Recurrent HCV is a major cause of allograft loss and mortality in liver transplant recipients with chronic HCV infection. The development of strategies designed to optimize patient and graft survival in this population is critical, as HCV is currently the most common indication for liver transplantation. A greater understanding of the risk factors for progressive disease and vigilant post- transplant monitoring through histologic assessment may guide management aimed toward reducing the potential for graft failure as well as helping identify candidates for antiviral therapy. Read the rest of this entry »
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Ultimately, repeat liver transplantation may be considered in select patients with HCV recurrence and allograft failure. Although prior data have identified HCV infection as an independent predictor of mortality following retrans- plantation, more recent reports have described similar rates of survival in HCV and non-HCV recipients. A key factor associated with the observed improvement in outcomes related to retransplantation for recurrent HCV is patient selection. It is well recognized that the development of fibrosing cholestatic HCV is a major risk factor for severe recurrent disease following repeat transplantation with a negative impact on post-transplant survival. In a recent multicenter retrospective study that reported similar survival in HCV-infected and non-HCV patients listed for retransplantation, the most common reasons for not relisting potential candidates included rapid recurrence of HCV within 6 months and fibrosing cholestatic HCV. A recent review of the United Network for Organ Sharing database noted improved 1-year patient and graft survival in HCV-infected individuals undergoing repeat transplantation over subsequent study periods from 1994 to 2005. In this study, factors independently associated with an increased risk of mortality following retransplantation in patients with HCV included increased recipient age, MELD score greater than 25, retransplantation within 1 year of the first transplant, donor age 60 years or greater, and prolonged warm ischemia time. These findings emphasize the importance of not only patient selection, but also donor selection when considering repeat liver transplantation in patients with recurrent HCV.
Immunosuppressive regimens initiated at the time of liver transplantation, as well as methods of treating acute cellular rejection during the post-transplant course, appear to have a significant role in the development of liver disease associated with HCV recurrence. Consequently, several strategies have emerged with the goal of minimizing the negative impact of high-dose or pulse corticosteroids. Some data have suggested that a treatment approach characterized by slow tapering of corticosteroids following transplantation may be associated with a reduced severity of recurrent HCV and fibrosis progression, in contrast to more rapid or abrupt decreases in corticosteroid doses. It is not clear that avoiding corticosteroids entirely may result in improved long-term outcomes; however, a recent meta-analysis noted a potential decrease in the risk of recurrent HCV based upon histologic parameters in addition to a decrease in the risk of CMV infection.
Management of Recurrent Hepatitis C Following Liver Transplantation: Predictors of Sustained Viral Clearance
Achievement of SVR in the setting of recurrent HCV following liver transplantation may have a major impact on long-term outcomes, including improved graft and patient survival. Identifying patients with a greater likelihood of achieving SVR is an important consideration in the selection of potential treatment candidates and is a key factor in developing strategies for optimizing response to therapy. HCV genotype remains an important predictor of SVR in the post-transplant setting, as sustained clearance may be significantly higher in non- genotype 1 patients, with reported SVR rates greater than 60%, particularly in patients with HCV genotype 2 or 3 infection. The most important predictor of successful response during a course of antiviral therapy before transplant is the serum HCV RNA level, with achievement of rapid virologic response (RVR) at week 4 and early virologic response (EVR) at week 12 providing the highest positive and negative predictive values of SVR, respectively. In the post-transplant setting, rapid HCV clearance during therapy is also a key predictor of sustained response, as demonstrated in several prospective studies, including the PROTECT study, in which the greatest response was observed in those who cleared HCV within 4 weeks (RVR), followed by those who achieved viral clearance within 12 weeks (complete EVR).
Treatment Before Transplantation
Although PegIFN in combination with RBV remains the gold standard for the treatment of chronic HCV infection in the pretransplant setting, long-term viral suppression can be achieved in only approximately one half of patients. Antiviral therapy in patients with HCV cirrhosis awaiting liver transplantation should be considered in select individuals; however, poor tolerability may limit virologic response. Although successful response to PegIFN therapy has been described in compensated cirrhotics, sustained virologic response (SVR) can be significantly reduced in those with decompensated disease. Up to 50% of decompensated cirrhotics may experience significant hematologic side effects associated with PegIFN and RBV, leading to dose reductions and treatment discontinuation. Consequently, low SVR rates have been reported in 7-13% of genotype 1 patients and up to 50% of nongenotype 1 patients. In light of the potential benefit of viral eradication and avoidance of allograft re-infection, antiviral therapy prior to liver transplantation is recommended in patients who are candidates, primarily those with Child-Turcotte-Pugh scores of no more than 7 and model for end-stage liver disease (MELD) scores of no more than 18.
Management of Recurrent Hepatitis C Following Liver Transplantation: Fibrosing Cholestatic Hepatitis C
Although it occurs in less than 10% of transplant recipients with chronic HCV, a severe and rapidly progressive form of recurrent HCV infection characterized by cholestatic disease has a major impact on survival. In contrast to a chronic hepatitis observed in most patients with recurrent HCV, this syndrome is defined by a total serum bilirubin of more than 6 mg/dL, elevated alkaline phosphatase or gamma glutamyltransferase levels more than 5 times the upper limit of normal, high serum HCV RNA levels, and histologic features including central hepatocyte ballooning without necrosis, cholangiolar proliferation without loss of bile ducts, and intrahepatic cholestasis in the absence of significant inflammation, biliary obstructive disease, or vascular complications.15,18 Onset typically occurs within the first 6 months following liver transplantation, and rapid progression to allograft failure may occur within 1 year. In addition, patient survival following repeat liver transplantation for fibrosing cholestatic HCV is severely compromised; thus, retransplantation is not an acceptable management option in this case.
Management of Recurrent Hepatitis C Following Liver Transplantation: Hepatitis C and the Transplanted Liver
Recurrence of Chronic Infection
Recurrence of hepatitis C viremia following liver transplantation occurs in all patients with chronic HCV infection who have detectable serum HCV RNA levels prior to transplant. A significant decline in serum HCV RNA levels has been observed during the anhepatic phase of transplantation and immediately following reperfusion of the allograft; however, this decline is followed by a rapid increase in HCV RNA levels within hours, and pretrans- plantation serum HCV RNA levels can be reached within days. A progressive rise in HCV RNA levels has been described over several weeks following transplantation, resulting in a new baseline viral load that is typically greater than the viral load prior to transplant.