Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) and is the most common indication for liver transplantation (LT) in the United States and Europe. In contrast to other indications for LT, HCV recurrence after LT is nearly universal. Death and allograft failure (much of it due to HCV recurrence) are more common in this population versus HCV− recipients1 (Fig. 1). The natural history of HCV disease is accelerated in the posttransplant setting and leads to cirrhosis in 10% to 25% of these patients within 5 to 10 years.2 Once cirrhosis has developed, complications are common: the rate of decompensated disease is greater than 40% within 1 year, and the survival rate 1 year after decompensation is less than 50%.2 The delicate immune balance required to prevent both rejection and rapid HCV recurrence remains elusive, and measures to prevent and control recurrent HCV with antiviral therapy have been disappointing. In the future, strategies for eradicating the virus in pre-LT and post-LT settings with novel therapeutics will be crucial to improving outcomes.
Predictors of Severe HCV Recurrence and the Impact of Immunosuppression
Given the variable clinical course of recurrence, much work has been done to identify factors predictive of severe recurrence (Table 1). Donor age appears to have the strongest impact on outcomes, with progressive increases in the risk of graft failure with donors more than 40 years old. Recipient factors such as the pre-LT HCV viral load,3, 4 sex,5 and graft quality (as measured by the donor risk index)6 also predict graft survival.
|Recipient factors||Advanced age|
|Degree of hepatic explant necroinflammation|
|HCV-specific T cell response|
|High-dose rejection treatment|
|Viral factor||High pretransplant viral load|
|Donor factors||Older age|
|Cold ischemia time|
The optimal immunosuppression regimen for patients with HCV also remains undetermined. Increasingly potent immunosuppression in recent years has been implicated in the lack of improvements in the posttransplant outcomes of HCV patients. In addition, the conclusive diagnosis of rejection in the setting of HCV remains challenging. The treatment of acute rejection has been associated with diminished survival in HCV+ recipients but not in HCV− recipients.7 Because the impact of immunosuppression on HCV recurrence is most pronounced when high-intensity regimens are used to combat acute rejection,8–11 mild acute rejection is now treated frequently via the modulation of the baseline immunosuppression without bolus steroids or anti-lymphocyte antibodies. A recent study also suggested a negative impact of rapid fluctuations in immunosuppression as patients with slow prednisone tapering experienced a lower incidence of severe HCV recurrence at 1 year in comparison with historical controls (29% versus 48%).12 Steroid-free regimens may also be beneficial, but the data are limited.
Although cyclosporine appears to have in vitro antiviral activity,13 in vivo viral suppression has not been evident when patients treated with cyclosporine or tacrolimus have been compared. Most studies, including meta-analyses, have shown that the severity of HCV recurrence is similar with cyclosporine- and tacrolimus-based regimens14; however, overall survival may be higher for patients on tacrolimus-based regimens.15 Mycophenolate mofetil may also have in vitro antiviral properties, and when it is used as long-term maintenance immunosuppression with low-dose calcineurin inhibitors, it may decrease the risk of fibrosis progression.16 However, clear evidence supporting any particular induction or maintenance regimen remains elusive, and additional data on these agents as well as mammalian target of rapamycin (mTOR) inhibitors are needed.
Antiviral Therapy to Prevent Histological HCV Recurrence
Three antiviral treatment strategies have been attempted with limited success: viral eradication before or at the time of LT, prophylactic or preemptive therapy early after LT, and the reactive treatment of established histologically recurrent disease. The ideal strategy would be a viral cure in the pre-LT setting, but interferon (IFN)-based treatments of patients with decompensated liver disease have been associated with serious adverse events, including the exacerbation of encephalopathy and serious infections (with a treatment-related mortality rate as high as 10%), and with low rates of sustained virological response (SVR). For these patients, modified regimens (e.g., the low accelerating-dose regimen of IFN and ribavirin) have been used17 (Fig. 2). With this approach, there were fewer adverse events (although 27% discontinued therapy), and the end-of-treatment response (EOTR) and SVR rates were 46% and 24%, respectively. Fifteen patients with SVR underwent transplantation, and 12 (80%) remained free of viral recurrence. This approach has also been used with similar results for select patients with potential living donors or Model for End-Stage Liver Disease exception points for HCC in the National Institutes of Health–sponsored Adult-to-Adult Living Donor Liver Transplantation (A2ALL) Cohort Study. In the A2ALL Cohort Study, 79 patients were enrolled [32 genotype 2/3 patients received HCV therapy, and 47 genotype 1/4/6 patients were randomized (2:1) to the treatment or control group].18 For the patients who were treated, the overall posttransplant virological response rate was 28% (18% for genotypes 1, 4, and 6 and 39% for genotypes 2 and 3), and the response was significantly associated with the pretransplant treatment duration. The immediate pretransplant setting may be ideal for investigating the use of potent combinations of direct-acting antivirals because even brief periods of therapy and viral clearance in the setting of LT may lead to a cure.
Data on prophylactic and preemptive treatment strategies are limited. In contrast to hepatitis B, HCV immunoglobulin formulations lead to only transient decreases in HCV viral loads and do not prevent graft reinfection. Treatment with IFN and ribavirin before histological recurrence has been attempted; however, in the first 2 months after transplantation, <50% of the patients will have the clinical and blood count stability to start IFN and ribavirin.19 In the most recent trial of this strategy, patients were randomized to a prophylactic treatment with pegylated interferon (PEG-IFN) and ribavirin or to observation (with the potential for a reactive treatment for significant recurrence) 10 to 26 weeks after transplantation.20 The SVR rate in the treatment arm was 22%, and the rates of significant recurrence at 120 weeks were similar in the treatment (62%) and observations arms (65%), as were the patient and graft survival rates. Therefore, prophylactic or preemptive therapy is not currently recommended, although this may change with safer and more effective antiviral regimens.
Antiviral Therapy for the Treatment of Significant Recurrent HCV
Currently, treatment is recommended only for established recurrent disease.21 Unfortunately, the high proportion of patients with genotype 1 or a prior nonresponse to IFN and the poor tolerability of IFN and ribavirin render the treatment of recurrent HCV challenging. Immunosuppression may also affect HCV viral load kinetics when patients are treated after transplantation, and this makes the interpretation of traditional stopping rules complex.22
IFN monotherapy has displayed little efficacy in this setting. In combination with ribavirin, PEG-IFN generally yields better response rates than IFN, and wide ranges have been reported for EOTR and SVR rates in the literature. When more than 40 treatment trials of ribavirin in combination with IFN or PEG-IFN were pooled, the composite SVR rates were 24% for patients treated with IFN and ribavirin and 27% for patients treated with PEG-IFN plus ribavirin23 (Table 2). The pooled discontinuation rates were 24% and 26%, respectively. Despite these variable results, when SVR is achieved, it does appear to improve graft survival24 and, therefore, remains an important goal.
|Studies (n)||Pooled Proportion (95% Confidence Interval)||Studies (n)||Pooled Proportion (95% Confidence Interval)|
|End-of-treatment biochemical response||19||57% (53%-61%)||10||54% (48%-60%)|
|End-of-treatment virological response||26||34% (30%-37%)||20||42% (38%-46%)|
|End-of-treatment histological response||14||53% (38%-68%)||6||68% (57%-79%)|
|End-of-follow-up biochemical response||15||37% (26%-48%)||2||32% (20%-43%)|
|SVR||22||24% (20%-27%)||16||27% (23%-31%)|
|End-of-follow-up histological response||6||59% (48%-70%)||2||85% (68%-100%)|
|Compliance and complications|
|Full duration, full dose||18||33% (28%-38%)||14||21% (9%-34%)|
|Full duration, reduced dose||18||44% (38%-50%)||14||66% (61%-70%)|
|Early cessation||26||24% (21%-27%)||20||26% (20%-32%)|
|Acute rejection||25||2% (1%-3%)||16||5% (3%-7%)|
The use of telaprevir and boceprevir in the posttransplant setting has not yet been studied and is not Food and Drug Administration–approved. The significant drug-drug interactions between these agents and immunosuppressive drugs, including calcineurin inhibitors25 and, to a lesser extent, prednisone, have led to the cautious implementation of triple therapy in transplant patients. Although formal studies are ongoing, several preliminary single-center reports have demonstrated promising initial viral responses, although EOTR and SVR data are not yet available.
Retransplantation for Recurrent HCV
When recurrent HCV progresses to end-stage liver disease, the only definitive treatment for graft failure is retransplantation. There is ongoing debate about who should undergo retransplantation and when this should occur, and practices vary widely between institutions.26 Patient and graft survival rates after retransplantation for HCV are worse than the rates after primary transplantation,27 and they may be worse than the rates for other indications.28, 29 Thus, retransplantation for recurrent HCV is not offered at some centers. Risk factors for poor retransplant outcomes include recipient age, poor conditioning, a high Model for End-Stage Liver Disease score, and early and aggressive HCV recurrence. As posttransplant HCV treatment improves and becomes more widespread, retransplantation for patients who achieve SVR will likely be a more accepted practice.
LT is a lifesaving therapy for hepatic failure or HCC due to HCV. Its long-term success is limited by diminished graft and patient survival due to recurrent HCV. Although the results of HCV treatment before and after LT have historically been disappointing, this field is rapidly evolving with the advent of direct-acting antiviral therapy. Combinations of potent direct-acting antivirals that achieve the goals of shorter, more effective, and less toxic treatment regimens (particularly IFN-free regimens) hold the promise of reliable viral eradication even in these difficult-to-treat populations, and they may thus significantly improve posttransplant graft and recipient survival.