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Calcineurin inhibitors are widely used as maintenance immunosuppressants in solid-organ transplantation to minimize the risk of allograft rejection. Although the use of these agents has transformed the outcomes for patient and graft survival, this has come at a cost, notably the well-known adverse events of nephrotoxicity and metabolic abnormalities, to name a few. Over the last decade, tremendous interest has also focused on the impact of these medications on the replication of hepatitis C virus (HCV), with cyclosporine in particular having a negative effect on viral replication in vitro. Although small retrospective studies suggested that there may be a beneficial effect with cyclosporine on the progression of recurrent HCV and response to interferon, these findings have not been validated in several well-designed randomized controlled trial studies. The authors will review the pharmacology and pharmacokinetics of these well-known drugs and discuss the impact of these medications on the natural history of HCV recurrence after liver transplantation.

Recurrent HCV is universal after liver transplantation in patients viremic at the time of transplantation and leads to cirrhosis in up to 30% of patients by five years. This has led to recurrent HCV emerging as an important yet controversial indication for liver retransplantation. Despite encouraging results with pegylated interferon and ribavirin therapy in the non-transplant HCV population, these findings have not translated to transplant recipients where viral eradication is frequently unsuccessful largely due to drug intolerance. The lack of effective therapies, severe side effects and reports of hepatic decompensation despite HCV eradication raises the question of whether recurrent HCV genotype 1 should be treated with interferon-based therapies. Although protease inhibitors were recently approved for the treatment of genotype 1 HCV patients in combination with pegylated interferon and ribavirin, these new agents are contraindicated in liver transplant patients due to severe drug toxicity.

Hepatitis C is one of the most common indications for liver transplantation in the United States, accounting for approximately 40%-45% of all liver transplants. Unfortunately, recurrent disease is universal in patients who are viremic before transplantation. This can lead to cirrhosis in at least 25% of patients 5 years after liver transplantation, and recurrent hepatitis C is now emerging as an important but occasionally contentious indication for retransplantation. Several attempts have been undertaken to identify patients at high risk for severe recurrent disease who may benefit from treatment, but unfortunately antiviral therapy frequently is ineffective and often is associated with numerous side effects. Although we have made significant strides in understanding the natural history of this disease in nontransplant patients, this does not hold true for the transplant population in which several uncertainties covering virtually the entire spectrum of liver transplantation persist. Despite these concerns, on a more practical level, it is usually only in the postoperative setting that clinicians truly can assess the impact of their interventions on the natural history of recurrent hepatitis C, for example, by adjusting immunosuppression or prescribing antiviral therapy. Preoperative and perioperative (including donor) factors often are outside the control of hepatologists and transplant surgeons. This review is not an inclusive review of the literature but summarizes what we believe are the more controversial topics of this disease.

Background: This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation., Methods: Between 1998 and 2004, 113 patients underwent liver transplantation for HCV-related cirrhosis. Time to histologic recurrence (fibrosis score >or=2) was the primary endpoint of the study. Recurrence was graded according to the system of Ludwig and Batts. A Cox's proportional hazard regression model was used to analyse the association between donor liver steatosis and HCV recurrence., Results: Recurrence-free survival for patients who received steatotic grafts was 82% and 47% at 1 and 4 years, respectively, and 81% and 52% for patients who received a non-steatotic liver. Donor macrovesicular steatosis (5-45%) was found to have no impact on HCV recurrence (P=0.47). Donor age (P=0.02) and cold ischaemia time (P=0.01) were found to increase the relative risk of HCV recurrence. The estimated risk of HCV recurrence increased by 23% for every 10-year increase in donor age. Similarly the risk of recurrence increased by 13% for every 1-h increase in cold ischaemia time., Conclusion: Mild-moderate donor liver macrovesicular steatosis has no impact on HCV recurrence after liver transplantation for HCV-related cirrhosis. Cold ischaemia time and donor age increased the likelihood of HCV recurrence.

Liver retransplantation for recurrent hepatitis C is usually not recommended for patients with early, severe disease. As it is difficult to predict which patients are at risk, interferon-based therapies are often used after histological confirmation of recurrent disease. Unfortunately, this treatment is poorly tolerated, costly and often unsuccessful. Three patients are described who developed decompensated cirrhosis requiring retransplantation despite sustained viral eradication. With the exception of one patient who developed post transplant nonalcoholic steatohepatitis, no etiology was identified in the others. All were retransplanted and remain hepatitis C negative at a mean follow-up of 25.6 months. Despite a lack of alternatives, the reflexive urge to use interferon-based therapy for recurrent hepatitis C in an attempt to prevent retransplantation at all costs should be resisted, particularly as recent studies suggest onset of recurrent disease after initial transplant does not predict onset of recurrence following retransplantation.

Background/aims: Patients with recurrent hepatitis C are often treated with interferon-based therapy in an attempt to prevent cirrhosis requiring retransplantation. We describe our experience with 32 patients with recurrent HCV., Methodology: Patients were followed prospectively after starting pegylated interferon alfa-2a 180 microg per week and ribavirin 1000-1200mg per day. HCV ribonucleic acid (HCVRNA) was repeated at three months, end of treatment (EOT) and six months after EOT for patients HCVRNA negative at EOT., Results: There were 22 males and 10 females. 21 patients have completed treatment, six remain on therapy and five were intolerant. In an intention-to-treat analysis, sustained viral eradication occurred in 40.6% of patients. Fibrosis scores were worse in eight patients of whom six were sustained responders. Three of these patients developed decompensated liver disease. Two were successfully retransplanted and remain HCVRNA negative after a mean follow-up of 11 months., Conclusions: Pegylated interferon alpha-2a and ribavirin were well tolerated in this small series. Sustained HCV eradication occurred in at least 40.6% of patients but progressive fibrosis occurred in 75% of sustained responders. This suggests that mechanisms other than recurrent HCV may be responsible for cirrhosis in sustained responders who remain at risk of developing decompensated liver disease.

Aim: Recurrent hepatitis C virus (HCV) is universal following liver transplantation. Patients are often treated with interferon and ribavirin in an attempt to eradicate the virus. We describe our experience with 38 patients with recurrent HCV from a single liver transplant program., Methods: Between October 2000 and November 2001, 38 patients with recurrent HCV were treated with interferon alpha 2b 3 million units three times a week and ribavirin 1000-1200 mg per day. HCV RNA and liver biopsies were performed before treatment at the end of treatment (EOT), and 6 months after EOT in patients who were HCV RNA negative at EOT., Results: There were 29 males and nine females. Median age was 49 years. In total, 34 patients were genotype 1 and two each were genotype 3 and 4. Six patients received HCV positive donors and 24 patients (63%) completed treatment. The most common indication for discontinuation of treatment was severe fatigue in 14 patients (37%). On intention to treat analysis, a sustained biochemical and virological response occurred in 10 patients (26%). Unchanged or improved fibrosis scores were present in 37% of patients, of whom 71% were non-responders to therapy., Conclusions: Interferon alpha 2b and ribavirin were poorly tolerated in this series of recurrent HCV patients, with sustained HCV eradication occurring in only 26% of patients. However, the majority of non-responders demonstrated unchanged or improved fibrosis scores, suggesting that a subset of patients may benefit from maintenance antiviral therapy to prevent the development of cirrhosis.

An all-oral therapy for treating hepatitis C (HCV) is now available for the most common genotypes although interferon-based therapy is still recommended for interferon-eligible patients with HCV genotype 1. For most patients, a prior history of treatment or presence of cirrhosis does not appear to significantly impact eradication rates with direct acting antivirals (DAA). The promising results from the numerous clinical trials of DAA's for HCV together with their tolerability represent a tremendous advance in our management of this disease, particularly as treatment is often well-tolerated, associated with few side effects and significantly shortened in duration. We will review several of the peer-reviewed landmark studies of DAA's for the treatment HCV and conclude with an expert commentary and five year view. [ABSTRACT FROM AUTHOR]

Patients with recurrent hepatitis C virus (HCV) are often treated with interferon-based therapy in an attempt to eradicate HCV and prevent cirrhosis requiring retransplantation. We describe our experience with pegylated interferon and ribavirin and the impact of this therapy on hepatic fibrosis. Methods: Patients were treated with pegylated interferon α-2b 1.5 mcg/kg/week and ribavirin 800 mg/day for 6–12 months according to genotype. HCV ribonucleic acid (HCV RNA) was repeated at 3 months, end of treatment (EOT) and 6 months after EOT for patients HCV RNA negative at EOT. Liver biopsies were performed prior to treatment and at EOT. Results: Thirty nine patients were eligible. Twenty two completed treatment and 17 (43.6%) were intolerant. Eleven of 22 (50%) patients who completed treatment developed sustained viral response (SVR). Two patients intolerant to treatment also developed SVR. Serial biopsies were performed in 17 patients and refused in five. Improved fibrosis scores were present in four patients (non-responders, n=2), unchanged in 10 (non-responders, n=4), and worse in three (all non-responders). Conclusions: Side effects are an important limiting factor in recurrent HCV treatment with SVR only 33.3% in an intention-to-treat analysis. However, improved or stable fibrosis scores were also demonstrated in 66.7% of non-responders. This suggests failure to eradicate HCV should not necessarily lead to treatment discontinuation as a subgroup of patients may benefit from maintenance therapy. [ABSTRACT FROM AUTHOR]

An abstract of the article "Pegylated Interferon Alfa-2b and Ribavirin for Acute Hepatitis C" by Sandeep Mukherjee is presented.