Hepatitis C virus infection in liver transplant candidates and recipients

INTRODUCTION — 

Hepatitis C virus (HCV) infection is a common cause of chronic liver disease in the United States. While HCV-associated cirrhosis was historically 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 significantly 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. However, with the availability of DAA therapy that results in high cure rates among both transplant candidates and recipients, contemporary outcomes for liver transplant in this setting are excellent.

The major issues related to HCV infection in liver transplant candidates and recipients will be reviewed here. Similar issues 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 "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults" and "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

TIMING OF ANTIVIRAL THERAPY (BEFORE OR AFTER TRANSPLANT) — 

An important consideration in the management of transplant candidates with HCV viremia is determining the optimal timing of therapy relative to transplantation. Antiviral therapy in liver transplant candidates, particularly those who have decompensated cirrhosis, should be administered at centers with appropriate expertise.

Considerations — 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 (Child-Pugh class B and C) [4,5]. 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 [6]. 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 [7-10].

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 [11]. 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 [7-10].

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 [12]. 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 [11,13,14]; 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. It would also avoid the need for ribavirin or a 24-week course of therapy, which are regimen adjustments recommended for patients with decompensated cirrhosis.

Approach — The decision to treat HCV infection before or after liver transplant should 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 [15]. (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).

We individualize the decision to treat before or after transplant for other patients. In particular, patients who have advanced disease with severe portal hypertension or high MELD (eg, MELD >27) are unlikely to improve clinically with antiviral therapy to an extent that would preclude the need for transplant. In some such cases, deferring therapy could maximize access to transplant and the likelihood of treatment response and thus may be an attractive option. Furthermore, 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 [16].

PRETRANSPLANT ANTIVIRAL THERAPY — 

In general, regimen selection for patients with chronic HCV infection depends on presence of cirrhosis, genotype, 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.

Liver transplant candidates often have decompensated cirrhosis. Regimen selection in the setting of decompensated cirrhosis and data to support their use are discussed elsewhere:

●Initial therapy – (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Decompensated cirrhosis (Child-Pugh class B or C)'.)

●Retreatment after relapse – (See "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults", section on 'Patients with decompensated cirrhosis'.)

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 [17].

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 [18].

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 [19-23]. 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 [21]. 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 [16]. 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 [24,25]. In the United States, the number of such transplants increased 35-fold, from 8 in 2016 to 280 in 2019 [26].

Increasing evidence suggests that using organs from HCV-viremic donors is an overall effective and safe strategy in selected HCV-negative recipients [23]. 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 [27]. 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 [28]. 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 [29].

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) [23]. 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 [12].

The feasibility of this approach has also been demonstrated among recipients of other organ transplants (eg, kidney, heart, lung). (See "Hepatitis C virus infection in kidney donors", section on 'Use of kidneys from donors with HCV infection' and "Infection in the solid organ transplant recipient", section on 'HIV, HTLV, and hepatitis viruses'.)

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 [30-32]. 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 [25]. 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; selection depends on liver and kidney function as well as potential drug-drug interactions. (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 [33]. 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 [27-29]. Early treatment is favored because of the potential risk of severe complications, such as fibrosing cholestatic HCV, a severe form of recurrent HCV. (See 'Post-transplant clinical course without treatment' below.)

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 [25,29].

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, this technique appears to be relatively accurate measure of fibrosis stage in liver transplant recipients. 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 [34]. (See "Noninvasive assessment of hepatic fibrosis: Ultrasound-based elastography".)

●Limitations of serum markers – Serum markers have also been evaluated in the transplant population, although they do not appear to be as accurate as ultrasound-based elastography [35,36]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

●Limited role for routine biopsy – 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 cellular rejection. 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.

●Limited role for routine staging following HCV cure – Following successful antiviral therapy, routine fibrosis staging is no longer needed. Liver biopsy or non-invasive fibrosis assessment is generally reserved for evaluation of abnormal liver enzymes or other potential concerns (eg, rejection or steatosis).

POST-TRANSPLANT ANTIVIRAL THERAPY

Benefits — All liver transplant recipients with HCV viremia should be treated as soon as clinically feasible to prevent graft damage.

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 [37,38]. 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 [39,40]. 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) [39]. 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 'Benefits of 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 [41,42], this is likely related to the low rates of SVR achieved with such regimens.

Timing — While the optimal timing of post-transplant treatment has not been definitively determined in clinical trials, we 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 'Post-transplant clinical course without treatment' below.)

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.

As in the non-transplant setting, regimen options depend on the HCV genotype, the presence of decompensated 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) [33].

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 — Regimen selection depends, in part, on the treatment history:

●Initial therapy – For HCV-infected liver transplant recipients who do not have decompensated cirrhosis and have not previously been treated with a DAA regimen for the HCV infection, we suggest:

•Glecaprevir-pibrentasvir for 12 weeks – 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 [43]. 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 for 12 weeks – In an open-label trial of liver transplant recipients with genotypes 1 through 4 infection, sofosbuvir-velpatasvir resulted in an SVR rate of 97 percent among the 65 patients without cirrhosis and 93 percent in the 14 patients with compensated cirrhosis [44]. No patients experienced acute rejection, and the few serious adverse events were deemed unrelated to therapy.

These are preferred options for any genotype. They have well-documented safety and efficacy in the post-transplant population.

For patients with genotype 1, 4, 5, or 6 infection, ledipasvir-sofosbuvir for 12 weeks is an alternative option. The addition of weight-based ribavirin (1000 mg daily for patients <75 kg or 1200 mg daily for patients ≥75 kg), if tolerated, is reasonable for patients with compensated cirrhosis. In two large trials (SOLAR-1 and SOLAR-2, which collectively included 212 patients without cirrhosis and 109 patients with compensated cirrhosis [Child-Pugh class A], all with genotype 1 or 4 infection), ledipasvir-sofosbuvir plus weight-based ribavirin for 12 weeks resulted in SVR rates of 93 to 96 percent in those without cirrhosis and 96 to 100 percent in those with cirrhosis [4,45]. The regimen was well tolerated with rare graft rejection. Large observational studies have also supported the high efficacy and safety of ledipasvir-sofosbuvir in the liver transplant population, and some have suggested that ribavirin is not necessary for optimal efficacy [46-49]. 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 patients who did not receive ribavirin and were not different with the addition of ribavirin [49]. However, the majority of the patients in that study did not have cirrhosis. 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.

●Retreatment after relapse following prior DAA therapy – For HCV-infected liver transplant recipients who do not have decompensated cirrhosis but have relapsed HCV infection after DAA therapy, we suggest:

•Sofosbuvir-velpatasvir-voxilaprevir for 12 weeks (for any genotype) – There are limited data on the treatment of liver transplant recipients with HCV and relapse after prior DAA therapy. This includes a case series of six patients who all achieved SVR with sofosbuvir-velpatasvir-voxilaprevir for 12 weeks [50]. Small reductions in calcineurin inhibitor dosing were required.

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 to 24 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 to 24 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. Specific potential drug interactions are listed in the table (table 1). Drug interactions can also be checked through the drug interactions program included with UpToDate.

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 mechanistic target of rapamycin (mTOR; sirolimus and everolimus); some combinations are not recommended, whereas other combinations warrant close monitoring of immunosuppressive drug levels. (See "Liver transplantation in adults: Initial and maintenance immunosuppression".)

Additionally, HCV cure has been associated with improved liver function and metabolism, which reduces levels of calcineurin inhibitors.

POST-TRANSPLANT CLINICAL COURSE WITHOUT TREATMENT — 

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. Sustained virologic response (an effective cure of HCV) either before or after transplant should be achievable in virtually all patients, and significant HCV-related progression of liver disease post-transplant should be extremely rare. With the widespread use of DAA therapy, post-transplant outcomes are similar to those in recipients without HCV infection. The impact of effective antiviral therapy with DAA regimens is discussed elsewhere. (See 'Benefits' above.)

Without effective treatment, chronic HCV infection is associated with worse prognosis in liver transplant recipients:

●Graft reinfection post-transplant – For patients with HCV viremia at the time of transplant, recurrence of HCV infection following liver transplantation is universal [51,52]. 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 [53]. Once the graft has been infected, serum HCV RNA levels increase from 4- to 100-fold following liver transplantation [54]. Peripheral monocytes may also harbor virus and act as a source for reinfection of the donor liver [55].

●Progression of liver disease post-transplant – Without successful antiviral therapy, the clinical course of HCV-associated liver disease following liver transplantation is variable, as in the pretransplant setting, although 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 [52,56-63].

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 [64-72].

●Risk factors for progressive disease – Historically, the variables that influence the progression of untreated HCV-associated liver disease following liver transplantation 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 [54,56-59,73-81]. In particular, the donor characteristic that most strongly predicts outcome in HCV-viremic liver transplant recipients is donor age [81-87].

●Overall post-transplant prognosis – Prior to the availability of DAAs, the five-year survival after transplantation for HCV-associated liver disease was approximately 60 to 80 percent, which was lower in HCV-viremic recipients compared with recipients without HCV infection [87,88]. Recurrent HCV-related graft failure was the leading cause of death in these patients [59].

RETRANSPLANTATION — 

Historically, disease recurrence could lead to graft failure and the need for retransplantation. In contemporary patient populations with effective antiviral therapy, this is extremely rare in the absence of another comorbid liver disease. Indications and contraindications for retransplantation remain patient- and center-specific.

Prior to widespread antiviral therapy, the prognosis for such patients was poor (similar to retransplantation for other indications) [89-97]. This was illustrated in a multicenter study that compared survival following retransplantation in patients with recurrent HCV with survival following retransplantation for other disorders [98]. 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 effective antiviral therapy, the safety and efficacy of retransplantation are likely much better, and the need for retransplantation will continue to decrease.

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: Hepatitis C virus infection" 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 without treatment' above and 'Benefits' above.)

●Timing of HCV treatment in relation to transplant – If not treated pretransplant, HCV reinfection of the transplanted liver is universal. However, pretransplant antiviral therapy may not be 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 clinical response to therapy, access to transplant, and other comorbidities. (See 'Considerations' above.)

In general, we suggest pretransplant antiviral therapy (Grade 2C). This is particularly the case for patients who have Child-Pugh score A or B and Model for End-Stage Liver Disease (MELD) score <20 or have access to transplant through living donation or MELD exception points (when the expected waiting time is less than one year). For those with severe portal hypertension and/or high MELD (eg, MELD >27), in whom pre-transplant response rates may be low and transplant is imminent, deferring antiviral therapy until after transplantation is a reasonable alternative. 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 and treatment history. In particular, for patients with decompensated cirrhosis, protease inhibitor-based regimens are contraindicated. Regimen selection by genotype is discussed elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults" and "Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse 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 antiviral treatment – We recommend that all liver transplant recipients with HCV viremia undergo antiviral therapy (Grade 1B). We aim to initiate antiviral therapy as soon as possible once the patient is clinically stable following transplant, within the first month at the latest.

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, presence of decompensated cirrhosis, and treatment history. (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 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, sofosbuvir-velpatasvir-voxilaprevir) 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).