Prophylaxis against HCV recurrence after liver transplantation: Effect of interferon and ribavirin combination

Recurrence of hepatitis C virus infection after liver transplantation is universal. A significant percentage of these patients develop progressive graft injury and cirrhosis. Those factors that modulate disease progression in liver transplant recipients with recurrent hepatitis C virus infection remain controversial and are poorly understood. Treatment of recurrent hepatitis C virus after liver transplantation with either interferon or interferon and ribavirin has yielded only limited success. Regardless of this, treatment is instituted. Peginterferon is more effective than standard interferon for treatment of chronic hepatitis C virus infection in the nontransplantation setting when used either alone or with ribavirin. The effectiveness of peginterferon, both with and without ribavirin in the posttransplantation setting, is currently being explored. In this review those factors thought to affect disease progression in patients with recurrent hepatitis C virus will be discussed, strategies that have been used to treat recurrent hepatitis C virus will be reviewed, and the impact that peginterferon may have on hepatitis C virus infection in the pretransplantation and posttransplantation setting will be explored. C irrhosis secondary to chronic infection with the hepatitis C virus (HCV) is the leading indication for liver transplantation. 1,2 Although transplantation is an effective treatment for end-stage liver disease secondary to chronic HCV infection, virus recurs in essentially all patients. 1-3 Progressive graft injury leading to cirrhosis occurs in about 25% to 33% of patients within just 5 years. [4][5][6][7][8] In addition, a limited group of patients (about 1% to 5% of recipients) develop rapidly progressive cholestatic hepatitis and liver failure within just 1 to 2 years. [8][9][10][11] Numerous studies have attempted to identify those factors that affect disease progression in these patients. Unfortunately, nearly all studies in this area have been retrospective in nature, conducted in patient populations of limited size, at single centers, utilized an array of immune suppressive medications in an uncontrolled manner, and have failed to consistently utilize protocol liver biopsy to investigate histologic progression. In addition, allograft rejection has not been either universally defined or treated and assays to measure serum HCV RNA have varied between centers and changed over time. As a result, data from many studies seem to contradict each other and the interpretation of these findings has varied widely. It is therefore not surprising how little progress has been made in our understanding of recurrent HCV over the past decade and that no universally accepted algorithm for managing these patients has emerged.Interferon (IFN) alfa with or without ribavirin (RBV) is the treatment of choice for patients with chronic HCV infection. 12,13 These medications have also been used to treat recurrent HCV after liver transplantation, but the interpretation of these data has been plagued by a similar set of limit...

Section: Pre-emptive Therapy For Hcv After Liver Transplantationmentioning

confidence: 99%

Controversies in the management of hepatitis C virus infection after liver transplantation

Shiffman¹,

Vargas²,

Everson³

2003

“…24,25 Leukopenia, hemolytic anemia, and asthenia were the most common side effects reported. 20,26 Liver transplant recipients have greater rates of renal dysfunction than nontransplantation patients, which would be predicted to increase the risk for ribavirin-associated hemolytic anemia. 25 Use of growth factors to prevent or treat leukopenia or anemia may allow a greater proportion of patients to remain on full-dose therapy, but this issue has not been formally studied.…”

Section: Efficacy Of Preemptive Antiviral Therapymentioning

confidence: 99%

Prophylactic and preemptive therapies for hepatitis C virus-infected patients undergoing liver transplantation

Terrault

2003

Key Points 1. Preclinical data from chimpanzees and studies in hepatitis B virus/hepatitis C virus (HCV) coinfected transplant recipients suggest prophylactic HCV antibody therapy may have a role in the prevention of HCV recurrence. 2. There are insufficient data available to evaluate the efficacy of this therapeutic approach. A small study found no benefit. Other ongoing studies using alternative antibody preparations and more intensive dosing schedules are underway. 3. Preemptive antiviral therapy, started within the first 4 weeks posttransplantation and prior to the onset of clinical signs and symptoms, is effective in some patients (5-33%) and is not associated with an increased risk of acute rejection. Tolerability of antiviral agents in the early posttransplantation period may be a factor limiting treatment efficacy. 4. It is unclear whether the preemptive antiviral treatment is superior to delaying treatment until recurrent disease is present and controlled trials addressing this issue are needed. (Liver Transpl 2003;9:S95-S100.) R ecurrent disease is universal in patients who are viremic pretransplantation. 1 Progression of histological disease is variable, but more accelerated in liver transplant recipients compared with nontransplantation patients. The incidence of bridging fibrosis and cirrhosis is low during the first 1 to 2 years posttransplantation, but reaches 10% to 30% within 5 to 8 years posttransplantation. [2][3][4] After cirrhosis develops in the transplanted graft, complications are common, with a cumulative probability of decompensation of 42% within a year. 5 Retransplantation is a option for those with recurrent disease, but its application to those who have lost a graft because of recurrent disease, especially if within the first 5 years posttransplantation, is controversial because prognosis after retransplantation generally is poor.Thus, interventions to prevent or ameliorate recurrent hepatitis C virus (HCV) disease have been sought. Treatment strategies generally fall into four categories: (1) pretransplantation antiviral therapy, (2) prophylactic therapies started in the peritransplantation period and continued posttransplantation, (3) preemptive therapies started in the early posttransplantation period before the development of clinically apparent hepatitis, and (4) posttransplantation antiviral therapy for patients with established recurrent HCV disease. The rationale and efficacy of prophylactic and preemptive therapies are the focus of this review. Prophylactic TherapyProphylactic therapies typically are started during the anhepatic phase of the transplantation operation and continued for variable and often indefinite periods posttransplantation. The goal of therapy is to prevent reinfection of the graft by HCV. Rationale for Prophylactic TherapySeveral lines of evidence support the use of antibody to HCV (anti-HCV) therapy in the prevention or amelioration of HCV disease posttransplantation.In chimpanzees, administration of a hyperimmune rabbit serum raised against a synthetic...

“…Other studies have suggested that 48 weeks' treatment with pegylated interferon and ribavirin will lead to a virologic response at least. 35,36 Prophylactic treatment is limited by tolerability in the early postoperative period. 37 …”

Section: Treatment Of Established Hepatitismentioning

confidence: 99%

Treatment of hepatitis C virus infection in the allograft

Neuberger

2003

Key Points 1. Recurrence of hepatitis C virus (HCV) in the graft is associated with a reduced quality of life and worse graft survival. 2. Pretransplantation, the severity of HCV recurrence may be reduced by reducing the pretransplantation load, by avoiding the use of organs from older donors, and by reducing the ischemic times. The effect of split livers on recurrence rates is uncertain. 3. The optimal immunosuppression regime has not been established but a heavy induction regime and treatment for acute rejection are associated with more viral replication and more graft damage. 4. Presently, there is no convincing evidence for preemptive treatment of HCV. 5. There are many studies on the effect of interferon with and without ribavirin for the treatment of HCV hepatitis. However, few are prospective, randomized, and controlled. 6. The current best treatment is with pegylated interferon and ribavirin; the dose and duration of treatment need to be established. Side-effects of treatment are common and reduction/withdrawal is frequent, but the regime is costeffective. 7. The role of newer treatments remains to be established. (Liver Transpl 2003;9:S101-S108.)I nfection of the liver allograft with hepatitis C virus (HCV) is associated with graft fibrosis, cirrhosis, and graft loss and a reduced quality of life. 1,2 The success of combination therapy with pegylated interferon and ribavirin in the treatment of HCV in the native liver and the development of newer and potentially more effective treatments has encouraged clinicians to treat recurrent HCV. Treatment of the Patient With HCVThe treatment of patients with HCV cannot be totally evidence-based, but given the current data, the following approaches seem reasonable. Reduction of Severity of HCV RecurrenceDonor. Where possible, avoid using grafts from older donors, avoid prolonged warm and cold ischemic times, and avoid using split livers (from cadaveric or living donors). It is appreciated that this approach is not always possible.Pretransplantation reduction of HCV load. given the side effects of treatment and the uncertainty of timing of transplantation, the balance seems against routine use of interferon to reduce viral load Avoidance of factors that may exacerbate viral damage. it seems sensible to avoid those factors that exacerbate HCV-related damage in the native liver, such as obesity, hyperglycemia, and alcohol. Immunosuppression RegimenOverimmunosuppression leads not only to an increased risk of sepsis, malignancy, and drug-specific complications, but will also enhance viral replication. Conversely, too little immunosuppression will lead to an increased risk of rejection (early acute rejection has little if any adverse impact on the graft), but the increased immunosuppression required to control such an episode will enhance viral replication. The optimal immunosuppressive regimen for such patients is discussed elsewhere in this issue.