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.
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.
II. MANAGEMENT OF HCV IN THE POST LIVER-TRANSPLANT RECIPIENT WITH RECURRENT CIRRHOSIS, INCLUDING DECOMPENSATION
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
- (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.
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
- (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.
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.
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.
III. MANAGEMENT OF HCV IN POST LIVER TRANSPLANT RECIPIENTS WITH SEVERE CHOLESTATIC HEPATITIS
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
- (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.
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.
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.
IV. MANAGEMENT OF HCV IN THE HUMAN IMMUNODEFICIENCY VIRUS/HCV COINFECTED LIVER TRANSPLANT RECIPIENTS
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
- (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
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.
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.
V. IMMUNOSUPPRESSION AND MONITORING DURING ANTIVIRAL THERAPY
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
- (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
- (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.
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
- (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.
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.
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.
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