Secondary Logo

Journal Logo

International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Recipients

Terrault, Norah A. MD, MPH1; Berenguer, Marina MD2; Strasser, Simone I. MBBS, MD3; Gadano, Adrian MD4; Lilly, Les MD5; Samuel, Didier MD6; Kwo, Paul Y. MD7; Agarwal, Kosh MD8; Curry, Michael P. MD9; Fagiuoli, Stefano MD10; Fung, James Y. Y. MD11; Gane, Edward MD12; Brown, Kimberly A. MD13; Burra, Patrizia MD14; Charlton, Michael MD15; Pessoa, Mario G. MD16; McCaughan, Geoff W. MD, PhD17

doi: 10.1097/TP.0000000000001704
Reviews
Free
SDC
Social Media Collection

The ILTS has convened an expert panel to review the approach to management of Hepatitis C Virus in the transplant recipient in the era of direct acting anti-virals. Considerations range from preemption of recurrence to the treatment of fibrosing cholestatic hepatitis. Supplemental digital content is available in the text.

1 Hepatology and Transplant Surgery, University of California San Francisco, San Francisco, CA.

2 Liver Unit, Hospital Universitario y Politécnico La Fe, Universidad Valencia and CIBEREHD, Valencia, Spain.

3 Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

4 Liver Unit, Hospital Italiano, Buenos Aires, Argentina.

5 Multiorgan Transplant, University Health Network/Toronto General Hospital, Toronto Hospital, Toronto, Ontario, Canada.

6 Hepatology, AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Univ Paris-Sud, Université Paris-Saclay, Villejuif, France.

7 Department of Medicine, Stanford University, Palo Alto, CA.

8 Institute of Liver Studies, Kings College Hospital, London, United Kingdom.

9 Liver Center, Beth Israel Deaconess Medical Center, Boston, MA.

10 Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Begamo, Italy.

11 The Liver Transplant Center, Queen Mary Hospital, Hong Kong.

12 New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.

13 Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, MI.

14 Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy.

15 Utah Intermountain Transplant and Regenerative Medicine Center, Salt Lake City, UT.

16 Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, São Paulo, Brazil.

17 Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.

Received 16 December 2016. Revision received 8 February 2017.

Accepted 16 February 2017.

NT: Consulting/Advisory board for Merck, Gilead. KA: advisory Boards: Abbvie, Achillion, BMS, Gilead, Intercept, Merck, Novartis. EG: Speakers bureau or advisory board for AbbVie, Alios Pharmaceuticals, Gilead Sciences, Janssen, Merck, Novartis, Novira. KB: Consulting: Gilead, Abbvie, Merck, BMS, Bayer. MB: Advisory boards: Gilead, Abbvie, MSD, BMS. MPC: Consulting: Gilead, BMS, Abbvie, Trio Health Analytics. MGP: Advisory Board/Speaker: Abbvie, Alexion, BMS, Gilead, MSD. DS: Consultancy for Astellas, BMS, Gilead, LFB, MSD, Novartis, Roche, Biotest, Abbvie, Intercept. SF: speaker’s bureau for Gilead Sciences, MSD, Abbvie, Bristol –Myers Squibb, Novartis. SIS: Advisory boards/speaker fees: Gilead Sciences, AbbVie, MSD, Bristol-Myers Squibb. AG: Advisory boards/speaker fees: Gilead Sciences, AbbVie, MSD, Bristol-Myers Squibb, Novartis. PYK: Advisory Committees or Review Panels: Abbvie, Abbott, BMS, Gilead, Janssen, Merck; Grant/Research Support: Abbvie, BMS, Gilead, Janssen, Merck. PB: Gilead, Novartis, Astellas, Teva, Sandoz, Kedrion, Biotest, Grifols. MC: Gilead, Merck, Janssen, Bristol Myers, Novartis, AbbVie

NT. participated in the conception, study design, acquisition interpretation of results, drafting original and revision of article. M.B. participated in conception, study design, acquisition interpretation of results, drafting editing of article. M.P.C. participated in study design, acquisition interpretation of results, drafting editing of the article. E.G. participated in the study design, acquisition interpretation of results, drafting editing of the article. S.F. participated in the study design, acquisition interpretation of results, drafting editing of article. J.F. participated in the study design, acquisition interpretation of results, drafting editing of article. K.A. participated in the study design, acquisition interpretation of results, editing of the article. L.L. participated in the study design, acquisition interpretation of results, editing of article. S.I.S. participated in the study design, acquisition interpretation of results, editing of the article. K.B. participated in the study design, interpretation of results, editing of article. A.G. participated in the study design, acquisition interpretation of results, editing of article. P.K. participated in the study design, acquisition interpretation of results, editing of article. P.B. participated in the study design, interpretation of results, editing of article. D.S. participated in study design, acquisition interpretation of results, drafting the editing of article. M.G.P. participated in the conception, study design, acquisition interpretation of results, drafting editing of article. G.W.M.C. participated in the conception, study design, acquisition interpretation of results, drafting editing of article.

Correspondence: Norah Terrault, MD, Hepatology and Transplant Surgery, University of California San Francisco, San Francisco, CA. (Norah.Terrault@ucsf.edu).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

The International Liver Transplantation Society convened a working group to develop a new guideline focused on use of direct-acting antiviral (DAA) therapy in the liver transplant (LT) setting. Eight predetermined Patient Intervention Comparison Outcome questions were developed to address the key management issues facing transplant physicians (Table S1, SDC,http://links.lww.com/TP/B417). These questions were addressed via a critical review of the literature and working group consensus. The guidelines are presented using the Grading of Recommendations Assessment Development and Evaluation approach.1 This method includes consideration of the quality of evidence, benefits and harms, values and preferences, resource use and cost-effectiveness. Quality of the evidence was rated as very low, low, moderate, or high. The strength of the recommendation was rated as strong or conditional (weak) and reflects confidence that adherence to guidance will result in more good than harm.

The consensus findings and recommendations on treatment of hepatitis C virus (HCV) in the posttransplant setting are presented here. The reader is referred to the ILTS Consensus Statement on HCV management in Liver Transplant Candidates for the findings and recommendations on treatment of HCV in the pre-LT setting.2 This updated guidance is intended primarily for healthcare professionals caring for patients on the waiting list or post-LT. Additionally, this guidance should assist policy makers in optimizing the care of LT candidates and recipients.

Back to Top | Article Outline

I. MANAGEMENT OF HCV IN THE POST LIVER-TRANSPLANT RECIPIENT WITH RECURRENT HEPATITIS C WITHOUT CIRRHOSIS

Background

Historically, HCV recurrence was a major management challenge and the most frequent cause of recurrent cirrhosis and graft loss. Recurrent hepatitis C infection after LT is universal in patients who are viremic at the time of transplant, and associated with an accelerated disease course.3 Untreated, HCV leads to recurrent cirrhosis within a decade, on average, and the overall graft survival of HCV-positive LT recipients is 30% lower than non-HCV LT recipients.4 Recurrent HCV disease is a major cause of graft dysfunction, graft loss and patient death. Prior studies with peg-IFN-based therapy were poorly tolerated with significant cytopenias and other adverse events and achieved only modest sustained virologic response (SVR) rates.5 However, among those that achieve SVR, graft survival is significantly improved.6,7 Thus, the availability of safe and effect DAAs to achieve viral clearance in a high proportion of patients is predicted to positively impact long-term graft and patient outcomes. With HCV eliminated post-LT, this potentially simplifies decisions regarding allograft dysfunction. Successful eradication of posttransplant HCV infection also reduces concerns regarding immunosuppression and how immunosuppression may be impacting the course of HCV infection.

Recommendation 1.1 We recommend that all liver transplant recipients with recurrent hepatitis C receive treatment with oral DAA therapy. Quality/Certainly of Evidence: Moderate Strength of Recommendation: Strong Recommendation 1.2 We suggest that antiviral therapy be undertaken once the patient is clinically stable rather than waiting until significant disease is documented. Quality/Certainly of Evidence: Low Strength of Recommendation: Conditional

Back to Top | Article Outline

Technical Remarks

  • (1)Stage of disease should be assessed by noninvasive means or by biopsy as available and warranted clinically. Liver biopsy is not required pretreatment unless there is concern for other causes of liver enzymes elevation (eg, acute rejection).
  • (2) Interferon-based therapy should not be used in liver transplant recipients with recurrent hepatitis C, as safe and better-tolerated therapies are available.
  • (3) When selecting a specific regimen (Table 1) and timing for treatment of patients with early hepatitis C recurrence, the following factors should be considered:
    • ▪ Clinical stability
    • ▪ Renal function
    • ▪ Level of hemoglobin
    • ▪ HCV genotype
    • ▪ Prior exposure to DAAs, particularly NS5a inhibitors
    • ▪ Possible drug-drug interaction (DDIs)
    • ▪ Access to and cost of treatment regimens
  • (4) Therapy for early disease may commence post-LT after postoperative issues have resolved and immunosuppression regimen stable, typically within the first 3 months.
  • (5) The combination of NS5B inhibitor, sofosbuvir, plus NS5A inhibitor (daclatasvir, ledipasvir) with ribavirin for 12 to 24 weeks is a safe and well-tolerated option for those with hemoglobin levels above 10 g/dL and preserved renal function (creatinine clearance [CrCl] > 30 mL/min) with mild to moderate disease (F0-3) posttransplantation. Although velpatasvir has not yet been studied post-LT, this NS5A inhibitor combined with sofosbuvir is also predicted to be safe.
  • (6) The combination of NS3a inhibitor, paritaprevir, plus NS5A inhibitor, ombitasivir with nonnucleoside polymerase, dasabuvir with ribavirin for 24 weeks is a safe and well-tolerated option for those with genotype 1 with mild to moderate disease post-LT who have hemoglobin levels above 10 g/dL and normal or impaired renal function (CrCl < 30 mL/min). Drug interactions with CNIs and mTOR inhibitors are present (Table 2).
  • (7) The combination of NS3a inhibitor, grazoprevir, plus NS5A inhibitor, elbasvir with or without ribavirin for 12 to 16 weeks (depending on presence of baseline NS5a resistance-associated substitutions [RASs]) has not yet been studied post-LT but is likely to be a safe and well-tolerated option for those with normal or impaired renal function (CrCl < 30 mL/min) with mild to moderate disease post-LT in patients receiving tacrolimus based anti-rejection therapy. Use with cyclosporine is contraindicated. Drug interactions with mTOR inhibitors have not been studied.
  • (8) The combination of NS3a inhibitor, simeprevir, plus NS5B inhibitor, sofosbuvir, with or without ribavirin for 12 to 24 weeks is a safe and well-tolerated option for those with hemoglobin levels above 10 g/dL and preserved renal function (CrCl > 30 mL/min) with mild to moderate disease posttransplantation, who are not on cyclosporine-based immunosuppression. Drug interactions with mTOR inhibitors have not been studied.
  • (9) Ribavirin has been used in most clinical trials of DAA therapy in post-LT patients and may reduce the risk of relapse. Limited data are available on ribavirin-free regimens post-LT. A study of treatment of HCV infection in renal transplant recipients (mostly genotype 1b) using ledipasvir-sofosbuvir without ribavirin for 12 or 24 weeks, reported high efficacy.19 Real-life cohort studies of liver transplant recipients report similar high efficacy of ledipasvir-sofosbuvir with and without ribavirin.8,17 However, with the aim of minimizing relapse, ribavirin should be considered for inclusion in all DAA regimens.
  • (10) Ribavirin may exacerbate anemia and the dose must be adjusted at initiation of and during therapy for CrCl and hemoglobin levels. As post-LT patients frequently have some degree of renal impairment, a lower dose of ribavirin (400-800 mg daily) is recommended that is titrated to tolerability. Patients receiving ribavirin should be monitored with laboratory tests (hematology, biochemistry). For patients on dialysis, a starting dose of 200 mg daily, adjusted for hemoglobin level is appropriate. The maximum dose recommended is 1000 mg (<75 kg) to 1200 mg (≥75 kg).
  • (11) Testing for the presence of RASs should be considered before treatment in those previously exposed to NS5a inhibitors.
  • (12) Duration of therapy is 12 to 24 weeks, depending on genotype, use of ribavirin and presence of negative prognostic factors. Patient subgroups with baseline RASs, prior treatment failure should be considered for a ribavirin-inclusive regimen. If ribavirin ineligible, 24 weeks therapy should be considered.
  • (13) Sofosbuvir-based therapy is not currently recommended in patients with CrCl < 30 mL/min due to lack of data on safety and efficacy. Large real-world studies and an ongoing Phase II study of sofosbuvir/ribavirin and ledipasvir/sofosbuvir in patients with chronic kidney disease stage 4/5 (CrCl < 30 mL/min) have not demonstrated any sofosbuvir-related nephrotoxicity or other toxicities. However, current labeling restrictions remain unchanged.
  • (14) Preemptive therapy using a 28-day course of ledipasvir/sofosbuvir initiated at the time of LT and continued for 28 days can lead to high SVR rates in genotype 1 patients with CrCl > 30 mL/min at the time of LT. While awaiting a larger experience to be reported, this regimen should be used selectively.
  • (15)Patients should be tested for HCV RNA at least 12 weeks after the completion of treatment to determine treatment response.
TABLE 1

TABLE 1

TABLE 2

TABLE 2

Back to Top | Article Outline

Evidence and Rationale

With the availability of safe and effective non-IFN therapies for treatment of HCV after LT, use of an IFN-containing regimen is not recommended. There may be unique clinical circumstances in which IFN plus DAAs may be considered, namely, in regions with limited access to DAAs. However, such use would be expected to be rare. The strength of evidence related to use of approved DAA combinations in LT recipients is presented in Table 1.

Prior attempts of so-called preemptive treatment using IFN-based regimens were associated with poor tolerability, low rates of SVR and were not applicable to many patients because of contraindications.20 Additionally, a randomized study of preemptive versus delayed HCV therapy showed no advantage of early treatment.21 As a result, recommendations emerged to wait until patients developed significant recurrence with at least F2 fibrosis prior to initiation of IFN treatment22,23 and IFN-based treatment was not recommended for prevention of recurrence. When SVR was achieved in patients with early recurrence treated with IFN, it was associated with significant improvements in clinical outcomes.24-26 The availability of DAA therapies provides an opportunity for early treatment before the development of significant graft dysfunction or fibrosis. Given the benefits of SVR and the potential for early treatment to simplify post-LT management, institution of antiviral treatment before the development of overt recurrence and/or fibrosis is the preferred strategy.

CORAL-1 was a phase-2 open-labeled study of paritaprevir/ritonavir/ombitasvir plus dasabuvir with and without ribavirin for 12 to 24 weeks in patients with genotype 1 infection focused on patients at least 12 months post-LT.12,13 SVR rates among patients without cirrhosis were 97% with ribavirin and treatment for 24 weeks (33/34), 95% (21/22) for genotype 1A (with ribavirin) and 100% (12/12) genotype 1B (without ribavirin) for 12 weeks.12,13 The rate of serious adverse events was low. Because of the ritonavir-boosted protease inhibitor (PI) in this regimen, potential DDIs with calcineurin inhibitors had to be carefully managed, and remain a consideration in clinical practice. Trials of sofosbuvir-based regimens have been reported for treatment of patients without advanced hepatic fibrosis posttransplant. Sofosbuvir plus ribavirin for 24 weeks was studied in 40 patients of any genotype (predominantly GT1 and 3) and with mild to moderate fibrosis (F0-3 in 24) or with cirrhosis (F4 in 16). In the patients with F0-3 fibrosis, SVR was achieved in 18 of 24 (75%) with all failures being due to virologic relapse.27 This regimen has been supplanted by regimens of sofosbuvir plus an NS5a inhibitor (ledipasvir or daclatasvir) and ribavirin due to much higher SVR rates. The SOLAR-1 (USA) and SOLAR-2 (rest of world) studies of sofosbuvir-ledipasvir and ribavirin for 12 or 24 weeks duration included posttransplant patients with genotypes 1 or 4 infection. Patients without advanced cirrhosis achieved high rates of SVR of 94% to 100%.9,10 In the ALLY-1 study, 53 patients with posttransplant HCV recurrence (70% F0-3) were treated with sofosbuvir plus daclatasvir and ribavirin. Overall, SVR12 was achieved in 94% (GT1 95% (39/41); GT3 91% (10/11).11 In the ANRS C023 CUPILT study group from France using sofosbuvir plus daclatasvir with or without ribavirin for 12 to 24 weeks in transplant recipients with recurrent HCV genotype 1 to 4 (66% noncirrhotic), the overall SVR rate was 96%.18 Tolerability was excellent, and DDIs were not of major concern. Real-world studies have supported high rates of SVR and excellent tolerability of DAA regimens in LT recipients with recurrent hepatitis C and mild to moderate fibrosis including combination regimens of ledipasvir-sofosbuvir,8,17 simeprevir plus sofosbuvir,14-16 and sofosbuvir plus daclatasvir.18

The evidence supports the use of ribavirin when treating patients with recurrent hepatitis C after LT as clinical trials incorporated ribavirin into the regimens.9-12 In general, ribavirin has been initiated at 400 to 800 mg daily, with increasing doses according to hemoglobin level and renal function. Limited real-world experiences with ledipasvir-sofosbuvir suggest SVR rates are similar with and without use of ribavirin8,17 but because these studies fail to adjust for all potential negative prognostic factors, the more conservative recommendation is to include ribavirin.

A small study evaluated the safety and efficacy of preemptive antiviral treatment.28 Sixteen patients received a single dose of ledipasvir-sofosbuvir the day they arrived at the hospital for LT and then once daily for 4 weeks postoperatively. Fourteen achieved SVR12 (88%). One patient relapsed by 4 weeks posttreatment and was successfully retreated with a further 12 weeks of therapy. One patient discontinued treatment because of a reduction in CrCl below 30 mL/min on posttransplant day 5. The major benefit of this preemptive strategy would be its lower cost and reduced need for post-LT monitoring of HCV infection. However, starting antiviral treatment immediately post-LT may be challenging in potentially unstable patients at risk of acute kidney injury, cardiac arrhythmias as other complications. Further studies of preemptive versus early treatment as well as the specific patient populations best suited for preemptive therapy are required.

Back to Top | Article Outline

Future Research

More studies involving ribavirin-free DAA regimens are needed and are underway. Avoidance of ribavirin is desirable given the reduction in renal perfusion due to the use of calcineurin inhibitors and reduced hemoglobin levels that may be encountered post-LT. The high efficacy of DAAs and preliminary data regarding preemptive therapy may alter the need for assessment of HCV–related changes before initiation of therapy. While efficacy data are expected to be similar to nontransplant populations, the combinations of grazoprevir/elbasvir and sofosbuvir/velpatasvir should be studied post-LT. Determination of the optimal regimens for genotype 3 post-LT requires further study. Finally, the safety and efficacy data for sofosbuvir-based combinations for those with CrCl <30 mL/min are needed.

Back to Top | Article Outline

II. MANAGEMENT OF HCV IN THE POST LIVER-TRANSPLANT RECIPIENT WITH RECURRENT CIRRHOSIS, INCLUDING DECOMPENSATION

Background

Once cirrhosis develops post-LT, decompensation occurs more rapidly than in non-LT patients, with one -year actuarial risk for decompensation of 42%.29 Moreover, the time from decompensation to death is very short, with 60% mortality within 12 months.29,30 This provides strong rationale for initiation of treatment before advanced liver disease occurs. In the current era of DAA therapy, it is anticipated the progression to cirrhosis will be a rare event, however, many transplanted patients under care currently have cirrhosis and they present a unique challenge.

Retransplantation was the only viable option for patients with allograft failure in the pre-DAA era. However, in the past, few (~15%) with advanced liver disease from recurrent HCV were actually evaluated and listed, with the most common reasons for not listing for repeat transplant being recurrent HCV within 6 months, cholestatic hepatitis, and renal dysfunction.31 With availability of DAAs, the outcomes of patients requiring retransplantation for advanced recurrent HCV may be anticipated to improve and the frequency of recurrent HCV as an indication for retransplantation to decrease.

Recommendation 2.1 We recommend that liver transplant recipients with recurrent hepatitis C and cirrhosis (compensated and decompensated) receive treatment with combination DAA therapy. Quality/Certainly of evidence: High Strength of Recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) Transplant recipients with recurrent HCV and cirrhosis are a high priority group for antiviral therapy.
  • (2) IFN-containing regimen is not recommended in compensated cirrhosis. Interferon-based therapy is contraindicated in LT recipients with decompensated HCV cirrhosis.
  • (3) When selecting a specific regimen for treatment of patients with graft cirrhosis (Tables 1 and 3), the following factors should be considered:
    • ▪ Child-Pugh Turcotte (CPT) score
    • ▪ Eligibility for ribavirin
    • ▪ HCV genotype
    • ▪ Prior exposure to DAAs, particularly NS5a inhibitors
    • ▪ DDIs
    • ▪ Renal function
    • ▪ Access to and cost of treatment regimens
  • (4) The combination of NS5B inhibitor (sofosbuvir) plus NS5A inhibitor (daclatasvir, ledipasvir) with ribavirin for 12 to 24 weeks is a safe and well-tolerated option for those with hemoglobin levels above 10 g/dL and preserved renal function (CrCl > 30 mL/min) with compensated or decompensated cirrhosis post-LT. Sofosbuvir-velpatasvir has not been studied post-LT but is predicted to be safe.
  • (5) Due to safety concerns and to interactions with immunosuppressive drugs, treatments with PIs are not considered as first line therapy in patients with compensated cirrhosis and are contraindicated in those with decompensated cirrhosis.
  • (6) Ribavirin appears to reduce the risk of relapse in decompensated patients and should be strongly considered for inclusion in anti-viral combinations. The initial dose should be no higher than 600 mg daily, and adjusted according to hemoglobin levels. The dose can be increased every 2 to 4 weeks as tolerated. Patients receiving ribavirin should be monitored with laboratory tests (hematology, biochemistry).
  • (7) Duration of therapy is 12 to 24 weeks, depending on genotype, use of ribavirin and presence of other negative prognostic factors. Treatment for 24 weeks should be considered for genotype 3 patients and cirrhosis, those with baseline RASs and those ineligible for ribavirin.
  • (8) Testing for the presence of RASs should be considered before treatment in those exposed to NS5a inhibitors.
  • (9) Sofosbuvir-based therapy is not recommended in patients with CrCl < 30 mL/min due to unknown safety and efficacy. Real-world studies of ledipasvir/sofosbuvir in patients with CKD stage 4/5 (CrCl < 30 mL/min) have not demonstrated any sofosbuvir-related toxicities but few patients in these cohorts had CrCl < 30 mL/min and decompensated cirrhosis.
  • (10) Patients should be tested for HCV RNA at least 12 weeks after the completion of treatment to determine treatment response.
TABLE 3

TABLE 3

Back to Top | Article Outline

Evidence and Rationale

The goals of antiviral treatment in those transplant recipients with compensated and decompensated cirrhosis are prevention of liver-related death or need for retransplantation, improved quality of life and achievement of “recompensation” among patients with decompensation. In addition, treatment of HCV-infected patients with decompensated graft cirrhosis will prevent HCV recurrence after liver retransplantation.

In the SOLAR-1 trial, transplant recipients with HCV genotype 1 or 4 recurrence were treated with the fixed-dose combination of sofosbuvir and ledipasvir for 12 or 24 weeks with ribavirin.9 In patients treated for 12 weeks with ribavirin, the SVR12 rates were 96% (25/26) in those with compensated (CPT A) cirrhosis, 85% (22/26) in those with CPT B decompensated cirrhosis, and 60% (3/5) in those with CPT C decompensated cirrhosis. The SVR12 rates were not higher in patients treated for 24 weeks with ribavirin: 96% (24/25), 88% (23/26), and 75% (3/4), respectively. Similar results were reported in the SOLAR-2 study in patients with genotype 1 receiving the same treatment regimens.10 In the ALLY-1 trial, LT recipients were treated with the combination of sofosbuvir, daclatasvir and ribavirin for 12 weeks. SVR was achieved in 95% (39/41) of genotype 1 and 91% (10/11) of genotype 3 patients.11 A real-world cohort from France of liver transplant recipients with genotypes 1 to 4 and cirrhosis (38% CPT B or C) treated with sofosbuvir-based therapy (mostly daclatasvir with or without ribavirin), the SVR was 92%.32 There are no published results of the fixed-dose combination of sofosbuvir and velpatasvir in LT recipients with HCV recurrence.

Whether ribavirin is needed in all patients with cirrhosis after LT who are treated with the fixed-dose combination of sofosbuvir and ledipasvir, the fixed-dose combination of sofosbuvir and velpatasvir, or the combination of sofosbuvir and daclatasvir remains to be determined. Patients receiving ribavirin-based treatment should be closely monitored with laboratory tests (hematology, biochemistry) every 1 to 2 weeks initially. Patients not receiving ribavirin require less frequent monitoring of laboratory tests (monthly).

Lower SVR rates are seen in patients with advanced decompensated cirrhosis, and those failing to achieve SVR will likely have RASs, making retreatment more challenging. Moreover, the possibility of drug toxicity and side effects is higher in patients with decompensated cirrhosis, especially if ribavirin is included. HCV regimens containing a PI are contraindicated in patients with decompensated cirrhosis (CPT B or C) due to increased drug levels and potential associated hepatotoxicity. Additionally, decompensated patients treated with the combination of sofosbuvir and ledipasvir or daclatasvir plus ribavirin should be followed closely for lactic acidosis, although this complication is very uncommonly observed.33

Recommendation 2.2 We recommend that HCV-positive liver transplant recipients with decompensated cirrhosis be considered for retransplantation, if suitable. Quality of evidence: Low Strength of Recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) Early consideration of the need for retransplantation is warranted in transplant recipients with cirrhosis and any signs of decompensation.
  • (2) For the patient listed for retransplantation, the decision to treat with antiviral therapy before repeat LT versus after repeat LT may be influenced by:
    • ▪ Anticipated time to LT
    • ▪Availability of anti-HCV positive donors as means to shorten time to LT
    • ▪ Waitlist drop-off rates due to progression of cirrhosis
    • ▪ Access to and costs of antiviral therapy
  • (3) HCV-infected patients undergoing repeat liver transplantation who are viremic at LT should be considered for early antiviral therapy post-LT.
Back to Top | Article Outline

Evidence and Rationale

Since the time from decompensation to death is very short, with 60% mortality within 12 months,29,30 there is need to consider retransplantation at the first signs of decompensation (biochemical or clinical). Patient and graft survival rates are inferior to those after primary LT and are associated with a greater cost,34 so reversing decompensation and avoiding retransplantation is desirable, though data are lacking on the frequency of achieving this goal. However, this is the primary reason for endorsing treatment of all transplant recipients with cirrhosis and decompensation.

Reversibility of hepatic decompensation has been described in the majority of LT recipients with decompensated cirrhosis who achieved SVR. In patients with CPT B cirrhosis achieving SVR12, approximately 60% of them had improvement in the Model for End-Stage Liver Disease score, with only 22% experiencing deterioration. None of the surviving CTP C patients who achieved SVR12 deteriorated by posttreatment week 12, and all but 2 patients had an improvement in MELD score.9,10 Ongoing improvements out to week 24 posttreatment have been reported and it is anticipated that further improvements will be observed with a longer duration of follow-up.35 However, because not all patients with decompensation will achieve improvement in clinical status, patients with decompensated HCV cirrhosis post-LT should be considered for retransplantation if suitable.

While a survival benefit for first transplants is evident at MELD scores of 15 or higher, the survival benefit for repeat transplants is evident at MELD of 21 or higher, and for HCV patients at MELD of 24 or higher.36 Thus, the therapeutic window for offering retransplantation when survival benefit is present but the patient is not too sick is quite narrow. A multicenter European study showed that factors associated with better survival after retransplantation included negative HCV viremia before retransplantation and antiviral therapy after retransplantation.37 These data suggest the treatment either before or early after repeat LT can be expected to improve patient outcomes.

Back to Top | Article Outline

Future Directions

Longitudinal studies to determine the long-term outcomes of DAA therapy in patients with cirrhosis with and without decompensation are important, in particular the risk of hepatocellular carcinoma and graft failure. The efficacy of treatment in non-1 genotypes with cirrhosis, those who have failed a prior DAA regimen and those with concurrent renal failure are largely unknown and real-life or clinical trials data are needed to guide treatment in these less frequently encountered subgroups.

Back to Top | Article Outline

III. MANAGEMENT OF HCV IN POST LIVER TRANSPLANT RECIPIENTS WITH SEVERE CHOLESTATIC HEPATITIS

Background

The cholestatic variant of recurrent hepatitis C develops in 5-10% of patients undergoing LT for hepatitis C. It is widely defined by the following criteria: 1) HCV recurrence must have occurred more than 1 month, but within 6 months, of transplantation; (2) serum bilirubin levels in excess of 6 mg/dL (100 μmol/L); (3) characteristic histology must be present, including ballooning of hepatocytes in the perivenular zone without necrosis or dropout, periportal or pericellular/perisinusoidal fibrosis, canalicular cholestasis with or without intracellular cholestasis, a paucity of inflammation, and variable degrees of cholangiolar proliferation without bile duct loss; (4) the presence of very high serum HCV-RNA levels; and (5) the absence of surgical biliary complications and any evidence of hepatic artery thrombosis.38,39 In the absence of successful antiviral treatment, severe cholestatic hepatitis is associated with poor graft survival, typically in the range of 50% at one year posttransplantation.40 Efforts to treat with IFN-based regimens proved largely unsuccessful, with sustained virological response (SVR) rates inferior to the 15% to 45% rates reported in more typical recurrent HCV.41-43 The availability of well-tolerated DAA-based regimens offers an important advance in managing this challenging entity. Moreover, with effective treatment of HCV before LT, the threat of developing this severe early form of HCV recurrence is mitigated.

Recommendation 3.1 We recommend that patients with severe cholestatic recurrent hepatitis C after liver transplantation be treated with combination DAA therapy. Quality of evidence: Moderate Strength of recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) The antihepatitis C therapy choice for LT recipients with cholestatic recurrent hepatitis C should be determined by the following:
    • ▪ Genotype
    • ▪ Available antiviral therapy
    • ▪ Prior treatment, if any, with NS5A-containing regimens
    • ▪ CPT class
    • ▪ Hemoglobin level
    • ▪ Renal function
    • ▪ Potential for DDIs
  • (2) There is limited experience with the use of PIs in this group of patients; several case reports suggest combination treatment with sofosbuvir and simeprevir, with or without ribavirin, is effective in genotype 1 patients. With concerns about PI use in hyperbilirubinemic patients and availability of non-PI regimens, the use of PIs is strongly discouraged in cholestatic hepatitis unless NS5A failure and/or resistance has/have been documented.
  • (3) Potential drug interactions between PIs and calcineurin inhibitors in LT recipients should prompt consideration of non-PI containing regimens, if available, in the treatment of cholestatic recurrent hepatitis C.
  • (4) Treatment of cholestatic hepatitis C with sofosbuvir-based regimens is effective therapy; the duration varies by genotype, and ribavirin was used in the majority of treated patients. Regimens that include an NS5A inhibitor (daclatasvir, ledipasvir) along with sofosbuvir also appear to be safe and effective in cholestatic patients. There is insufficient evidence to conclude whether any combination of DAAs requires the addition of ribavirin.
  • (5) The safety and efficacy of sofosbuvir in patients with CrCl less than 30 mL/min are not established. In the circumstances of cholestatic hepatitis C this must be weighed against the potential benefits of antiviral therapy.
  • (6) Studies to date report excellent safety profiles of DAAs in transplant recipients. Anemia, hyperbilirubinemia and renal dysfunction may be more frequently encountered in patients with cholestatic hepatitis and they should be monitored appropriately based on the choice of antiviral treatment.
  • (7) While early and successful treatment will likely prevent graft loss, retransplantation of patients who develop graft failure due to severe cholestatic hepatitis should be considered if antiviral therapy is available to successfully control the virus following retransplantation.
Back to Top | Article Outline

Evidence and Rationale

While there are more than a dozen publications describing the use of DAAs in cholestatic recurrent hepatitis C, most are case reports or small case series. The reported SVR rates range from 80% to 100%.10,27,44-52 These SVR rates are vastly superior to the pre-DAA era and thus the weight of the evidence must be considered disproportional to the number of patients treated and be given recognition in the absence of clinical trial data. The first report of a patient successfully treated for cholestatic recurrent hepatitis C with an antiviral regimen that included a DAA was a patient with genotype 1b who received daclatasvir in addition to peg-IFN and ribavirin, and achieved an SVR.44 Two sizeable studies of patients with cholestatic hepatitis, each including 23 patients, have been reported. In one, posttransplant patients with genotypes 1, 2, or 3 received sofosbuvir in combination with ribavirin and/or daclatasvir; 22 achieved SVR.53 The second included patients with genotypes 1, 3, or 4 who received sofosbuvir and daclatasvir with no ribavirin; there were 2 deaths but no virologic failures.54 Several other smaller studies have reported patients with cholestatic hepatitis C receiving treatment with sofosbuvir in combination with a variety of other DAAs, with ribavirin included in some cases. With the exception of a series in which sofosbuvir and ribavirin were the only agents used, with only 4 of 10 mostly genotype 1 patients achieving SVR, the others reported SVR rates of 80% or higher.10,45,46,48-50,55 In total, the published literature now includes more than 160 patients who have received DAA-based regimens for cholestatic hepatitis C, and more than 80% have gone on to SVR. Most of those treated were infected with genotype 1. There are insufficient numbers treated with each of the different regimens to conclude which is superior, although all but one patient received sofosbuvir as part of their antiviral treatment. It does appear that regimens that included an NS5A inhibitor were more effective than those without, but it is not clear whether ribavirin is necessary in the treatment of patients with cholestatic hepatitis.

Back to Top | Article Outline

Future Research

Further studies using newer regimens, especially those with pan-genotypic activity such as sofosbuvir-velpatasvir are awaited. Given that many patients with cholestatic hepatitis may not tolerate ribavirin due to their proximity to LT surgery, it is important that the role of ribavirin be clarified. Further the frequent development of significant renal dysfunction in combination with early graft injury should drive the search for regimens that are proven to be safe in patients with compromised renal function.

Back to Top | Article Outline

IV. MANAGEMENT OF HCV IN THE HUMAN IMMUNODEFICIENCY VIRUS/HCV COINFECTED LIVER TRANSPLANT RECIPIENTS

Background

The post-LT outcomes of HCV/human immunodeficiency virus (HIV) coinfected transplant recipients are inferior to HCV-monoinfected patients, with average cumulative patient survival rates of ~80% at year 1 and 55% at year 5 post-LT among those with HIV/HCV.56 Progression to an advanced fibrosis stage and development of cholestatic hepatitis (20% vs 5%) are higher than HCV monoinfected LT recipients. They also have higher rates of acute rejection than monoinfected patents (40% vs 20% at 3 months post-LT).56,57 In contrast, there was no acceleration of HIV infection after transplantation. Several poor prognostic factors have been associated with inferior outcomes post-LT: low CD4 count, low BMI, high MELD score pretransplant, sepsis, concurrent need for kidney transplant, very high HCV viral load, and use of HCV positive graft.56,57

The low efficacy of combination Peg-IFN plus ribavirin in HCV/HIV coinfected patients likely contributed to overall reduced survival. The overall SVR rates with peg-IFN and ribavirin were 10% to 15% in coinfected patients compared with 30% in HCV monoinfected transplant recipients.58 Tolerance of peg-IFN based treatment was extremely poor, with high rates of discontinuation. Thus, the advent of IFN-free DAA regimen to treat HCV infection in coinfected patients with decompensated cirrhosis and post-LT is a major therapeutic breakthrough.

Recommendation 4.1 We recommend that HIV/HCV coinfected liver transplant recipients be treated with combination DAA therapy early after liver transplantation. Quality/Certainty of Evidence: Low Strength of recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) Early initiation of antiviral therapy, typically within the first 3 months post-LT, allows sufficient time for the patient to stabilize from postoperative complications but treats HCV before significant liver disease occurs.
  • (2) Earlier or emergent initiation of antiviral therapy might be needed if cholestatic hepatitis develops.
  • (3) For patients with recurrent HCV infection, antiviral therapy is indicated regardless of the stage of fibrosis.
  • (4) Avoidance of PI-inclusive ART is recommended in LT patients due to DDIs with immunosuppressive drugs (calcineurin inhibitors, mTOR inhibitors) and potential to increase risk of acute rejection and immunosuppressive toxicity. Avoidance of PI-inclusive ART also reduces the complexity of DDIs with anti-HCV antiviral treatment. Change of ART may be necessary to avoid significant drug interaction with HCV antivirals. Advice from an HIV expert is highly recommended.
  • (5) Combination of Sofosbuvir, plus NS5A inhibitor (daclatasvir or ledipasvir) is a safe and well-tolerated option for in LT recipients with HCV. Sofosbuvir-velpatasvir has not been studied post-LT.
  • (6) PIs are contraindicated in coinfected LT recipients with decompensated cirrhosis.
  • (7) For patients with NS5A resistance, retreatment options may warrant inclusion of a PI. Due to risk of DDIs, consultation with an HIV expert is mandatory before embarking upon treatment.
  • (8) Duration of therapy is 12 weeks for patients who are able to tolerate ribavirin. Duration of therapy is 24 weeks for those ineligible for ribavirin and those with multiple negative prognostic factors, such as baseline RASs, genotype 3 with cirrhosis, and prior DAA treatment failure.
  • (9) Sofosbuvir-based therapy is not recommended in patients with CrCl below 30 mL/min due to unknown safety and efficacy. However the use of sofosbuvir should be balanced with the risk of progression of graft dysfunction.
  • (10) Treatment for LT recipients with decompensated cirrhosis should be approached in the same manner as pretransplant coinfected patients with decompensation of cirrhosis.2
Back to Top | Article Outline

Evidence and Rationale

The best evidence that prevention or early treatment of HCV and achievement of viral eradiation post-LT will lead to survival rates comparable to HCV monoinfected patients come from review of the outcomes of HBV-HIV coinfected LT recipients. In these patients, where prevention of recurrent HBV infection is uniformly effective, graft and patient survival in HIV/HBV LT recipients have been excellent and similar to HBV monoinfected recipients.59,60 The benefits of early treatment after LT are prevention of posttransplant recurrence of HCV, including cholestatic hepatitis, and achievement of prolonged graft survival. Preemptive therapy (starting at the time of LT and continued for 28 days post-LT) has not been studied in HIV-HCV coinfected patients.28 As in the management of HCV-monoinfected patients with recurrent HCV infection, treatment can be undertaken early after LT once the patient has stabilized postoperatively and is on stable immunosuppression. There are limited data on efficacy of DAA therapy in HCV-HIV coinfected patients post-LT and most reports are in patients with severe and/or decompensated liver disease.53,61-63 In a compassionate access program of sofosbuvir-based therapy, 20 coinfected patients from 10 centers, 9 with early severe recurrence and 11 with decompensated cirrhosis, 89% achieved SVR12; 100% of those with decompensated cirrhosis, and 78% (7/9) in those with severe early recurrence.62 Median MELD score decreased from 12 to 9 and CPT score from 8 to 5 one year after completing treatment. Similarly, in the CUPILT ANRS cohort, 94% of the 16 HCV-HIV LT recipients achieved SVR 12.64 Collectively, these results suggest high SVR rates and clinical responses are achievable in coinfected LT recipients. The approach to treatment of coinfected LT recipients with recurrent HCV infection is the same as HCV monoinfected LT recipient, with the exception that early treatment should be strongly considered and potential DDIs require particular attention.

Back to Top | Article Outline

Future Directions

Studies are needed to define the optimal duration of therapy in coinfected patients with and without cirrhosis and the role of ribavirin in achieving optimal SVR rates as well as the impact of SVR on long-term outcomes. Ultimately, it is hoped that such data will reduce the barriers to transplantation.

Back to Top | Article Outline

V. IMMUNOSUPPRESSION AND MONITORING DURING ANTIVIRAL THERAPY

Background

Most LT recipients require life-long immunosuppression to prevent allograft rejection. Of the common immunosuppressive agents used, tacrolimus, cyclosporine, mycophenolate mofetil, sirolimus and everolimus all may be associated with DDIs with PI-containing DAAs. Apart from a potential interaction between NS5A inhibitors and everolimus, other non-PI regimens pose little risk of DDIs. When treating patients early after transplantation, additional medications such as antibiotics, antivirals, and antifungals should be considered. In long-term recipients, medications to treat associated conditions such as hypertension, hyperlipidemia and diabetes may also interact with DAAs. The consequences of these interactions may be to dramatically alter exposure to either the immunosuppressive drug or the concomitant medication if dose adjustments are not made.

Recommendation 5.1 We recommend pretreatment assessment for DDIs between the DAA regimen with immunosuppressive drugs and other concomitant medications. Quality/Certainly of Evidence: High Strength of Recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) HCV PIs are associated with significant risk for DDIs, particularly in patients on immunosuppression with calcineurin inhibitors and mTOR inhibitors.
  • (2) Simeprevir and elbasvir/grazoprevir should not be used in patients on cyclosporine as simeprevir levels are increased.65 Simeprevir does not affect the immunosuppression levels.
  • (3) Sofosbuvir, ledipasvir, and daclatasvir are associated with a low risk of DDI with calcineurin inhibitors and mTOR inhibitors. There are no published data on velpatasvir but likelihood of DDIs is low.
  • (4) A reliable and frequently updated expert resource should be accessed to determine the risk and management recommendations for DDIs. One example of such a resource is the HEP Drug Interactions website from the University of Liverpool (http://www.hep-druginteractions.org).

Recommendation 5.2 We recommend regular monitoring of blood concentrations of immunosuppressive medications during DAA treatment and after completion of treatment. Quality/Certainly of Evidence: Moderate Strength of Recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) The dose of immunosuppressive medications may require modification at the time of initiation of antiviral treatment. For example, when ritonavir-boosted paritaprevir/ombitasvir/dasabuvir plus ribavirin is used, it is recommended to reduce tacrolimus to 0.5 mg every 7 to 14 days or cyclosporine to one-fifth of the pretreatment dose. Potential DDIs should always be checked before initiation of DAA therapy.
  • (2) Blood levels of immunosuppressive drugs may decline during and in the 12 weeks after treatment discontinuation and precipitate rejection. Monitoring and adjustment of immunosuppressive medications to maintain stable drug levels is advised.
Back to Top | Article Outline

Evidence and Rationale

Potential DDIs should be assessed and managed according to the DAA regimen and concomitant medications. PIs are more likely to be associated with significant DDIs, especially with calcineurin inhibitors and mTOR inhibitors.66,67 Sofosbuvir, ledipasvir, daclatasvir, and velpatasvir are predicted to have a low risk of DDIs with calcineurin inhibitors and mTOR inhibitors.

Apart from pharmacokinetic interactions, changes in immunosuppressive drug exposure related to improvement in liver function with antiviral treatment may occur. Blood concentrations of immunosuppressive medications should be monitored regularly during DAA treatment, and after completion of treatment until SVR12 is achieved. Serum levels of immunosuppressive medications have been noted to fall in association with viral clearance on and after therapy, and without upward adjustment of immunosuppressive doses may lead to allograft rejection.68 Modification of immunosuppressive drug doses is commonly required to maintain drug target levels.18,69 Acute rejection and alloimmune or plasma-cell hepatitis has been reported in the context of DAA therapy but is infrequent and typically responds to increased immunosuppression.15,18

Recommendation 5.3 We recommend assessment for DDIs between the DAA regimen, antiretroviral drugs and immunosuppressive drugs in liver transplant recipients with HCV-HIV coinfection. Quality/Certainly of Evidence: High Strength of Recommendation: Strong

Back to Top | Article Outline

Technical Remarks

  • (1) For HCV-HIV coinfected transplant recipients, comanagement with an HIV expert is advised during and after HCV treatment to minimize DDIs and toxicities.
  • (2) The following DDIs are noteworthy:
    • ▪ Sofosbuvir or sofosbuvir/ledipasvir combination should not be used with tipranavir.
    • ▪ Daclatasvir requires dose-adjustment with ritonavir-boosted atazanavir (reduction to 30 mg daily) and efavirenz or etravirine (an increase to 90 mg daily).
    • ▪ Ledipasvir increases tenofovir levels and should be used with caution in patients on tenofovir with CrCl below 30 mL/min and regular monitoring of CrCl undertaken during sofosbuvir/ledipasvir therapy. Ledipasvir should not be used in patients on tenofovir in conjunction with ritonavir-boosted or cobicistat-boosted regimens due to a risk of renal toxicity. A change to tenofovir alafenamide should be considered.
    • ▪ Treatment that includes ribavirin has been the standard approach in LT recipients. SVR rates with and without ribavirin are not available for comparison and thus currently ribavirin is recommended for coinfected LT recipients undergoing antiviral HCV treatment. Ribavirin should not be used with didanosine, stavudine, or zidovudine. The optimal dose has not been established. Experts recommend a starting dose of 600 mg daily with adjustment to tolerability and CrCl. The maximum dose recommended is 1000 mg(<75 kg) to 1200 mg (>75 kg).
    • ▪ Significant DDIs occur when PI-containing DAA regimens (simeprevir, elbasvir/grazoprevir or ombitasvir/paritaprevir/ritonavir) are administered with cobicistat-containing regimens, ritonavir-containing regimens, PIs and most NNRTIs.
  • (3) There is a risk of acute rejection and alloimmune hepatitis with HCV eradication and HIV/HCV coinfected patients are at higher risk. HIV/HCV coinfected patients should have blood levels of immunosuppressive drugs monitored carefully (eg, every 2 weeks) during and for 3 months posttreatment with adjustments in immunosuppressive drug doses made to maintain levels in target ranges.
  • (4) HIV RNA levels should be monitored during treatment to insure continued suppression.
Back to Top | Article Outline

Evidence and Rationale

A significantly higher incidence of rejection has been reported in HCV-HIV coinfected patients, with an incidence rate as high as 40% within the first 3 months.56,57 This is likely in part related to challenges in achieving optimal immunosuppressive levels due to DDIs as well as possibly immune dysregulation related to HIV and HCV. By using ART regimens that are without DDIs with the immunosuppressive drugs, the chances of rejection can be reduced. For the HCV-HIV coinfected transplant patient embarking upon HCV treatment, consideration of DDIs is essential to minimizing the risk of rejection and drug toxicities. In some cases, a change of ART may be required before commencement of HCV therapy. An HCV regimen that has the lowest likelihood of DDIs (with ART or immunosuppressives) should be selected. A non-PI-based HCV regimen is generally preferred. However, specific DDIs with NS5A inhibitors are well recognized and require either dose adjustment of the NS5A inhibitor or modification of the ART regimen.70 Consultation and comanagement with an HIV provider and transplant pharmacist is recommended for treatment of HCV-HIV coinfected transplant patients.

Back to Top | Article Outline

ACKNOWLEDGMENTS

The authors would like to acknowledge the contributions of panelists at the ILTS consensus meeting including: Michael Abecassis, Thomas Schiano, Helen Te, Gregory Everson, John Roberts, Roberta Fontana, Josh Levitsky, John Fung, Frederico Villamil and Maria Londano. We appreciate the support of the ILTS governing board, especially Elizabeth Pomfret, and the organizational support of Lisa Pedicone.

Back to Top | Article Outline

REFERENCES

1. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490.
2. Terrault N, McCaughan G, Curry M, et al. International Liver Transplantation Society Consensus Statement on hepatitis C management in liver transplant candidates. Transplantation. 2017;101:945–955.
3. Berenguer M, Ferrell L, Watson J, et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol. 2000;32:673–684.
4. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology. 2002;122:889–896.
5. Terrault NA, Berenguer M. Treating hepatitis C infection in liver transplant recipients. Liver Transpl. 2006;12:1192–1204.
6. Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol. 2007;46:459–465.
7. Dhanasekaran R, Sanchez W, Mounajjed T, et al. Impact of fibrosis progression on clinical outcome in patients treated for post-transplant hepatitis C recurrence. Liver Int. 2015;35:2433–2441.
8. Kwok RM, Ahn J, Schiano TD, et al. Sofosbuvir plus ledispasvir for recurrent hepatitis C in liver transplant recipients. Liver Transpl. 2016;22:1536–1543.
9. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology. 2015;48:108–116.
10. Manns M, Samuel D, Gane EJ, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016;16:685–697.
11. Poordad F, Schiff E, Vierling J, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology. 2016;63:1493–1505.
12. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med. 2014;371:2375–2382.
13. Agarwal K, Brown JR, Dumas E, et al. Safety and efficacy of ombitasvir/paritaprevir/ritonavir ± dasabuvir and ± ribavirin in adult renal or liver transplant recipients with HCV infection (CORAL-I: cohorts 3-6). EASL. 2017.
14. Nguyen NH, Yee BE, Chang C, et al. Tolerability and effectiveness of sofosbuvir and simeprevir in the post-transplant setting: systematic review and meta-analysis. BMJ Open Gastroenterol. 2016;3:e000066.
15. Brown RS Jr, O'Leary JG, Reddy KR, et al. Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: real-world experience from the hepatitis C therapeutic registry and research network. Liver Transpl. 2016;22:24–33.
16. Jackson WE, Hanouneh M, Apfel T, et al. Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience. Clin Transplant. 2016;30:709–713.
17. Reddy K, Sulkowski M, Hassan M, et al. Safety and Efficacy of New DAA Regimens in Kidney and Liver Transplant Recipients with Hepatitis C: interval results from the HCV-TARGET Study. J Hepatol. 2016;64:S783–S784.
18. Coilly A, Fougerou-Leurent C, de Ledinghen V, et al. Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence—the ANRS CUPILT study. J Hepatol. 2016;65:711–718.
19. Colombo M, Aghemo A, Liu H, et al. Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: a randomized trial. Ann Intern Med. 2017;166:109–117.
20. Shergill AK, Khalili M, Straley S, et al. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant. 2005;5:118–124.
21. Bzowej N, Nelson DR, Terrault NA, et al. PHOENIX: a randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 2011;17:528–538.
22. Wiesner R, Sorrell M, Villamil F, et al. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl. 2003;9:S1–S9.
23. Consensus conference: Indications for Liver Transplantation, January 19 and 20, 2005, Lyon-Palais Des Congres: text of recommendations (long version). Liver Transpl. 2006;12:998–1011.
24. Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology. 2007;132:1746–1756.
25. Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant. 2008;8:679–687.
26. Bizollon T, Ahmed S, Radenne S, et al. Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence. Gut. 2003;52:283–287.
27. Charlton M, Gane E, Manns M, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology. 2015;148:108–117.
28. Levitsky J, Verna E, O'Leary J, et al. Perioperative ledipasvir-sofosbuvir for HV in liver-transplant recipients. New Engl J Med. 2016;375:2106–2108.
29. Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology. 2000;32:852–858.
30. Saab S, Niho H, Comulada S, et al. Mortality predictors in liver transplant recipients with recurrent hepatitis C cirrhosis. Liver Int. 2005;25:940–945.
31. McCashland T, Watt K, Lyden E, et al. Retransplantation for hepatitis C: results of a U.S. multicenter retransplant study. Liver Transpl. 2007;13:1246–1253.
32. Dumortier J, Leroy V, Duvoux C, et al. Sofosbuvir-based treatment of hepatitis C with severe fibrosis (METAVIR F3/F4) after liver transplantation. Liver Transpl. 2016;22:1367–1378.
33. Dyson JK, Hutchinson J, Harrison L, et al. Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use. J Hepatol. 2016;64:234–238.
34. Rosen HR, Prieto M, Casanovas-Taltavull T, et al. Validation and refinement of survival models for liver retransplantation. Hepatology. 2003;38:460–469.
35. Gane E, Manns M, McCaughan G, et al. Ledipasvir/Sofosbuvir with ribavirin in patients with decompensated cirrhosis or liver transplantation and HCV infection: SOLAR-1 and -2 trials. Hepatol Int. 2016;10:S1.
36. Biggins SW, Gralla J, Dodge JL, et al. Survival benefit of repeat liver transplantation in the United States: a serial MELD analysis by hepatitis C status and donor risk index. Am J Transplant. 2014;14:2588–2594.
37. Song AT, Sobesky R, Vinaixa C, et al. Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence. World J Gastroenterol. 2016;22:4547–4558.
38. Taga S, Washington M, Terrault N, et al. Cholestatic hepatitis C in liver allografts. Liver Transpl Surg. 1998;4:304–310.
39. Verna EC, Abdelmessih R, Salomao MA, et al. Cholestatic hepatitis C following liver transplantation: an outcome-based histological definition, clinical predictors, and prognosis. Liver Transpl. 2013;19:78–88.
40. Satapathy SK, Sclair S, Fiel MI, et al. Clinical characterization of patients developing histologically-proven fibrosing cholestatic hepatitis C post-liver transplantation. Hepatol Res. 2011;41:328–339.
41. Antonini TM, Sebagh M, Roque-Afonso AM, et al. Fibrosing cholestatic hepatitis in HIV/HCV co-infected transplant patients—usefulness of early markers after liver transplantation. Am J Transplant. 2011;11:1686–1695.
42. Ong JP, Younossi ZM, Gramlich T, et al. Interferon alpha 2B and ribavirin in severe recurrent cholestatic hepatitis C. Transplantation. 2001;71:1486–1487.
43. Fukuhara T, Morita K, Takeishi K, et al. Early diagnosis and treatment resolved cholestatic hepatitis C without fibrosis after living donor liver transplantation: report of a case. Surg Today. 2010;40:982–985.
44. Fontana RJ, Hughes EA, Appelman H, et al. Case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation. Liver Transpl. 2012;18:1053–1059.
45. Gutierrez JA, Carrion AF, Avalos D, et al. Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients. Liver Transpl. 2015;21:823–830.
46. Herzer K, Welzel TM, Ferenci P, et al. Daclatasvir in combination with sofosbuvir with or without ribavirin is safe and efficacious in liver transplant recipients with HCV recurrence: interim results of a multicenter compassionate use program. Hepatology. 2015;62:341a.
47. Alqahtani SA, Afdhal N, Zeuzem S, et al. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: analysis of phase III ION trials. Hepatology. 2015;62:25–30.
48. Pungpapong S, Aqel B, Leise M, et al. Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 after liver transplant. Hepatology. 2015;61:1880–1886.
49. Saab S, Jimenez M, Bau S, et al. Treating fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin: a matched analysis. Clin Transplant. 2015;29:813–819.
50. Issa D, Eghtesad B, Zein NN, et al. Sofosbuvir and simeprevir for the treatment of recurrent hepatitis C with fibrosing cholestatic hepatitis after liver transplantation. Int J Organ Transplant Med. 2016;7:38–45.
51. Kim B, Trivedi A, Thung SN, et al. Case report of successful treatment of fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin after liver transplantation. Semin Liver Dis. 2014;34:108–112.
52. Pellicelli AM, Montalbano M, Lionetti R, et al. Sofosbuvir plus daclatasvir for post-transplant recurrent hepatitis C: potent antiviral activity but no clinical benefit if treatment is given late. Dig Liver Dis. 2014;46:923–927.
53. Leroy V, Dumortier J, Coilly A, et al. Efficacy of sofosbuvir and daclatasvir in patients with fibrosing cholestatic hepatitis C after liver transplantation. Clin Gastroenterol Hepatol. 2015;13:1993–2001. e1-2.
54. Salcedo-Plaza M, Vinaixa C, Castells L, et al. Efficacy and clinical impact of Daclatasvir-based antiviral therapy in severe recurrent hepatitis C after liver transplantation. Results from a Multicenter Spanish Group. Cohort SETH (Spanish Liver Transplantation Society). J Hepatol. 2016;64:S547.
55. Forns X, Charlton M, Denning J, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C after liver transplantation. Hepatology. 2015;61:1485–1494.
56. Terrault NA, Roland ME, Schiano T, et al. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 2012;18:716–726.
57. Miro JM, Montejo M, Castells L, et al. Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study. Am J Transplant. 2012;12:1866–1876.
58. Terrault N, Barin B, Schiano T, et al. Safety and efficacy of antiviral therapy in hepatitis C virus (HCV)-human immunodeficiency virus (HIV) coinfected liver transplant (LT) recipients. Am J Transplant. 2012;12:85.
59. Tateo M, Roque-Afonso AM, Antonini TM, et al. Long-term follow-up of liver transplanted HIV/hepatitis B virus coinfected patients: perfect control of hepatitis B virus replication and absence of mitochondrial toxicity. Aids. 2009;23:1069–1076.
60. Coffin CS, Stock PG, Dove LM, et al. Virologic and clinical outcomes of hepatitis B virus infection in HIV-HBV coinfected transplant recipients. Am J Transplant. 2010;10:1268–1275.
61. Londono M, Manzardo C, Rimola A, et al. IFN-free therapy for HIV/HCV-coinfected patients within the liver transplant setting. J Antimicrob Chemother. 2016;71:3195–3201.
62. Campos-Varela I, Straley S, Agudelo EZ, et al. Sofosbuvir, simeprevir, and ribavirin for the treatment of hepatitis C virus recurrence in human immunodeficiency virus/hepatitis C virus-coinfected liver transplant recipients. Liver Transpl. 2015;21:272–274.
63. Grant JL, Hawkins C, Brooks H, et al. Successful sofosbuvir-based therapy in HIV/hepatitis C virus coinfected liver transplant recipients with recurrent hepatitis C virus infection. Aids. 2016;30:93–98.
64. Antonini T, Coilly A, Radenne S, et al. P0804: efficacy of sofosbuvir-based treatment regimens in HIV/HCV co-infected patients after liver transplantation: the ANRS CO23 CUPILT study. J Hepatol. 2015;62:S635–S636.
65. Ouwerkerk-Mahadevan S, Snoeys J, Peeters M, et al. Drug-drug interactions with the NS3/4A protease inhibitor simeprevir. Clin Pharmacokinet. 2016;55:197–208.
66. Badri PS, Parikh A, Coakley EP, et al. Pharmacokinetics of tacrolimus and cyclosporine in liver transplant recipients receiving 3 direct-acting antivirals as treatment for hepatitis C infection. Ther Drug Monit. 2016;38:640–645.
67. Kwo PY, Badshah MB. New hepatitis C virus therapies: drug classes and metabolism, drug interactions relevant in the transplant settings, drug options in decompensated cirrhosis, and drug options in end-stage renal disease. Curr Opin Organ Transplant. 2015;20:235–241.
68. Raschzok N, Schott E, Reutzel-Selke A, et al. The impact of directly acting antivirals on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C. Transpl Infect Dis. 2016;18:896–903.
69. Saab S, Rheem J, Jimenez M, et al. Curing hepatitis C in liver transplant recipients is associated with changes in immunosuppressant use. J Clin Transl Hepatol. 2016;4:32–38.
70. Kiser JJ. Clinically significant drug-drug interactions between hepatitis C virus and HIV treatments. Top Antivir Med. 2016;24:106–110.

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.