Medicine Today Internal Medicine Webcast Series

Hepatitis C Management:

Management of Special Groups:
HCV Infection in Liver Transplant
Recipients

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Key Points

  • 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 in liver transplant recipients with recurrent HCV varies according to a variety of parameters. Facts that are accepted by all is the universal virological recurrence and increased risk of cirrhosis within 5 years.74

Another area of concern is the long-term survival in liver transplant recipients with HCV recurrence. Some reports from the United Network for Organ Sharing have described minimal differences in long-term outcomes75 while others have found significantly higher 5-year mortality in HCV-positive patients compared with HCV-negative patients (Figure 9).76 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.

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Recurrence of HCV Infection

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.77 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.76

Several risk factors have been associated with 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. 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 cadaver organs.78

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.79 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.80 After adjusting for illness severity, Russo et al79 did find a 44% greater risk of allograft failure in LDLT recipients compared with recipients of livers from deceased donors.

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Management after Transplant

Three major antiviral therapy strategies have been developed to lessen the burden of hepatitis C: treatment given before the transplant, soon after the transplant and before disease recurrence, and after transplant after HCV recurrence (Figure 10).

Many factors contribute to poorer outcomes at post-transplant treatment of HCV:

  • High prevalence of HCV Genotype 1,

  • High pretreament viremia level,

  • Inability to tolerate full dose,

  • Previous nonresponse to IFN,

  • Reduced sensitivity to IFN.

Data showing how sensitivity to IFN affects viral load outcomes is shown in Figure 11.

The management of liver transplant recipients prior to transplantation was discussed in the previous 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 absent or rare (occurring in less than 10% of patients) and toxicity has been high, often requiring dose reduction or discontinuation. Chronic allograft rejection has also been reported, at rates as high as 36%.81,82

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. In 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), 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 al83 used combination IFN alfa-2b and ribavirin in 54 patients who had histologic evidence of HCV recurrence. 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.

Pegylated products and long-term outcomes. Since the early reports of limited success with pegylated interferons with ribavirin, little has progressed.84,85 However, when to stop therapy remains an unanswered question.

Neff et al published 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).86 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. Another idea is the use of tissue PCR testing where a small number of patients maintained their sustained viral response when negative at time of discontinuation.

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.

Preemptive 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).87 Treated patients did not have more occurrences or more severe episodes of acute cellular rejection, and their 1- and 2-year survival rates were similar to those of the control group. One area of concern with this paper was the lack of liver biopsies at month 12 to determine efficacy. Terrault et al demonstrated ineffectiveness of therapy in patients with combination interferon and ribavirin.88 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.

Table 13 provides a list of patient-selection factors for treatment consideration.

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.89 Available data suggest that steroid pulses, use of muromonab-CD3 (OKT3), and presence of 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.90 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.

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Transplant Rejection

As mentioned earlier, some studies have found an increased risk of acute cellular rejection and chronic rejection associated with anti-HCV therapy, while others have not. Kugelmas et al studied 12 patients who had HCV RNA clearance and 18 patients who did not.91 They designated each patient's baseline immunosuppression level as 100%, and then remeasured these levels during therapy. They found a statistically significant difference in immunosuppression levels between anti-HCV treatment responders and nonresponders (Table 14). The authors hypothesized that it is not IFN or ribavirin therapy that predisposes patients to rejection, but that HCV eradication improves hepatocyte metabolic function, which leads to decreased immunosuppression and thus to an increased risk of rejection.

Table 14: Percent Change in Immunosuppression Levels In Responders vs. Non-Responders to Anti-HCV Therapy
 
Baseline
On-Rx
p values
Responders
100
71.8
=0.0001 vs. Baseline
Non-Responders
100
110.1
=0.015 vs. Responders

Kugelmas et al. Liver Transpl. October 2003.

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.92 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 seven 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 (three responders and five nonresponders) experienced acute cellular rejection characterized by bile duct injury with or without endothelialitis, and at least two 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 acute cellular rejection among 44 liver transplant recipients while on IFN therapy; nine patients were LDLT recipients and four had undergone retransplantation.93 Five of the 44 patients (11%) experienced acute cellular rejection, 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. Another important consideration is the variations in histology and the great difficulty in determining tissue activity to the immune event or recurrence of the virus. This area of interest will remain unanswered until clinical and histological parameters are in place that will designate the inciting clinical event.

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