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Recurrence of hepatitis C virus infection following liver transplantation
Authors:
Elizabeth C Verna, MD
Robert S Brown, Jr, MD, MPH
Section Editor:
Adrian M Di Bisceglie, MD
Deputy Editors:
Allyson Bloom, MD
Kristen M Robson, MD, MBA, FACG
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Feb 28, 2017.

INTRODUCTION — Hepatitis C virus (HCV) infection causes approximately 40 percent of all chronic liver disease in the United States, and HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation (OLT) among adults [1,2]. HCV infection remains a problem after transplantation, and recurrent hepatic infection is the leading cause of graft failure.

The major issues related to HCV following liver transplantation will be reviewed here. Similar problems arise in patients with HCV who undergo other forms of organ transplantation. (See "Hepatitis C virus infection in kidney donors".)

The natural history and treatment of HCV, as well as the selection of patients for liver transplantation, is discussed elsewhere. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Overview of the management of chronic hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults" and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

EPIDEMIOLOGY — Recurrence of hepatitis C virus (HCV) following orthotopic liver transplantation (OLT) occurs in more than 95 percent of patients [3,4]. Nucleotide sequence studies of HCV demonstrate that the disease following OLT results from the same viral strain present before OLT. Virologic reinfection at the time of transplantation is not surprising since almost all patients are viremic at this time [3]. Reinfection occurs during reperfusion of the allograft in the operating room, and although viral levels decline in the first days after removal of the infected liver, they rebound and reach pretransplant levels within 72 hours [5]. Furthermore, peripheral monocytes may also harbor virus and act as a source for reinfection of the donor liver [6].

RISK FACTORS FOR PROGRESSIVE DISEASE — Variables that influence the progression of recurrent hepatitis C virus (HCV) following orthotopic liver transplantation (OLT) are incompletely understood, but donor characteristics (donor type, age), viral characteristics (genotype, viral load), the inflammatory grade of the explanted liver, and the patient's immune status and immunosuppressive regimen may be important [7-20].

Donor characteristics

Age – The donor characteristic that most strongly predicts outcome is age. Although grafts from donors aged 60 to 80 years function without a survival disadvantage in non-HCV-infected patients [21], liver disease related to HCV recurrence may be more severe when older donors are used [20,22-26]. This diminished graft survival may even be seen with donors in their fourth and fifth decades, and the mechanism of interaction is unknown.

Donor type – The type of donor used may have an impact on patient and graft survival. Adult-to-adult living donor liver transplantation has been performed in the United States since 1998, and there were early reports of more severe HCV recurrence in this population [27,28]. However, several larger studies have not confirmed this finding [29-34]. A meta-analysis of 14 studies with 2024 patients with HCV who received a transplantation from a living donor found comparable patient survival rates at years 1 through 5 [35]. Graft survival rates at years 1 and 3 were lower among those who received a graft from a living donor but were similar at years 2, 4, and 5.

Transplant center expertise – A multicenter living donor liver transplantation cohort revealed that the experience of the transplantation center may be the driving factor in predicting patient outcomes in living donor recipients with HCV [36]. Patient and graft survival were similar among recipients of living or deceased organs when performed in centers that had performed at least 20 living donor transplants.

HLA match – The influence of having a human leukocyte antigen (HLA) mismatched donor on the severity of disease recurrence following OLT remains controversial [9,16]. No consistent site of mismatch associated with disease recurrence has been identified.

Genotype — The influence of HCV genotype (particularly genotype 1b) on the severity of disease recurrence following OLT is controversial [9,10,13-17,37]. The range of findings that have been reported can be illustrated by the following examples:

In a series of 652 patients from 15 European centers, genotype 1b was an independent risk factor for recurrent hepatitis but not for patient or graft survival [17].

In a retrospective series with 745 liver transplantation recipients with a median follow-up of 3.1 years, patients with genotype 1 were more likely than patients with genotype 2, 3, or 4 to develop advanced fibrosis [37]. HCV genotype was not associated with patient or graft survival.

In a prospective study of 60 patients from France and Japan who were followed for three years after OLT, patients infected with genotype 1b were more likely than those infected with other genotypes to develop both acute hepatitis (77 versus 40 percent) and chronic active hepatitis (59 versus 22 percent) [10].

In a series of 42 patients from the Mayo Clinic, histologic evidence of hepatitis occurred with similar frequency (90 percent) with all genotypes [13]. However, development of cirrhosis was more common in those with the 1b genotype: 6 of 17 (35 percent) compared with 2 of 25 (8 percent) infected with other genotypes.

In contrast to these findings, other larger series (124, 166, and 155 patients) found no difference in the rate or degree of hepatitis, or in graft or patient survival between 1b and non-1b patients [14-16].

The degree of divergence of HCV quasispecies may also be enhanced in patients with severe recurrent HCV, suggesting that the selection for or emergence of many new HCV variants may influence disease progression [38].

Viral load — Once the graft has been reinfected, serum HCV ribonucleic acid (RNA) levels increase from 4- to 100-fold following liver transplantation [18]. However, the relationships between pretransplant viral load, and viral load after transplantation on graft and patient survival are not well understood. Studies examining the effect of pretransplant HCV viral load on the likelihood of HCV recurrence have produced discordant results [10,14,15,38]. Several reports found that pretransplant viral load did not correlate with either the likelihood or timing of HCV recurrence following OLT and did not predict the severity of liver disease when it occurred [10,14,38]. By contrast, in one series of 166 HCV-infected liver transplantation recipients, those with HCV RNA titers greater than 1 million viral equivalents/mL had a significantly lower cumulative five-year survival compared with patients with lower pretransplant titers (57 versus 84 percent) [15]. High titers of HCV RNA in the explanted liver may also be a risk factor [39].

The influence of viral load following OLT is also uncertain. Some studies have suggested that viral levels in patients after transplantation do not correlate well with the severity of histologic disease [40-42], which is similar to the lack of correlation observed outside the transplantation setting. By contrast, other studies have found that an increase in viral titers was associated with worse histologic activity, increased risk of fibrosis, and decreased survival [18,19,43].

Inflammatory grade — The degree of inflammation present in the patient's explanted liver at the time of transplantation appears to predict fibrosis progression in recurrent HCV. This was examined in a retrospective study of 134 patients who underwent liver transplantation for HCV [44]. Patients were divided into two groups based upon the degree of fibrosis in the explanted liver (group 1 = Ishak grade ≤4; group 2 = Ishak grade >4). Five-year advanced fibrosis-free survival was significantly higher among patients in group 1 compared with group 2 (63 versus 28 percent). In addition, rates of graft loss at one and five years were significantly lower in patients in group 1 (3 versus 6 percent and 14 versus 36 percent, respectively). (See "Histologic scoring systems for chronic liver disease", section on 'Knodell score/histology activity index'.)

Immunosuppression — The level and type of immunosuppression following transplantation likely influence the severity of disease recurrence. The impact of immunosuppression is most pronounced when high-intensity regimens are used to treat acute rejection, particularly with high-dose bolus steroids and anti-lymphocyte antibody preparations [15,45,46]. There are no convincing data to support the use of any specific induction or maintenance regimen, and it is likely that choice of initial calcineurin inhibitor (tacrolimus or cyclosporine) does not significantly impact outcomes in HCV-positive liver transplant recipients overall. (See "Liver transplantation in adults: Overview of immunosuppression", section on 'Glucocorticoids and HCV' and "Liver transplantation in adults: Overview of immunosuppression", section on 'Calcineurin inhibitors and HCV'.)

CD4 cell response — The specific CD4 cell response to HCV appears to be an important determinant of the severity of histologic recurrence following liver transplantation [47,48]. This was illustrated in a series that included 43 patients transplanted for HCV in whom histologic recurrence of HCV was categorized as mild or absent (80 percent) or severe (20 percent). Patients with severe recurrence were far less likely to have a CD4 T-cell response to HCV antigens (0 versus 40 percent with a response to at least one HCV antigen).

CLINICAL COURSE — As in the pretransplantation setting, the clinical course of HCV infection following orthotopic liver transplantation (OLT) is variable. Five-year survival after transplantation is approximately 60 to 80 percent in most series, which is comparable to transplants performed for alcoholic liver disease, and better than historic rates for hepatitis B, hemochromatosis, or cancer [9,15,17,49-52]. However, examination of the Scientific Registry of Transplant Recipients in the United States has shown that over the last two decades, there has been a significant improvement in post-transplant survival in HCV-negative liver transplant recipients that was not seen in HCV-positive individuals, and that overall survival is lower in HCV-positive individuals compared with HCV-negative patients as a whole [26]. Recurrent HCV-related graft failure remains the leading cause of death in these patients, though hepatocellular carcinoma is also an important predictor of five-year patient or graft survival [17]. (See "Liver transplantation for hepatocellular carcinoma".)

The course of HCV infection after OLT is accelerated compared with the pretransplant setting, with 10 to 20 percent of patients developing cirrhosis only five years post-transplantation [7]. The favorable estimates of outcomes described above may reflect publication bias, since centers with worse outcomes may be less likely to report their findings. Survival statistics from the United Network of Organ Sharing (UNOS) may provide a more comprehensive profile of transplantation outcomes.

One such analysis of transplants conducted between 1992 and 1998 suggested that HCV-positive recipients had an increased rate of death (hazard ratio [HR] 1.23; 95% CI 1.12-1.35) and allograft failure (HR 1.30; 95% CI 1.21-1.39) compared with transplantation of HCV negative recipients [52]. One-, three-, and five-year patient survival rates were 86, 78, and 70 percent, respectively (compared with 88, 82, and 77 percent, respectively, for patients without HCV). The reduction in survival persisted even after adjusting for potential confounders. The effect on survival appeared to be most pronounced in HCV-infected women. These trends persisted at least through 2001 [53].

A second study also found that women are at increased risk for advanced recurrent HCV and graft loss [54]. In that study, 1264 patients who underwent liver transplantation for HCV between 2002 and 2007 were followed for a median of three years. Female sex was an independent predictor of advanced recurrent disease (HR 1.3), graft loss (HR 1.3), and death (HR 1.3). The unadjusted three-year cumulated patient and graft survival rates were 75 and 74 percent, respectively, for women, and 80 and 78 percent, respectively, for men.

Outcomes may also be influenced by the patient's race. An analysis of transplants performed in the United States between 1988 and 1996 suggested that overall survival may be slightly lower among African-Americans compared with white Americans and Hispanics (two-year survival 72 versus 80 and 77 percent, respectively) [55]. Thus, it is likely that short-term outcomes for HCV-infected patients are similar but diverge progressively over time due to the impact of recurrent HCV and graft cirrhosis.

Coinfection with HIV is another factor that influences outcomes [56]. It has been estimated that compared with patients who are infected with HCV alone, those with HCV and HIV have a survival rate that is approximately 10 percent lower, with three-year survival rates of 60 to 70 percent [57].

Patterns of disease recurrence — Although HCV RNA is universally detectable following transplantation, the clinical course of HCV recurrence is variable. HCV recurrence may be accompanied by the following clinical features [9,11,17,38,49,58]:

Normal or near-normal serum aminotransferases, and minimal inflammatory activity on liver biopsy (20 percent).

Mild to moderate elevation of serum aminotransferases, and mild to moderate inflammation on liver biopsy (50 percent).

Moderate elevation in serum aminotransferases with progressive histologic damage observed during the first 5 to 10 years (20 to 40 percent).

Rapidly progressive, cholestatic hepatitis leading to graft failure (5 to 10 percent), sometimes occurring within one year following OLT [4,59]. The development of cholestatic hepatitis may be more common in patients with higher HCV viral load, in patients who receive higher levels of immunosuppressive medications or had treated acute cellular rejection, and possibly in patients with an IL28B genotype other than CC [42,60,61]. While survival has improved among HCV recipients in recent years, rates of recurrent severe fibrosis have remained unchanged [62].

As described above, the variables leading to these patterns in individual patients are not well understood. Although several risk factors have been identified, none has been extensively validated or permitted clinically important intervention [28,30,39,51,62-65]. Early markers of likely progression to severe recurrence may include early hepatic stellate cell activation [66] and a hepatic venous pressure gradient of 6 mmHg [65].

Transplantation of HCV-infected grafts — Because of the shortage of organs, transplantation of livers from HCV-infected donors to HCV-infected recipients has been attempted. A study evaluating the outcome of 23 such patients found that five-year survival was similar to a control group of HCV-infected recipients who had received grafts from HCV-negative donors (89 versus 88 percent) [67]. Furthermore, an interesting observation was that patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival compared with patients who retained their original HCV strain (90 versus 15 percent). This observation was hypothesized to be related to impaired ability of CD8 and CD4 cells to recognize viral antigens presented in the context of liver transplantation with poorly matched class I and class II human leukocyte antigens (HLA). In addition, no differences in survival have been seen in large UNOS database studies [68]. However, a more recent multicenter retrospective study with detailed biopsy data showed that although overall survival was similar between patients who received HCV positive and negative grafts, the risk of advanced fibrosis was significantly higher in the HCV-infected grafts, especially with donor age over 65 years [69].

Combined liver-kidney transplantation — A subset of patients with chronic HCV infection has concurrent end-stage kidney disease, potentially requiring simultaneous liver and kidney transplantation [70-72]. In one report, patients who underwent combined liver-kidney transplantation had similar one-year patient and graft survival rates as those who underwent liver transplantation alone (93 versus 96 percent and 93 versus 90 percent, respectively) [70].

In a study using the UNOS database, 66,026 patients underwent a liver transplantation alone, and 2327 underwent simultaneous liver-kidney transplantation [72]. Approximately one-third of the patients had HCV, and another third had unknown HCV status. One-year survival rates were slightly lower for those who received a simultaneous liver-kidney transplantation compared with a liver transplantation alone (82 versus 84 percent), though after controlling for potential confounders, patients who received a simultaneous liver-kidney transplantation had a lower risk of death than those who received a liver transplantation alone (HR 0.92; 95% CI 0.86-0.99). Both groups had one-year graft survival rates of 80 percent, but on multivariable analysis, patients who received simultaneous liver-kidney transplantations were at decreased risk for graft loss (HR 0.85; 95% CI 0.79-0.92).

DIAGNOSIS — Histologic recurrence of hepatitis C virus (HCV) infection following orthotopic liver transplantation (OLT) may be difficult to diagnose clinically and may be confused with acute cellular rejection in the graft. Serum alanine aminotransferase levels are often normal or minimally elevated with HCV infection. In addition, ELISA-based HCV assays are insensitive in immunosuppressed patients and may revert from positive to negative after OLT. (See "Diagnosis and evaluation of chronic hepatitis C virus infection".)

There are two steps involved in establishing the diagnosis of new or recurrent HCV infection following OLT [11]:

The use of polymerase chain reaction or transcription mediated amplification to directly detect HCV ribonucleic acid.

Liver biopsy to confirm the diagnosis, stage the disease, and plan for treatment.

Biopsy findings are typically mild and nonspecific, particularly with early recurrence. They include periportal inflammation, lobular ballooning of hepatocytes, acidophilic bodies, or lobular apoptosis. Some of these features are also seen in acute cellular rejection. Features that are supportive of recurrent HCV are lobular activity, interface hepatitis, piecemeal necrosis, and lymphocyte predominance or lymphoid follicles. Features more suggestive of rejection include a mixed cellular infiltrate (eosinophils, polymorphonuclear cells, and lymphocytes) confined to the portal triad, bile duct damage, and endotheliitis (table 1). However, differentiating rejection with HCV from HCV infection alone can be difficult on pathologic grounds and is often a clinical diagnosis based on timing post-transplantation and clinical features (eg, the degree of baseline immunosuppression, prior rejection treatment) (table 1).

Studies have also looked for noninvasive markers of HCV-related recurrent fibrosis, including serologic panels as well as imaging assessments including ultrasound elastography [73]. As an example, one study with 133 patients looked at an algorithm that included three serum fibrosis markers (hyaluronic acid, amino-terminal propeptide of type III procollagen, and tissue inhibitor of matrix metalloproteinase type-1 concentration) [74]. The area under the receiver operator characteristic (ROC) curve for the algorithm predicting fibrosis of stage 2 or greater (using the Scheurer classification) at one year post-transplantation was 0.78. The area under the ROC curve for the algorithm predicting a hepatic venous pressure gradient of 6 or greater at one year was 0.90.

Ultrasound-based elastography may be more predictive of fibrosis stage in transplant patients. In a systematic review that pooled five studies of patients with recurrent HCV, the sensitivity and specificity for ultrasound-based elastography predicting significant fibrosis were both 83 percent, and for predicting cirrhosis were 98 percent and 84 percent, respectively [75]. Despite this progress in noninvasive tools, liver biopsy remains the gold standard for monitoring of fibrosis progression given the limitations of the available noninvasive markers, and the lack of serologic testing that can differentiate HCV from other pathology such as rejection. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic tests".)

PREVENTION OF RECURRENCE — Several strategies for hepatitis C virus (HCV) treatment in the setting of transplantation have been attempted: treatment prior to transplantation to prevent infection of the graft, immediate or perioperative prophylaxis, early preemptive HCV therapy, and treatment of established recurrent disease. Traditionally, due to limitations in our treatment armamentarium, most patients have been treated once they have significant histologic recurrence. However, with the implementation of safer, more effective direct-acting antiviral regimens, pretransplant and preemptive treatment strategies are likely to be of increasing importance.

Treatment prior to transplantation — Eradication of HCV infection prior to transplantation would be the ideal approach, as patients who undergo transplantation in the absence of viremia are much less likely to have recurrent infection. With the availability of direct-acting antiviral agents and the improved safety profile with these regimens, interferon-free treatment is the preferred approach for treatment of patients with cirrhosis when available. Treatment with interferon-based therapy in this setting had been associated with exacerbations of encephalopathy, infections, and other serious adverse events and results in low rates of viral clearance [76-78].

Even in the setting of interferon-free regimens, treatment of patients with decompensated cirrhosis warrants careful regimen selection and close monitoring. The appropriate regimens depend on the genotype and are discussed in detail elsewhere. Of note, regimens containing protease inhibitors (including simeprevir, elbasvir-grazoprevir, and ombitasvir-paritaprevir-ritonavir-based regimens) should not be used in patients with Child-Pugh classes B and C cirrhosis. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Patients with cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Patients with decompensated cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Patients with cirrhosis'.)

There is a growing literature regarding the use of interferon-free regimens in patients with cirrhosis, including those with compensated and decompensated disease (see "Direct-acting antivirals for the treatment of hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Patients with cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Patients with decompensated cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Patients with cirrhosis'). In a phase 2 open-label study that specifically aimed to treat patients in the immediate pre-transplant period, the use of direct-acting antiviral agents in 61 patients on the liver transplant waitlist with Child A cirrhosis, biologic MELD score <22, and hepatocellular carcinoma (and were thus listed with standard MELD exception points) [79]. The patients were treated with sofosbuvir 400 mg daily (a nucleotide polymerase inhibitor) and ribavirin 1000 to 1200 mg daily for up to 48 weeks prior to transplantation. Forty-six patients underwent liver transplantation, and 43 had undetectable viral loads at the time of transplantation. Among these 43 patients, the virologic response rate 12 weeks after transplantation was 70 percent (23 percent experienced post-liver transplant recurrence and 7 percent early post-liver transplant death related to nonfunctioning grafts or hepatic artery thrombosis). Thus, of patients who underwent transplantation, 63 percent had a post-transplant virologic response. Recurrence was inversely related to the number of days of undetectable HCV ribonucleic acid prior to transplantation. The most common adverse events were fatigue (38 percent), headache (23 percent), and anemia (21 percent).

However, as data are emerging with more potent DAA combinations, for patients with compensated or decompensated cirrhosis on the liver transplant waiting list, regimens that include sofosbuvir in combination with ledipasvir or daclatasvir are now recommended. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection" and "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Patients with cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Patients with decompensated cirrhosis' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Patients with cirrhosis'.)

Perioperative therapy — Limited evidence suggests that perioperative antiviral treatment in HCV positive patients may prevent reinfection of the new graft. In an open label study, 16 patients with chronic HCV undergoing their first liver transplantation received a single dose of ledipasvir–sofosbuvir the day they arrived at the hospital for transplantation and once daily for four weeks postoperatively [80]. The sustained virologic response rate 12 weeks after completion of treatment was 88 percent (95% CI 62-98). In one patient with a virologic relapse by four weeks post-treatment, a sustained virologic response was achieved after retreatment with 12 weeks of ledipasvir–sofosbuvir. Additional studies are needed to evaluate this approach.

Prophylactic therapy post-transplantation — Early treatment post-transplantation with interferon-based regimens has not been shown to improve patient and graft outcomes, and currently there is no established role for prophylactic or preemptive therapy following transplantation [2]. Instead, it has traditionally been reserved for patients with HCV-related liver injury from recurrent infection. Unlike hepatitis B virus, no effective immunoglobulin prophylaxis exists for HCV, though these preparations continue to be studied.

A meta-analysis of 10 randomized trials with 441 patients undergoing liver transplantation for chronic HCV infection found no differences in patient survival, graft rejection, retransplantation, or HCV recurrence between patients who received antiviral therapy following transplantation and those who did not [81]. Interventions included combination therapy (peginterferon or standard interferon and ribavirin), monotherapy (peginterferon, standard interferon, or ribavirin), and anti-HCV immune globulin. The timing of antiviral therapy varied significantly among the included trials. In some trials, treatment was initiated during the transplantation, whereas in others, patients started treatment up to 26 weeks following transplantation. However, in the majority of trials, treatment was initiated within six weeks of the transplantation.

A randomized trial with 115 patients not included in the meta-analysis compared early post-transplantation prophylactic therapy starting 10 to 26 weeks post-transplantation with treatment only once there was histologic recurrence (histological activity index ≥3 and/or fibrosis score ≥2 on liver biopsy) [82]. Patients in both groups were treated with pegylated interferon alfa-2a and ribavirin. Overall, rates of survival, significant histologic recurrence, and SVR (sustained virologic response) rates were similar between groups. The authors concluded that given the lack of clear benefit to the prophylactic approach and the cost and poor tolerability associated with treatment, the use of routine prophylactic therapy is not supported.

Interferon-based treatment is no longer recommended in liver transplant recipients. However, the use of DAA combinations in this setting has not yet been studied, and many centers now treat recurrent HCV with the regimens detailed below in the early post-operative period once the patient is stable. Studies of the safety and optimal timing of treatment in this setting are needed.

TREATMENT OF RECURRENCE — Treatment of significant recurrent disease is rapidly changing, though data are limited, and rigorous clinical trials are difficult to conduct in this population. Post-transplant treatment is currently centered on regimens containing direct-acting antiviral agents (eg, sofosbuvir), though therapy should be attempted only at centers with considerable experience in managing post-transplantation patients. (See 'Direct-acting antiviral agents' below.)

Direct-acting antiviral agents — Studies are now emerging showing efficacy of direct-acting antiviral agents for the treatment of HCV recurrence following liver transplantation.

Sofosbuvir-based regimens — Sofosbuvir is an NS5B nucleotide analog used for the treatment of HCV. It was initially studied in 40 liver transplant recipients with recurrent HCV who received sofosbuvir 400 mg daily and ribavirin 400 mg daily for 24 weeks [83]. Treatment resulted in persistently undetectable HCV ribonucleic acid (RNA) 12 weeks after stopping treatment in 28 of 40 patients (70 percent). All of the cases of virologic failure were due to relapse. As a result, sofosbuvir is usually now given in combination with one of several additional direct-acting antivirals (ledipasvir, simeprevir, and daclatasvir), with or without ribavirin [83-90]. Due to the hepatic metabolism of simeprevir, and the hyperbilirubinemia that has been reported as a side effect of regimens containing sofosbuvir and simeprevir, simeprevir should not be used in patients with advanced recurrent disease (Child-Turcott-Pugh [CTP] B or C cirrhosis) or with severe cholestatic recurrence. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Sofosbuvir plus peginterferon and ribavirin'.)

Studies of sofosbuvir combined with simeprevir with or without ribavirin for patients with genotype 1 HCV have shown the following:

In a phase 2, prospective trial, 33 patients without cirrhosis were randomized to three arms: simeprevir, sofosbuvir and weight-based ribavirin, 12 weeks, or simeprevir and sofosbuvir for 12 weeks, or simeprevir and sofosbuvir for 24 weeks; 13 additional subjects (two with cirrhosis, 11 without cirrhosis) were treated with simeprevir and sofosbuvir for 24 weeks. Sustained virologic response (SVR) was achieved in 81.8 percent, 100 percent, and 93.9 percent in each arm of the trial, respectively [91]. In a multicenter study, 151 patients with post-transplantation HCV genotype 1 were treated with sofosbuvir and simeprevir, with or without ribavirin [92]. The majority of patients (79 percent) received sofosbuvir and simeprevir without ribavirin. Most patients were treated for 12 weeks (90 percent), though 15 (10 percent) were treated for 24 weeks. The SVR at 12 weeks was 88 percent, and the relapse rate following therapy was 7 percent. Only one patient had virologic breakthrough on therapy. A total of six patients were lost to follow-up [83].

A retrospective multicenter analysis examined 123 patients who were treated with sofosbuvir (400 mg daily) plus simeprevir (150 mg daily) with or without ribavirin for 12 weeks [88]. The SVR 12 weeks after stopping treatment was 90 percent. The addition of ribavirin (given to 20 percent of the patients) did not influence the SVR rate.

A second retrospective study of sofosbuvir with simeprevir for 12 weeks found that the SVR 12 weeks after stopping therapy was 93 percent [89]. In this study, only three patients received ribavirin. Among patients with advanced fibrosis, the SVR rate was 67 percent.

Studies of the fixed dose combination of sofosbuvir with ledipasvir with or without ribavirin in patients with HCV genotypes 1 or 4 have shown the following:

Sofosbuvir in fixed-dose combination with ledipasvir 90 mg daily has also been studied in post-transplant patients with genotype 1 or 4 recurrent HCV in the SOLAR-1 study [84]. SOLAR-1 is a multicenter study with 229 patients with a broad range of liver disease severity (111 with METAVIR stage F0 to F3 fibrosis, 51 with compensated CTP class A cirrhosis, and 67 with decompensated CTP class B or C cirrhosis). Patients were randomly assigned to either 12 or 24 weeks of ledipasvir and sofosbuvir along with weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]). An SVR was achieved in 96 to 98 percent of patients with METAVIR stage F0 to F3 fibrosis in the 12- and 24-week arms, respectively, and in 96 percent of those with compensated cirrhosis in both the 12- and 24-week arms. Efficacy was lower in patients with CTP class B cirrhosis (85 and 88 percent SVR) or CTP class C cirrhosis (60 and 75 percent SVR) in the 12- and 24-week arms, respectively.

In a subsequent phase 2 study (SOLAR-2), post-transplant patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis received sofosbuvir in fixed-dose combination with ledipasvir 90 mg daily plus weight-based ribavirin for 12 or 24 weeks [93]. An SVR was achieved in 98 to 100 percent of patients with METAVIR stage F0 to F3 fibrosis in the 12- and 24-week arms, respectively, and in 100 and 96 percent of those with compensated cirrhosis in the 12- and 24-week arms, respectively. Although few patients with decompensated cirrhosis were enrolled, SVR in patients with CTP class B and C cirrhosis at 12 and 24 weeks were 95 and 100 percent; and 50 and 80 percent, respectively. SVR among patients with fibrosing cholestatic hepatitis C was 100 percent.

In a large retrospective cohort study that included 204 patients (21 percent with recurrent advanced fibrosis, 49 percent treatment-experienced) who were treated with fixed-dose combination of sofosbuvir and ledipasvir for 8, 12 or 24 weeks, with or without ribavirin, the overall SVR12 rate was 96 percent [94].

Studies of sofosbuvir combined with daclatasvir with or without ribavirin have shown the following:

In the phase 3 study, daily daclatasvir (60 mg daily) and sofosbuvir (400 mg) with ribavirin (initial dose, 600 mg) for 12 weeks was administered to patients with decompensated cirrhosis or to patients who had received a liver transplant with HCV genotypes 1, 2, 3, 4, and 6. The SVR12 rate among liver transplant recipients was 94 percent [95].

Another study included 97 liver-transplant recipients with severe recurrent HCV infection, who were treated with daclatasvir in combination with sofosbuvir (77 patients) or simeprevir (18 patients) or both (two patients), with or without ribavirin, for 24 weeks. In this study, 93 percent of the patients had HCV genotype 1, 31 percent had cirrhosis, 37 percent had severe cholestatic HCV, and 43 percent had recurrent decompensated cirrhosis (CTP class B or C). The SVR12 rate was 87 percent overall (91 percent in patients who received daclatasvir and sofosbuvir with or without ribavirin, and 72 percent in patients who received daclatasvir and simeprevir with or without ribavirin) [96].

In a study of 23 patients with fibrosing cholestatic HCV following liver transplantation, patients were treated with a combination of sofosbuvir plus daclatasvir (15 patients) or ribavirin (8 patients) [90]. An SVR was achieved in 22 patients (96 percent). The one patient who relapsed was coinfected with HIV and had received sofosbuvir with ribavirin [85,86].

Telaprevir and boceprevir — The American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guidelines suggest that telaprevir and boceprevir not be used in treatment-naïve patients with HCV following liver transplantation [97]. Of concern in treating patients with protease inhibitors following liver transplantation is the risk of drug interactions between telaprevir or boceprevir and immunosuppressant medications (particularly cyclosporine and tacrolimus), as well as the need for interferon in the regimen [98]. If these drugs are used, patients should have frequent trough levels of their immunosuppressant medications monitored during and after treatment to allow for dose reductions of their immunosuppressive medications as needed. Of note, boceprevir is no longer available in the United States or (effective March 31, 2016) in Canada.

Small studies of the protease inhibitors telaprevir and boceprevir in combination with interferon and ribavirin have suggested moderate to high end-of-treatment response rates and modest benefit in terms of sustained virologic responses [99-105].

In a series of 60 patients treated with triple therapy (peginterferon, ribavirin, and either telaprevir or boceprevir), an undetectable HCV RNA level was achieved in 86 percent of the patients treated with telaprevir and in 48 percent treated with boceprevir after an average of 6 and 11 weeks, respectively [101]. At the time of publication, data were not available regarding SVR rates.

In a series of 37 liver transplantation recipients with recurrent HCV, patients were treated with triple therapy that included either telaprevir (19 patients) or boceprevir (18 patients) [103]. The intended duration of therapy was 48 weeks. Overall, treatment was discontinued in 16 patients (43 percent; 58 percent of the telaprevir group and 28 percent of the boceprevir group). Reasons for discontinuation included serious adverse events (five patients, three of whom died), nonresponse to treatment (five patients), and virologic breakthrough (six patients). Of the 28 patients who had completed or discontinued treatment at the time of publication, 17 (60 percent) had undetectable HCV RNA (40 percent of the telaprevir group and 72 percent of the boceprevir group). Of the 12 patients who had been followed for at least 12 weeks after completing or discontinuing therapy, the SVR rate was 50 percent (20 percent in the telaprevir group and 71 percent in the boceprevir group).

In a retrospective series with nine patients with HCV recurrence, seven patients completed 12 weeks of therapy with telaprevir, peginterferon, and ribavirin, and five patients completed 48 weeks of therapy [99,102]. At week 48, six patients were HCV RNA-negative, five of whom achieved an SVR.

In a retrospective series with 81 patients with HCV genotype 1 who had recurrent HCV following liver transplantation, triple therapy for 48 weeks was associated with an SVR rate 12 weeks after completing therapy of 63 percent [104].

Paritaprevir/ritonavir/ombitasvir and dasabuvir — Due to the significant medication interactions with this regimen and calcineurin inhibitors (cyclosporine and tacrolimus) requiring dose reduction of the calcineurin inhibitor and frequent monitoring, this regimen is reserved for patients with genotype 1 recurrent HCV who need an alternative to fixed-dose sofosbuvir and ledipasvir along with ribavirin. (See 'Treatment guidelines in liver transplant recipients' below.)

In a study of 34 patients with HCV genotype 1 recurrence following liver transplantation and METAVIR stage F0 to F2 fibrosis, patients were given ombitasvir (an NS5A inhibitor), ritonavir-boosted ABT-450 (a protease inhibitor), dasabuvir (a nonnucleoside NS5B polymerase inhibitor), and ribavirin. Twenty-four patients (71 percent) had failed therapy with peginterferon and ribavirin prior to transplantation. Patients were treated for 24 weeks [106]. An SVR at 12 and 24 weeks post-treatment was achieved by 33 patients (97 percent). The patient who did not achieve an SVR had a viral load less than 25 international unit/mL at the end of treatment but relapsed on post-treatment day 3. Common adverse events included fatigue, headache, and cough. In addition, five patients required erythropoietin, but none required a blood transfusion. There were no episodes of graft rejection.

Peginterferon and ribavirin — Peginterferon, with or without ribavirin, has been associated with treatment response rates of 10 to 50 percent [107-119]. At least one decision-analysis suggested that such an approach was cost-effective [120]. However, due to the significant toxicities and overall poor response rates associated with interferon-based regimens, and the availability of effective interferon-free treatment, the use of interferon in post-transplant patients is currently not recommended [97].

Treatment guidelines in liver transplant recipients — Guidelines from the AASLD and IDSA are frequently updated and can be found online. Though there are few large trials of new direct-acting antiviral therapies in liver transplant recipients, especially in non-genotype 1 patients, and there are none with head-to-head comparisons of regimens, we agree with the 2016 update in the joint guidelines that recommends the following regimens [121]:

HCV genotype 1 or 4 including compensated cirrhosis: Daily fixed-dose combination of sofosbuvir 400 mg and ledipasvir 90 mg with weight-based ribavirin for 12 weeks, or daily daclatasvir 60mg and sofosbuvir 400mg with initial low-dose ribavirin (starting at 600 mg divided daily and increasing as tolerated) for 12 weeks. For ribavirin-ineligible patients, treatment options include 24 weeks of daily fixed-dose combination sofosbuvir and ledipasvir or daily daclatasvir and sofosbuvir.

Alternative regimens for patients with genotype 1 who do not have decompensated recurrent disease include:

24 weeks of daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg), plus twice-daily dosed dasabuvir (250 mg) and weight-based ribavirin, or

12 weeks of sofosbuvir 400 mg daily and simeprevir 150 mg daily, with or without ribavirin

Recurrent decompensated cirrhosis (CTP class B or C): Daily fixed-dose combination of sofosbuvir 400 mg and ledipasvir 90 mg with initial low-dose ribavirin (starting at 600 mg divided daily and increasing as tolerated) for 12 weeks.

HCV genotype 2 or 3 including compensated cirrhosis: Treatment with daily daclatasvir 60 mg and sofosbuvir 400 mg with initial low-dose ribavirin (starting at 600 mg divided daily and increasing as tolerated) for 12 weeks. Treatment duration may be increased to 24 weeks in patients who are ribavirin ineligible. Patients with genotype 2 HCV may also be treated with 24 weeks of sofosbuvir 400 mg daily and weight-based ribavirin.

When ribavirin is used, especially in patients with advanced recurrent disease, it may need be started at a dose of 600 mg daily, with subsequent increase in the dose as tolerated until reaching a dose of 1000 mg daily (for patients <75 kg) or 1200 mg daily (for patients ≥75 kg). The dosing of ribavirin should take into account the patient's creatinine clearance and hemoglobin level.

Retransplantation — Disease recurrence may ultimately lead to graft failure and the need for retransplantation. Indications and contraindications for retransplantation remain unclear, and practices vary widely among institutions.

Unfortunately, the prognosis for such patients is generally poor (similar to retransplantation for other indications) [122-130]. This was illustrated in a multicenter study that compared survival following retransplantation in patients with recurrent HCV with survival following retransplantation for other disorders [131]. The one-year (69 versus 73 percent) and three-year (49 versus 55 percent) survival rates were similar in the HCV and non-HCV groups. Model for End-stage Liver Disease (MELD) scores were not predictive of survival. Many patients were not considered eligible for retransplantation and died from recurrent disease.

With the rapidly changing field of HCV treatment, and likely improved safety and efficacy of pre- and post-transplant HCV treatment, transplantation outcomes in patients with advanced recurrent disease are likely to improve, and the need for retransplantation in this setting will hopefully diminish over time.

SUMMARY AND RECOMMENDATIONS

Hepatitis C virus (HCV)-associated cirrhosis is the most common indication for liver transplantation in the United States. Recurrent HCV infection following orthotopic liver transplantation (OLT) remains a major cause of morbidity and mortality in the post-transplantation setting.

The clinical course following OLT for HCV infection is variable. As a general rule, the course of HCV infection appears to be accelerated compared with the pretransplant setting. Several patterns of recurrence have been described. (See 'Clinical course' above.)

Many predictors of outcome following transplantation have been described, but their accuracy in predicting the course in individual patients or to guide interventions is uncertain. The use of older donors is likely associated with adverse outcomes. (See 'Risk factors for progressive disease' above.)

The diagnosis of recurrent HCV infection is based upon the detection of HCV ribonucleic acid, and compatible histologic characteristics. (See 'Diagnosis' above.)

No effective measure to prevent recurrence has been established, though treatment with interferon-free regimens on the transplant waitlist may soon become standard. (See 'Prevention of recurrence' above.)

Available treatment regimens are highly effective and well tolerated in both the pre- and post-transplant settings. Although all patients who do not achieve a sustained virologic response pre-transplant should be treated post-transplant, the optimal timing is uncertain, and the decision of when to treat must be made on an individual basis. Our approach is to treat patients between three and six months post-transplant as recurrent HCV should still be mild, any complications have been addressed, and immunosuppression levels are low. However, earlier therapy may be needed in patients with significant early histologic recurrence. Therapy should only be attempted at centers with considerable experience in managing post-transplantation patients. (See 'Treatment guidelines in liver transplant recipients' above.)

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