INTRODUCTION — Hepatitis C virus (HCV) infection causes approximately 40 percent of all chronic liver disease in the United States. While HCV-associated cirrhosis is one of the most common indications for liver transplantation among adults [1,2], the proportion of transplant waitlist additions for HCV-associated disease in the United States has declined since the introduction of interferon-free, direct-acting antiviral (DAA) therapy [3]. If not treated pretransplant, HCV reinfection of the transplanted liver is near universal and, without effective antiviral treatment post-transplant, can be a major cause of graft failure.
The major issues related to HCV infection in liver transplant candidates and recipients will be reviewed here. Similar problems arise in patients with HCV who undergo other forms of organ transplantation. (See "Hepatitis C infection in kidney transplant candidates and recipients".)
The natural history and treatment of HCV infection, as well as the selection of patients for liver transplantation, are 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".)
POST-TRANSPLANT CLINICAL COURSE
Graft reinfection post-transplant — For patients with HCV viremia at the time of transplant, recurrence of HCV infection following liver transplantation is universal [4,5]. Sequencing studies have confirmed that reinfection is with the same viral strain circulating prior to transplant.
Among individuals with pre-existing HCV infection, infection of the transplanted liver occurs during reperfusion of the allograft in the operating room, since patients remain viremic at the time of transplantation in the absence of antiviral therapy. Although viral levels decline in the first days after removal of the infected liver, they rebound and reach pretransplant levels within 72 hours [6]. Once the graft has been infected, serum HCV RNA levels increase from 4- to 100-fold following liver transplantation [7]. Peripheral monocytes may also harbor virus and act as a source for reinfection of the donor liver [8].
Progression of liver disease post-transplant — With the efficacy and increasing use of direct-acting antiviral (DAA) therapy before and after transplant, significant HCV-related progression of liver disease post-transplant should be extremely rare.
Without successful antiviral therapy, the clinical course of HCV-associated liver disease following liver transplantation is variable, as in the pretransplant setting; the course is overall accelerated compared with the nontransplant natural history. About 20 to 40 percent of post-transplant patients who have not been cured of HCV infection develop progressive histologic damage, with 10 to 20 percent developing cirrhosis in as little as five years post-transplant, and 5 to 10 percent will develop a severe form of recurrence known as fibrosing cholestatic HCV [5,9-16].
The risk factors leading to these variable patterns of recurrence in individual patients are not well understood. Although several risk factors have been identified, none have permitted clinically important intervention [17-25].
Risk factors for progressive disease — Variables that influence the progression of untreated HCV-associated liver disease following orthotopic liver transplantation (OLT) are incompletely understood, but donor characteristics (donor type, age), recipient characteristics (demographics, immune status, and immunosuppressive regimen), and disease characteristics (viral genotype, viral load, and the inflammatory grade of the explanted liver) may be important [7,9-12,26-34].
In particular, the donor characteristic that most strongly predicts outcome in HCV-viremic liver transplant recipients is donor age. Although grafts from donors aged 60 to 80 years function without a survival disadvantage in patients without HCV infection [35], liver disease related to HCV recurrence may be more severe when older donors are used [34,36-40]. This diminished graft survival may even be seen with donors in their fourth and fifth decades, and the mechanism of interaction is unknown.
Overall post-transplant prognosis — Five-year survival after transplantation for HCV-associated liver disease is approximately 60 to 80 percent in series performed prior to the widespread availability of DAA agents, which is comparable to transplants performed for alcohol-associated liver disease and better than historic rates for hepatitis B virus infection, hemochromatosis, or cancer [10,12,14,22,31,41,42]. Nevertheless, overall survival has historically been lower in HCV-viremic recipients compared with recipients without HCV infection [40,43]. Recurrent HCV-related graft failure was the leading cause of death in these patients, though hepatocellular carcinoma is also an important predictor of five-year patient or graft survival [12].
The impact of more effective antiviral therapy with DAA regimens is discussed elsewhere. (See 'Benefits' below.)
DECIDING TO TREAT BEFORE OR AFTER TRANSPLANT — The availability of safe and highly effective HCV therapy with direct-acting antivirals (DAAs) has revolutionized the approach to HCV management in liver transplant candidates and recipients. A major focus of management is determining the optimal timing of therapy relative to transplantation. Antiviral therapy of liver transplant candidates, particularly those who have advanced cirrhosis, should be administered at transplant centers with appropriate expertise.
Considerations — Deciding whether to treat HCV infection prior to transplant or defer therapy until after transplantation is a key management issue for liver transplant candidates. Although cure of HCV infection prior to transplantation prevents reinfection of the allograft and can improve survival on the transplant waiting list in some patients with HCV-related decompensated cirrhosis, pretransplant antiviral therapy may not be the optimal strategy for selected transplant candidates. Although data informing the decision are limited, the relative benefits of pre- versus post-transplant therapy depend on several factors:
●Likelihood of meaningful clinical response to pretransplant therapy – Sustained virologic response (SVR) following antiviral therapy can lead to stabilization or improvement in liver function in a majority of patients with decompensated cirrhosis (Childs-Pugh class B and C) [44,45]. As an example, in a trial of sofosbuvir-velpatasvir, among 27 patients with decompensated cirrhosis and a baseline Model for End-Stage Liver Disease (MELD) score ≥15, 81 percent had improvement, 11 percent had no change, and 7 percent had worsening of the MELD score at 12 weeks post-antiviral therapy [46]. In addition, observational studies have reported that 17 to 33 percent of patients on the transplant waiting list could achieve sufficient clinical improvement with successful antiviral treatment to be removed from the list [47-50].
However, while some improvement in MELD score is common with antiviral therapy, many patients have only modest decreases (eg, 1 to 3 MELD points) that do not correspond to substantial clinical improvements. Furthermore, whether improvements in MELD are sustained in the long term is uncertain. In a study of real-world data from patients with cirrhosis and MELD score ≥10 who underwent antiviral therapy, there was almost no change in median MELD scores from pretreatment values compared with follow-up at a median of four years [51]. It is possible that modest decreases in MELD without resolution of clinical symptoms could inadvertently disadvantage the patient in terms of transplant priority, thus delaying transplant (sometimes referred to as "MELD purgatory"). Thus, it may be overall beneficial to defer treatment until after transplant for selected patients.
The clinical features that predict which patients would benefit meaningfully from pretransplant therapy have not been well established. In observational studies, relatively low baseline MELD score (eg, <16), low baseline Child-Pugh score, and the absence of significant complications of portal hypertension including encephalopathy have been associated with meaningful clinical improvement with antiviral therapy [47-50].
Further attempts have been made to identify a specific MELD score under which pretransplant treatment is associated with an overall survival benefit. As an example, in one simulation model based on data from two randomized treatment trials (of ledipasvir-sofosbuvir plus ribavirin in patients with Child-Pugh class B and C cirrhosis) and data on organ allocation and outcomes from the United Network for Organ Sharing (UNOS), pretransplant antiviral therapy was associated with a survival benefit for patients with a MELD score of 23 to 27, depending on the UNOS region [52]. However, this study was limited by the lack of treatment efficacy data among patients with MELD scores >20 and the lack of sufficient data on risk of disease progression following SVR.
●Expected virologic response to therapy – Patients with Child-Pugh class C cirrhosis have lower SVR rates with antiviral therapy than patients with less advanced disease. Furthermore, if such patients are treated prior to transplant and fail therapy, there is a risk of resultant resistance associated mutations that make selection of a post-transplant antiviral regimen more complicated. Thus, for such patients, deferring therapy until after transplant could maximize the likelihood of treatment success.
Among patients with cirrhosis, HCC is also associated with lower SVR rates [51,53,54]; however, antiviral treatment is still successful in the majority of patients with HCC. Thus, in the absence of severe decompensation or short time to transplantation, the likelihood of SVR and its attendant benefits (eg, stabilization of clinical status and prevention of allograft reinfection) are sufficiently high to warrant treatment before transplant in most patients with HCC.
●Access to transplant – As above, if patients have a reduction in MELD score after SVR but symptoms of liver disease do not improve, their access to transplant may be decreased due to the decline in their MELD score ("MELD purgatory"). This potential outcome must be a consideration in deciding when to treat patients who do not have alternative access strategies, such as a living donor or MELD exception points.
Utilization of livers from HCV-viremic donors had traditionally reduced waiting time and improved access to transplant for HCV-viremic patients on the liver transplant waiting list. However, as use of HCV-viremic donors among HCV-negative recipients has become more widespread, deferring treatment to facilitate use of an HCV-viremic donor organ is less likely to impact access to transplant. (See 'Use of grafts from HCV-viremic donors' below.)
●Treatment options – Several HCV treatment regimens are contraindicated for patients with Child-Pugh class B or C cirrhosis, and such patients thus have fewer options to select among. Thus, deferring therapy until after transplant, with the resultant improvement in organ function, will allow for more treatment options. This may be of particular importance in patients with prior treatment failure.
Approach — The decision to treat HCV infection before or after liver transplant should be individualized and take into account the patient's short-term prognosis, the likelihood of a successful and clinically meaningful response to therapy, access to transplant, and comorbidities [55]. (See 'Considerations' above.)
Taking into account all of these factors, we generally suggest pretransplant antiviral therapy for:
●Patients with Child-Pugh A or B cirrhosis and MELD score <20. Such patients are likely to have virologic and clinically meaningful response to antiviral therapy and could potentially achieve long-term, transplant-free survival with antiviral therapy. However, the MELD threshold under which this is most likely to occur is uncertain, so a score of 20 should not be considered an absolute cut-off.
●Patients with access to transplant through living donation or MELD exception points (when the expected waiting time is less than one year). This includes patients with compensated cirrhosis and hepatocellular carcinoma (HCC)-related MELD exception points, who are likely to have improved clinical stability with SVR but are less likely to be disadvantaged by HCV clearance (since they have access to transplant through exception points).
Waiting to treat in the post-transplant setting may be a reasonable option for:
●Patients with advanced disease with severe portal hypertension or high MELD (eg, MELD >27). These patients are unlikely to improve with antiviral therapy to an extent that would preclude the need for transplant, and deferring therapy could maximize access to transplant and the likelihood of treatment response. In addition, transplant should not be delayed in this group to complete HCV therapy.
Our approach is largely consistent with a consensus statement from the International Liver Transplantation Society [56]. Specifically, that statement suggests:
●Pretransplant antiviral therapy for patients with:
•Compensated cirrhosis and HCC
•Decompensated cirrhosis but no HCC when the MELD score is relatively low (eg, <20) and there are no other conditions such as severe portal hypertension that warrant prompt transplantation
•Decompensated cirrhosis and HCC when expected wait time for transplantation is more than three to six months
●Defer antiviral therapy until post-transplant for patients with:
•Advanced decompensated cirrhosis with an anticipated wait time less than three months
•Decompensated cirrhosis and HCC with an anticipated wait time less than three to six months
●An individualized decision for patients with decompensated cirrhosis who do not fit into the groups above
PRETRANSPLANT ANTIVIRAL THERAPY — In general, regimen selection for patients with chronic HCV infection depends on genotype, presence of cirrhosis, degree of hepatic dysfunction, treatment history, and comorbidities. In particular, for patients with decompensated cirrhosis, protease inhibitor-based regimens are contraindicated and should not be used. Although interferon-based regimens are not recommended for any HCV-infected patients when DAA regimens are available, they should especially be avoided in patients with decompensated cirrhosis because of the risk of exacerbated liver disease and death as well as very low rates of response.
Regimen selection by genotype is discussed elsewhere. (See "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 "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)
The concept of using DAA regimens specifically for pretransplant treatment to prevent reinfection of the graft was first illustrated in an open-label study in which 61 patients on the liver transplant waitlist with Child A cirrhosis, biologic MELD score <22, and hepatocellular carcinoma (who were thus listed with standard MELD exception points) were treated with sofosbuvir and weight-based ribavirin for up to 48 weeks prior to transplantation [57]. Of the 46 who underwent liver transplantation, 43 had undetectable viral loads at the time of transplantation, and 70 percent of them maintained a virologic response rate 12 weeks after transplantation. Recurrence (seen in 23 percent) was inversely related to the number of days that HCV RNA was undetectable prior to transplantation. This specific regimen is no longer recommended because of the more potent combinations available.
Subsequent studies have demonstrated efficacy and safety of other DAA combinations in patients with decompensated cirrhosis, including ledipasvir-sofosbuvir [44,58,59], sofosbuvir-velpatasvir [46], and sofosbuvir plus daclatasvir [60], each with or without ribavirin for 12 or 24 weeks. Sustained virologic response (SVR) rates are quite high (83 to 96 percent) among patients with CTP class B cirrhosis but appear to be lower in patients with more advanced Child-Pugh class C disease (56 to 87 percent).
USE OF GRAFTS FROM HCV-VIREMIC DONORS
Outcomes
In HCV-viremic recipients — Given the high success rate of direct-acting antiviral (DAA) therapy and lack of sufficient liver allograft supply, use of livers from hepatitis C virus (HCV)-viremic donors for HCV-viremic recipients with subsequent DAA therapy is common. As an example, in the United States, the proportion of HCV-seropositive recipients who received a liver from a donor with chronic HCV infection increased from 7 to 17 percent between 2010 and 2015 [61].
Use of livers from HCV-viremic donors had previously decreased wait time for HCV-viremic recipients, but since such organs are now more commonly allocated for recipients without HCV infection as well, the wait-time advantage has decreased. Nevertheless, livers from HCV-viremic donors could be of relatively high quality, as they are often of relatively young age; the average age of HCV-viremic donors declined from 47 to 35 years between 2012 and 2016, coincident with a rise in deceased donor organs available due to overdose-related death [62].
Even prior to the widespread availability of DAAs, there did not appear to be a survival difference among HCV-viremic recipients who received a liver from an HCV-viremic versus nonviremic donor, although age and fibrosis stage of the donor were important considerations [63-67]. In one multicenter retrospective study with detailed biopsy data, overall survival was similar between patients who received livers from donors with or without HCV infection, but the risk of advanced fibrosis was significantly higher with grafts from HCV-viremic donors, especially from a donor older than 65 years [65]. When DAA therapy is given in the early post-transplant period, development of recurrent fibrosis is not a significant concern.
In recipients without HCV infection — Historically, organs from HCV-viremic donors were only used for recipients without HCV infection in urgent situations [56]. However, with the advent of highly effective DAA therapy, including pangenotypic regimens and effective salvage regimens for those who fail initial therapy, the use of livers from HCV-viremic donors for recipients without HCV infection followed by prompt DAA therapy has become more common [68,69]. In the United States, the number of such transplants increased 35-fold, from 8 in 2016 to 280 in 2019 [70].
Increasing evidence suggests that using organs from HCV-viremic donors is an overall effective and safe strategy in select HCV-negative recipients [67]. However, published cohorts describing this strategy for liver transplantation, specifically, have been relatively small:
●In one report of 10 HCV-negative recipients of livers from HCV-viremic donors, 100 percent achieved sustained virologic response (SVR) post-transplant with 12 to 24 weeks of therapy, with a median time from transplant to treatment of 43 days [71]. With a median 380 days of follow-up, there were no cases of graft loss.
●In another series of 9 HCV-negative recipients of livers from HCV-viremic donors, all patients achieved SVR with 12 weeks of glecaprevir-pibrentasvir, which was initiated within five days of transplant [72]. There were no deaths after a median of 46 weeks of follow-up.
●In another trial of HCV-negative recipients of livers (n = 13) or kidneys (n = 11), all achieved SVR with 12 weeks of sofosbuvir-velpatasvir, which was initiated once viremia was confirmed and the patient was clinically stable, a median of seven days after liver transplant [73].
In addition, in a retrospective study of deceased donor liver transplantations in the United States from 2008 to 2018, the two-year graft survival rates among HCV-negative recipients were similar whether they received a liver from an HCV-viremic donor (n = 87) or an HCV-nonviremic donor (n = 11,270, 86 versus 88 percent) [67]. One modeling study suggested that accepting any liver for transplantation (from either an HCV-viremic or nonviremic donor) rather than only those from nonviremic donors was associated with increased life expectancy among HCV-negative recipients with a Model for End-Stage Liver Disease (MELD) score ≥20 [52].
The feasibility of this approach has also been demonstrated among kidney transplant recipients. (See "Kidney transplantation in adults: Hepatitis C virus infection in kidney donors", section on 'Approach to the use of kidneys from donors with HCV infection'.)
Treatment approach for recipients of HCV-viremic donors — The risks and uncertainties of using livers from HCV-viremic donors followed by antiviral therapy should be discussed in detail with potential recipients, and adequate access to DAA therapy following transplantation should be ensured [74-76]. The optimal approach to timing of antiviral treatment and regimen selection for recipients of livers from HCV-viremic donors is uncertain.
●Regimen selection – In general, we agree with joint guidelines from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) that recommend pangenotypic regimens (glecaprevir-pibrentasvir or sofosbuvir-velpatasvir) as first-line treatment [69]. In contrast with other organs from HCV-viremic donors, short durations of HCV therapy should not be used in recipients of livers from HCV-viremic donors because of the large reservoir of HCV in the transplanted organ. The specific regimens are discussed below. (See 'Post-transplant regimen selection' below.)
●Timing of treatment – We also agree with guidelines that suggest early treatment, defined as starting within the first month after transplant, and preferably within the first week, once the patient is clinically stable [77]. Randomized trials have not been performed to support a particular timeline. However, in most published reports of using livers from HCV-viremic donors, antiviral treatment is generally initiated once the recipient has confirmed viremia following transplant and has achieved clinical stability; in some cases, these criteria were met within a week of transplantation [71-73]. Early treatment is favored because of the potential risk of severe complications, such as fibrosing cholestatic HCV, a severe form of recurrent HCV. (See 'Progression of liver disease post-transplant' above.)
The limited evidence supporting this approach is discussed elsewhere (see 'In recipients without HCV infection' above). The risk of immunologic complications (eg, rejection) in recipients of livers from HCV-viremic donors treated with DAA therapy requires further study [69,73].
EVALUATION OF HCV INFECTION POST-TRANSPLANT
Assessment of HCV recurrence — Hepatitis C virus (HCV) reinfection of the graft is detected by testing for HCV RNA. While there is no clear recommendation in terms of timing of this testing, we recommend testing viral load and confirming the HCV genotype when the patient is stable enough post-transplant to consider initiating antiviral therapy. (See 'Timing' below.)
Staging of recurrent disease — Stage of liver disease (ie, presence or absence of significant fibrosis or cirrhosis) may inform antiviral regimen selection (see 'Post-transplant regimen selection' below) and other management considerations. For routine assessment of post-treatment fibrosis stage, noninvasive measures of fibrosis are adequate, as in the non-transplant setting. We use transient elastography, since serum markers of fibrosis have not been well studied or validated in the post-transplant setting.
Elastography, whether done as vibration-controlled transient elastography (VCTE; eg, Fibroscan), ultrasound-based shear wave, or magnetic resonance elastography, all appear to be relatively accurate measure of fibrosis stage in transplant patients. For example, in a systematic review that pooled five studies of patients with recurrent HCV infection post-transplant, the sensitivity and specificity of ultrasound-based elastography for significant fibrosis were both 83 percent and for cirrhosis were 98 and 84 percent, respectively [78]. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)
Serum markers have also been evaluated in the transplant population, although do not appear to be as accurate as ultrasound-based elastography [79,80]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)
Prior to the availability of effective post-transplant treatment, many centers performed routine liver biopsies to risk stratify patients for treatment. This practice is now uncommon, and liver biopsy is generally reserved for patients with evidence of liver injury (eg, aminotransferase elevation) in whom other causes, including acute T cell-mediated (cellular) rejection (TCMR), are a concern. After the early post-transplant period (ie, three to six months), however, rejection is uncommon, and antiviral treatment for HCV infection may be undertaken empirically in the setting of abnormal liver biochemical tests instead of pursuing biopsy, since the likelihood that HCV is the cause is extremely high. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)
Biopsy findings related to HCV infection 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 TCMR. Particular features supportive of recurrent HCV are lobular activity, interface hepatitis, piecemeal necrosis, and lymphocyte predominance or lymphoid follicles. Features that are more suggestive of rejection include a mixed cellular infiltrate (eosinophils, polymorphonuclear cells, and lymphocytes) confined to the portal triad, bile duct damage, and endotheliitis. Nevertheless, differentiating rejection in the setting of HCV infection from HCV infection alone can be difficult on pathologic grounds.
POST-TRANSPLANT ANTIVIRAL THERAPY
Benefits — All liver transplant recipients with HCV viremia should be treated.
Patients who achieve sustained virologic response (SVR) with treatment post-transplant have lower rates of liver fibrosis progression and lower mortality rates compared to those who fail therapy [81,82]. Accordingly, the short-term post-transplant survival for HCV-associated liver disease has increased with increased use of highly effective direct-acting antiviral (DAA) therapy [83,84]. As an example, in a report of the United Network for Organ Sharing (UNOS) database, one-year post-transplant survival rates from the "DAA era" (transplanted in 2014 and 2015) were higher than from the "pre-DAA era" (transplanted in 2011 and 2012) (91.9 versus 89.8 percent) [83]. In addition, in a multivariable analysis, transplantation during the DAA era was associated with a 34 percent reduction in one-year post-liver transplant patient mortality, and post-transplant survival was similar or better among patients transplanted for HCV-associated liver disease compared with other indications.
The general benefits of SVR are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Rationale for treatment'.)
Although studies evaluating the impact of interferon-based therapy had failed to show differences in outcomes with early antiviral therapy post-transplant compared with no treatment or treatment only after the development of significant fibrosis [85,86], this is likely related to the low rates of SVR achieved with such regimens.
Timing — The optimal timing of post-transplant treatment is uncertain, and the decision must be made on an individual basis. Our approach is to treat patients as soon as possible once they are clinically stable following transplant. In particular, we prioritize treatment within the first month to prevent the risks of complications including fibrosing cholestatic HCV. (See 'Progression of liver disease post-transplant' above.)
Post-transplant regimen selection — Antiviral therapy should be administered at centers with experience in managing post-transplantation patients. DAA combination options for liver transplant recipients are more limited than in the general population due to drug-drug interactions (see 'Interactions with immunosuppressive agents' below), and fewer regimens have been formally studied in post-transplant patients. Details on the optimal regimen choice and durations are also evolving, as data informing these remain relatively limited.
As in the non-transplant setting, regimen options depend on the HCV genotype, the presence of cirrhosis, drug-drug interactions, and comorbidities. Overall, our suggestions are generally consistent with recommendations in the joint guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD/IDSA) [77]. Selection among the options for each patient population should also be informed by the potential for drug interactions, in particular with immunosuppressant medications. (See 'Patients without decompensated cirrhosis' below and 'Patients with decompensated cirrhosis' below.)
The doses for the individual DAA agents used post-transplant do not differ from those in the non-transplant setting and are discussed elsewhere (see "Direct-acting antivirals for the treatment of hepatitis C virus infection"). When ribavirin is used, the doses will be specified for the particular regimen (either low dose starting at 600 mg daily and increasing as tolerated or weight-based dosing at 1000 mg daily for patients <75 kg or 1200 mg daily for patients ≥75 kg). The dosing of ribavirin should also take into account the patient's creatinine clearance and hemoglobin level.
Peginterferon-based regimens are not recommended because of the toxicity, the overall poor response rates (in the absence of a DAA), and the risk of rejection.
Patients without decompensated cirrhosis — For HCV-infected liver transplant recipients who do not have cirrhosis or have compensated cirrhosis, we suggest:
●Glecaprevir-pibrentasvir for 12 weeks
●Sofosbuvir-velpatasvir for 12 weeks
These are preferred options for any genotype. For patients with genotype 1, 4, 5, or 6 infection, ledipasvir-sofosbuvir plus weight-based ribavirin (1000 mg daily for patients <75 kg or 1200 mg daily for patients ≥75 kg) for 12 weeks is an alternative option.
These regimens have well-documented safety and efficacy in the post-transplant population.
For patients without cirrhosis:
●Glecaprevir-pibrentasvir: In an open-label trial of 100 transplant recipients (80 were liver) with HCV infection of all genotypes and without cirrhosis, glecaprevir-pibrentasvir resulted in an SVR rate of 98 percent [87]. High SVR rates were observed in both treatment-naïve and interferon-experienced patients. The regimen was well tolerated; there was one mild liver transplant rejection, which was thought unrelated to antiviral therapy.
●Sofosbuvir-velpatasvir: In an open-label trial that included 65 liver transplant recipients with genotypes 1 through 4 infection and without cirrhosis, sofosbuvir-velpatasvir resulted in an SVR rate of 97 percent [88]. No patients experienced acute rejection, and the few serious adverse events were deemed unrelated to therapy.
●Ledipasvir-sofosbuvir plus ribavirin: In two large trials (SOLAR-1 and SOLAR-2, which respectively included 111 and 101 genotype 1- or 4-infected patients without cirrhosis), ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks resulted in SVR rates in 96 and 93 percent [44,58]. The regimen was well tolerated. Large observational studies have also supported the high efficacy and safety of ledipasvir-sofosbuvir in the liver transplant population; in these studies, ribavirin was not associated with a higher SVR rate, but it is unknown if unmeasured confounders impact the comparison [89-91]. Graft rejection was rare in these studies. Efficacy in genotypes 5 and 6 is extrapolated from studies in the non-transplant population. This regimen is not used for genotype 2 or 3.
One large observational study has suggested that ribavirin is not necessary in this population. Among approximately 500 post-transplant patients who were treated with sofosbuvir plus an NS5A inhibitor (ledipasvir or daclatasvir) with or without ribavirin for 12 to 24 weeks, SVR rates were 95 to 98 percent among the approximately 400 who did not receive ribavirin and were not different with the addition of ribavirin [92]. Nevertheless, pending further data, we continue to use ribavirin, if tolerated, with sofosbuvir-ledipasvir and sofosbuvir plus daclatasvir, since this is how the regimens were evaluated in the above prospective trials.
For patients with compensated cirrhosis:
●Sofosbuvir-velpatasvir: In an open-label trial that included 14 liver transplant recipients with genotypes 1 through 4 infection and cirrhosis, sofosbuvir-velpatasvir resulted in an SVR rate of 93 percent [88]. No patients experienced acute rejection, and the few serious adverse events were deemed unrelated to therapy.
●Ledipasvir-sofosbuvir plus ribavirin: In two large trials (SOLAR-1 and SOLAR-2, which respectively included 51 and 58 genotype 1- or 4-infected patients with compensated cirrhosis [Child-Pugh class A]), ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks resulted in SVR rates in 96 and 100 percent [44,58]. The regimen was well tolerated. As in patients without cirrhosis, large observational studies have also supported the high efficacy and safety of ledipasvir-sofosbuvir in the liver transplant population [89,90]. Graft rejection was rare in these studies. Efficacy in genotypes 5 and 6 is extrapolated from studies in the non-transplant population. This regimen is not used for genotypes 2 or 3.
One large observational study suggested that ribavirin was not associated with improved SVR rates when added to sofosbuvir plus an NS5A inhibitor (ledipasvir or daclatasvir), but the majority of patients in that study did not have cirrhosis [92]. We continue to use ribavirin, if tolerated, with sofosbuvir-ledipasvir and sofosbuvir plus daclatasvir, since this is how the regimens were evaluated in the above prospective trials, but not with sofosbuvir-velpatasvir (or glecaprevir-pibrentasvir).
Patients with decompensated cirrhosis — Antiviral treatment of post-transplant patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage; Child-Pugh class B or C) should only be undertaken by or in close consultation with an expert in the management of such patients. The main options for treatment-naïve patients include sofosbuvir-velpatasvir plus low-dose ribavirin (600 mg daily with increase to 1000 mg as tolerated) for 12 weeks or, for patients with genotypes 1, 4, 5, and 6 infection, ledipasvir-sofosbuvir plus low-dose ribavirin (600 mg daily with increase to 1000 mg as tolerated) for 12 weeks.
Several antiviral regimens that contain a protease inhibitor are contraindicated in patients with Child-Pugh classes B and C cirrhosis. These include glecaprevir-pibrentasvir, elbasvir-grazoprevir, and sofosbuvir-velpatasvir-voxilaprevir.
Interactions with immunosuppressive agents — The immunosuppressive regimen that an individual patient is on may limit the selection of the antiviral agent or need to be modified.
In general, DAA regimens that contain a protease inhibitor have the potential to increase drug levels of calcineurin inhibitors (cyclosporine and, to a lesser extent, tacrolimus) and inhibitors of mammalian target of rapamycin (mTOR; sirolimus and everolimus); some combinations are not recommended, whereas other combinations warrant close monitoring of immunosuppressive drug levels. Specific potential drug interactions are listed in the table (table 1). Drug interactions can also be checked through the Lexicomp drug interactions program included with UpToDate.
INVESTIGATIONAL THERAPIES — Preliminary evidence suggests that antiviral treatment initiated around the time of transplantation can 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 [93]. 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.
Unlike hepatitis B virus, no effective immunoglobulin prophylaxis agents are approved to prevent reinfection of the graft at the time of transplantation. Further, such strategies are not needed given the high success with direct-acting antivirals for HCV with a finite duration of therapy.
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.
Historically, the prognosis for such patients has been poor (similar to retransplantation for other indications) [94-102]. This was illustrated in a multicenter study that compared survival following retransplantation in patients with recurrent HCV with survival following retransplantation for other disorders [103]. 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.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C infection in solid organ transplant candidates and recipients" and "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Impact of DAA therapy – Hepatitis C virus (HCV)-associated cirrhosis has been a common indication for liver transplantation, but the introduction of well-tolerated, highly effective direct-acting antiviral (DAA) therapy for HCV is reducing the need for liver transplantation in such patients and has revolutionized the approach to management of transplant candidates and recipients. Successful antiviral treatment of liver transplant recipients with HCV infection reduces progression of liver fibrosis and mortality post-transplant. (See 'Introduction' above and 'Post-transplant clinical course' above and 'Benefits' above.)
●Deciding to treat before or after transplant – If not treated pretransplant, HCV reinfection of the transplanted liver is near universal and can be a major cause of graft failure without effective antiviral treatment post-transplant. However, pretransplant antiviral therapy is not the optimal treatment strategy for certain patients, and the decision to treat before or after transplant should be individualized, taking into account the short-term prognosis, the likelihood of meaningful response to therapy, access to transplant, and other comorbidities. (See 'Considerations' above.)
In general, we suggest pretransplant antiviral therapy for patients with Child-Pugh score A or B and Model for End-Stage Liver Disease (MELD) score <20 or access to transplant through living donation or MELD exception points (when the expected waiting time is less than one year) (Grade 2C). We suggest deferring antiviral therapy until after transplantation for those with severe portal hypertension or high MELD (eg, MELD >27) or with decompensated cirrhosis and severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) (Grade 2C). Data informing the optimal approach are limited. (See 'Approach' above.)
●Regimen selection for pretransplant antiviral treatment – Pretransplant regimen selection depends on genotype, presence of cirrhosis, degree of hepatic dysfunction, treatment history, and comorbidities. In particular, for patients with decompensated cirrhosis, protease inhibitor-based regimens are contraindicated. Regimen selection by genotype is discussed elsewhere. (See "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 "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)
●Use of livers from HCV-viremic donors – With the advent of highly effective antiviral therapy, including pangenotypic regimens and effective salvage regimens for those who fail initial therapy, allocating livers from HCV-viremic donors for HCV-negative recipients, in addition to HCV-viremic recipients, with subsequent DAA therapy has become more common. Limited evidence from small cohorts suggest this is a safe and effective strategy. (See 'Use of grafts from HCV-viremic donors' above.)
●Post-transplant evaluation for HCV – The diagnosis of recurrent HCV infection is based upon the detection of HCV RNA. We also perform genotype testing. Among patients with prolonged post-transplant viremia, we use transient elastography to assess fibrosis stage. (See 'Evaluation of HCV infection post-transplant' above.)
●Post-transplant antiviral treatment – We recommend that all liver transplant recipients with HCV viremia undergo antiviral therapy (Grade 1B). Antiviral therapy should be administered at centers with experience in managing post-transplantation patients. We aim to initiate antiviral therapy as soon as possible once the patient is clinically stable following transplant, ideally within the first month.
There are fewer data on the use of combination DAA regimens in liver transplant recipients than in the general population. Regimen selection depends on genotype and presence of decompensated cirrhosis. (See 'Post-transplant regimen selection' above.)
•For patients without cirrhosis or with compensated cirrhosis, we suggest glecaprevir-pibrentasvir for 12 weeks or sofosbuvir-velpatasvir for 12 weeks (Grade 2C). For patients with genotype 1, 4, 5, or 6 infection, ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks is an alternative option.
•Antiviral treatment of post-transplant patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage; Child-Pugh class B or C) should only be undertaken by or in close consultation with an expert in the management of such patients. Regimens containing protease inhibitors (eg, glecaprevir-pibrentasvir) should not be used in decompensated cirrhosis.
•The immunosuppressive regimen that an individual patient is on may limit the selection of the antiviral agent or need to be modified during antiviral therapy (table 1).
