels, predisposing the patient to ACR. Records of all patients receiving transplants for HCV infection at our center from 1993 to June 2002 were reviewed. Two hundred three patients were identified. Thirty-seven patients (18%) were treated with interferon-based therapies in combination with ribavirin. Twelve patients were selected for analysis because they became HCV RNA negative during therapy, and 18 patients with no antiviral response were selected as controls (7 other patients had incomplete data or had switched from one immunosuppression [IS] therapy to the other). Baseline IS levels were compared with the first available level after documented negative HCV RNA results in the study group and the last on-treatment IS level in the control group. We also compared frequency and percentage of change in IS levels during therapy. Mean decline in CyA trough levels in the study group was from 187.28 ng/mL at baseline to 118.14 ng/mL immediately after becoming HCV RNA negative (؊36.92%; P ‫؍‬ .018). Mean decline in TAC levels was from 7.34 ng/mL at baseline to 5.02 ng/mL immediately after becoming HCV RNA negative (؊29.17%; P ‫؍‬ .044). Overall, 6 of 12 patients who cleared HCV RNA during therapy experienced ACR; 1 patient died as a result of ACR. Using percentage of decrease from baseline IS level, we combined results for patients administered CyA and TAC and found a significant decrease from baseline IS levels in responders (؊31.8% after HCV RNA clearance on treatment; P ‫؍‬ .0001). Nonresponders experienced a 0.98% decline in IS levels while on treatment, and the difference was significant compared with the change in the responder group (P ‫؍‬ .006). A greater proportion of antiviral therapy responders also experienced trough IS levels 20% less than baseline than nonresponder controls during therapy (P ‫؍‬ .0006). In conclusion, IS levels decreased significantly in patients responding favorably to anti-HCV therapy. This decrease in IS levels may have a key role in predisposing these patients to ACR. (Liver Transpl 2003;9:1159-1165.)

What is the long-term outcome of the liver allograft?

“…Conversely, a higher incidence of AR and CR has been observed in HCV-positive patients compared with those transplanted for other disease [77][78][79][80][81]. This association probably reflects a number of factors -these include different approaches to immunosuppression in HCV-positive patients, shared pathways of immune-mediated damage between HCV and rejection and the effects of anti-viral therapy, which may result both in non-specific augmentation of the host's immune system and increased hepatocellular metabolism of immunosuppressive drugs following viral clearance from hepatocytes [81][82][83].…”

Treatment of recurrent hepatitis C following liver transplantation

“…Close monitoring of calcineurin inhibitor levels are necessary during antiviral therapy. A greater proportion of responders to antiviral therapy experience rejection than nonresponders, presumably because improved hepatic function leads to enhanced biotransformation and lower immunosuppression levels [38].…”

Prevention and treatment of hepatitis C virus recurrence after liver transplantation

“…Chronic rejection led to retransplantation in three cases. Moreover, several cases of acute cellular rejection have been reported during antiviral therapy in patients with hepatitis C [41,42]. A recent report suggests that HCV clearance during treatment might predispose to acute cellular rejection by improving hepatic microsomal function (and thereby decreasing levels of cycosporine or tacrolimus) [42].…”

“…Moreover, several cases of acute cellular rejection have been reported during antiviral therapy in patients with hepatitis C [41,42]. A recent report suggests that HCV clearance during treatment might predispose to acute cellular rejection by improving hepatic microsomal function (and thereby decreasing levels of cycosporine or tacrolimus) [42]. Controlled studies have not confirmed an association between interferon therapy and acute cellular or chronic rejection [43], but this might be explained by the relatively small size of the published series.…”