For citation purposes: Koppala J, Mukherjee S. Risk factors and management of hepatitis C recurrence after liver transplantation. OA Hepatology 2013 May 01;1(1):3.


Viral Hepatitis

Risk factors and management of hepatitis C recurrence after liver transplantation

J Koppala1, S Mukherjee2*

Authors affiliations

(1) Creighton University Medical Center, Suite 5107, 601 N 30th Street, Omaha NE 68131

(2) Division of Gastroenterology-Hepatology, 983285 Nebraska Medical Center, Omaha NE 68198-3285

*Corresponding author Email:



Liver disease associated with Hepatitis C virus infection is the most common indication for liver transplantation. Patients with detectable hepatitis C virus ribonucleic acid at the time of liver transplantation inevitably experience graft re-infection. This results in 30% of patients to develop cirrhosis in 5 years post liver transplantation, with a rate of decompensation at 1 year of 40%. Achievement of sustained virological response is associated with stabilisation of fibrosis and improvement in graft survival. Standard antiviral therapies using pegylated interferon, ribavirin and retransplantation in decompensated patients were the only options for the treatment.

Direct acting antivirals such as protease inhibitors, polymerase or other non-structural protein inhibitors are new modalities of treatment of Hepatitis C. However, their use in the field of liver transplant is limited due to their safety and tolerance issues. Combination therapy with telaprevir or boceprevir added to pegylated interferon and ribavirin is anticipated to be beneficial but with increased rates of adverse effects and challenges in managing drug–drug interactions between the protease inhibitors and calcineurin inhibitors or sirolimus. The aim of this review was to discuss the risk factors and management of hepatitis C recurrence after liver transplantation.


Hepatitis C virus recurrence is a serious complication in liver transplant patients, where it can cause cirrhosis, graft loss and death in up to 30% of Hepatitis C virus-infected patients. Several strategies to control and minimise the Hepatitis C virus re-infection have been evolving. Direct acting antiviral represents a new era in Hepatitis C virus treatment; however, careful evaluation for drug–drug interactions, tolerance and adverse effects are required.


Chronic hepatitis C is one of the leading causes of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) worldwide and the main indication for liver transplantation (LT). This reflects the changes in prioritisation of HCC for LT and an increased prevalence of HCC in the Hepatitis C virus (HCV)-infected patients[1]. Post LT HCV recurrence is universal in patients with detectable serum Hepatitis C virus ribonucleic acid (HCV RNA) at the time of transplantation. The 5-year graft and patient survival rates are 23% lower in HCV-infected LT recipients compared to non-HCV-infected recipients[2]. The most successful approach to the treatment of recurrent HCV is eradication of the HCV infection with either pre-transplant or post-transplant antiviral therapy, before hepatic decompensation occurs. Nonetheless, these patients commonly develop hepatic decompensation, and antiviral therapy is associated with poor tolerability in pre-transplant patients. Furthermore, it is associated with decreased drug efficacy and an increased risk of adverse effects in post-transplant patients[3]. In this article, we will review the natural history of HCV disease in LT recipients, identification of risk factors, current and future advances in the treatment of HCV recurrence.


The authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies.

Natural history of HCV recurrence

HCV infection of the allograft occurs at the time of transplantation and HCV RNA is detectable in the first post-operative week. The natural history of HCV disease is accelerated in post-transplant recipients compared to pre-transplant patients, presenting with high HCV RNA levels[3]. The HCV RNA levels progressively increase and peak at the fourth post–operative month[4]. Acute hepatitis develops between 1 and 4 months. Chronic hepatitis develops at 2–4 months. Cases with severe HCV recurrence have been described as early as the ninth post-operative day[5]. About 10% of patients develop severe disease with cholestatic features with the first year post LT, which can lead to graft loss[6]. Between 20% and 30% of patients develop cirrhosis within 5 years after LT and the rate of decompensation is 40% within the following year. Once decompensated cirrhosis occurs, the risk of death is high, with 60% dying within a year of their first decompensating event[7].

Risk factors associated with the progression of HCV disease

Recipient-, donor-, and transplant-related factors contribute to the risk of recurrent cirrhosis and graft loss.

Recipient factors

Among the transplant recipients, older age is associated with reduced survival but not disease progression[7]. Female gender, African American race, HIV co-infection are all associated with both higher rates of severe HCV disease and reduced graft survival. The risk of fibrosis is 23% higher in women compared to men[8]. The risk of advanced fibrosis is 47% higher in African-American patients compared to non-African-American patients; however, this can be improved using African-American donors[9].

The graft survival rates are 53% for HIV co-infected patients compared to 74% for HCV mono-infected recipients. In co-infected patients, factors associated with worse outcome are older donor age, high donor risk index, genotype 1, combined kidney–liver transplant, body mass index <21 kg/m[2] and anti-HCV-positive donor[10]. Interleukin (IL)-28B polymorphisms in recipient and donor are associated with viral response to therapy.

Donor factors

Older donor age is associated with progressive HCV disease and graft loss, and the risk increases with age.There is a 67% higher rate of graft loss for donors aged 41–50 years, 86% higher rate of graft loss for donors aged 51–60 years, and 221% higher rate of graft loss for donors over 60 years of age; so, it is recommended not to use elderly donors[11][12]. Recipients from anti-HCV-positive antibody donors do not have worse outcome compared to recipients from anti-HCV-negative donors, although donor age more than 45 years is associated with a 58% increased risk of advanced fibrosis[13].

Donation after cardiac death (DCD) for LT has been increasing mainly because of the shortage of organ donors. Donation after brain death (DBD) is associated with inferior graft survival in HCV recipients compared to non-HCV recipients. Additionally, DCD in HCV recipients showed no difference in graft survival in relation to non-HCV patients[14]. Living and deceased donors have similar post-transplant outcomes and is dependent on the transplant centre’s experience with living donors[7].

IL-28B gene polymorphisms

IL-28 modulates CD 8 T cell function, and has interferon-like antiviral properties. Both recipient and donor IL-28B gene polymorphisms are associated with viral response to therapy. Decreased fibrosis and SVR to HCV therapy were 100% if both recipient and donor were CC genotype; whereas SVR was only 25% if neither donor nor recipient had CC genotype. However, the IL-28 genotype did not seem to play a role in the overall survival in these patients[15]. Additionally, IL-28 B gene polymorphisms affect post-transplant outcomes like the time to recurrence, HCV RNA titres, histological progression, alanine aminotransferase levels and development of HCC. The complex interactions between the donor and recipient IL-28 B gene polymorphisms may also affect outcomes not related to HCV infection like the acute cellular rejection and metabolic disease like post-transplant diabetes mellitus[16]. Routine IL-28 genotyping of recipients and donors may allow for the identification of patients who are at higher risk of developing severe and progressive disease.

Transplant-related factors

HCV transplant patients with evidence of early preservation injury on biopsy are associated with poorer survival outcomes than non-HCV transplant patients with preservation injury or HCV transplant patients without preservation injury[17]. Organ cold and warm ischaemia are other risk factors associated with the severity of recurrence[17]. CMV infection at the time of transplantation is associated with severe fibrosis in patients with HCV infection, and may warrant an extended course of CMV prophylaxis for the CMV-negative recipient and the CMV-positive donor group[18]. Treatment of acute rejection is associated with HCV disease severity, so mild rejection is not recommended to be treated, especially with corticosteroid boluses and anti-lymphocyte preparations, but with increased maintenance of immunosuppression. Acute cellular rejection and progressive fibrosis are associated with YKL-40 genotypes[19]. Post-LT diabetes mellitus and steatosis, which are actually influenced by the immunosuppressive choices, are associated with a higher risk of progressive fibrosis in HCV recurrence patients[20][21].

Viral factors

High pretransplant viral load and HCV genotype 1b are associated with increased severity in HCV disease and also poor graft survival (Table 1)[22]. Eradicating HCV before LT would have a major impact on decreasing the incidence of recurrent HCV and its complications[23].

Table 1

Implications for the management of different risk factors

Role of immunosuppressive agents

Immunosuppressive regimen is directly related to the HCV recurrence for two reasons. First reason is that the degree and composition of the immunosuppressive agents influence the progression of fibrosis. The second reason is the potential drug–drug interactions between the immunosuppressive agents and the direct antiviral agents (DAAs).

Induction therapy

Antithymocyte globulin: The use of rabbit antithymocyte globulin (ATG) initially gained popularity, but later waned off when several centres reported conflicting results when compared to steroids during induction. A recent study conducted by Uemura et al. analysed 16,898 adult primary LT patients from United Network for Organ Sharing (UNOS) database, who received ATG alone, ATG and steroids, daclizumab alone or steroids alone as induction immunosuppression. The use of ATG with steroids in HCV patients was associated with inferior graft survival compared with daclizumab or steroids alone[24].

Alemtuzumab is an anti-CD52 monoclonal antibody that acts on mature lymphocytes but not stem cells. When used with low-dose tacrolimus (Tac) and compared to Tac and steroids in adult LT patients, there was no difference in patient and graft survival, but there was a significant benefit in rejection rates and decreased nephrotoxicity[25][26].

IL-2 receptor antibodies (basiliximab and daclizumab): Induction with basiliximab or ATG is effective in controlling acute rejection rate at 1 year of LDLT (living donor LT) but may increase the risk of HCV recurrence[27]. Basiliximab used alone or in combination with steroids for induction showed that a steroid-free therapy is associated with a significantly lower treatment failure rate, although histological recurrence rate of HCV was similar in the two groups[28]. A number of studies have been conducted where daclizumab is used in the steroid-free protocol along with Tac and mycophenolate mofetil (MMF) versus Tac, MMF and corticosteroids and no differences in fibrosis were identified. However, there was a significant association between ACR and fibrosis stage at 1 year[29]. As a follow-up of the HCV-3 study, there was no statistical difference in the incidence of ACR, HCV RNA levels, HCV recurrence or patient or graft survival, and these results suggest that a corticosteroid-free regimen of Tac and MMF following daclizumab induction is safe and effective in HCV(+) LT recipients[30].

Maintenance therapy

Calcineurin inhibitors (CNI), Tac and cyclosporine (CsA) are the currenyl used main agents. In vitro, CsA is noted to have antiviral property due to Cyclophilin A as the main protein, but its effect in vivo seems questionable. Several studies have compared Tac and CsA regarding the patient and graft survival as endpoints and have shown no difference. A recent study by Irish et al. retrospectively analysed 8809 chronic HCV LT recipients from the UNOS/Organ Procurement and Transplantation Network (OPTN), who received either Tac or CsA as maintenance immunosuppression prior to discharge. Endpoints were death, graft failure and graft failure due to recurrent disease and ACR. Propensity score-adjusted results suggest that CsA-treated patients are at an increased risk of patient death and graft failure [hazard ratio (HR) = 1.17; 95% CI = 1.01 – 1.36and HR = 1.19; 95% CI = 1.04 – 1.35, respectively] and biopsy-confirmed AR (HR = 2.03; 95% CI = 1.54 – 2.67) compared to Tac-treated patients[31]. While considering histologic HCV recurrence, fibrosis, cholestatic hepatitis, several studies have shown no significant differences[32].

Azathioprine and MMF: A retrospective study in 2005 studied 3463 HCV post-LT patients from Scientific Registry of Transplant Recipients. Researchers compared LT recipients discharged on Tac, MMF and steroids with the group receiving only Tac and steroids, and found that MMF had no impact on the rate of graft loss due to HCV recurrence, though they had less ACR and better patient and graft survival rates[33].

The benefit of MMF on azathioprine is based on very few studies and the results are not conclusive. However, the overall degree of immunosuppression may have an impact on the HCV recurrence rather than the independent action of each drug. There is a need for additional trials and analysis.

Mammalian target of rapamycin inhibitors (sirolimus and everolimus): Sirolimus slowed progression and fibrosis in LT recipients with recurrent HCV disease[34][35].

Role of steroids

Steroids were mainly used either as bolus therapy for the treatment of ACR or for maintenance immunosuppression. The use of steroid boluses to treat ACR should be avoided, as it worsens the progression of fibrosis, increases rate and decreases time of HCV recurrence. It also increases the frequency of acute hepatitis and high risk of early transplant mortality[36]. The role of steroids in maintenance therapy remains debated, as aforementioned. A steroid-free immunosuppressive regimen was safe and effective, but did not show any advantage for HCV recurrence compared to traditional regimen[37][38]. The undesirable side-effects of steroids like post-LT diabetes mellitus, hypertension, increased cardiovascular risk, increased risk of infection and bone disease are leading to minimised use of steroids at several transplant centres.

Diagnosis and monitoring

The diagnosis of HCV reinfection is established by persistently detectable HCV RNA in the serum after LT and demonstration of hepatitis in the liver biopsy. Non-invasive tests have a role in the monitoring of HCV recurrence, but liver biopsy is the gold standard diagnostic test[39]. Liver enzymes can be elevated post LT preservation injury, acute and chronic rejection, biliary complications and steatohepatitis; so, liver biopsy is the only test to rely on[7]. It is imperative to monitor the histological progression of the disease, as this will aid in appropriate intervention of antiviral therapy. Treatment at earlier stage of fibrosis is associated with higher likelihood of achieving sustained viral clearance[40].

Histopathology features of recurrent HCV

Recurrent HCV can manifest as multiple presentations: (1) Acute hepatitis presents with apoptotic hepatocytes, lobular disarray, spotty inflammation, and portal mononuclear inflammation. (2) Chronic hepatitis presents after 2–3 months, with initial portal-based fibrosis and then accelerated fibrosis[40]. (3) Severe cholestatic hepatitis (CH) presents with hepatocyte ballooning, spotty acidophilic bodies, kupffer cell hypertrophy and prominent cholestasis. Here, early perisinusoidal fibrosis rapidly progresses to bridging fibrosis and cirrhosis. It is due to direct cytopathic effect of HCV[41]. It is seen in 2–9% of HCV disease in post-LT patients[41]. Onset is rapid within the first 6 months after LT, with very high HCV RNA >10 million IU/ml, high bilirubin >6 mg/dl and high liver function tests. Progressive graft failure occurs within 2–12 months if untreated with antiviral therapy[41]. (4) Plasma cell hepatitis presents with perivenular inflammation, necrosis and plasma cell-rich infiltrate, likely representing de novo autoimmnune disease or a variant of alloimmnune response[42]. This is seen in patients treated with interferon-based therapy. There may be elevation of autoimmune markers and manifestation of other autoimmune diseases. It can progress rapidly leading to graft loss, so early intervention with discontinuation of interferon and optimising immunosuppression is necessary[42].

Non-invasive tests to assess severity of fibrosis

Ultrasound hepatic elastography has 98% sensitivity and 84% specificity, and area under receiver operating curve (AUROC) was 0.98 for the presence or absence of cirrhosis and has 83% sensitivity and 83% specificity, and AUROC of 0.90 for defining significant fibrosis. Hence, its utility is limited in detecting early stages of fibrosis when antiviral therapy is recommended. However, ultrasound elastography is useful for assessing transition to cirrhosis, especially when complementing to serum liver fibrosis markers[43].

Prognostic tests

Identifying rapidly progressive HCV disease is essential, as this is helpful for guiding antiviral therapy. Liver biopsy with stage 2 fibrosis, hepatic venous gradient >6 mmHg at 12 months, and hepatic elastography with liver stiffness value >9.0 kPa at 6 months are good predictors for progressive fibrosis(Table 2)[44][45].

Table 2

Prognostic tests for severe post-transplant HCV recurrence[44,45,46,47,48]

Differential diagnosis

Differentiating recurrent HCV from mild-to-moderate rejection is the main problem, as inappropriate treatment can lead to adverse outcomes. Several parameters like time from LT, degree of immunosuppression,HCV RNA levels, and degree of biochemical abnormalities in addition to histopathology are considered to differentiate the two. Ancillary investigations like anti-HCV core titres, immunoperoxidase staining for HCV antigens were also reported, but are not in widespread use. C4d, a marker of complement activation, has a specificity of 90% and sensitivity of 68% in distinguishing ACR from HCV recurrence[49]. About 25 genes associated with major histocompatibility complexes 1 and 2, T cell activation, apoptosis and insulin growth factor (IGF) 1 and 2 were found to be overexpressed in patients with ACR[50]. Recently, specific microRNA expression signatures that can differentiate between slow and fast fibrosis in HCV recurrence, HCV and ACR have been demonstrated. Specifically, profibrogenic miRNAs that regulate through IGF1 receptor and vascular endothelial growth factor (VEGF) pathways were identified, which could help differentiate between HCV recurrence and ACR; however, larger translational studies are required to validate their routine use on post-LT patients[51].

Treatment of HCV recurrence

The goal of the treatment is to attenuate liver-related complications and graft failure. Two approaches are used: the pre-transplant therapy and the post-transplant antiviral therapy, which can be early, within first 6 months post LT, or delayed when there is evidence of significant fibrosis.

Pretransplant antiviral therapy

Pre-transplant antiviral therapy is given with an intent of preventing the graft infection either by achieving an SVR before LT or by achieving undetectable HCV RNA for >8 weeks before LT[52]. Patients with compensated or mildly decompensated cirrhosis are candidates for the treatment. Treatment of patients with severe decompensated disease, with an MELD score >18and Child-Pugh Class B or C is contraindicated due to high risk of complications[53]. In mildly decompensated disease, therapy is discontinued in 20–35% of patients due to adverse effects. The risk of infectious complications is high in the first 30 days post LT compared to untreated patients. This risk worsens in patients with high Child-Pugh/MELD score, ascites and low baseline albumin[53][54]. Several factors predict the response to antiviral therapy like baseline HCV RNA, genotype 2 or 3, receipt of growth factors, duration and adherence to therapy[52].

Severe adverse effects have been reported with the combination of PI to PEG-INF and RBV compared to standard therapy in wait list patients. Anaemia, infection-related complication and death were reported to be higher with PI[55].

Post-transplant antiviral treatment

Post-transplant antiviral therapy is given either as early pre-emptive antiviral therapy or as delayed, when evidence of fibrosis is present. Early treatment is considered when there is CH or rapidly progressive disease[56]. The goal is achievement of a sustained viral clearance, as it improves histology as well as graft survival in majority of patients[57]. Antiviral treatment at a mild histologic disease, stage 1–2 fibrosis report higher SVR compared to advanced fibrosis 3–4[40]. SVR rates are about 30% for genotype 1 and 30–100% for genotype 2 and 3[58,59,60]. Predictors for SVR are genotype, IL-28B gene polymorphisms with the donor IL-28 B status being more important, viral response and pre-treatment viral load (Table 3). Early virological response is the principal factor for predicting SVR[40,61]. Undetectable HCV RNA at 4 weeks likely predicts an SVR of >80% by 48 weeks; conversely, failure to achieve an undetectable HCV RNA by 12 weeks is associated with <2% chance of SVR at 48 weeks[62][63].

Table 3

Factors influencing sustained virologic response with standard therapy

Role of DAAs

Combination therapy with PI, PEG-INF and RBV will presumably improve SVR rates, but tolerability is a major concern. Both telaprevir and boceprevir are strong CYP3A4/5 inhibitors. Consequently, they increase the bioavailability of the CNI, CsA and Tac. The dosage of CsA and Tac needs to be reduced when PI is given and increased when PI is stopped. Intense monitoring of the CNI levels is necessary to assess the risk of toxicity or rejection due to improper dosage[64][65]. PI does not need any dose adjustment. A recent study on boceprevir showed that an estimated oral clearance was reduced by 50% with CsA and up to 80% with Tac[66].

In a case report, daclatasvir, an NS5A inhibitor, is elucidated to have minimal drug–drug interactions and CNI levels were stable throughout the treatment without alterations in the CNI dosage[67]. A recent study showed amelioration of viral response rates in patients with advanced fibrosis, non-responders, and patients with CH while using triple therapy. The rapid virologic response (RVR) at 4 weeks of triple therapy was 43% with boceprevir and 45% with telaprevir. The early virologic response (EVR) at 12 weeks was 71% with boceprevir and 73% with telaprevir. The CsA dose was reduced by 1.3-fold with boceprevir and 4-fold with telaprevir, and the Tac dose was reduced by 5-fold with boceprevir and 35-fold with telaprevir[68].

Complications and tolerability of antiviral therapy

Several immunological complications have been reported with interferon-based therapy like acute rejection, chronic rejection, and autoimmune-like hepatitis/plasma cell hepatitis, with an incidence of 7.2%. Patients developing these complications had a lower graft survival rate of 38.5% compared to treated patients without immune-mediated complications with a graft survival rate of 85.6%[69]. High alkaline phosphatase at the time of initiation of treatment and lack of SVR are the important predictive factors for immunological complications. Another major issue with antiviral therapy is tolerance. Haematological toxicity secondary to haemolysis and infections are common with PEG-INF and RBV. These adverse effects have led to reduction in dosage and discontinuation of antiviral therapy and amplification of immunosuppression[58,59,60]. DAAs cause dermatological side-effects and worsen anaemia, with a 20% increase in the incidence and severity of anaemia. Serious infections leading to death have also been reported[55]. Future use of second-generation DAA and PEG-INF free regimens should optimistically improve tolerance and complications[70].


Retransplantation (reLT) is usually the sole option for transplant patients with complications of recurrent cirrhosis. The 1-year graft survival among reLT patients is 63–70%. Highly selected eligibility criteria are used for reLT, although they vary at different LT programmes. The most common criteria for not considering reLT are recurrent HCV within 6 months, fibrosing CH and renal dysfunction[71]. Various scores for risk stratification have been created to identify patients with high mortality before considering reLT. This situation might evolve in future with the development of neoteric antiviral drugs.


HCV recurrence is a serious complication in liver transplant patients where it can cause cirrhosis, graft loss and death in up to 30% of HCV-infected patients. Several strategies to control and minimise the HCV re-infection have been evolving. Modulation of the recipient-, donor-, and transplant-related factors, and early diagnosis and treatment of CMV have demonstrated improved outcomes. It is beneficial to curtail immunosuppression with T cell-depleting therapies and pulsed corticosteroid therapy for the treatment of acute cellular rejection, although it complicates the choice of immunosuppression. As cirrhosis can progress rapidly, it is crucial to identify and treat these patients. PEG-INF and RBV treatment had been the standard of care, but the preliminary data on DAA like PI/polymerase/non-structural protein inhibitors seem promising. The DAA represents a new era in HCV treatment; however, careful evaluation for drug–drug interactions, tolerance and adverse effects is required.

Abbreviations list

ATG, antithymocyte globulin; AUROC, area under the receiver operating curve; Boce, Boceprevir; CH, cholestatic hepatitis; CNI, calcinurin inhibitors; CsA, cyclosporine; CYP, cytochrome; DAA, direct acting antiviral; DBD, donation after brain death; DCD, donation after cardiac death; EPO, erythropoietin; ESLD, end-stage liver disease; EVR, early virologic response; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leucocyte antigen; HPVG, hepatic venous pressure gradient; IGF, insulin growth factor; IL-28, interleukin-28; LT, liver transplantation; MELD, model of end-stage liver disease; MMF, mycophenolate mofetil; OPTN, Organ Procurement and Transplantation Network; PEG-INF, pegylated interferon; PI, protease inhibitors; RBV, ribavirin; ReLT, retransplantation; RNA, ribonucleic acid; RVR, rapid virologic response; SVR, sustained virologic response; Tac, tacrolimus; tela, telaprevir; UNOS, United Network for Organ Sharing; VEGFA, vascular endothelial growth factor.

Authors contribution

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.


All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.


  • 1. Kim WR, Terrault NA, Pedersen RA, Therneau TM, Edwards E, Hindman AA. Trends in waiting list registration for liver transplantation for viral hepatitis in the United States. Gastroenterology 2009 Nov;137(5):1680-6.
  • 2. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002 Apr;122(4):889-96.
  • 3. Mukherjee S . Natural history, risk factors and management of hepatitis C after liver transplantation. Inflamm Allergy Drug Targets 2012 Apr;11(2):124-30.
  • 4. Charlton M . Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence. Liver Transpl 2003 Nov;9(11):S58-62.
  • 5. Saraf N, Fiel MI, Deboccardo G, Emre S, Schiano TD. Rapidly progressive recurrent hepatitis C virus infection starting 9 days after liver transplantation. Liver Transpl 2007 Jun;13(6):913-7.
  • 6. Neumann UP, Berg T, Bahra M, Seehofer D, Langrehr JM, Neuhaus R. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 2004 Nov;41(5):830-6.
  • 7. Terrault N . Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol 2012 Aug;26(4):531-48.
  • 8. Lai JC, Verna EC, Brown RS Jr, O’Leary JG, Trotter JF, Forman LM. Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men. Hepatology 2011 Aug;54(2):418-24.
  • 9. Saxena V, Lai JC, O’Leary JG, Verna EC, Brown RS Jr, Stravitz RT. Recipient-donor race mismatch for AfricanAmerican liver transplant patients with chronic hepatitis C. Liver Transpl 2012 May;18(5):524-31.
  • 10. Terrault NA, Roland ME, Schiano T, Dove L, Wong MT, Poordad F. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl 2012 Jun;18(6):716-26.
  • 11. Lake JR, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Wiesner RH. Differential effects of donor age in liver transplant recipients infected with hepatitis B, hepatitis C and without viral hepatitis. Am J Transplant 2005 Mar;5(3):549-57.
  • 12. Durand F, Renz JF, Alkofer B, Burra P, Clavien PA, Porte RJ. Report of the Paris consensus meeting on expanded criteria donors in liver transplantation. Liver Transpl 2008 Dec;14(12):1694-707.
  • 13. Lai JC, O’Leary JG, Trotter JF, Verna EC, Brown RS Jr, Stravitz RT. Risk of advanced fibrosis with grafts from hepatitis C antibody-positive donors: a multicenter cohort study. Liver Transpl 2012 May;18(5):532-8.
  • 14. Uemura T, Ramprasad V, Hollenbeak CS, Bezinover D, Kadry Z. Liver transplantation for hepatitis C from donation after cardiac death donors: an analysis of OPTN/UNOS data. Am J Transplant 2012 Apr;12(4):984-91.
  • 15. Firpi RJ, Dong H, Clark VC, Soldevila-Pico C, Morelli G, Cabrera R. CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant. Liver Int 2013 Jan;33(1):72-8.
  • 16. Duarte-Rojo A, Deneke MG, Charlton MR. Interleukin-28B polymorphism in hepatitis C and liver transplantation. Liver Transpl 2013 Jan;19(1):49-58.
  • 17. Watt KD, Lyden ER, Gulizia JM, McCashland TM. Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome. Liver Transpl 2006 Jan;12(1):134-9.
  • 18. Bosch W, Heckman MG, Pungpapong S, Diehl NN, Shalev JA, Hellinger WC. Association of cytomegalovirus infection and disease with recurrent hepatitis C after liver transplantation. Transplantation 2012 Apr;93(7):723-8.
  • 19. Eurich D, Neumann UP, Boas-Knoop S, Neuhaus R, Kiessling A, Yahyazadeh A. YKL-40-gene polymorphism affects acute cellular rejection and fibrosis progression after transplantation for hepatitis C virus-induced liver disease. J Gastroenterol Hepatol 2013 Jan;28(1):153-60.
  • 20. Brandman D, Pingitore A, Lai JC, Roberts JP, Ferrell L, Bass NM. Hepatic steatosis at 1 year is an additional predictor of subsequent fibrosis severity in liver transplant recipients with recurrent hepatitis C virus. Liver Transpl 2011 Dec;17(12):1380-6.
  • 21. Foxton MR, Quaglia A, Muiesan P, Heneghan MA, Portmann B, Norris S. The impact of diabetes mellitus on fibrosis progression in patients transplanted for hepatitis C. Am J Transplant 2006 Aug;6(8):1922-9.
  • 22. Ponziani FR, Milani A, Gasbarrini A, Zaccaria R, Vigano R, Iemmolo RM. Treatment of genotype-1 hepatitis C recurrence after liver transplant improves survival in both sustained responders and relapsers. 2013 Mar;26(3):281-9.
  • 23. Tanaka T, Selzner N, Therapondos G, Renner EL, Lilly LB. Virological response for recurrent hepatitis C improves long-term survival in liver transplant recipients. Transpl Int 2013 Jan;26(1):42-9.
  • 24. Uemura T, Schaefer E, Hollenbeak CS, Khan A, Kadry Z. Outcome of inductionimmunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid. Transpl Int 2011 Jul;24(7):640-50.
  • 25. Tzakis AG, Tryphonopoulos P, Kato T, Nishida S, Levi DM, Madariaga JR. Preliminary experience with alemtuzumab (campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Transplantation 2004 Apr;77(8):1209-14.
  • 26. Tryphonopoulos P, Madariaga JR, Kato T, Nishida S, Levi DM, Moon J. The impact of Campath 1H induction in adult liver allotransplantation. Transplant Proc 2005 Mar;37(2):1203-4.
  • 27. Ghanekar A, Kashfi A, Cattral M, Selzner N, McGilvray I, Selzner M. Routine induction therapy in living donor liver transplantation prevents rejection but may promote recurrence of hepatitis C. Transplant Proc 2012 Jun;44(5):1351-6.
  • 28. Filipponi F, Callea F, Salizzoni M, Grazi GL, Fassati LR, Rossi M. Double-blind comparison of hepatitis C histological recurrence rate in HCV+ liver transplant recipients given basiliximab + steroids or basiliximab + placebo, in addition to cyclosporine and azathioprine. Transplantation 2004 Nov;78(10):1488-95.
  • 29. Kato T, Gaynor JJ, Yoshida H, Montalvano M, Takahashi H, Pyrsopoulos N. Randomized trial of steroid-free induction versus corticosteroid maintenance among orthotopic liver transplant recipients with hepatitis C virus: Impact on hepatic fibrosis progression at one year. Transplantation 2007 Oct;84(7):829-35.
  • 30. Klintmalm GB, Washburn WK, Rudich SM, Heffron TG, Teperman LW, Fasola C. Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl 2007 Nov;13(11):1521-31.
  • 31. Irish WD, Arcona S, Bowers D, Trotter JF. Cyclosporine versus tacrolimus treated liver transplant recipients with chronic hepatitis C: outcomes analysis of the UNOS/OPTN database. Am J Transplant 2011 Aug;11(8):1676-85.
  • 32. Berenguer M, Aguilera V, San Juan F, Benlloch S, Rubin A, Lopez-Andujar R. Effect of calcineurin inhibitors in the outcome of liver transplantation in hepatitis C virus-positive recipients. Transplantation 2010 Dec;90(11):1204-9.
  • 33. Wiesner RH, Shorr JS, Steffen BJ, Chu AH, Gordon RD, Lake JR. Mycophenolatemofetil combination therapy improves long-term outcomes after liver transplantationin patients with and without hepatitis C. Liver Transpl 2005 Jul;11(7):750-9.
  • 34. Asthana S, Toso C, Meeberg G, Bigam DL, Mason A, Shapiro J. The impact of sirolimus on hepatitis C recurrence after liver transplantation. Can J Gastroenterol 2011 Jan;25(1):28-34.
  • 35. McKenna GJ, Trotter JF, Klintmalm E, Onaca N, Ruiz R, Jennings LW. Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression. Am J Transplant 2011 Nov;11(11):2379-87.
  • 36. Chan AJ, Lake JR. Immunosuppression in HCV-positive liver-transplant recipients. Curr Opin Organ Transplant 2012 Dec;17(6):648-54.
  • 37. Klintmalm GB, Davis GL, Teperman L, Netto GJ, Washburn K, Rudich SM. A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C. Liver Transpl 2011 Dec;17(12):1394-403.
  • 38. Neumann U, Samuel D, Trunečka P, Gugenheim J, Gerunda GE, Friman S. A randomized multicenter study comparing a tacrolimus-based protocol with and without steroids in HCV-positive liver allograft recipients. J Transplant 2012;2012894215.
  • 39. Wiesner RH, Sorrell M, Villamil F. International Liver Transplantation Society Expert Panel. Report of the first international liver transplantation society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003 Nov;9(11):S1-9.
  • 40. Roche B, Sebagh M, Canfora ML, Antonini T, Roque-Afonso AM, Delvart V. Hepatitis C virus therapy in liver transplant recipients: Response predictors, effect on fibrosis progression, and importance of the initial stage of fibrosis. Liver Transpl 2008 Dec;14(12):1766-77.
  • 41. Narang TK, Ahrens W, Russo MW. Post-liver transplant cholestatic hepatitis C: a systematic review of clinical and pathological findings and application of consensus criteria. Liver Transpl 2010 Nov;16(11):1228-35.
  • 42. Fiel MI, Agarwal K, Stanca C, Elhajj N, Kontorinis N, Thung SN. Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus. Liver Transpl 2008 Jun;14(6):861-71.
  • 43. Adebajo CO, Talwalkar JA, Poterucha JJ, Kim WR, Charlton MR. Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis. Liver Transpl 2012 Mar;18(3):323-31.
  • 44. Carrion JA, Fernandez-Varo G, Bruguera M, Garcia-Pagan JC, Garcia-Valdecasas JC, Perez-Del-Pulgar S. Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation. Gastroenterology 2010 Jan;138(1):147.
  • 45. Blasco A, Forns X, Carrion JA, Garcia-Pagan JC, Gilabert R, Rimola A. Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation. Hepatology 2006 Mar;43(3):492-9.
  • 46. Gallegos-Orozco JF, Yosephy A, Noble B, Aqel BA, Byrne TJ, Carey EJ. Natural history of post-liver transplantation hepatitis C: A review of factors that may influence its course. Liver Transpl 2009 Dec;15(12):1872-81.
  • 47. Carrion JA, Torres F, Crespo G, Miquel R, Garcia-Valdecasas JC, Navasa M. Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation. Hepatology 2010 Jan;51(1):23-34.
  • 48. Pungpapong S, Nunes DP, Krishna M, Nakhleh R, Chambers K, Ghabril M. Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C. Liver Transpl 2008 Sep;14(9):1294-302.
  • 49. Schmeding M, Dankof A, Krenn V, Krukemeyer MG, Koch M, Spinelli A. C4d in acute rejection after liver transplantation–a valuable tool in differential diagnosis to hepatitis C recurrence. Am J Transplant 2006 Mar;6(3):523-30.
  • 50. Sreekumar R, Rasmussen DL, Wiesner RH, Charlton MR. Differential allograft gene expression in acute cellular rejection and recurrence of hepatitis C after liver transplantation. Liver Transpl 2002 Sep;8(9):814-21.
  • 51. Joshi D, Salehi S, Brereton H, Arno M, Quaglia A, Heaton N. Distinct microRNA profiles are associated with the severity of hepatitis C virus recurrenceand acute cellular rejection after liver transplantation. Liver Transpl 2013 Apr;19(4):383-94.
  • 52. Everson GT, Terrault NA, Lok AS, Rodrigo del R, Brown RS Jr, Saab S. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis C after liver transplantation. Hepatology 2013 May;57(5):1752-62.
  • 53. Iacobellis A, Siciliano M, Perri F, Annicchiarico BE, Leandro G, Caruso N. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study. J Hepatol 2007 Feb;46(2):206-12.
  • 54. Carrion JA, Martinez-Bauer E, Crespo G, Ramirez S, Perez-del-Pulgar S, Garcia-Valdecasas JC. Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: A retrospective study. J Hepatol 2009 Apr;50(4):719-28.
  • 55. Hezode C, Dorival C, Zoulim F, Poynard T, Mathurin P, Pol S. 8 Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. First Results of the French Early Access Program (ANRS CO20-CUPIC). J Hepatol 2012 Apr;56(Suppl 2):S4.
  • 56. Verna EC, Abdelmessih R, Salomao MA, Lefkowitch J, Moreira RK, Brown RS Jr. Cholestatic hepatitis C following liver transplantation: An outcome-based histological definition, clinical predictors, and prognosis. Liver Transpl 2013 Jan;19(1):78-88.
  • 57. Berenguer M, Palau A, Aguilera V, Rayón JM, Juan FS, Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008 Mar;8(3):679-87.
  • 58. Xirouchakis E, Triantos C, Manousou P, Sigalas A, Calvaruso V, Corbani A. Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and meta-analysis of prospective controlled studies. J Viral Hepat 2008 Oct;15(10):699-709.
  • 59. Berenguer M . Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol 2008 Aug;49(2):274-87.
  • 60. Wang CS, Ko HH, Yoshida EM, Marra CA, Richardson K. Interferon-based combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis. Am J Transplant 2006 Jul;6(7):1586-99.
  • 61. Berenquer M, Palau A, Fernandez A, Benlloch S, Aquilera V, Prieto M. Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C. Liver Transpl 2006 Jul;12(7):1067-76.
  • 62. Oton E, Barcena R, Moreno-Planas JM, Cuervas-Mons V, Moreno-Zamora A, Barrios C. Hepatitis C recurrence after liver transplantation: Viral and histologic response to full-dose PEG-interferon and ribavirin. Am J Transplant 2006 Oct;6(10):2348-55.
  • 63. Gordon FD, Kwo P, Ghalib R, Crippin J, Vargas HE, Brown KA. Peginterferon--2b and ribavirin for hepatitis C recurrence postorthotopic liver transplantation. J Clin Gastroenterol 2012 Sep;46(8):700-8.
  • 64. Hulskotte E, Gupta S, Xuan F, van Zutven M, O’Mara E, Feng HP. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012 Nov;56(5):1622-30.
  • 65. Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011 Jul;54(1):20-7.
  • 66. Coilly A, Furlan V, Roche B, Barau C, Noël C, Bonhomme-Faivre L. Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence. Antimicrob Agents Chemother 2012 Nov;56(11):5728-34.
  • 67. Fontana RJ, Hughes EA, Appelman H, Hindes R, Dimitrova D, Bifano M. Case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation. Liver Transpl 2012 Sep;18(9):1053-9.
  • 68. Coilly A, Roche B, Dumortier J, Leroy V, Botta-Fridlund D, Radenne S. Safety and efficacy and safety of protease inhibitors to treath hepatitis C after liver transplantation: a multicenter experience. J Hepatol 2014 Jan;60(1):78-86.
  • 69. Levitsky J, Fiel MI, Norvell JP, Wang E, Watt KD, Curry MP. Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon. Gastroenterology 2012 May;142(5):1132-1139.
  • 70. Coilly A, Roche B, Samuel D. Current management and perspectives for HCV recurrence after liver transplantation. Liver Int 2013 Feb;33(Suppl 1):56-62.
  • 71. McCashland T, Watt K, Lyden E, Adams L, Charlton M, Smith AD. Retransplantation for hepatitis C: results of a U.S. multicenter retransplant study. Liver Transpl 2007 Sep;13(9):1246-53.
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Implications for the management of different risk factors

Risk factors Modifying strategies
Recipient factors
AA race
HIV coinfection
Utilise AA donor
Avoid LT if genotype 1 requires kidney transplant, with BMI <21 kg/m2, anti-HCV antibody-positive donor
Donor factors
Older age
HCV positive
IL-28 genotype CC
Select younger age donors
Avoid donors more than 45 years
Early antiviral therapy
Preservation injury
CMV infection
Acute rejection
Post-LT diabetes
Post-LT steatosis
Reconcile transplant procedure
Extended 6 months prophylaxis if donor is CMV-positive and recipient is CMV-negative
Avoid corticosteroid boluses, and lymphocyte-depleting drugs. Avoid treatment for mild rejection.
Avoid immunosuppressive drugs that are diabetogenic
Management of body weight and metabolic syndrome
Pre-transplant HCV viraemia Clearance of HCV RNA before transplantation

Prognostic tests for severe post-transplant HCV recurrence44,45,46,47,48

Type of test When to assess (months) Predictors for cirrhosis and hepatic decompensation
Liver biopsy 12 Stage 2 fibrosis
Hepatic elastography 6 LSM > 9.0 kPa
Hepatic venous pressure gradient (HPVG) 12 HVPG > 6
Serum fibrosis markers 12 Serum hyaluronic acid, serum procollagen type III N terminal peptide, tissue inhibitor of metalloproteinase, all >2
Or serum markers 5 Serum hyaluronic acid >90 μg/L and YKL-40 > 2000 μg/L

Factors influencing sustained virologic response with standard therapy

HCV genotype
Baseline viral load
Degree of baseline fibrosis
IL-28B gene polymorphisms in donor and recipient
Body weight in recipient
Gender of recipient
Donor age
Prior antiviral therapy
Adherence of antiviral therapy
Duration of antiviral therapy
Rapid virological response
Early virological response
Use of growth factors