Treating chronic hepatitis C virus after liver transplantation: Balancing the risks against the chance for success

Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and the most common indication for undergoing liver transplantation (LT) in the United States and many other countries throughout the world.1, 2 Approximately 40 to 45% of all liver transplants recipients have chronic HCV and nearly all of these patients develop recurrence of this virus and are at risk to develop graft dysfunction. Cirrhosis secondary to chronic HCV is also the leading indication for adult-to-adult living donor LT.1, 3 Although it was initially suggested that recurrence of chronic HCV was more “severe” in the recipients of a living donor,4 several controlled trials have now clearly demonstrated that both the rate of fibrosis progression and survival are not significantly different in patients with chronic HCV who are the recipients of a living or a decreased donor liver.5, 6 HCV, hepatitis C virus; LT, liver transplantation; SVR, sustained virologic response; RNA, ribonucleic acid. The survival of liver transplant recipients with recurrent HCV is reduced compared to patients who undergo LT for other indications.1, 7 For the past decade, this reduction in survival was thought to be secondary to the development of cirrhosis and, subsequently, graft failure from recurrent HCV. However, several recent studies have now demonstrated that only about 25 to 33% of patients with recurrent HCV develop advanced bridging fibrosis or cirrhosis within 5 yr of undergoing transplantation,8-10 and it has recently been recognized that extrahepatic manifestations such as diabetes mellitus, chronic renal insufficiency, and infections also contribute to morbidity and mortality in liver transplant recipients with recurrent HCV.9-12 The great majority of liver transplant recipients have genotype 1. Patients with genotypes 2 and 3 have a much higher rate of sustained virologic response (SVR) when treated with peginterferon and ribavirin and can therefore be successfully treated even if they have developed cirrhosis and hepatic decompensation.23 In most cases this eliminates the need for such patients to undergo LT; but even if such patients still require transplantation they do not appear to develop recurrent HCV. Those patients with HCV genotypes 2 and 3 who cannot be treated prior to undergoing LT are excellent candidates for treatment after LT; an SVR rate of at least 50% has been reported.15-22 Immunosuppression reduces the effectiveness of peginterferon and ribavirin to eradicate HCV.24 The virologic response to HCV treatment in patients who are immune suppressed secondary to coinfection with the human immunodeficiency virus is similar to that observed in liver transplant recipients.25 The level of HCV ribonucleic acid (RNA) in serum significantly increases in patients treated with immunosuppressive medications26 and a higher serum HCV RNA level is associated with a reduced virologic response to treatment.13, 14 Finally, since immune stimulation is one of the proposed mechanisms by which interferon is effective in eradicating HCV,24 immune suppression would likely reduce this effect. Despite this, immunosuppression should probably not be reduced prior to initiating HCV treatment because this may increase the risk of interferon-induced rejection.27, 28 Nearly all liver transplant recipients have some degree of chronic renal insufficiency, even those patients with a normal serum creatinine.12 This is secondary to the effects of calcineurin immunosuppressive agents, which are taken by over 80% of these patients. This significantly increases the rate of ribavirin-induced anemia and requires that the dose of this medication be reduced in up to 50% of patients and discontinued in another 33%.15-22 Although utilizing epoetin alfa along with peginterferon and ribavirin can either correct or prevent anemia in the nontransplant setting;29 approximately 25% of liver transplant recipients develop profound anemia and cannot remain on ribavirin despite the use of this growth factor.15-22 The approval to initiate a hematologic growth factor simultaneously with HCV treatment, before the onset of anemia, should be obtained even in patients with normal values for hemoglobin and serum creatinine. This will limit the need to dose reduce and prematurely discontinue peginterferon and ribavirin and should enhance SVR. Many patients continue to have some degree of long-term neutropenia and thrombocytopenia after LT. This may reflect bone marrow toxicity from various medications or from other less understood factors. Regardless, this frequently reduces the ability to utilize full doses of peginterferon in up 50% of these patients. The approval to utilize granulocyte colony stimulating factor should therefore be obtained prior to initiating HCV treatment and this agent should be utilized before the absolute neutrophil count declines to levels that would require the peginterferon dose to be reduced. Many liver transplant recipients have previously received an adequate course of peginterferon and ribavirin and have already failed to respond to this treatment before undergoing transplantation. It is extremely unlikely that retreatment after transplantation would be effective given the above noted limitations. In contrast, if a patient received less-than-adequate doses of HCV treatment, relapsed, or was responding to treatment but could not complete therapy because of adverse events, retreatment in the posttransplantation setting would be very reasonable. Interferon may stimulate allograft rejection. Although initial reports claimed that the use of interferon was safe in liver transplant recipients; interferon-induced acute and chronic rejection has now been documented by several groups.27, 28 Overall, it appears that rejection occurs in about 10 to 25% of patients being treated for chronic HCV. In most cases this can be adequately treated. However, interferon-induced severe resistant rejection requiring retransplantation has been observed. Interestingly, the greatest risk for rejection appears to be after HCV RNA becomes undetectable, suggesting that this virus plays a role in suppressing the immune response.30 Maintaining “adequate” immunosuppression is a reasonable approach to reduce the risk of interferon-induced allograft rejection. Given the many limitations of HCV therapy in this population, many of which were observed in the recent study by Sharma et al.,22 it is paramount that this therapy not be utilized indiscriminately. Rather, only those patients in whom the potential benefit of treatment clearly outweighs these risks should be considered candidates for HCV therapy. This is primarily true in those patents in whom fibrosis progression has been demonstrated by serial liver biopsy. Assessing changes in HCV RNA over time is an important aspect of managing HCV treatment.13, 14 For example, it is well know that patients who fail to achieve an early virologic response (i.e., a 2 log decline in HCV RNA from the pretreatment baseline or undetectable HCV RNA at treatment week 12) do not have any further decline in HCV RNA even if treated for a longer duration. Such patients are referred to as having a null response to therapy; they have no chance of achieving a SVR and treatment should be discontinued as soon as this response pattern is recognized. More recently, it has become apparent that the time at which a patient becomes HCV RNA undetectable after initiating HCV treatment is one of the most important predictors of SVR.31 HCV genotype 1 patients who achieve a rapid virologic response, defined as becoming HCV RNA undetectable within 4 weeks of initiating treatment, have an SVR of 90%. This declines to about 66% and then 45% in patients who become HCV RNA undetectable at treatment weeks 12 and 24, respectively. Thus, the later a patient becomes HCV RNA undetectable during treatment the greater the risk for relapse once this therapy is discontinued; and it has recently been demonstrated that prolonging peginterferon and ribavirin treatment from 48 to 72 weeks in patients who become HCV RNA undetectable late during the course of treatment will reduce the risk of relapse by approximately two-thirds.32, 33 Patients with genotypes 2 and 3 who achieve a rapid virologic response and are HCV RNA undetectable 4 weeks into treatment also have an SVR of 90%. However, SVR declines to only 50% if these patients become HCV RNA undetectable after week 4.34 It is logical to assume, but not yet demonstrated, that prolonging treatment from 24 to 48 weeks in a patient with genotype 2 or 3 who became HCV RNA undetectable after week 4 would reduce this high rate of relapse. It has recently become apparent that the viral response characteristics utilized to assess the efficacy of peginterferon and ribavirin therapy in the nontransplant setting apply equally well to liver transplant recipients. The recent articles by Sharma et al.22 and Oton et al.21 demonstrated that only those patients who achieved an early virologic response were able to go onto SVR. Treatment should therefore be discontinued as soon as the lack of an early virologic response is recognized; continuing peginterferon in patients without early virologic response merely increases the risk of developing new or worsening adverse events without any demonstrable offsetting benefit. As in the nontransplant setting, the time at which a patient becomes HCV RNA undetectable during treatment is also highly predictive of SVR. For example, 16 of 16 (100%) liver transplant patients who became HCV RNA undetectable after just 4 weeks of peginterferon and ribavirin treatment achieved an SVR and this declined to 70% in those patients who became HCV RNA undetectable at treatment week 12.21 These data strongly suggest that prolonging therapy in liver transplant recipients who become HCV RNA undetectable later during the course of therapy will be just as effective at reducing relapse and enhancing SVR as it is in the nontransplant setting. All future studies designed to treat recurrent HCV in liver transplant recipients should incorporate these new concepts. Only after we improve the outcome of treatment in liver transplant recipients with recurrent HCV will we be better able to balance the risks of treatment against the chance for success.