Management of Special Groups: HCV Infection in Liver Transplant Recipients

• HCV recurrence is nearly universal in liver transplant recipients.
• Progression of HCV infection after liver transplantation is accelerated.
• Recipients of living-donor liver grafts may develop a more aggressive HCV recurrence and may have a greater chance of graft loss compared with cadaveric organ recipients.
• Liver transplant recipients with recurrent hepatitis C should be considered candidates for antiviral therapy.
• Treatment of established, recurrent HCV infection after liver transplantation is characterized by lower rates of sustained virologic response, severe bone marrow toxicity, and the risk of allograft rejection.
• For patients with established, recurrent HCV infection, treatment with PEG-IFN and reduced-dose ribavirin as well as growth factors should be considered, as it may favorably affect the natural history of the disease.
• Twelve-week "stopping rules" for antiviral therapy do not apply to liver transplant recipients.

The natural history of HCV infection clearly is accelerated following liver transplantation. Berenguer reviewed seven studies on the progression of liver disease to cirrhosis in patients who had HCV infection following liver transplantation.⁹⁹ Follow-up ranged from 23 to 43 months. The rates of cirrhosis in these patients ranged from 6% to 23%.

Forman et al published a study of 5-year survival among liver transplant recipients and found that HCV-positive patients had significantly higher mortality than did HCV-negative patients (Figure 8).¹⁰⁰ Although short-term differences in survival are probably minimal, differences may be statistically significant over the medium term (3 to 7 years). They are certainly significant over the long term.

Hepatitis C-induced end-stage liver disease is the most common indication for liver transplantation in the United States. HCV infection recurs almost universally, and it leads to allograft hepatitis in as many as 88% of cases.¹⁰¹ Allograft cirrhosis is seen in approximately 20% of recipients within 5 years of liver transplantation, and long-term graft survival and patient survival are lower in these patients than in patients who receive transplants because of other causes of end-stage liver disease.¹⁰⁰ Recipients of living-donor liver transplants (LDLTs) may be at a greater risk for more aggressive HCV recurrence and faster graft loss than are patients who receive cadaveric organs.^102-104

Several reasons have been proposed to explain this more aggressive recurrence, including higher viral titers immediately after liver transplantation, faster biochemical and histologic recurrence, cholestatic hepatitis, nonwhite race, increased age, poorer health among transplant recipients, the use of marginal organs, the occurrence of allograft rejection requiring steroid bolus therapy, and the use of induction therapies.

The impact of recurrent hepatitis C in LDLT recipients has also sparked recent controversy. Russo et al reviewed data in the Scientific Registry of Transplantation Recipients to compare patient and graft survival between LDLT recipients and those who received livers from deceased donors.¹⁰³ They found no difference at 1 or 2 years after transplantation. In an accompanying editorial, Forman et al noted that LDLT recipients were significantly less sick at the time of liver transplant: LDLT recipients were younger, thinner, less likely to be in the intensive care unit, and had a lower model for end-stage liver disease (MELD) score.¹⁰⁴ After adjusting for illness severity, Russo et al did find a 44% greater risk of allograft failure in LDLT recipients compared with recipients of livers from deceased donors.

The management of liver transplant recipients prior to transplantation is discussed in the above section on cirrhosis. Following liver transplantation, the decision to initiate preemptive therapy should be made before the onset of allograft hepatitis, usually by 1 to 2 months after transplantation.

Interferon monotherapy. IFN monotherapy to treat recurrence of established HCV infection following liver transplantation has been used since the early 1990s, but the overall results have been poor. Sustained virologic response has been absent¹⁰⁵ or rare (occurring in less than 10% of patients),¹⁰⁶ and toxicity has been high, often requiring dose reduction or discontinuation. Chronic allograft rejection has also been reported, at rates as high as 36%.¹⁰⁶

Ribavirin monotherapy. Ribavirin monotherapy has also been tried in this setting, but without evidence of sustained virologic response or histologic benefit and with a high rate of dose-limiting hematologic side effects.¹⁰⁷

Interferon-ribavirin combination therapy. Trials of combination therapy have yielded better rates of sustained virologic response, particularly in patients with mild recurrences of HCV infection, although the incidence of side effects is still high. Menon et al reported on 26 liver transplant recipients with recurrent HCV infection who were treated with IFN alfa-2b and low-dose ribavirin (800 mg/d for patients weighing <70 kg and 1,000 mg/d for the remaining patients).¹⁰⁸ Eight patients (31%) achieved a sustained virologic response, but only 13 (50%) were able to complete 1 year of therapy. Adverse events were seen in 18 patients (69%), 12 of whom required either a dose reduction or cessation of therapy. The most common adverse effect that led to dose modification or cessation was anemia, which occurred in 12 patients (46%).

Firpi et al used combination IFN alfa-2b and ribavirin in 54 patients who had histologic evidence of HCV recurrence.¹⁰⁹ Treatment was started at low doses, and the target ribavirin dose was 200 mg/d less than that used in pretransplant populations (800 and 1,000 mg/d for patients who weigh <75 kg or >75 kg, respectively). Sixteen patients (30%) achieved a sustained virologic response, but only 11 (20%) tolerated full-dose therapy. Thirty-nine patients (72%) required at least one dose modification because of adverse effects; again, the most common was anemia, which occurred in 21 patients (39%). Three patients (5.6%) experienced acute cellular rejection.

Sicker patients have not fared as well. In a study of patients with more severe HCV recurrence, Gopal et al reported that only 8.3% achieved a sustained virologic response.¹¹⁰

Early virologic response. In a study of 34 liver transplant recipients treated for HCV recurrence after transplantation, Kennedy et al observed a lower rate of early virologic response than that seen in pretransplant cohorts.¹¹¹ This post-transplant population was characterized by intolerance to PEG-IFN and ribavirin despite a high frequency of growth factor use. Anti-HCV therapy was started at a median of 19.6 months after transplantation; 71% of patients were men, and 89% were infected with HCV genotype 1. The median calculated creatinine clearance was 87.2 mL/min; the creatinine clearance was less than 60 mL/min in 4 patients and between 60 and 90 mL/min in 16 patients. At week 12, 15 patients (44%) achieved an early virologic response. The mean target ribavirin dose for the group was 1,065 mg/d. The overall median ribavirin dose received was 600 mg/d; the mean dose (+/- SD) was 569 +/- 300 mg (53.4% of the target dose). Fourteen patients (41%) received granulocyte colony-stimulating factor therapy, and 11 (32%) received erythropoietin. The researchers concluded that early virologic response and early stopping rules for anti-HCV therapy should not apply following liver transplantation because of the difficulty of achieving target doses and maintaining adequate adherence.

Long-term outcomes. Abdelmalek et al reported long-term follow-up data on 29 liver transplant recipients after they had achieved a sustained virologic response to treatment for HCV recurrence (24 treated with IFN + ribavirin, 4 with PEG-IFN + ribavirin, and 1 with IFN monotherapy).¹¹² These patients were followed for a mean of 24.7 months with yearly HCV RNA assays and liver biopsies. No recurrence of HCV was detected by serum HCV RNA testing; all 29 patients remained persistently negative. Evaluation of paired liver histology at 3 to 5 years after sustained virologic response in 15 of these patients revealed improvement of =2 points on the Histologic Activity Index in 60% of patients and no change in 33%, as well as fibrosis improvement of >1 stage in 67% and no change in 13%. Interestingly, one patient died of cholestatic hepatitis and three others exhibited progression of fibrosis and ductopenia on follow-up biopsies.

These findings suggest that most patients who achieve sustained virologic response to treatment of HCV recurrence following liver transplantation will have extended virologic and histologic benefits, although a small minority will get worse, developing allograft rejection or failure. Despite the potential histologic benefits described in this study, data are still lacking on long-term maintenance therapy for liver transplant recipients with recurrent HCV who do not respond to standard antiviral therapy.

Prophylactic therapy. Others have proposed that prophylactic IFN therapy would delay and/or prevent HCV recurrence. Sheiner et al found that post-transplant patients who received IFN monotherapy (n = 30) were less likely to develop recurrent hepatitis than were untreated controls (n = 41).¹¹³ Treated patients did not have more or more severe episodes of acute cellular rejection, and their 1- and 2-year survival rates were similar to those of the control group. Yet despite these encouraging results, prophylactic therapy has not been completely accepted because it would involve treating all patients, including the significant proportion who would not require it given the variable course of recurrent HCV infection. Still, prophylaxis should be considered for patients at higher risk of aggressive occurrence.

Immunosuppressive drugs. As far as which immunosuppressive regimen is best for HCV-infected patients, the data are sketchy at best. In a recent review of the literature, Everson concluded that it is the global immunosuppression level—not any single immunosuppressive agent—that dominates the effect of therapy on recurrence of HCV infection.¹¹⁴ Available data do suggest that steroid pulses, muromonab-CD3 (OKT3), and anti-interleukin-2 receptor antibodies negatively affect HCV recurrence.

Mycophenolate mofetil (MMF) is an immunosuppressive drug that acts by inhibiting inosine monophosphate dehydrogenase and has antiviral properties against Epstein-Barr virus and other herpesviruses, yellow fever virus, and HBV. These properties have led to studies of whether MMF may have a beneficial role in HCV infection after liver transplantation, but results have been mixed. Zekry et al conducted a prospective crossover study to examine whether substituting MMF for azathioprine (in addition to prednisone and either cyclosporine or tacrolimus) would reduce HCV viral load and improve allograft function.¹¹⁵ Thirteen patients who had been receiving azathioprine were switched to 3 months of MMF therapy and then switched back to azathioprine for 3 more months of observation. HCV RNA load increased significantly with MMF therapy, with no significant change in AST or ALT levels. Thus, this study showed no beneficial effect of MMF therapy in HCV-infected liver transplant recipients.

Stravitz et al reviewed the histologic findings in 23 post-liver transplant patients with recurrent chronic hepatitis C treated with IFN-based regimens for at least 24 weeks.¹¹⁷ Eight patients with HCV genotype 1 who were HCV RNA negative at week 24 continued therapy until week 48. Seven patients received long-term maintenance therapy (3 responders and 4 nonresponders). Liver biopsy was repeated in responders at a mean of 23 months after the first test showing HCV RNA undetectability. Necroinflammatory activity improved significantly but was still moderate to severe in 7 of the 11 patients. There was no significant change in liver biopsy fibrosis score in the 11 responders. Twelve nonresponders also underwent paired liver biopsies within 2 months of discontinuation of anti-HCV therapy. These biopsies showed no improvement in necroinflammatory activity or fibrosis. Eight patients (3 responders and 5 nonresponders) experienced ACR characterized by bile duct injury with or without endothelialitis, and at least 2 patients went on to chronic rejection. Patients who experienced allograft rejection associated with anti-HCV therapy had received their liver transplant at a younger age than did those without allograft rejection.

Saab et al reviewed the incidence of ACR among 44 liver transplant recipients while on IFN therapy; 9 of the patients were LDLT recipients and 4 had undergone retransplantation.¹¹⁸ Five of the 44 patients (11%) experienced ACR, at a mean of 3.3 months into anti-HCV therapy. Two of these five patients' rejection episodes were nonresponsive to immunosuppression and resulted in graft loss secondary to chronic allograft rejection.

In summary, despite some literature suggesting that anti-HCV therapy may be associated with an increased risk of graft rejection in liver transplant recipients, this risk does not appear to be sufficient for avoiding treatment, which may favorably affect the natural history of the disease.