Use of a hepatitis C virus (HCV) RNA‐positive donor in a treated HCV RNA‐negative liver transplant recipient

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA‐positive donor organs are typically not given to patients who have cleared HCV. A 64‐year‐old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15 IU/mL by week 10. At week 18 of a planned 24‐week treatment course, the patient underwent deceased‐donor LT and received an organ from an anti‐HCV‐positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12 weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV‐infected transplant patients.     

Spontaneous clearance of hepatitis C infection after liver transplantation from IL28B rs12979860 CC donors

Genetic polymorphisms adjacent to IL28B have been previously associated with spontaneous clearance of hepatitis C virus (HCV) and a higher rate of sustained virological response to interferon-based treatment in HCV genotype 1-infected patients. A recent study has shown that patients with the CC genotype of the rs12979860 single nucleotide polymorphism upstream from the IL28B gene are more likely to clear HCV spontaneously relative to the CT or TT genotype. In the liver transplant cohort, HCV recurs almost universally in patients with detectable HCV RNA at the time of transplantation. The spontaneous clearance of HCV infection after transplant is very rare. We report two cases of spontaneous clearance of HCV genotype 1 infection after liver transplantation from homozygous IL28B CC donors. This finding may be explained by alterations in the host immune responses to HCV after transplantation with a CC donor liver, which has potential implications for donor selection in HCV-positive recipients.     

Chronic hepatitis C and chronic kidney disease: Advances,limitations and unchartered territories

Over the past few years, treatment options for chronic hepatitis C virus (HCV) infection have evolved dramatically. The current approved interferon‐free direct‐acting antiviral (DAA) regimens have been shown to be safe and effective with sustained virologic response (SVR) rates of >90% in most patients. Unique issues yet remain such as the challenges in patients with impaired renal function or decompensated cirrhosis. Patients with stages 4‐5 chronic kidney disease (CKD) have a higher prevalence of HCV infection compared with the general population. Chronic HCV in those on dialysis and in kidney transplant recipients is associated with higher morbidity and mortality than uninfected patients. The HCV‐infected population is also at risk of developing extrahepatic manifestations associated with altered immune system function and chronic inflammation with cryoglobulinaemic vasculitis being the most common of these manifestations. Therefore, patients with CKD stages 4‐5 have to be considered priority patients for HCV therapy. New antiviral therapies have the potential to improve outcomes in this vulnerable patient population, including those on haemodialysis. Recently published studies conducted in kidney transplant recipients have demonstrated successful outcomes. It is thus essential that we carefully select the most appropriate DAA regimen and the best time for treatment in the context of kidney transplantation or cryoglobulinaemic vasculitis. While sofosbuvir, the only approved nucleotide NS5B inhibitor, has been the backbone of most pangenotypic therapeutic regimens, it has a limitation in those with advanced kidney disease. The currently approved regimens for those with stage 4/5 CKD, while effective, have challenges in that they apply to genotype 1/4 and may require RBV for genotype 1a. Globally, genotype 3 is a common infection, and thus, this group with CKD presents a huge unmet need for effective therapies. As therapy of HCV in renal transplant recipients has been highly successful, it provides an opportunity to expand the use of HCV‐infected organs in solid organ transplantation.     

Use of HCV‐infected organs in solid organ transplantation: An ethical challenge but plausible option

Due to the unfortunate epidemic of opioid overdose deaths among people who inject drugs (PWID) in North America, there has been an increase in the availability of hepatitis C (HCV)‐positive organs for transplantation and consequently the potential to decrease waiting times for solid organ transplantation if an HCV‐uninfected recipient is willing to accept an HCV‐positive donor. The confidence in this potential new strategy comes as a result of the advent of safe and highly effective pan‐genotypic direct‐acting antivirals (DAAs). This promising strategy has been the most widely studied in kidney transplantation. Liver transplantation has positive results preliminarily, but has even less available data because viable HCV‐infected donor livers are typically transplanted into HCV‐infected individuals. Further, while HCV‐infected heart and lung transplantation, which face additional post‐transplant issues, have shown encouraging results, these studies are small scale and are limited by short‐term follow‐up. Thus, it would be premature to implement this strategy as standard of care without large scale clinical and real‐world trials and longer‐term follow‐up studies. Further, the ethics of this practice need to be considered. While some transplant professionals argue that more harm will be done by not utilizing HCV‐infected organs, others contend that cautiously conducted multi‐centre studies involving extensive post‐transplant follow‐up are paramount prior to endorsing widespread implementation of this strategy. The ethical permissibility of this practice hinges on whether access to DAA therapy can be secured in advance, and prospective recipients understand and accept all the risks associated with acquiring HCV.     

Successful heart‐kidney transplantation from a Hepatitis C viremic donor to negative recipient: One year of follow‐up

Every year the number of patients waiting for a heart transplant increases faster than the number of available donor organs. Some potential donor organs are from donors with active communicable diseases, including hepatitis C virus (HCV), potentially making donation prohibitive. The advent of direct‐acting antiviral agents for HCV has drastically changed the treatment of HCV. Recently, these agents have been used to treat HCV in organ donor recipients who acquired the disease from the donor organ. We report a case of heart‐kidney transplantation from an HCV viremic donor to HCV negative recipient with successful treatment and sustained virologic response.     

Treatment of hepatitis C in potential kidney and heart transplant patients

Hepatitis C virus (HCV) is common in certain solid organ transplant recipients, most notably in those undergoing liver or kidney transplantation. Infection typically antedates transplantation but may have been acquired at the time of transplantation via infected blood products or organs. A more rapid and aggressive course of HCV-related infection and liver disease is the major concern in organ transplant recipients compared with immunocompetent patients. HCV-related liver disease is an important cause of morbidity and mortality in patients with end-stage renal disease treated by dialysis or transplantation. The outcome of HCV infection in renal and liver transplant recipients has been extensively investigated, whereas literature on HCV-related liver disease among patients with orthotopic heart transplantation is scanty. This article reviews the literature concerning the treatment of HCV-related liver disease in renal and orthotopic heart transplantation.     

Viral hepatitis C in patients with renal disease

Hepatitis C in patients with chronic renal failure. Infection with hepatitis C virus (HCV) is a common complication in those patients under chronic dialysis. Prevalence varies from 8% to 65 percent. Immunization against hepatitis A and B for renal patients is always recommended, especially in countries with high prevalence of this type of hepatitis. Interferon as the only antiviral treatment is recommended for patients with chronic renal failure and chronic hepatitis who depend on dialysis. Viral hepatitis is the first cause of morbidity and mortality among renal recipients. Prevalence varies between 4 and 38%, depending on the geographic area. Infection with HCV usually begins before the transplant, although the patient is sometimes infected during the transplant because the donor organs carry the virus. The chronic HCV infection dosen't seem to affect the survival rate of the patient or the organ, compared to the survival rate in patients without the infection. Chronic hepatitis C without cirrhosis is not a contraindication for renal transplant, but cirrhosis is. Liver failure is the cause of death in 8-28% of renal transplant recipients infected with hepatitis C virus.     

Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.     

To transplant or not to transplant recurrent hepatitis C and liver failure

In summary, re-OLT accounts for 10% of all OLTs performed and is associated with significantly increased resource use, and decreased survival compared with primary OLT. After transplantation into an HCV-infected recipient, infection of the allograft by HCV is invariable. As patients survive longer after liver transplantation, it is likely that allograft failure related to HCV recurrence will occur. Results of re-OLT for HCV are inferior to those of primary grafting, paralleling the results for retransplantation for other indications. Many studies have demonstrated that HCV infection significantly impairs patient and allograft survival after liver retransplantation, regardless of etiology of allograft failure. Patient survival rates with HCV infection are 57% to 65% at 1 year, as compared with 65% to 82% among patients without HCV infection. Experience with retransplantation is limited, however, and studies are difficult to interpret because of small sample sizes and lack of uniform definitions of survival, HCV recurrence, and allograft failure. Similar to outcomes after retransplantation for non-HCV related indications, the most common causes of death are sepsis and multi-organ failure. The high mortality associated with retransplantation has not universally been caused by recurrent disease, however recent studies have demonstrated that re-recurrent HCV occurs and the natural history is similar, if not more accelerated, after the second transplant. HCV infection may, in fact, increase mortality in a group of patients already predisposed to an inferior outcome. Preoperative serum creatinine and bilirubin have been consistently associated with survival after retransplantation and favorable results are attainable with strict selection criteria. The increasing use of expanded donor criteria, in particular, LRLT, raises important practical and ethical issues with regards to the HCV-positive transplant recipient and will become a challenge to the transplant community as a whole. With the donor morbidity and mortality associated with LRLT currently estimated at 32% and 0.3%, respectively, one must determine how much risk is acceptable to the donor in relation to the outcome in the recipient. This is especially true in HCV-infected recipients, in whom HCV re-recurrence may occur in the second allograft and lead to accelerated failure. LRLT, however, would not deplete the organ pool and would lead to the use of scarce cadaveric organs to patients who are awaiting primary liver transplantation. Despite inferior outcomes, a better tactic may be to consider retransplantation for recurrent HCV in those whose primary transplant was a LDLT, as the initial allograft did not deplete the donor pool. Given the shortage of donor organs and the increasing number of patients with HCV-induced allograft cirrhosis, identifying ways to improve allograft survival in HCV-infected patients represents an important focus for further research. Additional studies are needed to further explore the mechanisms underlying the reduction in survival and to identify which HCV-positive individuals are at greatest risk for poor survival. Studies are beginning to emerge that demonstrate that HCV recurrence can be modified with combination antiviral therapy and that the HCV virus can be eliminated. Additional longitudinal prospective studies are needed to assess the exact impact of HCV on survival after retransplantation, the effects of the newer immunosuppressive agents such as sirolimus and mycophenolate mofetil on HCV, the use of preemptive antiviral therapy on HCV eradication and fibrosis modification, and the appropriateness of expanded donor criteria. Until we have longer follow-up and greater experience with the HCV-positive recipient with allograft failure, retransplantation should be considered a viable option for highly selected patients, particularly in patients in whom renal failure and severe hyperbilirubinemia have not occurred.     

Long-term outcome of hepatitis C infection after bone marrow transplantation

Chronic hepatitis C is often asymptomatic, at least during the first decade following hematopoietic stem cell transplantation. Progression to advanced liver disease or cirrhosis in patients surviving more than 10 years is currently thought to be rare. Among 1078 patients who underwent an allogeneic transplantation between January 1973 and January 1995, 96 patients infected by hepatitis C virus (HCV) during the transplantation period were studied. Cumulative incidence and analysis of risk factors for cirrhosis were analyzed, and the rate and risk of cirrhosis in transplant recipients were compared with those of 158 HCV-infected controls who did not receive transplants. At a median follow-up of 15.7 years, 15 patients developed biopsy-proven cirrhosis, leading to a cumulative incidence of cirrhosis of 11% and 24% at 15 and 20 years, respectively. By multivariate analysis, extrahepatic HCV manifestations and HCV genotype 3 were associated with risk of cirrhosis. The median time to cirrhosis in transplant recipients was 18 years as compared with 40 years in the control population. The risk of cirrhosis in transplant recipients relative to controls was significantly higher by multivariate analysis (P =.0008). Roughly a quarter of long-term HCV-infected survivors with transplants progressed to cirrhosis that is much more rapid than in patients without transplants. Systematic detection of HCV infection, liver biopsy, and therapeutic intervention are therefore warranted in long-term marrow transplant recipients.     

Hepatitis C virus kinetics after liver transplantation to study the role of a small molecule inhibitor of viral entry

BackgroundAfter liver transplantation in patients infected with hepatitis C virus (HCV), reinfection of the transplanted liver is universal. The targeting of viral entry at the time of transplantation is therefore an attractive strategy. An understanding of the mechanisms and kinetics of this process will allow rational studies of small molecule inhibitors or neutralising antibodies that target HCV entry.MethodsAs part of a proof of concept study of ITX5061 (a small molecule antagonist of the HCV entry receptor, scavenger receptor B-I), we have studied detailed HCV kinetics. HCV RNA was quantified in plasma before and after liver transplantation. This study is registered with ClinicalTrials.gov, number NCT01292824.Findings13 patients were studied (median age 57 years, 11 male). Seven patients were infected with genotype 1, four with genotype 3, and one each with genotypes 2 and 4. During the period when no blood flowed through the liver there was a slow decline in plasma HCV RNA. After implantation of the donor liver there was a rapid decrease in HCV RNA in the plasma indicating entry of viral particles into the liver. Typically, there was a 90–99% decrease in HCV RNA at 4 h after implantation. This decrease continued until 12 h after implantation in all patients, and the initial rapidity of HCV RNA decline suggests the presence of specialised clearance systems in the liver. After this decrease, five patients showed a steady increase in plasma HCV RNA, which returned to baseline within 96 h indicating a rapid establishment of productive infection in the allograft. In the remaining eight patients there was a prolonged nadir for up to 21 days after transplant suggesting innate immune control in the transplanted liver. No differences in kinetics were observed between patients infected with different viral genotypes, or in the degree of liver injury at the time of transplantation.InterpretationThese marked differences in viral kinetics have major implications for trial design and probably have important biological significance in innate control of infection.FundingNational Institute for Health Research.     

Liver transplantation with hepatitis C virus-infected graft: interaction between donor and recipient viral strains

Superinfection of different viral strains within a single host provides an opportunity for studying host-virus and virus-virus interactions, including viral interference and genetic recombination, which cannot be studied in infections with single viral strains. Hepatitis C virus (HCV) is a positive single-strand RNA virus that establishes persistent infection in as many as 85% of infected individuals. However, there are few reports regarding coinfection or superinfection of HCV. Because of the lack of tissue culture systems and small animal models supporting efficient HCV replication, we explored these issues in the setting of liver transplantation where both recipient and donor were infected with different HCV strains and therefore represent a distinct model for HCV superinfection. Serial serum samples collected at multiple time points were obtained from 6 HCV-positive liver donor/recipient pairs from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database. At each time point, HCV genotype was determined by both restriction fragment length polymorphism analysis and phylogenetic analysis. Furthermore, we selectively sequenced 3 full-length HCV isolates at the earliest time points after liver transplantation, including both 5' and 3' ends. Detailed genetic analyses showed that only one strain of HCV could be identified at each time point in all 6 cases. Recipient HCV strains took over in 3 cases, whereas donor HCV strains dominated after liver transplantation in the remaining 3 cases. In conclusion, in all 6 cases studied, there was no genetic recombination detected among HCV quasispecies or between donor and recipient HCV strains.     

Use of Hepatitis C–Infected Deceased Donors in Liver Transplantation

The use of hepatitis C–infected (HCV⁺) liver donors for HCV⁺ transplant recipients was previously controversial, but mounting evidence now supports this practice. HCV-related cirrhosis accounts for 45% of the liver transplants in the United States; however, these transplant recipients have worse transplant outcomes when compared to non–HCV infected (HCV^-) recipients. The optimal utility of the donor graft is therefore decreased with transplantation of HCV⁺ recipients because the largest percentage of organs are transplanted into patients with inferior survival outcomes. Increased use of HCV⁺ livers, which can only be transplanted into HCV⁺ recipients, provides additional transplant liver allografts directly targeted to the recipient population at greatest need. As HCV⁺ recipients are transplanted with previously unusable organs, more HCV^- donor livers are available for the HCV^- recipient population, thereby increasing the utility of HCV^- grafts. Therefore, increased use of HCV⁺ donors results in increased utility of all available liver allografts and a shorter waitlist time to transplant, because the total number of available organs is increased. This review discusses the use of HCV⁺ donor livers in transplantation, including donor organ evaluation, hepatitis C in liver transplantation, a review of the available literature, and the future direction of HCV⁺ donors in transplantation.     

Healthcare-associated hepatitis C virus transmission among patients in an abdominal organ transplant center

Background. De novo hepatitis C virus (HCV) infection among transplant patients is rarely recognized but can have severe consequences. We investigated the scope, source, and mode of HCV transmission within a transplant center after incident HCV infection was identified in 2 patients who had liver transplantation in late 2006.
Methods. Patients were interviewed, and transplant logs, medical records, and staff practices were reviewed to identify opportunities for HCV transmission. Infection via receipt of blood or organs was evaluated. Molecular epidemiology was used to determine the relatedness between persons with incident and chronic HCV infection.
Results. HCV from infected blood or organ donors was ruled out. Among the 308 patients who underwent transplant in 2006, no additional incident HCV infections were identified. Eighty-five (28%) had pre-transplant chronic HCV infection; 13 were considered possible HCV source patients based upon shared days on the inpatient unit, nursing assignment, or invasive procedures in common with incident HCV case-patients. Viral isolates from 1 HCV source patient and 1 incident case-patient were found to be highly related by quasispecies analysis, confirming patient-to-patient HCV transmission. Possible modes of transmission identified were the improper use of multidose vials, sharing of blood-contaminated glucometers, and touch contamination.
Conclusion. Sporadic transmission or endemic levels of HCV transmission might be overlooked in a setting with high HCV prevalence, such as liver transplant units, where multiple, repeated opportunities for patient-to-patient HCV transmission can occur. Surveillance through pre- and post-transplant screening is necessary to identify incident HCV infection in this setting. Constant, meticulous attention must be paid to maintaining aseptic technique and good infection control practices to eliminate HCV transmission opportunities.     

Course and treatment of recurrent Hepatitis C after liver transplantation

Hepatitis C virus (HCV) related liver cirrhosis is the most common indication for orthotopic liver transplantation (OLT) in most transplant centers. However, recurrence of hepatitis C-infection after OLT in HCV positive patients is almost universal. Severity of graft hepatitis increases during the long term follow-up and up to 30% of patients develop severe graft hepatitis and cirrhosis. This led to decreased patient and graft survival in HCV positive patients. A number of variables like genotype, donor age, rejection treatment, cytomegalo-virus disease and liver retransplantation for HCV recurrence have shown to be associated with early and severe graft hepatitis. Prophylactic or therapeutic regimens which alter the course of disease in HCV positive patients are not established yet, and with longer follow-up the prevalence of HCV-related graft failure is likely to increase. New immunosuppressive regimens and anti-viral treatment with ribavarin in combination with pegylated interferon a have to be investigated to reduce the complications of HCV recurrence in the future.     

Living donor liver transplantation and hepatitis C

Preliminary results indicate that living donor liver transplantation patients infected with hepatitis C virus (HCV) develop earlier and more severe recurrence than their cadaveric counterparts. The mechanisms underlying this observation are unknown, but could include hepatic regeneration, differences in living donor liver transplantation recipient demographics, immune homology between donor and recipients, or other factors not previously considered. The optimum clinical approach is to only consider living donor liver transplantation in HCV-infected recipients as a life-saving procedure and to attempt to eradicate HCV before transplantation to prevent recurrent infection.     

Hepatitis C: Current Controversies and Future Potential in Solid Organ Transplantation

Purpose of Review

To highlight the changing landscape of hepatitis C virus (HCV) infection in the context of organ transplantation. This focuses on areas of controversy and future potential in the era of highly effective direct-acting antiviral (DAA) agents.

Recent Findings

Since the advent of safe and highly effective DAA therapy, HCV infection is now curable in virtually all cases, including organ transplant recipients. Excellent drug tolerability and safety combined with high cure rates across all organ groups means that HCV is no longer a barrier to transplantation or its outcomes. Mounting data demonstrate the safety of using organs from HCV-infected donors with subsequent treatment of HCV in the recipient and a potential to expand the donor pool.

Summary

Historical data demonstrating inferior survival in transplant recipients with HCV is of limited relevance in the DAA era. Virtually all transplant recipients with HCV infection can be cured, while early data also suggest excellent outcomes in recipients of organs from HCV viremic donors. The optimal timing of HCV therapy in relation to transplantation and the optimal use of organs from HCV viremic donors remain areas of controversy and ongoing research efforts.

     

Hepatitis C Virus Recurrence in Living Donor Liver Transplant Recipients

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) is a universal phenomenon. Recent reports have suggested an earlier and more aggressive recurrence in the living donor liver transplant (LDLT) population. The aim of this study was to compare the histological recurrence of HCV after LDLT versus deceased donor transplantation (DDT). Twenty-nine patients underwent LT for HCV-related end-stage liver disease at our institution between April 2001 and March 2003 (42 months). Twenty patients underwent DDT, and nine patients LDLT. Laboratory data were collected on a weekly to biweekly basis and HCV PCR was performed before LT and 3-4 months and yearly post-LT. Liver biopsies were performed as needed and per institutional protocol at 7 days, at 4 months, and yearly thereafter. All biopsies were evaluated by a single pathologist and scored for rejection (Banff score) and chronic hepatitis (Ishak score system). The predominant genotype in the DDT and LDLT groups was genotype 1 (DDT = 70%, LDLT = 79%). HCV RNA titers pre-LT and 3-4 months after LT did not differ. The incidence of rejection was higher in the DDT group (P < 0.05). There was a trend toward improved Ishak stage and grade in the LDLT group at 4 and 12 months post-LT, however, this trend did not reach statistical significance. No histological difference in the recurrence or severity rate was observed at 4 or 12 months post-LT in the DDT group vs. the LDLT group.     

Chronic viral hepatitis in kidney transplantation

Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in potential kidney transplant candidates-once considered absolute contraindications to kidney transplantation-no longer creates overt barriers to transplantation. Advances in the medical management of HBV and HCV infection have created opportunities for a substantial number of patients to be effectively treated with antiviral therapy before transplantation. For HBV infection, a number of new drugs enable clearance of the virus with minimal adverse effects and drug resistance. Pretransplantation antiviral therapy is advisable for patients with HCV infection, but adverse effects are common and viral eradication remains challenging. Regardless of viral clearance, pretransplant patients without bridging fibrosis (as confirmed by liver biopsy) or clinical stigmata of cirrhosis should be considered for kidney transplantation as survival is superior when compared to treatment with dialysis, and progression of liver disease is unlikely. For patients with advanced liver disease, simultaneous liver-kidney transplantation is an important consideration. These treatment advances further increase the burden of organ donor shortage; however, organs from deceased donors with chronic HBV or HCV infection could be efficiently allocated to certain individuals with a viral infection of the same type to increase the pool of available transplant organs.     

Recurrent hepatitis C following liver transplantation: a review of factors associated with graft injury

Recurrence of Hepatitis C virus (HCV) occurs in virtually all patients transplanted for HCV-related liver disease. Although the clinical and histological course of recurrent HCV is highly variable, recurrent disease is accelerated compared with HCV disease in the non transplant setting, leading to cirrhosis in 5-30% of patients within 5 years after transplantation. We outline factors associated with the severity of HCV recurrence (e.g. level of pretransplant viremia, living donor liver transplant, donor age, cytomegalo-virus infection, treatment of rejection), providing insight into mechanisms of liver injury and potential measures to prevent or minimize this injury.