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Abstract

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Chronic infection with hepatitis C virus (HCV) is a growing problem worldwide, with up to 300 million individuals infected, and those with chronic infection are at risk for cirrhosis and hepatocellular carcinoma. HCV infection is the most common indication for liver transplantation in the United States and Europe. Unfortunately, although transplantation is effective for treating decompensated cirrhosis and limited hepatocellular carcinoma associated with hepatitis C, HCV reinfection is virtually the rule among transplant recipients. Reinfection of the graft is associated with more rapidly progressive disease, with a median time to cirrhosis of 8 to 10 yr. Unfortunately, treatment of chronic HCV in liver transplant recipients is suboptimal. Combination therapy with interferon (pegylated and nonpegylated forms) plus ribavirin appears to provide maximum benefits. Drug therapy is usually administered for recurrent disease. No prophylactic therapy is available. Preemptive regimens offer no distinctive advantages over treatments begun for recurrent disease. Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially from cytopenias, and drug discontinuations in up to 50% of patients. Optimizing drug doses is important in maximizing sustained virological response rates. Future therapies may include ribavirin alternatives with lower rates of anemia, alternative interferons with lower rates of cytopenias, and new antiviral drugs that can be used alone or in combination with either interferon or ribavirin to enhance sustained virological response rates and improve tolerability. Liver Transpl 12:1192–1204, 2006. © 2006 AASLD.

Chronic infection with hepatitis C virus (HCV) is a common cause of cirrhosis and hepatocellular carcinoma in the United States and worldwide, and HCV now ranks as the number one indication for liver transplantation in the United States and Europe. Although orthotopic liver transplantation is effective for treating decompensated cirrhosis and small hepatocellular carcinoma secondary to hepatitis C, HCV reinfection is virtually the rule among patients with pretransplantation viremia.1 Recurrent infection leading to cirrhosis occurs in 10 to 25% of transplant recipients within 5 to 10 yr of transplantation, and once cirrhosis occurs, the 1-yr actuarial risk of hepatic decompensation is approximately 40%.2 HCV-positive transplant recipients have higher rates of mortality (hazard ratio, HR, 1.23; 95% confidence interval, 1.12-1.35) and allograft failure (HR 1.30; 95% confidence interval, 1.21-1.39) than do HCV-negative recipients,3 and the excess mortality among HCV-positive patients is caused by complications of recurrent HCV disease.4, 5

CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

HCV circulating in the blood at the time of surgery is the likely source of virus that reinfects the new graft, although other extrahepatic sources of HCV may contribute. As in the nontransplantation setting, recurrent HCV disease presents in acute and chronic forms, and in the chronic form, 2 patterns have been described: the typical chronic hepatitis and a severe cholestatic form.6

Recurrent hepatitis C generally becomes manifest with abnormal liver test results or as histological changes of acute or chronic hepatitis within 6 months of transplantation.6 Viral levels fall during the anhepatic phase and rise rapidly within hours to days after transplantation, to peak within weeks to months.7 HCV ribonucleic acid (RNA) levels after transplantation are approximately 1 log higher than they are immediately before transplantation.7, 8 Most cross-sectional studies find that HCV viral levels posttransplantation are poorly correlated with the histological severity of disease.9 However, cholestatic hepatitis C, the most severe presentation of HCV recurrence, is frequently associated with high HCV viral levels and the rapid development of graft failure.10

FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Donor and recipient factors, viral factors, and transplant-associated events have been linked with an increased severity of HCV disease (Table 1) and higher rates of graft loss. Factors linked most consistently with disease severity are older donor age, treatment of acute rejection (including use of OKT3 and corticosteroid boluses), and cytomegalovirus infection. A better understanding of the factors contributing to disease progression may identify potential mechanisms for modifying disease outcomes, although some of these factors cannot be changed. For example, although older donor age is associated with worse HCV outcomes, few programs have the luxury of pairing only younger donors with HCV-infected recipients. Other factors such as treatment of acute rejection need to be prospectively assessed to determine the best means of minimizing effects of acute rejection treatment on HCV disease progression.

Table 1. Factors Predicting Worse Severity of Hepatitis C Virus Disease
CategoryFactor linked with disease severitySpecifics
Donor factorsDonor ageIncreased risk begins at age 30 or 40 yr
 Cold ischemia timeRisk increases with time
 Donor sexFemale donor organs confer higher risk
 Donor status (live vs. deceased)Related to number of live donor transplants performed by center
Viral factorsHCV genotypeGenotype 1 is associated with more severe disease (some not all studies)
 HCV viral load at transplantationHigh viral load (>106 IU/mL) is associated with more severe disease and graft loss
Transplant-related factorsCytomegalovirus infectionIncreased severity of fibrosis
 Treated acute rejectionIncreased with ≥1 episode
 OKT3 useRelated to acute rejection treatment
 Corticosteroid bolusesRelated to acute rejection treatment

Donor and Recipient Factors

Older donor age affects the rate of progression of fibrosis. Wali et al.11 found that a 10-yr difference in donor age (40 vs. 50 yr) was associated with an increase in the fibrosis progression rate from 0.6 to 2.1 units/yr and with a decreased interval to the occurrence of cirrhosis by almost 8 yr. Lake et al.12 found that the risk of graft loss was increased for each additional decade of donor age, beginning at age 40 years. Other studies using either fibrosis progression or graft survival as end-points confirm these findings.13, 14

The rising age of donors over time is one reason proposed for the occurrence of a more severe recurrent HCV disease in recent years.5, 15 In a U.K. study, the median donor age increased by 10 yr in 1 decade.11 In a large study from 1 U.S. center, 49% of the 402 consecutive donors were more than 50 yr old.16 Older donor age was associated with poorer graft survival in the HCV-infected patients, whereas donor age did not affect graft survival in patients without HCV (P < 0.001).

HCV antibody-positive donors are used when the urgency for liver transplantation precludes a prolonged wait for an antibody-negative donor. In general, organs from these donors should be restricted to HCV RNA-positive recipients; use of antibody-positive organs in uninfected persons is not recommended, as effective prophylactic therapy is unavailable and the majority of the donors are viremic.17 Longitudinal studies of up to 10 yr of follow-up indicate that outcomes in HCV-positive recipients of antibody-positive grafts are comparable to those in HCV-positive recipients of antibody-negative grafts.17–21 Superinfection by genotype 1 HCV from the donor organ is possible, and because the efficacy of antiviral therapy in HCV genotype 1-infected patients is lower than for HCV nongenotype 1 patients, grafts from HCV antibody-positive donors are best used in HCV genotype 1-infected recipients.17 The severity of histological disease should be another factor influencing the decision to use an organ from an antibody-positive donor. A full discussion of the risks and benefits of receiving an antibody-positive organ is required with potential recipients.

Other donor factors requiring further investigation for their role in recurrence and outcome in patients with HCV disease include donor type (live vs. deceased donor),7, 22–26 the immunogenetic background of recipient,27 hepatic iron content,28 and presence of hepatic steatosis.29

Viral Factors

Some studies have linked a high viral load before transplantation with more severe HCV recurrence after transplantation. A retrospective analysis of 284 patients from Spain and the United States identified pretransplantation viral load as an independent predictor of HCV disease progression.15 In a separate U.S. analysis of 166 HCV-infected liver transplantation recipients, those with high viral load (HCV RNA titers >1 million vEq/mL) had a substantially decreased cumulative 5-yr survival rate compared with those with lower viral titers.30 However, this study did not evaluate histological findings, and survival may have been reduced by causes other than recurrent cirrhosis. Several cross-sectional studies have found poor correlations between posttransplantation HCV viral loads and the severity of histological disease.31, 32 The importance of HCV genotype in HCV disease progression remains controversial.31–35

Transplant-Related Factors

Treatment of acute rejection has been linked to more severe HCV disease recurrence.15, 36, 37 In 284 consecutive transplant recipients, treatment with methylprednisolone boluses during the first yr after transplantation significantly impaired prognosis.15 In a separate study, HCV-positive patients who experienced a single episode of acute rejection had reduced survival, whereas HCV-negative patients did not.37 This association led to the recommendation that use of steroid pulses and antilymphocyte preparations for treatment of acute rejection be avoided in patients with HCV.38 The immunosuppressive regimen used in HCV-infected patients should be sufficient to prevent moderate to severe acute rejection, as treatment with corticosteroid boluses and OKT3 is detrimental but not excessive so as to exacerbate HCV disease progression or cause other long-term complications.39

Since the potency of immunosuppression has been hypothesized to be one of the reasons for more severe HCV disease in more recent years, weaning or minimization of immunosuppression therapy may be beneficial to patients with HCV disease. Recent studies evaluating weaning of minimization of immunosuppression show divergent results, possibly related to the intensity of the initial immunosuppression and/or the timing and rate of immunosuppressant weaning.40–42 In studies from the University of Pittsburgh, weaning off of immunosuppression following induction with antithymocyte globulin or alemtuzumab was associated with severe HCV disease and graft loss due to recurrent HCV.41, 42 In contrast, a study from Italy of therapy with cyclosporine, azathioprine, and steroids weaned after 5 yr showed significant improvements or stabilization of HCV disease after successful weaning of immunosuppression.40 Several retrospective studies seeking to determine whether tapering of corticosteroids is beneficial in patients with HCV disease showed no consistent effect (positive or negative).43–45

Control of HCV infection posttransplantation has been correlated with early restoration of HCV-specific CD4+ T-cell responses.46 The optimal immunosuppressive regimen that will achieve immune control of HCV while simultaneously controlling the alloimmune response is unknown. As highlighted previously, the only immunosuppressive agents identified consistently with worsening of disease severity are those used to treat acute rejection; namely, corticosteroid boluses and antilymphocyte therapies.4, 36, 38, 47 Whether lymphocyte-depleting drugs used outside the context of acute rejection cause more severe HCV disease is controversial.41, 48 Very few prospective, controlled studies have investigated specific immunosuppressants in HCV-infected patients, particularly newer immunosuppressants such as sirolimus and interleukin-2 receptor antagonists. Limitations of the studies conducted to date include: 1) a focus on graft loss due to all causes rather than to HCV disease; 2) a lack of protocol biopsies to assess hepatitis C disease severity; and 3) use of multiple-drug immunosuppressive regimens with more than 1 drug differing between comparison groups. In addition, few of these trials were carried out during the Model for End-Stage Liver Disease era, when a higher prevalence of renal dysfunction in the early posttransplantation period may influence immunosuppression choices.

Several studies have also linked cytomegalovirus infection with worsening of HCV disease recurrence, especially severity of fibrosis.47, 49–51

In conclusion, multiple factors have been linked with disease outcome in HCV-infected transplant recipients. Currently, the status of the harvested graft and the immunological events related to preventing allograft rejection in the HCV setting appear to be important. Although models to predict outcomes in these patients have been proposed, they were created from cohorts treated a decade ago, before the current immunosuppressants and antiviral agents were available.52–54 Based upon current knowledge of the factors influencing disease severity, the main focus of management is as follows: 1) prevention of acute rejection requiring corticosteroid boluses or OKT3; 2) prevention of cytomegalovirus infection; and 3) treatment of recurrent disease. Donor factors, though often not modifiable, may be used to make decisions regarding timing of treatment and retransplantation candidacy.

TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Recurrent infection will progress to cirrhosis in a substantial proportion of HCV-infected patients. Once cirrhosis develops, the risk of graft loss is high and approximately one-half of patients develop decompensated liver disease within 1 yr.2 Though retransplantation is generally a consideration for any patient with graft failure, HCV disease is a controversial indication, especially with the current organ shortage.

Antiviral therapy has been the mainstay of managing recurrent HCV disease in transplant recipients. The optimal time to intervene is unknown, but the majority of studies have focused on treating liver transplant recipients with evidence of histological disease (Table 2). Alternative approaches include the use of antiviral therapy before transplantation,55–58 or early after transplantation before there is clinical evidence of recurrent disease (preemptive therapy)59–63 (Table 2). Novel prophylactic therapies have been studied, but no effective form of prophylaxis has been identified.64, 65 In general, antiviral therapy is less effective in transplant recipients than in non-transplant patients, and tolerability is a major challenge.

Table 2. Treatment Strategies for Hepatitis C Virus-Infected Liver Transplant Recipients
Treatment strategyTiming of treatmentTarget populationOutcomes achieved in studies to date
  1. Abbreviations: LDLT, live donor liver transplantation; MELD, Model for End-Stage Liver Disease.

PretransplantationInitiated before transplantation with goal of achieving an undetectable viral load before transplantationBest results in patients with mildly to moderately decompensated cirrhosisPrevents HCV recurrence
ProphylacticInitiated at the time of transplantation and continued posttransplantation with goal of preventing recurrent infectionUnknownDoes not prevent infection of new graft
PreemptiveInitiated early in the post-transplantation period (typically within first 8 weeks) before onset of biochemical and histological evidence of diseaseBest tolerated by LDLT patients and patients with lower MELD scores. Absence of current or recent rejection.Viral eradication in proportion of treated patients. Possibly milder histological disease, even in virological nonresponders.
PosttransplantationInitiated only after biochemical and histological evidence of recurrent (and typically progressive) diseaseAny stage eligible; whether earlier treatment is more likely to yield SVR is unknown. Given high risk of decompensation once cirrhosis occurs, treatment should be initiated at early stage. Absence of rejection.Viral eradication in proportion of treated patients. Histological improvements in majority of responders.

Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis Awaiting Liver Transplantation

Hepatitis C in cirrhotic patients is treated before transplantation for 2 reasons (Fig. 1). First, clearing or suppressing HCV before transplantation may reduce or eliminate the risk of recurrent hepatitis C in the transplanted liver and thereby improve graft survival. Second, clearing HCV in a cirrhotic patient may halt disease progression and avoid the need for transplantation. Antiviral treatment before transplantation is a potential option for some patients.55–58 Treatment appears to be best tolerated and most efficacious in those with less advanced decompensation.56–58

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Figure 1. Strategies to decrease morbidity and mortality of recurrent chronic hepatitis C before and after orthotopic liver transplantation. Treatment may be most effective within 3 months of transplantation, when viral loads are lowest and histological evidence of disease is minimal. However, immunosuppression is greatest during this time, and combination therapy in conjunction with immunosuppressive therapy increases the risk of bone marrow suppression. OLT, orthotopic liver transplantation; Comp, compensated; Decomp, decompensated; Tx, transplantation. Reprinted with permission from Berenguer and Wright59.

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Everson et al.66 treated 102 patients with decompensated HCV-related cirrhosis using a low-dose accelerating regimen of conventional interferon (IFN) and ribavirin (RBV). Most patients had mildly to moderately decompensated cirrhosis; 2 of 3 had a history of clinical decompensation. The mean (standard deviation) Child-Turcotte-Pugh (CTP) score was 7.1 (2.0), with about 1 of 2 having CTP A cirrhosis, and the mean Model for End-Stage Liver Disease score was about 18. The end-of-treatment virological response rate was 39%, and the overall rate of sustained virological response (SVR) was 22%. Genotype was an important determinant of response: the SVR rate was 60% among patients with HCV genotype 2 or 3 and 11% among patients with genotype 1. Patients who had an SVR before transplantation did not experience recurrent disease after transplantation, confirming the effectiveness of this strategy in eliminating the risk of HCV recurrence. Adverse events required discontinuation of therapy in 20% of patients.

A second study evaluated the efficacy of an “on-treatment virological response” vs. an SVR. Forns et al.56 evaluated 30 patients undergoing liver transplantation who had CTP class A cirrhosis (N = 15), B (N = 13), or C (N = 2) and were receiving combination treatment. Nine patients were negative for HCV RNA at the time of transplantation (median duration of treatment, 4 months), and HCV infection recurred in three. Among patients achieving SVR before transplantation, none had HCV recurrence posttransplantation. Recurrence in patients treated only to achieve an on-treatment response may be explained by the persistence of very low level of virus in a second compartment, such as peripheral blood mononuclear cells. A high rate of side effects was reported, and 6 of the 9 patients achieving an on-treatment response required dose reductions.56

Finally, a third study by Crippin et al.55 highlights the limitations of this therapy in patients with advanced liver decompensation. In a randomized study of 15 patients with CTP class B or C cirrhosis (median pretreatment CTP score 12), 13 patients experienced 20 serious adverse events during treatment. The study was terminated early because of a high rate of adverse events, and the authors concluded that patients with advanced liver disease are not candidates for antiviral therapy.

In summary, pretransplantation antiviral therapy may be an option for cirrhotic patients with stable CTP class A or early class B disease only and who have no contraindications to antiviral treatment. Given the frequency of complications, treatment should be provided only at experienced centers and to patients listed and ready for liver transplantation. The primary goal of treatment is SVR, but an undetectable HCV RNA level at the time of transplantation reduces the risk of recurrence.

Prophylactic Therapy in Patients With Chronic Hepatitis C Undergoing Liver Transplantation

The term “prophylactic therapy” has been used to refer to therapy given after transplantation,60, 61 but since reinfection occurs within days of transplantation, the term is most appropriately used to describe therapy given to prevent reinfection. Such therapy is typically started before or at the time of transplantation and continued post transplantation for a specific period of time.64 Preclinical studies in nonhuman primates suggest that hepatitis C immune globulin may prevent HCV reinfection.64, 67 Additionally, the success of hepatitis B immune globulin in preventing hepatitis B virus infection after transplantation prompted interest in antibody therapy for HCV-infected transplant recipients. Unfortunately, study results have been disappointing and no effective prophylactic therapies are currently available. In the only published study, 15 patients received human hepatitis C immune globulin 75 or 150 mg/kg (Civacir; Nabi Biopharmaceuticals, Boca Raton, FL) or placebo.65 Although patients receiving the high dose of hepatitis C immune globulin had lower alanine aminotransferase activity and lower HCV antigen levels in liver tissue during treatment than the other groups, serum HCV RNA levels did not differ and infection recurred in all patients.

Preemptive Treatment in Liver Transplant Recipients With Chronic Hepatitis C

Preemptive treatment may be more effective than treatment started only with recurrence is clinically apparent because it is initiated soon after transplantation when viral loads tend to be low and fibrosis is absent. These 2 factors are associated with increased response to antiviral therapy in nontransplant recipients. However, in the early posttransplantation period, antiviral therapy may be less effective due to the presence of higher doses of immunosuppressants, and tolerability may be more limited as a result of concurrent posttransplantation complications. Additionally, the risk of acute rejection is the highest in the early posttransplantation period and there are concerns that the immunomodulating effects of IFN may increase the risk of rejection.

IFN and RBV combination therapy appears to be more effective than IFN monotherapy. In controlled trials, IFN monotherapy for 12 months delayed the time to recurrence and reduced the severity of histological disease compared with no treatment.60 Chalasani et al.62 tested the efficacy of preemptive pegylated interferon (peg-IFN) alfa-2a 180 μg/week given within 3 weeks after transplantation (N = 26) vs. no antiviral treatment (N = 28) for 48 weeks. Treated patients had significantly lower HCV RNA levels and better histological profiles; fibrosis scores improved or stabilized in 23 (88%) treated patients but in only 11 (38%) untreated patients. However, only 2 of 26 (8%) treated patients achieved an SVR.

In the largest trial of preemptive therapy in the United States, Shergill et al.63 compared IFN 3 million units thrice weekly or peg-IFN 1.5 μg/kg per week (peg-IFN was introduced during the study when the standard of care changed) alone or in combination with RBV 600 mg increased to 1,000 to 1,200 mg/day (Table 3). Treatment was initiated 2 to 8 weeks after transplantation and continued for 48 weeks. In the monotherapy (N = 22) and combination therapy (N = 22) treatment groups, the respective end-of-treatment virological response rates were 4.5% and 22.7% and the SVR rates were 4.5% and 18.2%. The challenges of using antiviral therapy in the early posttransplantation period were highlighted in this study, in which only 41% of 124 transplanted patients met treatment eligibility criteria. Living donor graft recipients were eligible for therapy more frequently, and eligible patients had lower Model for End-Stage Liver Disease and CTP scores before transplantation. Dose reductions were required in 85% of patients (more frequent for RBV than IFN) and drug discontinuations in 37%.63

Table 3. Studies of Preemptive Combination Antiviral Therapy in Liver Transplant Recipients
StudyHCV positive patients, nTreatmentsOutcomes
  1. Abbreviations: HAI, hepatic activity index; LDLT, living donor liver transplantation; IFN, interferon; RBV, ribavarin; SVR, sustained virologic response.

Sugawara et al. (2004)6823 patients who underwent LDLT for HCV cirrhosis started treatment 1 month after transplantationIFN 3-6 MU thrice weekly plus RBV 400-600 mg/day; treatment continued 12 months after HCV RNA became negative or for 12 months in patients persistent HCV positivitySVR obtained in 39% of patients; cumulative 3-yr survival was 85%; comparable to the 90% survival of HCV negative patients after transplantation; acute rejection in 33% of patients
Shergill et al. (2005)6351 of 124 transplant recipients eligible for preemptive therapy; 44 received at least 1 dose of therapy initiated 2-6 weeks after transplantationIFN 3 MU thrice weekly or peg IFN 1.5 μg/kg/wk plus RBV 600 = 1200 mg/day for 48 weeksSVR obtained in 9.1% of patients; dose reductions in 85% of patients and drug discontinuations in 37%; serious adverse events in 27% of patients; growth factor support in the latter half of the study did not significantly affect frequency of dose reductions; acute rejection episodes in 40.9% of patients

Sugawara et al.68 also concluded that living-donor transplant recipients are good candidates for preemptive therapy. They gave 23 HCV-infected, living-donor liver transplant recipients IFN alfa-2b (3 million units thrice weekly increased to 6 million units if tolerated) and RBV (400 mg daily increased to 600 mg if tolerated) starting within the first month after surgery and continued for 12 months after the first negative HCV RNA test result (Table 3). Based on an intent-to-treat analysis, the SVR rate for the 23 patients was 39% (N = 9) and virological responders had a significant improvement in the histological activity index.68

In summary, this therapeutic strategy is not applicable to all transplantation candidates; those who are less sick before transplantation appear to be the best candidates. If preemptive therapy is used, combination therapy is the treatment of choice. However, based on the available data, preemptive therapy cannot be considered the strategy of choice because SVR rates are not clearly higher than those achieved with antiviral therapy given later in the posttransplantation period. A definitive study comparing preemptive versus delayed therapy is needed to address the effect of timing on SVR rates. Tolerability of therapy is a major challenge, especially with preemptive therapy, because cytopenias are common in the early posttransplant period. Dose reductions and discontinuations are common, especially for RBV. The frequent presence of renal dysfunction and the presence of anemia related to other transplant complications makes RBV use especially difficult in this population. The tolerability and safety of preemptive therapy using short- vs. long-acting IFN in combination with RBV has not been studied. Most experts recommend using growth factors to assist with management of cytopenias, but whether growth factors increase SVR rates is unknown.

Treatment of HCV-Infected Transplant Patients With Recurrent HCV Disease

Antiviral therapy is given most commonly when HCV-infected transplant recipients have histological evidence of disease recurrence (Fig. 1).69 Unfortunately, the majority of studies supporting this treatment strategy are uncontrolled, which limits the assessment of treatment-related risks, especially of acute and chronic rejection, and makes assessing histological benefits difficult. Although IFN monotherapy has not been compared with combination IFN plus RBV in randomized studies, the available studies indicate that combination therapy achieves superior results.70 Uncontrolled studies suggest that IFN plus RBV combination therapy achieves SVR rates of 20 to 35% in transplant recipients with chronic hepatitis C.69, 71–73 Peg-IFN plus RBV has not been compared head-to-head with conventional IFN plus RBV. The reported SVR rates with peg-IFN and RBV range from 17 to 45%74–79 (Table 4). Tolerability is a major issue, with 69 to 83% of patients requiring dose reductions and 6 to 49% requiring drug discontinuations. One small, nonrandomized study of 24 patients reported a higher frequency of dose reductions in patients receiving peg-IFN 0.5 μg/kg per week plus RBV (92%; 11/12) than in patients treated with conventional IFN 3 million units thrice weekly plus RBV (50%; 6/12).76 Balancing efficacy and tolerability in order to maximize response rates is the main challenge in treating HCV-infected transplant recipients.

Table 4. Uncontrolled Studies of Combination Antiviral Therapy for Recurrent HCV Disease
StudyDrug regimenDiscontinuation rateSVR rateComments
  1. NOTE: Limited to studies with ≥20 treated patients.

  2. Abbreviations: NA, not available, data not provided in paper; RT-PCR, reverse transcription polymerase chain reaction.

Standard interferon and ribavirin    
 Bizollon et al. (2003)73 (N = 54)IFN 3 MU thrice weekly plus RBV 1,000 mg/day for 24 weeks; RBV maintenance 600-800 mg/day for 48 weeksNA26%14/54 patients achieved SVR; liver histology improved in 86%; normal or near-normal biopsy results in 36%; no HCV RNA detected in graft at end of follow-up
 Giostra et al. (2004)72 (N = 31)RBV monotherapy 10 mg/kg/day for 12 weeks followed by IFN 3 MU thrice weekly plus RBV 10 mg/kg/day for 48 weeks22.6%29%Patients with SVR had significant decreases in hepatic inflammation but not fibrosis; SVR correlated with duration of therapy but not genotype or viral load; discontinuations in 7/31 (22.6%): severe anemia in 5/14 receiving RBV
Standard or pegylated interferon and ribavirin    
 Abdelmalek et al. (2004)71 (N = 119)IFN 1.5-3.0 MU thrice weekly or peg-IFN: 90-180 μg/week or in combination with RBV 400-1,000 mg/day for 48 weeks. Therapy initiated at one-half dose and then increased if tolerated; IFN used before 2000, peg-IFN used thereafter.NA24%29/119 patients (24%) with SVR reported; 28/29 treated with combination therapy and 1/29 with monotherapy; study reported characteristics of those with SVR; all patients remained HCV RNA negative for 5 yr of follow-up; the durability of the remission was associated with decreased inflammation and regression of fibrosis
 Toniutto et al. (2005)76 (N = 24)IFN 3 MU thrice weekly or peg-IFN 0.5 μg/kg/week in combination with RBV 600-800 mg/day for 48 weeks50%NAEnd-of-treatment virological responses in 17%, in equal numbers in IFN and peg-IFN groups; end-of-treatment response associated with younger age, completion of 48 weeks of therapy, and longer recurrence-free interval
Pegylated interferon and ribavirin    
 Castells et al. (2005)75 (N = 24)Peg-IFN 1.5 μg/kg/week plus RBV 600 mg/day for 24-48 weeks12.5%34.7%Early virological response in 62.5%; no drug discontinuations for peg-IFN adverse events; RBV dose reductions for anemia in 58%; leukopenia in 96%
 Dumortier et al. (2004)78 (N = 20)Peg-IFN 0.5-1.0 μg/kg/week plus RBV 400-1,000/1,200 mg/day for 48 weeks20%45%Early virological response in 55%; RBV dose reductions for anemia in 81%; significant decreases in mean METAVIR score at end of treatment
 Neff et al. (2004)77  (N = 57)Peg-IFN 1.5 μg/kg/week plus RBV 400-600 mg/day for 48 weeks14% (naive); 18% (nonresponder)NAEnd-of-treatment virological responses in 27.6% and 21% of naive patients and nonresponders, respectively; RBV dose reductions in ∼40% of patients in both groups; 44/57 (77%) received some type of therapeutic intervention for adverse events
 Rodriguez-Luna et al.  (2004)79 (N = 37)Peg-IFN 0.5-1.5 μg/kg/week plus RBV 400-1,000 mg/day for ≥48 weeks. Treatment continued for 1 yr after HCV replication undetectable by RT-PCR; Without end-of-treatment response, therapy discontinued at 48 weeks37%26%Significant decrease in necroinflammatory score (P < 0.05) but no change in fibrosis; HCV genotype 1 significantly less likely to respond to therapy; Bone marrow toxicity, depression, and rejection are limiting factors that must be managed aggressively

Two randomized controlled studies compared antiviral therapy to no treatment.60, 62 In a study by Chalasani et al.,62 65 transplant recipients were given peg-IFN alfa-2a 180 μg/week (N = 33) or no antiviral treatment (N = 32) for 48 weeks and were followed for 24 weeks thereafter. Only 4 of the 33 treated patients (12%) achieved an SVR. In addition, 10 treated patients (30%) and 6 untreated patients (19%) withdrew from the study. The incidence of acute rejection did not differ significantly between groups; rejection occurred in 4 (12%) treated patients and in no untreated patient.

The second randomized trial, by Samuel et al.,80 evaluated the safety and efficacy of IFN alfa-2b plus RBV for recurrent hepatitis C in 52 patients after liver transplantation. Approximately 80% of patients had HCV genotype 1. Patients were randomly assigned to receive either IFN alfa-2b 3 million units thrice weekly plus RBV 1,000 to 1,200 mg/day or no treatment. After 1 yr, SVR was noted in 6 (21%) treated patients but in none of the untreated patients. Improvements in necroinflammation on biopsy were evident in the treated patients at the end of treatment (51% improved vs. 21%), but the benefits were not sustained off treatment. Fibrosis scores did not differ significantly between groups at the end of follow-up (14% of treated and 4% of untreated patients improved). As noted in other studies in transplantation patients, adverse events were common: 43% of treated patients and 17% of untreated patients were withdrawn from the study as a result of adverse effects. The most common cause for discontinuing treatment was anemia, which affected 25% of patients. No patient experienced acute rejection, but chronic rejection occurred in 1 treated patient.

Whether IFN increases the risk of acute or chronic rejection remains uncertain. In uncontrolled trials of IFN and RBV combination therapy, the rate of acute rejection varies from 0 to 35% and the rate of chronic rejection varies from 0 to 4%.81 Controlled trials have shown no differences in rejection rates,62, 80 but these studies were not powered to detect small differences in rejection rates. Additionally, the histological difficulty in distinguishing rejection from ongoing hepatitis82 and the lack of biopsies performed during and at the end of therapy further limit the interpretation of these data. Factors potentially influencing the risk of acute rejection include: 1) the degree of immunosuppression at the initiation of antiviral therapy; 2) changes in immunosuppression during antiviral therapy; 3) the presence or absence of RBV, a drug with possible immunomodulatory properties that may modulate the rejection risk; and 4) whether the IFN used is long-acting (pegylated) rather than short-acting (nonpegylated). Monitoring of immunosuppressive drug levels and avoidance of dose reductions during antiviral therapy are recommended to minimize the risk of rejection during therapy.

The optimal time to initiate therapy also needs to be determined. Most studies have focused on patients with histologically confirmed disease, typically at least 6 months after transplantation. Treatment initiated at the first clinical signs of recurrence may be more likely to result in an SVR. In a recent study by Castells et al.,75 24 patients with genotype 1b infection were treated with peg-IFN alfa-2b and RBV 400 or 800 mg/day in the early, acute phase of HCV recurrence. Of 23 patients who reached week 24 of treatment, 8 (35%) achieved an SVR. Surprisingly, no patients dropped out because of adverse effects, and hematological effects were managed effectively by dose reductions, growth factors, or transfusions.

The optimal duration of therapy is also unclear. The treatment period in the majority of published studies is 48 to 52 weeks. In the presence of immunosuppressive therapy, longer treatment periods may reduce the risk of relapse in those achieving end-of-treatment response. In 1 study of 15 patients who had achieved an end-of-treatment virological response, the persistence of HCV RNA in liver tissue predicted relapse, whereas its absence predicted long-term SVR.77

In transplantation and nontransplantation patients, HCV genotype and viral load are important determinants of response.56, 72, 80 In addition, the decline in viral load during treatment predicts response. In a recent study of peg-IFN plus RBV combination therapy in transplant recipients, the 3-month, early virological response predicted SVR, with 10 of 11 sustained responders having undetectable viremia at 3 months compared with none of the 9 nonresponders.78 In another study evaluating therapy in the acute phase of HCV recurrence, 7 of 8 patients having an SVR had a negative HCV RNA result 12 weeks after starting therapy.75

Most studies show biochemical and histological improvements in disease among virological responders,62, 80, 83 but whether antiviral therapy slows disease progression in virological nonresponders has not been established.71, 84 Although necroinflammatory activity is typically improved by the end of treatment and in the first years after viral eradication,79, 83 improvement in fibrosis is slower. In studies evaluating patients 3 to 5 yr after viral eradication, most have improved or stable fibrosis scores,71, 83 but progression is reported in up to 20%. In these latter cases, coexistent diseases such as nonalcoholic steatosis, occult viral infections, underlying unrecognized rejection, or the persistence of HCV RNA in liver tissue may be the cause.

The use of IFN and RBV in transplantation patients is plagued by the frequent need for dose reductions and discontinuations, which in turn, presumably lower SVR rates. In studies of transplant recipients with recurrent hepatitis C, hemolysis was reported in all patients, with 50% experiencing marked anemia.69 Anemia is strongly associated with renal function, a finding consistent with the known renal route of RBV elimination, and RBV doses must be adjusted to prevent serious hematological complications and drug discontinuation.85 Investigational alternatives to RBV, such as viramidine, are aimed at lowering toxicity while maintaining an efficacy equal to or greater than that of RBV when used in combination with IFN. Preliminary studies of viramidine in combination with peg-IFN show a significantly lower incidence of anemia than with peg-IFN plus RBV (4% vs. 27%; P < 0.001).68 Drugs such as viramidine may offer special advantages in anemia-prone populations, such as liver transplant recipients. Leukopenia and thrombocytopenia are less frequently dose limiting than anemia, but have been associated with dose reductions and drug discontinuations. Clinical trials evaluating the efficacy of growth factors in optimizing treatment response in transplant recipients have not been conducted.

Most studies of IFN and RBV combination therapy report SVR rates of less than 50%, so the need for new and more efficacious therapies is obvious. Drugs targeting specific viral enzymes required for replication, the internal ribosomal entry site, or the cascade of factors involved in inflammation, apoptosis, and fibrosis, are among the potential therapies that may be useful in the future management of HCV-infected transplantation patients.

RETRANSPLANTATION

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Retransplantation is typically the only option for patients with decompensated cirrhosis caused by recurrent disease. In fact, the number of patients infected with HCV who need a second transplant is expected to increase as primary transplant recipients survive long enough to experience graft failure from recurrent disease. Single-center reports of HCV-infected patients undergoing repeat transplantation highlight a poor outcome.86–88 However, multicenter studies indicate that outcomes in HCV-infected patients with comparable severities of illness at retransplantation are not worse (Fig. 2).89 Recipient age, total serum bilirubin,89 high prothrombin time,89, 90 older donor age,90, 91 stay in an intensive care unit,91 inability to maintain normal activity levels,77 elevated creatinine concentrations,89, 91, 92 and higher Model for End-Stage Liver Disease scores89 have been identified as predictors of poor survival after retransplantation. Several of these predictors are reflective of patients with advanced liver failure. Thus, if postretransplantation outcomes are to be optimized, retransplantation needs to undertaken early in those who have recurrent cirrhosis in their grafts. Natural history data indicate rapid progression to decompensation and liver-related death in those with recurrent cirrhosis.2, 86, 93 In 39 patients with clinically compensated graft cirrhosis, the cumulative probability of decompensation was 8% at 1 month, 17% at 6 months, and 42% at 12 months, and decompensation significantly reduced patient survival.2 Thus, the window of opportunity for retransplantation is relatively narrow. One debatable issue is whether the severity of recurrent HCV disease in the second graft is related to that in the first graft. One small series showed that the 2 were related.86 While time to retransplantation was thought to predict outcome,89 recent data13 suggest that the timing of clinical recurrence after initial liver transplantation is not predictive of the timing of recurrence after retransplantation. In that sense, patients experiencing early graft failure due to accelerated forms of HCV should not be denied consideration of retransplantation categorically. Finally, as treatments for HCV disease improve, patients who undergo retransplantation may be expected to have improved outcomes. Initiation of antiviral therapy at an earlier time point after transplantation may be one way to positively affect the natural history of recurrent HCV disease.

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Figure 2. Kaplan-Meier analysis for patients undergoing retransplantation according to HCV status. HCV-infected recipients undergoing retransplantation for HCV-related graft failure (“HCV alone”; N = 19), HCV-negative recipients undergoing retransplantation (N = 187), and HCV-infected recipients undergoing retransplantation for causes other than recurrent HCV (“HCV other”; N = 51). Patients undergoing transplantation before 1990 (HCV antibody testing) were excluded. Inset: Kaplan-Meier analysis for the same cohort based solely on HCV status (negative/positive). P = NS for all analyses. Reprinted with permission from Rosen et al.89

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Under the current Model for End-Stage Liver Disease organ allocation system, patients with recurrent HCV cirrhosis have little realistic hope of receiving an organ until they have advanced graft failure. As a result, patients with hepatitis C-related graft failure will receive an organ only when they have a low chance of survival with retransplantation. To improve outcomes, policies regarding the allocation of organs will have to be revised so that retransplantation is offered to patients with recurrent hepatitis C at a time when they have a reasonable expectation of long-term survival. While antiviral therapy has improved outcomes in transplant and non-transplant recipients, there are almost no reports on the efficacy and tolerability of IFN therapy in patients awaiting retransplantation. In most cases though, the disease is too advanced for the patient to tolerate antiviral agents. In some patients, chronic rejection induced by antiviral therapy after achieving viral clearance might become the primary reason for retransplantation. In these instances, the outcome is no longer associated with HCV infection but rather the overall state of health of the patient at the time of retransplantation.94

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES

Chronic hepatitis C is a major concern in liver transplant patients. Chronic hepatitis C is the most common indication for liver transplantation in the United States and Europe. However, there is no satisfactory strategy for managing chronic hepatitis C infection in liver transplant recipients. Pretransplantation and preemptive posttransplantation therapies are limited by low applicability and tolerability, both of which lower rates of viral eradication. Pretransplantation therapy may be considered in selected patients awaiting a graft who have mildly decompensated and stable disease. Posttransplantation, treating those with acute early recurrence and chronic, progressive histological disease is recommended.38

Combination therapy with RBV and IFN is superior to monotherapy with IFN, but overall SVR rates remain suboptimal. Higher SVR rates may be achievable with peg-IFN plus RBV, although large-scale studies are still lacking. Additional issues requiring study include the optimal timing of treatment initiation, the best determinants of treatment duration, and whether growth factor use enhances SVR rates. Because current overall response rates are less than 50%, and because those with persistent infection are at substantial risk of graft loss from recurrent cirrhosis, the need for alternative drug therapies with enhanced SVR rates is obvious and urgent.

REFERENCES

  1. Top of page
  2. Abstract
  3. CLINICAL COURSE OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  4. FACTORS INFLUENCING THE SEVERITY OF RECURRENT HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS
  5. TREATMENT CONSIDERATIONS IN HCV-INFECTED TRANSPLANT RECIPIENTS
  6. RETRANSPLANTATION
  7. CONCLUSIONS
  8. Acknowledgements
  9. REFERENCES