The challenge of progressive hepatitis C following liver transplantation

The complications of cirrhosis due to chronic hepatitis C are the leading indications for liver transplantation in the United States and currently account for more than 40% of cases. This proportion has risen steadily over the 15 yr since the hepatitis C virus (HCV) was identified and it is projected that the number will continue to rise for another 10 to 20 yr. The overwhelming majority of patients who present for liver transplantation have either never been treated with antiviral therapy, have been unable to tolerate it, or have failed to respond. Thus, viremia persists after transplantation in nearly all patients and commonly results in recurrent liver injury. Progression of liver injury after transplant is frighteningly rapid in comparison to immune competent patients with cirrhosis developing in 10 to 25% within 5 yr. In perhaps the most distressing report, Berenguer et al. reported that half of patients have bridging fibrosis or cirrhosis within 5 yr of the date of transplant. A large proportion of cirrhotic patients will develop decompensation and death within 1 yr. In contrast, only 20% of immune competent patients develop cirrhosis after 20 yr and only 3 to 6% of these decompensate each year; most remain well compensated without significant threat to their survival. Given the number of patients and the dire implications of disease recurrence, chronic hepatitis C has become perhaps the most difficult problem currently facing physicians who manage liver transplant recipients. Management of persistent HCV infection and recurrent chronic hepatitis is difficult. Hyperimmune antiHCV immune globulin preparations have not yet been shown to be effective in this setting as they have been in hepatitis B. Antiviral therapy with interferon-based regimens, as expected, is relatively ineffective in these patients since many have previously failed treatment, most are genotype 1 with high viral levels, and many have significant cytopenia due to hypersplenism and medication effects. Preemptive therapy with interferon-based therapy administered shortly after transplantation is especially difficult because of these issues, the debility of many patients, and the potential for drug interactions. Furthermore, this requires treatment of all HCV infected patients including the half who are not destined to have rapidly progressive graft injury. Thus, most hepatologists prefer to wait at least 6 to 12 months until patients have recovered from transplant and surveillance liver biopsies have identified those with progressive disease before considering antiviral treatment. Nonetheless, treatment still remains a substantial commitment for both patient and physician. Approximately 70% of cases require dose reduction; ribavirin, in particular, is poorly tolerated in these patients, who almost always have some degree of renal impairment from their calcineurin inhibitor. Despite these challenges, many centers have reported a surprisingly high 20 to 30% sustained viral clearance rate. Of course, considering the difficulty of treatment in this setting, these responses are far from what we would hope for. Considerable effort is being invested in investigating other ways to improve response to antiviral therapy in these patients. Recent reports of potent HCV protease and polymerase inhibitors raise the possibility that these might increase the effectiveness of interferon-based treatment in the transplant setting, though these studies are undoubtedly some distance in the future. Another potential way to influence the course of posttransplant HCV infection might be to alter the immunosuppressive regimen. The more rapid progression of