Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation

Journal of Hepatology Update: Hepatitis C

Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation Martina Gambato, Sabela Lens, Miquel Navasa, Xavier Forns⇑ Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain

Treatment

Summary Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon-free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon-free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multidrug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant

Keywords: Decompensated cirrhosis; Waiting list; Liver transplantation; HCV recurrence; DAA; Sustained virologic response; Adverse events; Fibrosis regression. Received 24 May 2014; received in revised form 3 July 2014; accepted 11 July 2014 ⇑ Corresponding author. Address: Liver Unit, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. Tel.: +34 93 227 5753; fax: +34 93 227 1779. E-mail address: [email protected] (X. Forns). Abbreviations: HCV, hepatitis C; LT, liver transplantation; DDI, drug-drug interactions; DAAs, direct-acting antivirals; PegINF, peginterferon; RBV, ribavirin; MELD, model of end-stage liver disease; PI, protease inhibitor; PR, peginterferon plus ribavirin; SAEs, serious adverse events; HCC, hepatocellular carcinoma; SMV, simeprevir; DCV, daclatasvir; SOF, sofosbuvir; SVR, sustained virological response; SVR12, sustained virologic response 12-week after the end of treatment; LDV, ledipasvir; FDV, faldaprevir; ASV, asunaprevir; DBV, deleobuvir; ABT-267, ombitasvir; ABT-333, dasabuvir; US, United States; PK, drug pharmacokinetics; RAVs, resistant-associated viral strains; LLOD, lower limit of detection; ECM, extracellular matrix; HSCs, hepatic stellate cells; FCH, fibrosing cholestatic hepatitis; EPO, erythropoietin; CsA, cyclosporine A; INR, international normalized ratio; GFR, glomerular filtration rate; EAP, expanded access program.

setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT. Ó 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction In the last year, the approval of the first interferon-free regimens for the treatment of chronic hepatitis C has been a major step forward in hepatology. The safety and efficacy of the combination of several direct-acting antivirals (DAAs), compared to interferoncontaining regimens [1], has opened hope for groups of patients in whom interferon-based regimens were contraindicated or in whom these regimens had a very limited efficacy and poor tolerance. In particular, the negative impact of hepatitis C recurrence on graft and patient survival following LT [2,3] makes gaining information on how to treat these patients urgent. There are three well-defined groups of individuals for which there is an urgent need to assess the safety and efficacy of interferon-free regimens: (1) patients awaiting liver transplantation, (2) patients with decompensated cirrhosis not included in a waiting transplant list and; (3) individuals with hepatitis C recurrence after transplantation.

Management of patients awaiting liver transplantation Patients with advanced cirrhosis, particularly those awaiting LT, are one of the most difficult-to-treat population. The main aim of antiviral treatment for patients on the waiting list is to prevent HCV infection of the new liver, since HCV recurrence reduces graft and patient survival. Most centres indicate short term therapy in order to achieve undetectable HCV-RNA at LT, which is associated with a high chance of preventing graft infection following transplantation [4]. In a setting of shorting organ availability, a second potential aim is to improve liver function, and perhaps regain compensation for finally delisting. This has been shown in some patients with HBV-related cirrhosis treated with nucleo(s)tide analogues [5,6], but in HCV-infected cirrhotic patients this has not been demonstrated [7].

Journal of Hepatology 2014 vol. 61 j S120–S131

Key Points •

Treatment with IFN-free regimens will prevent hepatitis C recurrence in a significant proportion of patients with compensated cirrhosis and hepatocellular carcinoma awaiting LT. The best treatment regimen in this scenario is still not defined, but most likely will consist of the combination of sofosbuvir with a second DAA (daclatasvir, ledipasvir, simeprevir depending on the HCV genotype). In areas where these drugs are not available, IFN-based regimens may still prevent hepatitis C recurrence in a small proportion of patients.

•

Patients with decompensated cirrhosis cannot undergo IFN-based regimens. Data on safety and efficacy of IFN-free regimens in this population are very limited and thus, recommendations are not supported by data. In decompensated cirrhotic patients awaiting LT, IFNfree regimens may allow viral clearance and prevent hepatitis C recurrence. In addition, viral clearance may be associated with liver function improvement, keeping some patients away from LT (with a better use of this valuable resource). Pharmacokinetics and safety data in this patient population are available for sofosbuvir, simeprevir and daclatasvir.

•

In decompensated cirrhotic patients not enlisted for transplantation, treatment with IFN-free regimens should aim at reducing clinical events and particularly at improving survival. Treatment in this population might be considered in cases without life-threatening comorbidities. Nevertheless, well designed trials are necessary to address the clinical benefit of treating this population.

•

IFN-free regimens should be the goal for individuals with severe hepatitis C recurrence after LT. Early treatment of individuals with aggressive HCV recurrence may allow for a full recovery of liver function and fibrosis regression.

•

In liver transplant recipients with decompensated cirrhosis IFN-free regimens may be associated with improvement in liver function in some patients. In those who do not improve, retransplantation might become a choice in the case of a high MELD score and HCV clearance.

donor liver transplantation recipients and patients with HCC with MELD exception points (typically patients with better liver function) demonstrated SVR rates around 50% if pre-transplant therapy lasted >16 weeks [9]. In patients with more advanced disease, serious adverse events (i.e., bacterial infections, such as spontaneous bacterial peritonitis or spontaneous bacteraemia [8], grade 3 and 4 cytopenias and clinical decompensation) are frequent and can be life-threatening. Thus, only a small proportion of HCV-infected patients can undergo interferon-based treatment. The addition of first-generation protease inhibitors (PIs), boceprevir and telaprevir, to PR is clearly associated with an increase in response rates in G1 infected patients [12–16], including some patients awaiting LT. Verna et al. [17] reported the results of triple therapy in a small cohort of HCV-infected cirrhotic patients (n = 29) on the waiting list for LT (Child-Pugh A 62%, Child-Pugh B 38%). The median duration of treatment was 27 weeks. Post-transplant SVR12 was 67% (8 out of 12 transplanted patients). From a perspective of safety, serious adverse events occurred in nine patients (31%), including one death (3%) and 8 hospitalizations (28%). Despite these results, the proportion of patients on the waiting list that may benefit from triple therapy with telaprevir or boceprevir is small, for several reasons. First, in decompensated patients (Child-Pugh C) IFN-based therapies are contraindicated. Second, SVR rates are very low in cirrhotic patients who are previous null-responders to PR (a common situation in patients awaiting LT). Third, PI-based regimens in real-life compensated cirrhotic patients are associated with serious adverse events (SAEs), such as severe infections (4–6%), clinical decompensation (3–4%) and even death [18,19]. Patients with a platelet count below 100,000/mm3 and serum albumin levels below 35 g/L have a higher risk than 40% to life-threatening side effects [18]. More importantly, with the recent approval of sofosbuvir, simeprevir and daclatasvir, the use of boceprevir and telaprevir should not be recommended in this population [20]. Despite not having data on the efficacy of PR combined with new DAAs in patients awaiting LT, studies assessing these combinations which include a sufficient number of patients with cirrhosis, suggest good safety and efficacy in individuals with well-compensated disease in whom the indication for LT is HCC. SVR rates in cirrhotic patients treated with PR plus simeprevir (SMV), daclatasvir (DCV) and sofosbuvir (SOF) are summarized in Fig. 1 100

60%

60%

58%

12/20

29/48

83/142

60 40

F

+

+

PR

43/54

SMV + PR

DC V

0

PR

20

SO

Current interferon-based treatments are not optimal in patients with advanced cirrhosis. Some studies have shown that peginterferon (PegIFN) plus ribavirin (RBV) administered to patients on the waiting list can prevent graft infection in patients who achieve undetectable HCV RNA [4,8–10]. Virological responses maintained after LT are around 25%, even when using a low accelerating dose regimen (LADR) [10]. Sustained virological response (SVR) rates are higher in individuals infected with HCV genotypes 2 and 3, as well as in those with the IL28B CC genotype [11]. Nevertheless, interferon-based therapy can only be administered in cirrhotic patients with good liver function (Child-Pugh 67 or MELD 618), in whom the indication of transplantation is hepatocellular carcinoma (HCC) [3]. A recent study including living

SVR12 (%)

80

Interferon-based regimens

Naive Treatment-exp.

80%

Fig. 1. Efficacy results of IFN-based therapies in cirrhotic patients. SOF + PR, sofosbuvir plus PegIFN and RBV during 12 weeks, genotype 1 (NEUTRINO study [21]). SMV + PR, simeprevir (12 weeks) plus PegIFN and RBV (24–48 weeks), genotype 1 (pooled data of QUEST-1 [22], QUEST-2 [23], PROMISE [24], ASPIRE [25], and ATTAIN studies [26]). DCV + PR: daclatasvir (12–24 weeks) plus PegIFN and RBV (24–48 weeks), genotypes 1 and 4 (COMMAND-1 study) [27].

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Journal of Hepatology Update: Hepatitis C

Sofosbuvir and ribavirin in patients awaiting LT In a phase 2 open-label study, 61 HCV-infected patients (G1–4) awaiting LT, received sofosbuvir and ribavirin until transplantation or up to 48 weeks [29]. The indication for LT was HCC; nearly 75% of patients were Child-Pugh A, all had MELD score below 15 and most individuals were previous non-responders to interferon-based regimens (75%). The median duration of therapy was 17 weeks. Forty-six patients underwent LT and of these, 43 (92%) had HCV RNA <25 IU/ml at time of LT. Of them, 42 reached 12 weeks of follow-up after transplantation and 29 (69%) achieved SVR at 12 weeks after the end of therapy (SVR 12). The strongest predictor of post-LT SVR was the number of consecutive days with undetectable HCV RNA prior to transplant, with only one relapse among the 25 individuals with undetectable HCV-RNA for >28 days while on treatment. Treatment with SOF + RBV was generally well tolerated. The most frequently reported adverse events were mild, and only 1 patient discontinued treatment due to anaemia. These efficacious results are encouraging. Longer treatment duration and/or the addition of a second DAA (currently under evaluation with ledipasvir [LDV]), may reduce the rate of virological relapse.

in the non-RBV arms (Fig. 2A). In the second study (ION-2), which included treatment-experienced patients (with a significant number of failures to PI), there were 88 cirrhotic patients: SVR rates were 100% in the 24-week regimen, but the figure decreased to 85% in the 12-week arms (Fig. 2A). The latter suggests that a regimen containing sofosbuvir and ledipasvir is excellent in compensated cirrhotics; extension to 24 weeks may be necessary in previous non-responders. A large randomized clinical trial performed specifically in cirrhotic patients with an all-oral DAA combination [34] has recently evaluated the safety and efficacy of ABT-450 boosted with ritonavir, ombitasvir, and dasabuvir co-administered with RBV for 12 or 24 weeks in HCV genotype 1-infected patients (both treatment-naïve and -experienced). SVR rates reached 92% and 96% in the 12-week and 24-week arms, respectively (Fig 2A). A trend toward slightly lower SVR rates were observed in G1a previous null-responders, as well as in patients with more significant portal hypertension (platelets <100,000/mm3) or more advanced cirrhosis (albumin <35 g/L) in the 12-week arm. Finally, a combination of daclatasvir and asunaprevir (ASV) for 24 weeks was evaluated in 223 genotype 1b cirrhotics; SVR rates were 91% in treatment-naïve, 81% in ineligible/intolerant patients and 87% in treatment-experienced individuals [35]. For genotype 2 and 3-infected patients, results from four phase 3 trials assessing sofosbuvir plus ribavirin have been published (Fig. 2B). Overall, SVR rates in G2 were consistently lower in cirrhotic patients compared to non-cirrhotics, but 12 or 16week regimens achieved SVR rates of around 80%. Regarding genotype 3, it became clear that a 12-week regimen of sofosbuvir and ribavirin was insufficient for cirrhotic patients [21], in whom treatment extension up to 24 weeks increased SVR rates up to 92% in treatment-naïve patients and to 61% in previous nonresponders to PR [36] (Fig. 2B). For G4-infected patients there is very little data on interferon-free regimens, and no solid recommendations can be given in case of cirrhosis [20].

Future interferon-free regimens in patients awaiting LT In most phase 2 and registration trials, the proportion of cirrhotics is small and those with clinically significant portal hypertension are usually excluded. The data available so far are not enough for indicating IFN-free regimens to all patients awaiting a transplant, particularly for decompensated cirrhotics. However, patients with platelet counts above 50,000–60,000/mm3 (and thus with significant portal hypertension) were included in a few trials and safety and efficacy results were still good (Tables 1 and 2). The available data support the use of IFN-free regimens in patients with compensated cirrhosis and hepatocellular carcinoma awaiting LT. For genotype 1 cirrhotic patients, the combination of sofosbuvir and ribavirin appears suboptimal, particularly in previous non-responders. Data from phase 2 studies [30,31] strongly suggest that the addition of simeprevir or daclatasvir to sofosbuvir (with or without ribavirin) significantly increases SVR rates up to 90% (Table 1). The data are yet to be confirmed in clinical trials including a larger number of cirrhotic patients (Table 2). Two registration phase 3 studies have assessed the safety and efficacy of sofosbuvir and ledipasvir (with or without ribavirin) for 12 vs. 24 weeks in G1 infected patients [32,33]. In the first study (ION-1), which included naive patients, there were 136 cirrhotic patients and SVR rates were 100% in the RBV arms and 97%

Specific features of interferon-free regimens in patients awaiting LT With the current approval of sofosbuvir, simeprevir and daclatasvir in the US and Europe, interferon-free regimens are being used in those cirrhotic patients with compensated liver disease awaiting LT. In patients with decompensated liver disease, on the waiting list for LT, safety and efficacy data are still lacking and thus no clear recommendations can be given. In any case, there are some distinct features that should be taken into consideration in individuals awaiting LT. The primary goal of treatment in these patients is to prevent HCV graft infection. Since the main source of virions (if not all) will be removed, this may be accomplished by a short course of antiviral therapy [29]. As shown above, sofosbuvir and ribavirin seem to be a good choice in this setting. There are, however, some problems associated with this strategy: (1) timing of treatment is difficult (when to start?), (2) there is the possibility of post-LT relapse, and (3) if a second DAA is added, there are no safety data in Child-Pugh B and Child-Pugh C patients and pharmacokinetic studies are not available for all drugs (Table 3). A second approach for treating patients on the waiting list may be to complete a full treatment course to achieve SVR, not only to prevent graft infection but to assess if liver function improves. In some patients without HCC, the improvement in liver function and/or portal hypertension could imply delisting. In others, however, improvement may not occur or may be insufficient for avoiding LT.

[21–27]. The combination of PR plus sofosbuvir for 12 weeks seems to offer the highest efficacy and the best safety profile: this regimen was evaluated in the NEUTRINO phase 3 trial in treatment-naïve G1, 4, 5, and 6 patients (most G1) [21]. The overall SVR rate was 90%: cirrhotic patients had a lower sustained virologic response (SVR) rate than non-cirrhotic patients (80% vs. 92%, respectively). Regretfully, data in treatment-experienced cirrhotic patients using this combination, are only available in a small number of G2 and G3 infected patients, with SVR rates over 80% [28]. Interferon-free regimens in patients awaiting LT

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JOURNAL OF HEPATOLOGY Table 1. Phase 2 clinical trials with IFN-free regimens including cirrhotic patients.

Response to previous IFN based therapy

Treatment duration in the specific arm (wk) 24

Cirrhotic patients enrolled in the study N (%) 13 (26) F3-4

Genotype spectrum

SVR in cirrhotic patients

Naïve

Lower limit of platelets (mm3) 75,000

1 (G1a 70%)

SOF + RBV or GS-0938 or GS-0938 + SOF (± RBV) (QUANTUM) [95] SOF + LDV ± RBV (6th and 7th arms) (ELECTRON) [96]

Naïve

50,000

12 24

21 (9)

1-4

SVR24 50% and 29% (weight-based and low-dose RBV respectively) SVR12 50% (SOF + RBV arm, 24 wk)

Null-responder

n.s.

12

19 (100)

1

SOF + LDV ± RBV (Cohort B) (LONESTAR) [97]

Non-responder to protease inhibitor regimen

n.s.

12

22 (55)

1 (G1a 85%)

SOF + LDV (arm A) (NIAID SYNERGY) [98] SMV + SOF ± RBV (Cohort 2) (COSMOS) [30] DCV + ASV + BMS-791325 [99]

Naïve

50,000

12

3 (15)

1 (G1a 55%)

Naïve and nullresponder

n.s.

12 24

41 (25)

1 (G1a 78%)

Naïve

n.s.

12

15 (9)

1 (G1a 86%)

FDV + DBV ± RBV (SOUND C2) [100]

Naïve

90,000

16, 28, 40

33 (9)

1

FDV + DBV + RBV (SOUND C3) [101] SOF + DCV ± RBV (A1444040) [31]

Naïve

75,000

16

4 (20)

1

Naïve and treatment- n.s. experienced (also to protease inhibitors) Naïve and treatment- 50,000 experienced (CTP-A)

12 24

32 (15)

1-3

12

20 (100) G1* 8 (16) in G3

1,3

MK-5172 + MK-8742 ± RBV (WORTHY) [103]

Null-responder

12 18

123 (100) naïve and 51 (39) in NR

1

SOF + RBV [39]*

Naïve and treatment- n.s. experienced

48

50 (100)

1-4

SOF/LDV FDC ± RBV (ELECTRON-2) [102]

70,000

SVR12 100% and 70% (with and without RBV respectively) SVR12 100% and 95% (with and without RBV respectively) SVR12 100% SVR12 91% null-responders (21/33) 94% naïve (17/18) SVR12 71% and 100% with 75 mg and 100 mg of BMS-791325 respectively SVR12 33%-67% according to different regimen SVR12 100% SVR12 100% SVR12 G1 65% SVR12 G3 100% in LDV/ SOF + RBV arm SVR8 94 and 100% in G1a and G1b respectively (both naïve and treatmentexperienced) Week 24 of therapy HCV-RNA
⁄

Including patients with decompensated cirrhosis. n.s., no specified platelet lower limit. wk, weeks; G, genotype; CTP, Child-Pugh; SVR12, sustained virologic response 12 weeks after the end of treatment; SVR24, sustained virologic response 24 weeks after the end of treatment.

A second distinct feature, particularly in those with decompensated disease, is the impact of liver function on drug pharmacokinetics (PK): metabolic liver functions are significantly involved in the total clearance of a number of drugs. PK studies in patients with liver disease are an important clinical pharmacology component of drug development [37]. PK data on a number of new antivirals are already available and summarized in Table 3.

As an example, exposure to sofosbuvir was 2-fold higher in HCV-infected patients without hepatic impairment, as compared to patients with advanced liver disease. The latter group experienced a less profound viral decline than those with normal liver function when sofosbuvir was administered [38]. These data, supported by a recent study performed in decompensated cirrhotics [39], may have clinical consequences and explain why in patients with advanced liver disease longer treatment duration

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Therapeutic regimen in trial arm including cirrhotic population (trial name) SOF + RBV NIH SPARE [94]

Journal of Hepatology Update: Hepatitis C

Treatment

Table 2. Phase 3 clinical trials with IFN-free regimens including cirrhotic patients.

Therapeutic regimen in trial arm including cirrhotic population (Trial name) SOF + RBV [104]

Response to previous IFN based therapy

Lower limit of platelets (mm3) Naïve and treatment- n.s. experienced

Treatment duration in the specific arm (wk) 12 24

Cirrhotic patients enrolled in the study N (%) 14 (23)

Genotype spectrum

SVR in cirrhotic patients

4

DCV + ASV + BMS-791325 [105] SOF + RBV (FISSION) [21] SOF + RBV (POSITRON) [106]

Naïve

n.s.

12

2 (10)

4

Naïve

75,000

12

50 (20)

2, 3

IFN intolerant

No lower limit

12

31 (15)

2, 3

SOF + RBV (FUSION) [106]

Non-responder

50,000

12 16

36 (35) 32 (33)

2, 3

SOF + RBV (VALENCE) [36]

Naïve and treatment- 50,000 experienced

12 G2 24 G3

10 (14) G2 59 (22) G3

2, 3 (G3 78%)

LDV/SOF ± RBV (ION-1) [32] LDV/SOF ± RBV (ION-2) [33]

Naïve

50,000

136 (16)

1

Treatmentexperienced

50,000

12 24 12 24

88 (20)

1

DCV + ASV [107]

IFN ineligible naïve/ n.s. intolerant and nonresponder Naïve, IFN ineligible/ n.s. intolerant and nonresponder

24

22 (10)

1b

SVR12 79% and 100% in naïve 59% and 87% in treatmentexperienced (12 and 24 wk respectively) SVR12 100% SVR12 47% SVR12 61% (G2 94% and G3 21%) SVR12 G2 60% and 78% G3 19% and 61% (12 and 16 wk respectively) SVR12 G2 100% and 88% G3 92% and 60% (naïve and treatmentexperienced respectively) SVR12 97 and 100% ± RBV (both 12 and 24 wk) SVR12 82-86% 12 wk arm (± RBV) and 100% 24 wk arm SVR24 90.9%

24

223 (30)

1b

12 24

380 (100)

1

DCV + ASV (HALLMARK-DUAL) [35]

ABT-450/r + ombitasvir + Naïve and treatment- 60,000 dasabuvir + RBV experienced (TURQUOISE II) [34]

SVR12 91%, 87% and 81% in naïve, non-responders and ineligible/intolerant respectively SVR12 91.8% and 95.9% in 12 and 24 wk

n.s., no specified platelet lower limit; W, weeks; G, genotype; CTP, Child-Pugh; SVR12, sustained virologic response 12 weeks after the end of treatment; SVR24, sustained virologic response 24 weeks after the end of treatment.

could be necessary to reduce the rates of virological relapse. From a safety point of view, exposure to some new compounds (such as ABT450/r) is significantly increased in Child-Pugh C patients and its use is currently not recommended. Adjustment of simeprevir is not required in Child-Pugh class A or B patients [40], but particular caution is recommended when prescribing simeprevir to HCV-infected patients with moderate or severe hepatic impairment since no studies in HCV-infected individuals are available yet. In patients with severe hepatic impairment (Child-Pugh class C) simeprevir exposure is significantly increased and should be avoided [40] (Table 3). A third distinct feature of patients awaiting LT is the potential risk of viral breakthrough or relapse during or after treatment, which may theoretically induce flares that could trigger liver decompensation. It is thus very relevant to choose the best treatment combination (high potency and high genetic S124

barrier) in order to minimize the possibility of virological relapse or the selection of resistant-associated viral strains (RAVs). S282T is the only variant shown to confer reduced susceptibility to sofosbuvir in vitro, but it has not been detected in patients after virological failure. Differently, resistance to NS5A, non-nucleotide NS5B and NS3 protease inhibitors are frequently detected in individuals with virological failure. The fitness of resistant strains is usually lower than that of the wildtype viruses, which tend to progressively replace RAVs. NS5A RAVs, however, seem to persist for a long time. This is relevant, since the presence of multi-resistant strains may hamper antiviral therapy if urgent treatment is required (such as in cases of decompensated cirrhosis with virological relapse or severe hepatitis C recurrence after LT). A nucleotide-based regimen (such as sofosbuvir) appears to be the best salvage strategy in such cases.

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JOURNAL OF HEPATOLOGY Management of patients with decompensated cirrhosis without an indication for LT

Naive Treatment-exp. or IFN ineligible 98%

100

92%

91%

94% 93%

84%

SVR12 (%)

80 60 40 20

SOF + LDV ± RBV

B

0

0

22

1/

20

15

5/

16

3 17 5/

DCV + ASV

ABT-450/r/ O/D + RBV

G2 Naive G2 Treatment-exp./IFN ineligible G3 Naive G3 Treatment-exp./IFN ineligible

100 SVR12 (%)

29 /3 2

14

13 2/ 13

81 /8 8

4

0

92%

83% 78%

80

61%

60%

60 40

60%

34% 19%

20

12 12

27 /4 5

5/ 26

14 /2 3

13 /3 8 12 /1 3

7/ 9

6/ 10

10 /1 2

0 16 12 24 12 16 24 SOF + RBV (wk)

Fig. 2. Efficacy results of phase 3 IFN-free therapies in cirrhotic patients genotype-1 (A) and genotypes 2/3 (B). SOF + LDV: sofosbuvir plus ledipasvir with or without ribavirin 12-24 weeks (ION-1 [32] and 2 [33]). DCV + ASV: daclatasvir and asunaprevir for 24 weeks (only genotype 1b patients) [35]. ABT450/r/O/D: ABT-450 boosted with ritonavir plus ombitasvir, dasabuvir and ribavirin 12-24 weeks [34]. SOF + RBV: pooled data of sofosbuvir plus ribavirin 12/16/24 weeks in the FISSION [21], FUSION [106] and VALENCE [36] studies.

Table 3. Pharmacokinetics (change in AUC) of DAAs in hepatic impairment (graded according to CTP score) and recommendation.

Drug Sofosbuvir [38,108] Simeprevir [109]† Daclatasvir [110, 111] ¥ Asunaprevir [112] Ledipasvir [113] ABT-450/r [114]§ Dasabuvir [114] Ombitasvir [114] MK-8742 [103] MK-5172 [103]

CTP A (5-6 points) NR NR NR NR NR NR NR NR NR NR

CTP B (7-9 points) NPD NR NR AUC x 9.8 NR NR NR NR NR NR

CTP C (≥10 points) NPD AUC x 3 NR AUC x 32 NR AUC x 11 NR NR NPD NPD

NR, dose adjustment not required; NPD, no pharmacokinetic data or studies ongoing.   AUC14 is given. ¥ AUCtau is given. § AUCinf is given.

Patients with decompensated cirrhosis who are not candidates for LT are usually the elderly or those in whom the presence of comorbidities contraindicate a LT [41,42]. In these patients, the only chance to improve or stabilize liver function is to eradicate HCV with an interferon-free regimen. Indeed, in those individuals without comorbidities impairing their life expectancy, HCV eradication may be associated with clinical improvement and finally with increased survival. Clinical trials in patients with decompensated disease should include ‘‘hard’’ end points: improvement in liver function, a decrease in clinical decompensation episodes and an increase in survival. However, the impact of SVR in patients with decompensated cirrhosis may be heterogeneous, since it encompasses a wide spectrum of disease, ranging from patients with relatively wellpreserved liver function (mild ascites or recent variceal bleeding) to patients with very poor liver function and a short life expectancy (Child-Pugh C >10 points) [43]. It is likely that in the latter group viral clearance will not significantly modify patients’ clinical outcomes or survival. Nevertheless, only well-designed studies including appropriate control groups will be able to answer these questions. Moreover, safety issues need to be carefully addressed in this patient population. Preliminary results of the first study assessing the effect of viral suppression on liver function were recently presented at the EASL meeting (ILC 2014) [39]. In this study, cirrhotic patients with documented portal hypertension and compensated or decompensated cirrhosis (Child-Pugh 5–9 points) were randomized to sofosbuvir and ribavirin for 48 weeks vs. an observational arm (after 6 months these patients crossed over to the treatment arm). From a virological point of view, it was interesting to learn that 2 and 4 weeks after treatment initiation 56% and 100% of Child-Pugh A patients had undetectable HCV-RNA; figures for Child-Pugh B patients were only 44% and 75%, respectively. This might be particularly relevant in patients awaiting LT (see above) where a short treatment course of therapy might not be sufficient to prevent post-LT relapse. After a 24-week period, the results suggested a reduction of ascites and hepatic encephalopathy episodes in patients included in the treatment arm. However the study was not blinded (and a bias when assessing clinical outcomes cannot be excluded). More importantly, data on the effect of treatment on portal pressure are not available yet. There are several studies assessing interferon-free combinations in patients with decompensated cirrhosis (Child-Pugh B and C) (Supplementary Table 1).

Treatment of hepatitis C recurrence after liver transplantation HCV-related cirrhosis is the leading indication for LT in industrialized countries [44]. Virological recurrence after transplantation is constant in patients with detectable viraemia at the time of LT [45]. The main characteristic of hepatitis C recurrence after LT is the accelerated course of the disease when compared to immunocompetent patients [46–50]. Approximately one third of the patients progress to graft cirrhosis within only 5 years after transplantation [51,52]. This accelerated

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A

Journal of Hepatology Update: Hepatitis C Table 4. Drug-drug interactions between DAAs and calcineurin inhibitors.

DAA Boceprevir [115, 116] ¥ Telaprevir [77, 117] ¥ ABT450/r [86] Simeprevir [118]§ Sofosbuvir [119]¥ Daclatasvir [120]

Cyclosporine Healthy volunteers Dose adjustment AUC ↑ 2.7 fold ↓ 2 fold AUC ↑ 4.6 fold ↓ 4 fold AUC ↑ 5.8 fold ↓ 5 fold AUC ↑ 19% Under investigation No change Not necessary No change Not necessary

Healthy volunteers AUC ↑ 17 fold AUC ↑ 70 fold AUC ↑ 58 fold AUC ↓ 17% No change No change

Tacrolimus Dose adjustment ↓ 5 fold ↓ 35 fold ↓ 100 fold Not necessary Not necessary Not necessary

¥

Treatment

§

AUCinf is given. AUCLast is given.

fibrosis rate impacts both the allograft and recipient survivals, which are significantly reduced when compared with non-HCV LT recipients [46,50,51]. The effect of SVR on disease progression has been analysed in large cohorts of non-immune compromised patients, comparing pre- and post-treatment liver biopsies. The data demonstrate improvements in inflammation and fibrosis scores following SVR [53–60], although in a non-homogeneous pattern (a subset of patients remains at the same stage, and some even display persistent inflammation and/or fibrosis progression) [61]. The most important factor that determines fibrosis regression after SVR is the baseline liver fibrosis stage [60]. Actually, the rate of cirrhosis regression has been estimated at 5–15% after ten years [60,61]. Early cirrhosis might be more likely to regress than established cirrhosis. Old fibrous septa contain high-density fibrillar collagens (I and III) and proteoglycans, pauci-cellularity and an increase in extracellular matrix (ECM) cross-linking, which may contribute to the resistance to fibrosis regression [62–65]. Elastin, which accumulates in mature cirrhosis, is another non-collagenous matrix component that negatively influences fibrosis reversion [66,67]. Moreover, the presence of established significant portal hypertension may also be determinant in fibrosis irreversibility, since it is associated with an inflammatory state of the endothelium that in turn, may activate hepatic stellate cells (HSCs) and fibrogenesis [68–70]. The information available in liver transplant patients is scarce, but most likely these assumptions can be translated into LT patients, particularly those who have developed cirrhosis over the years. In patients who develop significant fibrosis (METAVIR F P2) during the first year, the situation may be different and fibrosis appears to be more reversible. Several studies have shown a significant histological improvement or stabilization after SVR, in opposition to non-responders [71,72]. Similarly, portal pressure measurements and determinations of transient elastography also suggest a beneficial effect of antiviral treatment on liver fibrosis when SVR is achieved [72]. Probably the most striking case is that of fibrosing cholestatic hepatitis (FCH), where a very early massive fibrosis deposition can reverse if treated promptly and viral clearance is achieved. Interferon-based regimens to treat hepatitis C recurrence after LT The most common approach to treat hepatitis C after LT has been to start antiviral therapy once the histological damage (in particular liver fibrosis) is confirmed in the graft. The presence of

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significant fibrosis beyond the portal tract (METAVIR F P2), portal hypertension (HVPG P6 mmHg) or high liver stiffness (>8.7 kPa) one year after LT accurately identify patients at higher risk for clinical decompensation and death [73,74], who are in urgent need of treatment. In patients with a severe recurrence occurring during the first months after transplantation (i.e., FCH), antiviral therapy is critical, but IFN-based regimens are unable to eradicate HCV in many cases, and patients die or need re-transplantation. The overall SVR rates with PegIFN plus RBV are low; ranging between 30% and 40% across different series [71,75,76]. These modest virological results are mainly explained by high rates of treatment discontinuation (20–38%) and dose reductions (66– 73%) due to adverse events. Liver transplant recipients are prone to haematological toxicity (particularly anaemia). RBV dose reductions and the use of erythropoietin (EPO) are very frequent (75–80%) in this setting [77]. The risk of rejection is small; in the order of 5% in treated patients [78,79]. Regarding triple therapy with PIs in the post-LT setting, several studies have evaluated the safety and efficacy of such regimens in over 300 patients with hepatitis C recurrence [80–82]. Two thirds of them received telaprevir and the rest were treated with boceprevir. Most of the patients had an advanced fibrosis stage (METAVIR F P2) or FCH. Approximately half of the patients had received a previous course of antiviral therapy. SVR12 rates ranged between 48% and 62% [80–82]. Despite the increased efficacy, the major concern of triple therapy in LT recipients is the high rate of SAEs leading to treatment discontinuation. Drug-drug interactions (DDIs) are an additional challenge when using telaprevir and boceprevir. First generation PIs are not only substrates, but also inhibitors of the CYP3A4 system, thus strongly interacting with many drugs. Due to the narrow therapeutic range of cyclosporine (CsA) and tacrolimus, dose adjustments are crucial and require very close monitoring when combined with PIs (Table 4). Data from the only clinical trial assessing the safety and efficacy of telaprevir in the liver transplant setting were presented at the recent EASL meeting [83]. This was an open-label, singlearm, study including 20 sites in Europe. Patients with hepatitis C recurrence, naïve to PR and with a METAVIR score of F0–F3 underwent 12 weeks of triple therapy followed by 36 weeks of PR. Tacrolimus or cyclosporine doses were adjusted on telaprevir initiation and discontinuation. Final data from 74 patients included in the study were available at time of writing this review and 53 (72%) had achieved SVR12. Nine (12%) patients had 11 SAEs and no rejection episodes were diagnosed during the study period.

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JOURNAL OF HEPATOLOGY Interferon-free regimens after LT

96%

100 80 SVR12 (%)

72%

70% 63%

60 40

* 62%

50%

PegIFNα + RBV PegIFNα + RBV + PI SOF + RBV SOF + RBV + PegIFNα ABT 450/r/O/D + RBV

30%

20

48

48 24 24 Weeks of treatment

25 /2 6

13 /3 0

28 /4 0

6/ 12

51 /8 1

0 53 /7 4

24

Fig. 3. Efficacy results of IFN-based and IFN-free regimens in liver transplant recipients with hepatitis C recurrence after LT. ⁄Compassionate sofosbuvir use program including only patients with severe hepatitis C recurrence and a life expectancy <12 months. O, ombitasvir; D, dasabuvir. PegIFN + RBV [75] and [76]; PegIFN + RBV + PI: SVR12 72% [83]; SVR12 63% [82]; SVR12 50% [81]; SOF/RBV [84]; SOF/RBV ± PegIFN [85]; ABT450/r/O/D [86].

ABT450/r, ombitasvir + dasabuvir and ribavirin in HCV-infected LT recipients In this phase 2 study [86] the safety and efficacy of this 3 drug combination, plus ribavirin administered during 24 weeks, was assessed in 34 HCV-infected liver transplant patients. The initial ribavirin dose was decided by the investigators. Individuals were infected with G1, were naïve after transplantation and had a METAVIR score 6F2. Based on a previous DDI study, recommendations regarding immunosuppression were to reduce the tacrolimus dose by 0.5 mg/week and cyclosporine to 1/5 at time of antiviral treatment initiation. Preliminary analysis has shown that all 34 patients had undetectable HCV-RNA at the end of treatment, and 25 (96%) of 26 with sufficient follow-up achieved SVR12. The only patient who experienced relapse had RAVs (R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B); none of these mutations present at baseline. Tolerance of this regimen was good; no episodes of rejection were reported. Other IFN-free regimens Several clinical trials using different DAA combinations are currently recruiting patients (Supplementary Table 1). In addition, analysis of expanded access programs (such as sofosbuvir and daclatasvir) will also provide relevant practical information in the next few months [87]. Specific features of interferon-free regimens in HCV-infected liver transplant recipients Treatment with interferon-free regimens in patients with hepatitis C recurrence is challenging for several reasons. Treatment may be indicated in individuals with very aggressive forms of hepatitis C (such as FCH), which occur very early after transplantation. The latter poses several difficulties, since at this early period individuals are still under strong immunosuppression, at risk of opportunistic infections, not uncommonly recovering or being treated from surgical complications and undergoing treatment with multiple drugs. Fortunately, many new anti-HCV compounds do not seem to have clinically significant interactions with CsA and tacrolimus (Table 4).

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Sofosbuvir and ribavirin Sofosbuvir and RBV is the first interferon-free combination that has been assessed in hepatitis C recurrence in a clinical trial [84]. A pilot single-arm study assessed the safety and efficacy of sofosbuvir 400 mg/d and RBV (dose escalating regimen starting at 400 mg/d) for 24 weeks in 40 patients with HCV recurrence (any genotype) at least 6 months after LT. From the 40 patients, 33 were infected with G1. The study included treatment-naïve and treatment-experienced patients (some with PIs); 40% were compensated cirrhotic patients. The primary efficacy end point was SVR12. Despite these characteristics, all individuals had HCV RNA <25 IU/ml at week 4 of treatment initiation. SVR12 was achieved in 28 (70%) of the 40 patients (Fig 3). Ribavirin dose adjustments did not influence SVR. These results can be considered excellent, particularly due to the good tolerance: most side effects were mild and no rejection episodes occurred during therapy. Despite the small sample size and the lack of an interferon-based control arm in the study, the safety and tolerance profile of this combination seem significantly better than that of the current standard-of-care. Results from 104 HCV-infected LT recipients included in the compassionate use program of sofosbuvir were recently presented at the EASL meeting (ILC 2014) [85]. The antiviral regimen included sofosbuvir 400 mg/d for up to 48 weeks, with appropriate doses of RBV. PegIFN was added at the investigator’s discretion. The patients included in this program differed substantially from those included in the pilot study described above: approximately half of these patients had severe cholestatic hepatitis (some of them well-documented FCH) or were rapid fibrosers (METAVIR F P2 one year after LT); the remaining half had compensated or decompensated cirrhosis. Sixty patients (58%) presented an improved clinical condition (decrease of hepatic encephalopathy episodes and/or improvement/disappearance of ascites). Although clinical improvement was assessed by the investigators (and a bias cannot be ruled out), liver function tests (bilirubin, albumin, INR) improved remarkably over time. The other 22 patients (21%) remained stable, while in 22 (21%) the disease progressed or the patient died (n = 18). From the 93 patients from whom HCV-RNA testing was available at the end of treatment, 76 (82%) had HCV-RNA below LLOD; 53 (62%) of 85 patients with more than 12 weeks of follow-up after LT achieved SVR12. Severe adverse events were frequent, but they were mostly attributed to disease progression. Overall, the preliminary results of this program indicate that a regimen containing sofosbuvir was able to inhibit hepatitis C replication in most patients, and that this was associated with an improvement in the clinical condition in a significant number of patients. Although longer follow-up is needed to assess the rate of SVR and its impact on disease progression, these results can be considered very encouraging. A particularly relevant result of this study was the excellent response in patients with cholestatic hepatitis (including FCH), in which deeply perturbed laboratory values (bilirubin, albumin, INR) returned to normal a few weeks after treatment initiation and viral clearance. SVR12 in patients with acute cholestatic hepatitis/fibrosing cholestatic hepatitis was 70%, whereas SVR12 in those with compensated or decompensated cirrhosis points was 40% (Forns, personal communication). The latter strongly suggests the benefit of early treatment in severe forms of hepatitis C recurrence.

Studies including also Studies including patients with severe hepatitis C patients with recurrence METAVIR (METAVIR F4 or FCH) fibrosis score F <4

Journal of Hepatology Update: Hepatitis C Waiting list

No indication for liver transplantation

Decompensated cirrhosis CTP B-C Awaiting data from clinical trials

Clinical trials and/or EAP SOF + RBV SOF/DCV + RBV SOF/LDV + RBV# MK-5172/MK-8742*

Compensated cirrhosis CTP-A (HCC) SOF + RBV (± PegIFNα) SOF/SMV + RBV#§ SOF/DCV + RBV §

Compassionate use/EAP or clinical trials SOF/LDV + RBV# SOF/DCV + RBV

After liver transplantation

Decompensated cirrhosis CTP B-C SOF + RBV SOF/SMV + RBV#§ SOF/DCV + RBV §

Compassionate use/ EAP or clinical trials SOF + RBV SOF/LDV + RBV#

Mild recurrence F0-1

Individualize (no urgent need for therapy)

Clinical trials SOF + RBV SOF/DCV + RBV SOF/LDV + RBV# ABT-450/r/O/D + RBV¥ SMV/DCV + RBV#

Cholestatic HCV severe recurrence F2-4 SOF + RBV SOF/SMV + RBV#§ SOF/DCV + RBV§

Compassionate use/EAP or clinical trials SOF/LDV + RBV# SOF/DCV + RBV SMV/DCV + RBV# ABT-450/r/O/D + RBV¥

Treatment

Fig. 4. Therapeutic approaches of HCV infection in 3 different patient populations: cirrhotic patients with decompensated disease without the indication of LT, patients on waiting list for LT and liver transplant recipients with hepatitis C recurrence after LT. #Only GT1,4; ⁄only GT1,4–6; ¥only GT1 (pending regulatory approval); EAP, expanded access program; O, ombitasvir; D, dasabuvir. § Very few data are available at this time.

Renal failure is also common in liver transplant recipients. Most patients have decreased glomerular filtration rate (GFR) due (at least in part) to the long-term use of cyclosporine or tacrolimus. Sofosbuvir, for instance, is not recommended if GFR is below 30 ml/min [88]. An issue that needs particular consideration in the liver transplant setting is that these patients usually have high viral loads, making it easier to select for drug resistant strains. The latter might be particularly relevant in patients with FCH.

cirrhosis. In the latter group, viral clearance in individuals with high MELD scores might permit considering them for retransplantation [93]. We will probably start answering all these questions in the next months, when real-life data and results from ongoing clinical trials will gather relevant information that will help us choose the best choice for each patient. Meanwhile, a suggested approach to these difficult-to-treat patients is shown in Fig 4.

Financial support Treating before or after liver transplantation? The negative impact of hepatitis C infection on liver transplant recipients is well known. With a progressive increase in the age of the donors in recent years [89–91], the proportion of patients with severe forms of hepatitis C recurrence has increased and these patients will require antiviral treatment [47,73,92]. Furthermore, they will have a complex follow-up and consume a lot of resources: in most cases differential diagnosis from other frequent pathologies (such as rejection) is not easy. Adjustment of immunosuppressive drugs is complicated and patients often require hospitalization. Thus, from a theoretical point of view, treatment before transplantation seems ideal, because it may substantially improve the post-transplant course, it may increase survival, and in some cases viral clearance may be associated with liver function improvement and delisting (important in a context of organ shortage). However, before this strategy can be implemented in clinical practice, we need data on the safety and efficacy of interferon-free regimens in patients with decompensated cirrhosis and data on the impact of viral clearance on liver function. Furthermore, the time on waiting list for completing antiviral therapy is usually unpredictable. There are a number of patients who have already developed graft damage following transplantation and for whom the only choice in the coming years will be interferon-free regimens. These patients include individuals with early severe recurrence after transplantation, non-responders and intolerant-tointerferon-based regimens, and patients with decompensated S128

X. Forns received support in part by grants from Instituto de Salud Carlos III (PI11/01907), Ministerio de Economía y Competitividad, co-funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa. X. Forns also received a grant from the Roche Organ Transplantation Research Foundation (ROTRF, CI: 442035057). M. Gambato has been awarded with the EASL Entry Level Research Fellowship 2014 (Dame Sheila Sherlock EASL Fellowship Programme).

Conflict of interest X. Forns has acted as advisor for Janssen, Gilead and Abbvie, and has received unrestricted grant support from MSD and Roche. S. Lens has acted as advisor for Gilead, MSD and Janssen. M. Navasa has acted as advisor for Novartis and Astellas. M. Gambato has nothing to declare.

Authors’ contribution All authors have substantially contributed to the conception, analysis, and interpretation of the data. All authors have contributed in the drafting of the article, its critical revision for important intellectual content, have given final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the article.

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Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jhep.2014.07. 020.

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[21] Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878–1887. [22] Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014;384(9941):403–413. [23] Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2014; 384(9941):414–426. [24] Forns X, Lawitz E, Zeuzem S, Gane E, Bronowicki JP, Andreone P, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology 2014;146(7):1669–1679. [25] Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014;146:430–441. [26] Reddy K, Zeuzem S, Zoulim F, Weiland O, Horban A, Stanciu C, et al. A Phase III randomised, double-blind study to evaluate the efficacy, safety and tolerability of simeprevir vs. telaprevir in combination with pegylated interferon and ribavirin in chronic hepatitis C virus genotype 1 treatmentexperienced patients: the ATTAIN study. In: (APASL) 24th Conference of the Asian Pacific Association for the Study of the Liver. Brisbane, Australia; 2014. [27] Hezode C, Hirschfield GM, Ghesquiere W, Sievert W, Rodriguez M, Shafran SD, et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon Alfa-2a and ribavirin in treatment-naive HCV-genotype 1 or 4 subjects: phase 2b COMMAND-1 SVR12 results. Hepatology 2012;56:553A. [28] Lawitz E, Poordad F, Brainard DM, Hyland RH, An D, Symonds WT, et al. Sofosbuvir in combination with PegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment- experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Hepatology 2013;58(6):LB–4. [29] Curry MP, Forns X, Chung RT, Terrault N, Brown Jr RS, Fenkel JM, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology 2013;58:314A. [30] Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatmentnaive patients: the COSMOS randomised study. Lancet 2014;58. http:// dx.doi.org/10.1016/S0140-6736(14)61036-9, [Epub ahead of print]. [31] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211–221. [32] Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:1889–1898. [33] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483–1493. [34] Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370:1973–1982. [35] Manns M, Pol S, Jacobson I, Marcellin P, Gordon S, Peng C-Y, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: phase 3 study results. J Hepatol 2014;60:S524. [36] Zeuzem S, Dusheiko GM, Salupere R, Mangia A, Flisiak R, Hyland RH, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370:1993–2001. [37] Guidance for industry pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. [cited; Available from] . [38] Lawitz E, Rodriguez-Torres M, Cornpropst M, Denning JM, Clemons D, McNair L, et al. The effect of hepatic impairment on the pharmacokinetics and antiviral activity of PSI-7977 in hepatitis C infected subjects treated for seven days. J Hepatol 2012;56:S398. [39] Afdhal N, Everson G, Calleja JL, McCaughan G, Symonds WT, Denning J, et al. Sofosbuvir and ribavirin for the treatment of chronic HCV with cirrhosis and portal hypertension with and without decompensation: early virologic response and safety. J Hepatol 2014;60:S28.

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JOURNAL OF HEPATOLOGY

Treatment

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