July 4, 2013

This study is currently recruiting participants.

Verified June 2013 by AbbVie
Sponsor:
Information provided by (Responsible Party):
AbbVie
ClinicalTrials.gov Identifier:
NCT01782495
First received: January 22, 2013
Last updated: June 27, 2013
Last verified: June 2013
Purpose

This is a study to evaluate chronic Hepatitis C Virus infection.


Condition Intervention Phase
Chronic Hepatitis C Infection
Drug: ABT-450/r/ABT-267
Drug: ABT-333
Drug: ribavirin (RBV)

Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label, Single Arm, Phase 2 Study to Evaluate the Safety and Efficacy of the Combination of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered With Ribavirin (RBV) in Adult Liver Transplant Recipients With Genotype 1 Hepatitis C Virus (HCV) Infection

Resource links provided by NLM:


Further study details as provided by AbbVie:

Primary Outcome Measures:
  • Percentage of subjects with sustained virologic response 12 weeks post-treatment [ Time Frame: 12 weeks after the last actual dose of study drug ] [ Designated as safety issue: No ]
    Hepatitis C virus ribonucleic acid less than the lower limit of quantification

Secondary Outcome Measures:
  • Percentage of subjects with sustained virologic response 24 weeks post treatment [ Time Frame: 24 weeks after the last actual dose of study drug ] [ Designated as safety issue: No ]
    Hepatitis C virus ribonucleic acid less than the lower limit of quantification
  • Percentage of subjects with virologic failure during treatment [ Time Frame: Treatment Day 1 up to 24 weeks ] [ Designated as safety issue: No ]
    Hepatitis C virus (HCV) ribonucleic acid (RNA) confirmed greater than or equal to the lower limit of quantification, after HCV RNA less than the lower limit of quantification or HCV RNA greater than or equal to the lower limit of quantification at the end of treatment
  • Percentage of subjects with post-treatment relapse [ Time Frame: Within 12 weeks post treatment ] [ Designated as safety issue: No ]
    Hepatitis C Virus (HCV) ribonucleic acid (RNA) confirmed greater than or equal to the lower limit of quantification between the end of treatment and 12 weeks post treatment among subjects completing treatment and with HCV RNA less than the lower limit of quantification at the end of treatment

Estimated Enrollment: 30
Study Start Date: February 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ARM A
ABT-450/r/ABT-267 and ABT-333 coadministered with ribavirin (RBV) for 24 weeks
Drug: ABT-450/r/ABT-267
tablet
Drug: ABT-333
tablet
Drug: ribavirin (RBV)
tablet

Detailed Description:

The purpose of this study is to evaluate the safety and efficacy of ABT-450, ritonavir, ABT-267 (ABT-450/r/ABT-267) and ABT-333 co-administered with ribavirin in adult liver transplant recipients with hepatitis C virus (HCV) infection.

Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and females 18-70 years old, inclusive.
  • Liver transplantation as a consequence of HCV infection no less than 12 months before screening.
  • Must have a liver biopsy which shows evidence of fibrosis <= F2 (Metavir scale) and which is obtained within the 6 months prior to the screening period but not less than 9 months post transplant or during the Screening Period
  • Chronic hepatitis C genotype 1 infection.
  • On an immunosuppressant regimen based on either tacrolimus or cyclosporine where the dose of immunosuppressant has not been increased at least 2 months before Screening and no new immunosuppressant drugs have been added for at leas 2 months before Screening.

Exclusion Criteria:

  • Positive hepatitis B surface antigen and anti-Human Immunodeficiency Virus Antibody.
  • Use of contraindicated medications within 2 weeks of dosing or 10 half-lives, whichever is longer.
  • Clinically significant abnormalities, other than HCV infection post transplant.
  • Recent history of drug or alcohol abuse.
  • Previous use of any investigational or commercially available anti-HCV agent other than interferon (IFN)-based therapy, i.e. conventional (c) IFN and/or pegylated (Peg) IFN, with or without RBV

.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01782495

Contacts
Contact: Melissa Cook, MS 847-937-1399 melissa.cook@abbvie.com
Contact: Jennifer Moseley, BS 847-938-1394 jennifer.r.moseley@abbvie.com

Locations
United States, Arizona
Site Reference ID/Investigator# 90539 Recruiting
Phoenix, Arizona, United States, 85054
Principal Investigator: Site Reference ID/Investigator# 90539            
United States, Colorado
Site Reference ID/Investigator# 90535 Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Site Reference ID/Investigator# 90535            
United States, Illinois
Site Reference ID/Investigator# 90562 Recruiting
Chicago, Illinois, United States, 60611
Principal Investigator: Site Reference ID/Investigator# 90562            
Site Reference ID/Investigator# 90563 Recruiting
Chicago, Illinois, United States, 60637
Principal Investigator: Site Reference ID/Investigator# 90563            
United States, Indiana
Site Reference ID/Investigator# 90536 Recruiting
Indianapolis, Indiana, United States, 46202-5121
Principal Investigator: Site Reference ID/Investigator# 90536            
United States, Massachusetts
Site Reference ID/Investigator# 100055 Recruiting
Burlington, Massachusetts, United States, 01805
Principal Investigator: Site Reference ID/Investigator# 100055            
United States, New York
Site Reference ID/Investigator# 90533 Recruiting
New York, New York, United States, 10032
Principal Investigator: Site Reference ID/Investigator# 90533            
United States, Texas
Site Reference ID/Investigator# 90537 Recruiting
Dallas, Texas, United States, 75203
Principal Investigator: Site Reference ID/Investigator# 90537            
Spain
Site Reference ID/Investigator# 90573 Recruiting
Barcelona, Spain, 08028
Principal Investigator: Site Reference ID/Investigator# 90573            
Sponsors and Collaborators
AbbVie
Investigators
Study Director: Eoin Coakley, MD AbbVie
More Information

No publications provided

Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT01782495     History of Changes
Other Study ID Numbers: M12-999, 2012-004792-39
Study First Received: January 22, 2013
Last Updated: June 27, 2013
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
United States: Food and Drug Administration


Keywords provided by AbbVie:
Chronic Hepatitis
Hepatitis C Virus
Hepatitis C Genotype 1
Interferon-Free
Liver Transplant


Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Hepatitis C, Chronic
Hepatitis, Viral, Human
Liver Diseases
Digestive System Diseases
Virus Diseases
Enterovirus Infections

Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Ribavirin
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites
Molecular Mechanisms of Pharmacological Action


ClinicalTrials.gov processed this record on July 02, 2013

NS5A inhibitors in the treatment of hepatitis C

Journal of Hepatology

Article in Press

Jean-Michel Pawlotsky

Received 28 February 2013; received in revised form 22 March 2013; accepted 27 March 2013. published online 08 April 2013.
Corrected Proof

Summary 

Hepatitis C virus infection is a major health problem worldwide and no vaccine has yet been developed against this virus. In addition, currently approved pharmacotherapies achieve suboptimal cure rates and have side effects that result in non-compliance and premature treatment discontinuation. Significant research has been devoted to developing direct-acting antiviral agents that inhibit key viral functions. In particular, several novel drug candidates that inhibit the viral non-structural protein 5A (NS5A) have been demonstrated to possess high potency, pan-genotypic activity, and a high barrier to resistance. Clinical trials using combination therapies containing NS5A inhibitors have reported results that promise high cure rates and raise the possibility of developing interferon-free, all-oral regimens.

Abbreviations: HCV, hepatitis C virus, DAA, direct acting antiviral, NS, nonstructural, RdRp, RNA-dependent RNA polymerase, IFN, interferon, UTR, untranslated region, IRES, internal ribosome entry site, SVR, sustained virological response, RVR, rapid virologic response, cEVR, complete early virologic response

Keywords: Hepatitis C virus, NS5A inhibitor, Daclatasvir, Resistance

Introduction

Recent estimates indicate that there are more than 120–130million chronic hepatitis C virus (HCV) carriers worldwide [1], who are at risk of developing cirrhosis and/or hepatocellular carcinoma (primary liver cancer). As many as 4million persons are thought to be chronically infected in the US [2], 5–10million in Europe [2], 12million in India [2], and 1.2million in Japan (2004 figure) [3]. Most of these individuals are not aware of their infection. The incidence of acute infection in the US has declined from 7.4/100,000 in 1982 to 0.7/100,000 in recent years, primarily due to screening of blood in transfusion centres and improved safety of intravenous drug use [4]. It is estimated that approximately 150,000 new cases occur annually in the United States and in Western Europe, and about 350,000 in Japan. Only 25% of acute cases are symptomatic, but up to 80% of these acute cases progress to chronic infection and liver disease, and up to 20% of chronic infections progress to cirrhosis [2]. Every year, 4–5% of cirrhotic patients develop hepatocellular carcinoma [5]. Despite the decrease in HCV incidence, the number of patients with chronic HCV-related complications is increasing in those aging patients who have been infected for many years, and chronic hepatitis C infection will continue to be a significant cause of premature mortality, causing at least 200,000–300,000 deaths per year worldwide [4].

A number of direct-acting antiviral agents (DAAs) are under development for the treatment of chronic HCV infection. These agents block viral production by directly inhibiting one of several steps of the HCV lifecycle. As shown in Fig. 1, the genomic organization of HCV has been elucidated, and several viral proteins involved in the HCV lifecycle, such as the non-structural (NS) 3/4A serine protease, the NS5B RNA-dependent RNA polymerase (RdRp), and the NS5A protein, have been targeted for drug development [4]. Two NS3/4A protease inhibitors, telaprevir and boceprevir, which inhibit post-translational processing of the HCV polyprotein into individual non-structural proteins, have been approved by the US Food and Drug Administration, the European Medicines Agency, and several other regulatory agencies for the treatment of chronic HCV genotype 1 infection in combination with pegylated interferon (IFN)-α and ribavirin [6], [7].

PIIS0168827813002092_gr1_lrgFig,1. Structural organization of HCV RNA and viral proteins. NS, non-structural; UTR, untranslated region.

HCV structure and lifecycle, and physiological role of the NS5A protein 

HCV is an enveloped virus with a single-stranded positive RNA genome of approximately 9.6kb. At the flanking ends of the genome are 2 highly conserved untranslated regions (UTRs). The 5′ UTR is highly structured and contains the internal ribosome entry site (IRES), which is important for the initiation of the cap-independent translation of the polyprotein [8]. The 3′ UTR consists of a short genotype-specific variable region, a tract consisting solely of pyrimidine residues (predominantly uridine) and a conserved 98-nucleotide sequence, known as X region, containing 3 stem-loops [9], [10]. The HCV open reading frame is situated between the two UTRs.

After entering the bloodstream, HCV binds to a receptor complex at the surface of its target cells, the hepatocytes. The envelope glycoproteins E1 and E2 are essential for target cell recognition, binding, and internalization [11]. The bound virus then undergoes clathrin-mediated endocytosis [12]. Acidification of the endocytosis vesicle frees the genomic RNA from the nucleocapsid for release into the cytoplasm. Along with host RNA molecules, the viral RNA migrates to the endoplasmic reticulum (ER). Binding of the 40S ribosomal subunit to the HCV IRES produces a stable pre-initiation complex that begins translation of the viral open reading frame to generate an approximately 3000 amino acid polyprotein. Following translation, the polyprotein is cleaved by both cellular and viral proteases to produce at least 10 viral proteins, including structural proteins (core, E1 and E2) and non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) [13], [14].

Viral replication (i.e., the synthesis of new positive RNA genomes that may also serve as messenger RNAs for viral protein synthesis) is catalyzed by the viral RdRp, or NS5B protein. A negative-strand intermediate of replication is initially produced, which then serves as a template for the synthesis of numerous positive strands. The NS5A viral protein has been shown to play an important role in the regulation of replication. In addition, host cell proteins, such as cyclophilin A, act as necessary co-factors of HCV replication through their interactions with both NS5A and the RdRp in the replication complex [15], [16].

The non-structural NS5A protein bears pleiotropic functions, including roles in viral replication and assembly, and complex interactions with cellular functions. The latter include inhibition of apoptosis and promotion of tumorigenesis, both of which may play a role in the triggering of the hepatocarcinogenic process [17], [18], [19], [20]. The protein is comprised of approximately 447 amino acids and localizes to ER-derived membranes. It basally exists in phosphorylated (p56) and hyperphosphorylated (p58) forms that are implicated in different functions [21], [22], [23]. Its cytoplasmic moiety contains 3 domains, of which Domain I is the most conserved [24]. The mechanism by which NS5A regulates replication regardless of the HCV genotype is still unclear [25]. Considerable information has been gathered on its molecular interactions and role in the viral lifecycle. NS5A and the RdRp directly interact, both in vivo and in vitro [26]. In vitro, this interaction stimulates RdRp-catalyzed synthesis of the negative RNA strand [27]. It was shown that all 3 domains of NS5A bind to RNA [9]. The interactions of Domain I with the polypyrimidine tract of 3′ UTR suggest it may affect the efficiency of RNA replication by the RdRp; however, these results also suggested the binding of RdRp and NS5A to RNA are mutually exclusive. In addition, Domain II of NS5A interacts with cyclophilin A, a host cell protein required for replication, and this interaction is vital for RNA binding [28]. NS5A also plays a role in viral packaging and assembly. Domain III appears to be essential for this function [29], [30]. This may be due, at least in part, to NS5A recruiting apolipoprotein E, a component of the HCV production process [29], [31]. Indeed, inhibiting apolipoprotein E expression results in marked reduction of infectious particle production without affecting viral entry and replication [31].

NS5A inhibitor mechanism of action 

Several viral proteins have generated interest as potential targets for specific inhibitory drugs. In addition to the two NS3/4A protease inhibitors already approved for clinical use, numerous other protease inhibitors are being developed as well as inhibitors of viral replication, including nucleoside/nucleotide analogue inhibitors of HCV RdRp, non-nucleoside inhibitors of RdRp, cyclophilin inhibitors, and NS5A inhibitors.

Because of its critical involvement in viral replication and assembly [32], NS5A has been identified as a target for viral inhibition, leading to development of therapeutic agents. In HCV replicon-containing cells, inhibition of NS5A, but not other HCV proteins, resulted in redistribution of NS5A from the ER to lipid droplets. NS5A-targeting agents did not cause similar alterations in the localization of other HCV-encoded proteins, and the transfer of NS5A to lipid droplets coincided with the onset of inhibition of replication [33]. Inhibition of NS5A at picomolar concentrations has been associated with significant reductions in HCV RNA levels in cell culture-based models, which makes these agents among the most potent antiviral molecules yet developed [34], [35], [36]. NS5A inhibitors have pan-genotypic activity, i.e., they suppress replication of all HCV genotypes, but their antiviral effectiveness against genotypes other than 1 may vary from one molecule to another [35]. Use of multiple DAAs including an NS5A inhibitor in replicon systems in cell culture has resulted in additive/synergistic inhibition of viral production and an increased barrier to resistance [37].

The exact mechanism of antiviral action of NS5A inhibitors is unknown. Available evidence suggests that they have multiple effects, which contribute to their potency [32]. One putative mechanism is the inhibition of hyperphosphorylation. Phosphorylation of NS5A seems required for viral production [38], but the relative roles of the phosphorylated and hyperphosphorylated forms are unclear, and conflicting results have been reported suggesting that reduced hyperphosphorylation may either enhance or reduce replication [21], [39]. It is thought that a tightly regulated control of phosphorylation vs. hyperphosphorylation is required for efficient viral function. It was also shown that NS5A acts in two different pathways in RNA replication, and one of them likely requires hyperphosphorylation [23]. However, other mechanisms may also play a role. For instance, NS5A inhibitors alter the subcellular localization of NS5A, which may cause faulty viral assembly [33], [40].

Resistance to NS5A inhibitors 

HCV displays a large degree of genomic variability, resulting in its quasispecies distribution [41]. Variants that confer resistance to NS5A inhibitors pre-exist within HCV quasispecies populations in the absence of any previous exposure to these drugs. These variants generally replicate at low levels and are thus undetectable by currently available techniques. However, they can be selected if an NS5A inhibitor is administered and may be grown to high levels. Clinically significant resistance is usually associated with an escape pattern whereby viral replication returns to pretreatment levels and the dominant virus harbours amino acid substitutions that confer high levels of drug resistance without impairing fitness of the virus. Very high levels of the drug may be required to suppress highly resistant viruses, which may not be achievable without compromising safety [42].

At present, only genotype 1, the most prevalent HCV genotype, has been studied in detail for resistant variants. Table 1, adapted from Fridell et al. [43], describes the resistance profile of the NS5A inhibitor daclatasvir in genotype 1a and 1b replicons. The barrier to resistance is lower for genotype 1a than for genotype 1b. Substitutions at positions L31 and Y93 have the greatest ability to confer resistance to daclatasvir, and double mutations may increase the EC50 to a far greater extent (Table 1). These substitutions also confer resistance to other first-generation NS5A inhibitors. In addition, studies with daclatasvir have shown that double and triple inhibitor combinations in replicon systems can generate resistance pathways that differ from those observed during NS5A inhibitor monotherapy [37]. Agents without cross-resistance with NS5A inhibitors should thus be used in combination with this class of drugs.

Table 1. Resistance profile of daclatasvir in the in vitro genotype 1a and 1b replicon systems. Adapted from Fridell et al. [43].

PIIS0168827813002092_fx1_lrg

NS5A inhibitors undergoing clinical trials 

Although no NS5A inhibitor has yet been approved for therapeutic use, these agents are viewed with optimism due to their favourable characteristics, including the requirement for low dosing to inhibit HCV replication; pan-genotypic activity; once-daily dosing; resistance profiles that do not overlap with those of other DAAs in development; and successful suppression of HCV replication with an acceptable safety profile in early clinical trials [34].

Daclatasvir (BMS790052) 

Daclatasvir is an oral, once-daily, highly selective NS5A inhibitor with broad coverage of HCV genotypes in vitro developed by Bristol-Myers Squibb. Daclatasvir currently is in Phase III clinical trials. Its inhibitory target maps to Domain I, and it has been shown to block hyperphosphorylation of NS5A [23], as well as alter the subcellular localization of the viral protein [33], [40]. Daclatasvir has an EC50 of 50pM against genotype 1a, 9pM against genotype 1b, and 28pM against genotype 2a [35]. Daclatasvir has been tested in Phase II clinical trials in combination with pegylated IFN-α and ribavirin; in quadruple combination with asunaprevir, an NS3/4A protease inhibitor, and pegylated IFN-α/ribavirin; and with asunaprevir, the nucleotide analogue sofosbuvir and the non-nucleoside inhibitor of HCV RdRp BMS-791325 in IFN-free regimens.

In a randomized, parallel-group, double-blind, placebo-controlled, dose-finding Phase IIa trial of treatment-naïve patients infected with HCV genotype 1, 5 of 12 patients who received 3mg daclatasvir with pegylated IFN-α and ribavirin for 48weeks achieved extended rapid virologic response (eRVR), compared with 10 of 12 who received 10mg daclatasvir, 9 of 12 who received 60mg daclatasvir, and 1 of 12 who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across treatment groups [44]. In another Phase IIa trial in genotype 1-infected patients who were non-responders to a prior course of pegylated IFN-α and ribavirin, all 10 patients who received quadruple therapy with daclatasvir, asunaprevir, and pegylated IFN-α/ribavirin showed a sustained virologic response (SVR) after 12weeks, as opposed to 4 of 11 who received daclatasvir and asunaprevir only [45]. A higher incidence of viral breakthrough due to resistance was observed in genotype 1a patients who were given only the 2 DAAs without pegylated IFN-α/ribavirin vs. genotype 1b patients receiving the same treatment regimen, as a result of the lower barrier to resistance in genotype 1a [45]. Among patients who experienced virologic failure, the most common variants harboured Y93H and L31M, two substitutions well known for conferring resistance to daclatasvir.

In a 24-week dual-oral Phase II trial with daclatasvir and asunaprevir in genotype 1b-infected patients, 90.5% of null responders and 63.6% of patients ineligible for or intolerant to pegylated IFN-α/ribavirin achieved SVR 24weeks after the end of treatment (SVR24) [46]. Interestingly, many patients in this study with pre-existing resistance-associated NS5A polymorphisms were cured of their chronic HCV infection.

In a Phase IIb study with daclatasvir, pegylated IFN-α, and ribavirin, 100% of genotype 4-infected patients achieved SVR at 12weeks post-treatment (SVR12) [47]. A combination of daclatasvir and sofosbuvir (formerly GS-7977), a nucleotide analogue inhibitor of HCV RdRp developed by Gilead Sciences, given for 24weeks achieved SVR in 100% (44/44) of treatment-naïve patients infected with HCV genotype 1, and in 91% (40/44) of patients infected with HCV genotypes 2 and 3 at 4weeks post-treatment. Addition of ribavirin had no effect on SVR rates [48]. Finally, the triple combination of daclatasvir, asunaprevir and BMS-791325, a non-nucleoside inhibitor of HCV RdRp, resulted in an SVR12 in 15 of 16 patients (94%) treated for 12weeks (data missing in the remaining patient) [49].

ABT-267 

This drug candidate, developed by AbbVie, is in Phase II clinical trials. It is an oral, once-daily NS5A inhibitor that significantly reduces HCV RNA levels in vitro and in vivo. In a study of treatment-naïve genotype 1-infected patients, ABT-267 in combination with pegylated IFN-α and ribavirin produced a rapid virologic response (RVR) at 4weeks in 22 of 28 patients as compared with 2 of 22 who received placebo; after 12weeks, 25 of 28 patients receiving the NS5A inhibitor in combination with pegylated IFN-α and ribavirin showed complete early virologic response (cEVR) compared with 6 of 9 patients in the placebo group. A recently presented Phase IIb clinical trial, which used a 4-drug combination of ABT-267, ritonavir-boosted ABT-450 (a protease inhibitor), ABT-333 (a non-nucleoside inhibitor of HCV RdRp), and ribavirin achieved SVR12 in 97.5% of treatment-naïve patients and in 93.3% of prior null-responders infected with genotype 1 [50], [51]. In treatment-naïve patients, the SVR rates were 87.5% when the three drugs and ribavirin were administered for 8weeks, 89.9% when ABT-267 was administered with ABT-450 and ribavirin for 12weeks, and 87.3% when the three DAAs were administered without ribavirin for 12weeks. In null responders, the SVR rate was 88.9% with the combination of ABT-450, ABT-267, and ribavirin. Based on these results, Phase III trials with the 3 DAAs with and without ribavirin are planned [51].

Ledispasvir (GS-5885) 

This oral, once-daily drug candidate, developed by Gilead Sciences, is a potent NS5A inhibitor against genotypes 1a, 1b, 4a, and 5a in vitro, but has lower activity against genotypes 2a and 3a [52]. In a randomized, placebo-controlled study of 14days of ledipasvir monotherapy in genotype 1-infected patients, significant HCV RNA reductions (up to 1000-fold) were observed. Several resistance-associated substitutions were selected, including the aforementioned Y93H and L31M. In patients infected with HCV genotype 1b, daclatasvir has been reported to be more active than ledipasvir, whereas ledipasvir has been found to be 4–5times more active than daclatasvir for the M28T and Q30H substitutions in HCV genotype 1a infection. In addition, daclatasvir has been demonstrated to be 2-fold more active against the L31M substitution as compared with ledipasvir [53]. Ledipasvir is now in a Phase II trial as a component of a 4-drug regimen with tegobuvir (a non-nucleoside inhibitor of HCV RdRp), GS-9451 (an NS3/4A protease inhibitor), and ribavirin [52]. Recent results from the ELECTRON Phase II trial have shown SVR rates 12weeks after the end of treatment of 100% in 25 treatment-naïve and 10 null responder patients infected with HCV genotype 1 with the combination of sofosbuvir, ledipasvir and ribavirin [54]. A Phase III trial with a fixed-dose combination of sofosbuvir and ledipasvir, with or without ribavirin, is in progress in treatment-naïve patients infected with HCV genotype 1 [55]. A recent presentation also showed that ledipasvir, in combination with GS-9451, pegylated IFN-α, and ribavirin achieved SVR at 4weeks post-treatment in 100% of CC IL28B patients infected with HCV genotype 1 [56].

GSK-2336805 

This oral, once-daily drug candidate is being developed by GlaxoSmithKline. Preliminary studies show that GSK-2336805 is particularly effective against HCV genotype 1b, and has potent antiviral activity against other genotypes as well. A placebo-controlled Phase I study of treatment-naïve patients with chronic genotype 1 infection found a reduction in HCV RNA level of up to 1000-fold following 14days of monotherapy. This NS5A inhibitor is currently in Phase II clinical trials in treatment-naïve patients infected with HCV genotype 1 in combination with pegylated IFN-α, ribavirin, and telaprevir [57]. Resistance to GSK-2336805 maps to NS5A [58].

ACH-2928 

This oral, once-daily drug candidate, developed by Achillion Pharmaceuticals, displays highly potent activity in vitro against genotype 1a replicons as well as chimeric replicons of genotypes 2–6. ACH-2928 has demonstrated in vitro synergistic activity in combination with sovaprevir (formerly ACH-1625), an HCV NS3/4A protease inhibitor, which is further enhanced by ribavirin [59]. In Phase I trials, ACH-2928 monotherapy for 3days produced up to a 3.7log10 reduction in HCV RNA levels in patients with chronic HCV genotype 1 infection [60].

BMS824393

This NS5A inhibitor is being developed by Bristol-Myers Squibb. It has shown strong in vitro potency against genotypes 1a and 1b. In a Phase I study in which this agent was used as a monotherapy for 3days in genotype 1-infected patients, a decline of up to 3.9log10 was observed [61].

IDX719

This drug candidate, developed by Idenix Pharmaceuticals, has shown greater potency in vitro than daclatasvir against HCV genotypes 1a, 1b, 2a, 3a, 4a, and 5a [62]. In Phase I studies, HCV RNA levels declined by more than 3 log10 in single-dose trials for all genotype 1, 2, and 3 patients after 24hours. Similar reductions in HCV RNA levels (over 3log10) were observed for genotype 1, 3, and 4 patients, and reductions of 2log10 for genotype 2, in 3-day monotherapy studies [63], [64]. However, evidence indicates that the Y93H substitution confers resistance to this NS5A inhibitor [62]. A Phase II clinical trial using IDX719, simeprevir (a protease inhibitor developed by Janssen and Medivir), and TMC647055, a non-nucleoside polymerase inhibitor developed by Janssen, has been announced [65].

PPI461

This oral drug candidate is under development by Presidio Pharmaceuticals. A Phase Ib trial of monotherapy for 3days in patients with HCV genotype 1 infection showed a decrease of HCV RNA level of up to 3.6log10. However, widespread resistance emerged rapidly, mapping to amino acids 28, 30, 31, and 93 [66].

PPI668

Also under development by Presidio Pharmaceuticals, this NS5A inhibitor has been shown to possess high efficacy against HCV genotype 1, with up to 3.7log10 mean HCV RNA reductions, in a Phase Ib clinical trial [67], [68]. Activity was demonstrated against variants harbouring the L31M substitution. In an added genotype-2/3 cohort, the first 2 patients achieved mean 3.0log10 RNA level reductions [68]. PPI668 will be studied in combination with two DAAs developed by Boehringer-Ingelheim, faldaprevir, an NS3/4A protease inhibitor, and BI207127, a non-nucleoside inhibitor of HCV RdRp.

ACH-3102 

This NS5A inhibitor, developed by Achillion Pharmaceuticals, has a modified structure designed to have a higher pharmacologic barrier to resistance. Pharmacokinetic studies support once-daily oral dosing with this agent. ACH-3102 has shown potent antiviral activity against all genotypes in preclinical studies. In replicon studies, ACH-3102 has shown the smallest difference in potency between genotype 1a and 1b replicons, compared with daclatasvir and ACH-2928 [69]. ACH-3102 is potent against mutants harbouring substitutions that confer resistance to first-generation NS5A inhibitors (Fig. 2), such as those at positions Y93 and L31 [69]. Antiviral efficacy is also strong against double mutants that are highly resistant to other NS5A inhibitors (unpublished data). In addition, this inhibitor has shown very low potential for emergence of resistant variants in genotype 1b replicons (unpublished data). For these reasons, ACH-3102 is considered a “second-generation” NS5A inhibitor.

Fig. 2. Antiviral efficacy of ACH-3102 (second-generation NS5A inhibitor) compared with ACH-2928 and daclatasvir (first-generation NS5A inhibitors) on wild-type (parent) and mutated HCV replicons [69].

PIIS0168827813002092_gr2_lrg

A recently reported preclinical study using ACH-3102 and ACH-2684 (an NS3/4A protease inhibitor) has shown an additive to synergistic antiviral effect against genotypes 1a and 1b without the emergence of resistance variants [70]. Recently announced results from a Phase Ia trial in patients infected with HCV genotype 1 show that a single dose of ACH-3102 produces a mean HCV RNA level reduction of up to 3.9log10, with an upper range of 4.6log10, with inhibition lasting for 4days after dosing. Moreover, ACH-3102 has a half-life of approximately 250hours (unpublished data), compared with 13–15hours for daclatasvir [71], 22–50hours for ledipasvir [53], and 25–32hours for ABT-267 [72]. A single Phase II trial has been initiated in genotype 1b patients using ACH-3102 in combination with ribavirin [73].

Progress toward all-oral combination therapies for HCV and the role of NS5A inhibitors 

Currently, the standard of care for chronic HCV genotype 1 infection is a combination of pegylated IFN-α, ribavirin, and an NS3/4A protease inhibitor (i.e., boceprevir or telaprevir), whereas patients infected with other HCV genotypes continue to be treated with pegylated IFN-α and ribavirin. The SVR rates observed with the triple combination in patients infected with HCV genotype 1 range from 67% to 75% in clinical trials [74], [75]. They are probably lower in the real-life setting, indicating that a significant proportion of patients will still experience virologic failure and that improved therapeutic regimens are needed. In addition, patients receiving pegylated IFN-α and ribavirin experience a plethora of adverse effects, some of which are aggravated by the protease inhibitor [6], [7], [76]. Clinical trials of NS5A inhibitors in combination with pegylated IFN-α and ribavirin have shown promising results. However, the trials conducted thus far have included only small numbers of patients, and more studies are needed before the efficacy of such 3-drug combinations can be fully ascertained. In this respect, the results of a Phase III trial with daclatasvir, pegylated IFN-α, and ribavirin are awaited. Quadruple therapies including an NS5A inhibitor, pegylated IFN-α, ribavirin, and another DAA also appear promising. However, recent reports of very high SVR rates, over 90%, in patients treated with all-oral, IFN-free regimens with or without ribavirin clearly indicate that the IFN era is coming to an end. It is also noteworthy that NS5A inhibitors developed by one company have been used with different classes of DAAs developed by other companies [48]; as such, a highly potent NS5A inhibitor may find uses in combinations with various other DAAs to achieve high cure rates.

Due to their specificity, potency, and low EC50, NS5A inhibitors will likely be a critical component of future all-oral, IFN-free combinations. It is interesting to note that the most attractive all-oral combinations presented at the last annual meetings of the American and European liver societies all contained an NS5A inhibitor, combined either with a nucleotide analogue or a protease inhibitor and a non-nucleoside inhibitor of HCV RdRp, with or without ribavirin. Fixed-dose combinations (i.e., 2-drug combinations in 1 pill) including an NS5A inhibitor are already available in Phase II and III clinical trials. The advent of second-generation NS5A inhibitors, with a modified structure and near-equal efficacy against variants known to resist first-generation NS5A inhibitors, is also promising.

PIIS0168827813002092_fx2_lrg

Conclusions 

Although blood screening and other preventive measures have reduced the incidence of HCV in some parts of the world, infection with this virus remains a significant worldwide health concern. The multiple genotypes of HCV, as well as rapid development of mutations, have complicated the development of effective drugs. Until recently, a non-specific antiviral combination, pegylated IFN-α and ribavirin, was the mainstay of HCV therapy. The approval of two NS3/4A protease inhibitors has allowed the addition of a DAA to this treatment regimen. Although the first-generation protease inhibitors, telaprevir and boceprevir, in combination with pegylated IFN-α and ribavirin, have improved treatment of chronic HCV genotype 1 infection, response rates remain suboptimal. In addition, many patients are unable to tolerate this therapy and, among those who can, adverse events associated with the drugs can compromise patient compliance and lead to premature treatment discontinuations. Thus, there has been a strong desire to develop all-oral, IFN-free therapies with high efficacy. The discovery of the multiple roles of the NS5A protein in viral replication has been paralleled by the development of specific NS5A inhibitors. Evidence gathered thus far indicates that these agents are potent and possess antiviral activity against multiple HCV genotypes with acceptable safety profiles. In addition, clinical trial data support the efficacy of NS5A inhibitors with and without pegylated IFN-α and ribavirin, suggesting an important role for these agents as a component of all-oral therapeutic regimens for the treatment of HCV.

Financial support 

Editorial assistance from ACCESS Medical was funded by Achillion Pharmaceuticals.

Conflict of interest 

The author has received research grants from Gilead. He has served as an advisor for Abbott, Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen-Cilag, Madaus-Rottapharm, Merck, Novartis, and Roche.

Acknowledgments

The author would like to thank Amlan RayChaudhury, PhD, of ACCESS Medical, LLC, for editorial assistance in preparing the manuscript.

References

Source

Journal of Clinical & Experimental Hepatology

Article in Press

Presented in the plenary session of the annual scientific meeting of the American College of Gastroenterology, October 27–November 2, 2011, Washington, D.C, and was awarded the 2011 Astra-Zenica/Senior Fellow Award.

Sanjaya K. Satapathy, Yun Ju Kim, Ashish Kataria, Arash Shifteh, Rohan Bhansali, Maurice A. Cerulli, David Bernstein

Received 21 March 2013; accepted 9 May 2013. published online 24 May 2013.
Corrected Proof

Abstract

Background

An association of Coronary artery disease (CAD) with hepatitis C (HCV) has been suggested, but definitive data are still lacking.

Aim

Our study sought to estimate the prevalence and severity of CAD in HCV patients compared to with age-, sex-, and race-matched controls without HCV infection.

Subjects and methods

63 HCV-infected patients were compared with 63 age, race, and sex-matched controls without HCV infection undergoing coronary angiography for evaluation of CAD. CAD was defined as more than a 50% blockage in any of the proximal coronary arteries on angiogram. The severity of the stenosis was defined by the modified Reardon severity scoring system: <50% stenosis of the luminal diameter, 1 point; 50–74%, 2 points; 75–99%, 3 points; 100% or total obstruction, 4 points. The points for each lesion in the proximal coronary circulation were summed to give the score for severity.

Results

A significantly higher prevalence of CAD was noted in the HCV population (69.8% vs. 47.6%, = 0.01). The combined Reardon's severity score in the HCV group was significantly higher compared to the controls (6.26 ± 5.39 vs. 2.6 ± 3.03, P < 0.0005). Additionally, significant multivessel CAD (>50% stenosis and ≥2 vessels involved) was also noted significantly more commonly in the HCV group compared to controls (57.1% vs. 15.9%, P < 0.0005).

Conclusion

In this retrospective study the prevalence and severity of CAD was higher in HCV patients who were evaluated for CAD by angiogram compared with matched non-HCV patients. HCV-positive status is potentially a risk factor for CAD.

Keywords: hepatitis C, coronary artery disease, prevalence

Abbreviations: CAD, coronary artery disease, HCV, hepatitis C virus, DM, diabetes mellitus, HDL, high density lipoprotein, LDL, low density lipoprotein, IVDU, intravenous drug use, ACE, angiotensin converting enzyme, IR, insulin resistance

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Read full text here …

Journal of Clinical & Experimental Hepatology

Article in Press

Chantal Bémeur, Roger F. Butterworth

Received 12 March 2013; accepted 19 May 2013. published online 29 May 2013.
Corrected Proof

Malnutrition is a common feature of chronic liver diseases that is often associated with a poor prognosis including worsening of clinical outcome, neuropsychiatric complications as well as outcome following liver transplantation. Nutritional assessment in patients with cirrhosis is challenging owing to confounding factors related to liver failure. The objectives of nutritional intervention in cirrhotic patients are the support of liver regeneration, the prevention or correction of specific nutritional deficiencies and the prevention and/or treatment of the complications of liver disease per se and of liver transplantation. Nutritional recommendations target the optimal supply of adequate substrates related to requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals. Some issues relating to malnutrition in chronic liver disease remain to be addressed including the development of an appropriate well-validated nutritional assessment tool, the identification of mechanistic targets or therapy for sarcopenia, the development of nutritional recommendations for obese cirrhotic patients and liver-transplant recipients and the elucidation of the roles of vitamin A hepatotoxicity, as well as the impact of deficiencies in riboflavin and zinc on clinical outcomes. Early identification and treatment of malnutrition in chronic liver disease has the potential to lead to better disease outcome as well as prevention of the complications of chronic liver disease and improved transplant outcomes.

Keywords: nutritional status, liver disease, liver transplantation, complications, hepatic encephalopathy

Abbreviations: CNS, central nervous system, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steato-hepatitis, HE, hepatic encephalopathy, AAAs, aromatic amino acids, BCAAs, branched-chain amino acids, BMI, body mass index, PNI, prognostic nutritional index, CONUT, controlling nutritional status, ISHEN, International Society for Hepatic Encephalopathy and Nitrogen metabolism

Malnutrition is common in end-stage liver disease (cirrhosis) and is often associated with a poor prognosis.1, 2 Malnutrition occurs in all forms of cirrhosis3 as shown by studies of nutritional status in cirrhosis of differing etiology and of varying degrees of liver insufficiency.4, 5 The prevalence of malnutrition in cirrhosis ranges from 65 to 100% depending upon the methods used for nutritional assessment and the severity of liver disease.6, 7, 8, 9

Nutritional intervention in cirrhotic patients should aim to support hepatic regeneration, prevent or correct malnutrition and prevent and/or treat the complications associated with cirrhosis. There is a general consensus of opinion that nutritional intervention in patients with cirrhosis improves survival, surgical outcome, liver function, and attenuates complications. Hence, the recognition and treatment of malnutrition is an important issue in the clinical management of these patients.

The aim of the present review is to highlight the implications of malnutrition in patients with cirrhosis on disease outcome, on management of the central nervous system (CNS) complications of cirrhosis and on outcomes following liver transplantation. Nutritional recommendations are also formulated and some areas for future research needs are identified.

Selection of published articles included and cited in the review was based upon PubMed searches using appropriate keywords and their combinations, on articles cited in recently published reviews on the topic of nutrition in cirrhosis and on published abstracts on the topic presented at international meetings of EASL and AASLD.

Malnutrition in liver disease 

The functional integrity of the liver is essential for the supply and inter-organ trafficking of essential nutrients (proteins, fat and carbohydrates) and the liver plays a crucial role in their metabolism. Many factors disrupt this metabolic balance in the cirrhotic liver. Such factors include increased protein catabolism, decreased hepatic and skeletal muscle glycogen synthesis and increased lipolysis. The pathogenesis of malnutrition in chronic liver disease is multifactorial and includes reduced nutrient intake due to anorexia and dietary restrictions, altered nutrient biosynthesis, impaired intestinal absorption, increased protein loss, disturbances in substrate utilization, abnormalities of carbohydrate, lipid and protein metabolism and increased levels of pro-inflammatory cytokines resulting in a hypermetabolic state.10

Sarcopenia or loss of muscle mass is a common complication of cirrhosis and adversely affects survival, quality of life, outcome after liver transplantation, and responses to stress including infection and surgery.9 Sarcopenia contributes to the aggravation of other complications of cirrhosis including encephalopathy, ascites, and portal hypertension.11, 12, 13, 14 In addition, other complications such as infection have the potential to exacerbate skeletal muscle proteolysis and impaired protein synthesis in cirrhosis.

Over-nutrition in the form of obesity is now occurring more frequently in patients with liver disease. Obesity (defined as body mass index (BMI) ≥ 30) poses specific and important issues regarding the nutritional management of patients with liver disease, and is a potential etiologic factor for the progression to advanced liver disease.9 Non-alcoholic fatty liver disease (NAFLD) may also lead to altered nutrient intake associated with obesity. NAFLD is a spectrum ranging from the relatively-benign steatosis to non-alcoholic steato-hepatitis (NASH), with progression to cirrhosis. The prevalence of NAFLD will likely increase secondary to the rising prevalence of obesity, a new reality that will require the design of both adapted and specific nutritional assessments as well as appropriate interventions.

Recently, a group of clinicians and scientists was appointed by the International Society for Hepatic Encephalopathy and Nitrogen metabolism (ISHEN) to develop a consensus document on the nutritional management of patients with cirrhosis and hepatic encephalopathy (HE) upon which best practice guidelines would be based.15 The resulting consensus document emphasizes the need for nutritional assessment and lists requirements for supply of energy, protein, fiber and micronutrients. The following sections discuss in more detail these changes in relation to chronic liver disease.

Energy and protein 

Alterations of energy metabolism in chronic liver disease result in amino acid oxidation leading to protein deficiency, which occurs in all forms of cirrhosis. In addition, underlying pathophysiologic factors may cause loss of protein stores. Resting energy expenditure has been shown to be increased in cirrhotic patients16 and alterations in energy metabolism related to survival in these patients17 may even precede malnutrition in some cases.18

Vitamins

In general, vitamin deficiencies in liver disease are related to disorders of hepatic function and diminished reserves and, with increasing severity of the disease, to inadequate dietary intake and/or malabsorption. Fat soluble vitamin deficiencies are common manifestations of malnutrition and liver disease.19, 20 A retrospective study reported that the majority of liver disease patients being considered for liver transplantation present with vitamin A and D deficiencies.19

Vitamin A

Vitamin A (retinol) is implicated in ocular retinoid metabolism, tissue repair and immunity, and is principally stored in hepatic stellate cells. As quiescent stellate cells become activated, they lose their vitamin A stores and are then capable of producing collagen and subsequent fibrosis. Vitamin A deficiency has been reported in patients with hepatitis C-related chronic liver disease21, 22 and is associated with non-response to antiviral therapy.22 Vitamin A deficiency is also present in approximately 50% of patients with alcoholic cirrhosis21, 23 and patients with chronic alcoholism have been shown to have very low concentrations of hepatic vitamin A at all stages of their disease.24 The presence of HE, a complex neuropsychiatric complication associated with liver disease, is associated with reduced serum retinol levels.21 Serum retinol levels below ≤0.78 μmol/L are associated with liver-related death.21 Because high doses of vitamin A are potentially hepatotoxic, care must be taken to avoid excessive supplementation.

Vitamin D

Vitamin D undergoes hepatic 25-hydroxylation, rendering the liver critical to the metabolic activation of this vitamin. Chronic liver disease commonly results in vitamin D deficiency.25, 26, 27, 28 In particular, a large proportion of patients with alcoholic liver disease have compromised vitamin D status.29 Vitamin D deficiency has also been linked to poor outcomes in patients with hepatitis C. Recently, it was demonstrated that extremely low serum levels of vitamin D are associated with increased mortality in patients with chronic liver disease30 and the authors speculated that an impaired immune function due to vitamin D deficiency could explain this observation. Low vitamin D levels are also associated with poor survival, and with the degree of liver dysfunction and severity of the disease as assessed according to the Child-Pugh system.26, 29, 31 It was postulated that a key mechanism responsible for the low serum 25-hydroxy-vitamin D levels in patients with end-stage liver disease may relate to decreased hepatic production of vitamin D binding protein.20

Vitamin E

Vitamin E deficiency has been well documented in alcoholic liver disease.32 However the beneficial effects of vitamin E supplementation in liver disease are dependent upon the nature of the disorder. For example, vitamin E supplementation in ambulatory patients with decompensated alcoholic cirrhosis was not beneficial at 1-year follow-up33 and, in a study of patients with mild-to-moderate alcoholic hepatitis, vitamin E supplementation had no beneficial effects on tests of liver function or mortality at 3-month follow-up when compared with placebo.34 On the other hand, since oxidative stress has been proposed as an important mediator of hepatic injury in NASH,35, 36, 37 vitamin E supplements were evaluated in a double-blind placebo-controlled trial in adults with histologically confirmed NASH.38 The study demonstrated that vitamin E supplementation resulted in significant improvement in pathologic features of NASH including improvement in liver enzymes, as well as decreases in markers of steatosis and inflammation on liver biopsy.

Vitamin B1

Thiamine (vitamin B1) in the form of its diphosphate ester, is an enzyme cofactor involved in glucose and amino acid metabolism and is also, as its triphosphate ester, a component of neuronal membranes. Thiamine deficiency is common in many forms of cirrhosis particularly alcoholic liver disease where it is caused by inadequate dietary intake, decreased hepatic storage, and impairment of intestinal thiamine absorption by ethanol.39 Wernicke's encephalopathy is a seriously under-diagnosed metabolic encephalopathy with severe neurological symptoms and region-selective neuronal cell death caused by thiamine deficiency is often encountered in chronic alcoholism.40, 41 A neuropathologic study examining brain tissue from patients with autopsy-proven cirrhosis revealed evidence of both acute and chronic hemorrhagic lesions in thalamus and mammillary bodies that are typical of Wernicke's encephalopathy as well as mild-to-severe cerebellar degeneration in cirrhotic patients, suggesting a role of chronic liver disease per se on brain thiamine status, a finding that has been attributed to a loss of liver thiamine stores.42 Unsuspected and irreversible thalamic and cerebellar lesions due to thiamine deficiency could explain the incomplete resolution of neuropsychiatric symptoms following the use of treatment strategies or liver transplantation in patients with end-stage liver failure.

Vitamin B2

Vitamin B2 is a cofactor implicated in energy metabolism and also in antioxidant responses. Riboflavin (vitamin B2) deficiency has been described in patients with either alcoholic or non-alcoholic cirrhosis43 and has been explained by inadequate intake, increased utilization, deficient absorption and storage, or abnormal metabolism of the vitamin.44 However, a clear link between riboflavin deficiency and malnutrition in chronic liver disease has not, so far, been definitively established.

Vitamins B6, B9 and B12

Deficiencies in pyridoxine (vitamin B6), folate (vitamin B9) and cobalamin (vitamin B12) may develop rapidly in chronic liver disease due to diminished hepatic storage. It was reported that alcoholic liver disease patients had low pyridoxine levels with elevated cystathionine and decreased alpha-aminobutyrate/cystathionine ratios, consistent with decreased activity of pyridoxine-dependent cystathionase.45 Cobalamin is an enzyme cofactor for metabolism of homocysteine to methionine and the metabolism of homocysteine is affected by alcohol abuse. In a recent study, the levels of vitamin B12 correlated negatively with homocysteine and positively with the markers of alcohol-related liver injury.46 Another study showed that plasma levels of vitamin B12 in patients with decompensated chronic liver disease were high, whereas plasma folate levels were low.47 However, whether or not the above changes in vitamin status are of significance for the nutritional management of chronic liver disease or its complications awaits further studies.

Minerals and trace elements

Zinc

Zinc is an essential trace element required for normal cell growth, development and differentiation and zinc deficiency is common in many types of chronic liver disease.48 Zinc supplementation reportedly reverses clinical signs of zinc deficiency in patients with liver disease49 and a recent randomized, double-blind, placebo-controlled clinical trial demonstrated that low dose zinc supplementation prevents deterioration of clinical status of cirrhosis.50 Furthermore, zinc supplementation produced metabolic effects and trended toward improvements in liver function, HE and overall nutritional status.50 However, a previous double-blind clinical trial showed only a marginal effect of zinc supplementation on HE.51

Magnesium

Magnesium deficiency is common in chronic liver disease.52 It has been demonstrated that alcohol impairs magnesium transport and homeostasis in brain, skeletal muscle, heart and liver.53 Magnesium deficiency is also associated with peripheral insulin resistance, which is common in alcoholic liver disease54 and, in a randomized clinical trial, magnesium treatment was reported to improve hepatic enzyme levels.55

Selenium

Selenium is incorporated into the active sites of multiple seleno-proteins with established antioxidant functions56, 57 and several studies have shown that chronic liver disease is associated with decreases in serum, whole blood, and hepatic selenium content58, 59, 60 where selenium status correlated with severity of liver disease being most profoundly decreased in patients with decompensated cirrhosis. It was recently shown that selenium deficiency was also related to the severity of hepatic fibrosis in patients with hepatitis C-related chronic liver disease being one of the factors contributing to insulin resistance in these patients.61

Manganese

Total body manganese stores are increased in patients with liver disease,62, 63 which may lead to selective manganese accumulation in several areas of the brain.64, 65, 66 Manganese deposition in basal ganglia structures of the brain has been proposed as the cause of T1-weighted magnetic resonance signal hyperintensities65 and cirrhosis-related Parkinsonism.67 Recent reports describe dysfunction of the nigrostriatal dopaminergic neuronal pathway related to manganese toxicity in patients with end-stage liver disease.68, 69

Iron and Copper

Iron overload and excessive alcohol consumption might act in synergy to promote hepatic fibrogenesis. It was demonstrated that transferrin-iron saturation is associated with an increased incidence of cirrhosis, particularly in the presence of alcohol misuse.70 Also, untreated iron overload can lead to liver cirrhosis.71 Copper and copper-associated protein accumulation may be observed in chronic biliary obstructive processes and cirrhosis.72

Nutrition and disease outcome 

Protein-calorie malnutrition is more common in patients with cirrhosis compared to the general population, and is associated with higher in-hospital mortality rates.73 The severity of liver disease generally correlates with the severity of malnutrition, and protein-calorie malnutrition correlates with worsening clinical outcome.7 In addition, the degree of malnutrition correlates with the development of serious complications such as ascites, and hepatorenal syndrome7, 12 as well as with a greater risk of post-operative complications and mortality rates in patients with cirrhosis.74, 75

Even at early stages of the disease, impaired nutritional status is associated with poor clinical outcome. Child-Pugh A patients have a higher 1 year-rate of major complications (refractory ascites, HE, variceal bleeding or hepatorenal syndrome) and/or death.76 In addition to clinical outcome, a range of physiological functions are also affected by a poor nutritional status in cirrhotic patients. For example, knee and ankle muscle strength and handgrip strength are decreased in these patients.76, 77, 78 Furthermore, malnutrition in cirrhotic patients is related to impaired immunocompetence.44, 79, 80 Infections and sepsis are also associated with liver cirrhosis and malnutrition.81, 82

Nutrition and the CENTRAL NERVOUS SYSTEM complications of cirrhosis 

Malnutrition is implicated in disorders of neuropsychiatric function in cirrhotic patients who are prone to developing HE and it has been demonstrated that low energy intake and poor nutritional status may facilitate the development of this complication.83 For example, a recent prospective study demonstrated that cirrhotic patients with muscle depletion are at higher risk of HE and that the amelioration of nutritional status is an effective goal to decrease the prevalence of cognitive impairment in these patients.84

As mentioned above, cirrhosis is often associated with thiamine (vitamin B1) deficiency leading to increased prevalence of Wernicke's encephalopathy, a finding that has been attributed to loss of liver stores of thiamine.85 In addition, cirrhosis is characterized by an imbalance in plasma levels of aromatic amino acids (AAAs) and branched-chain amino acids (BCAAs) and it has been suggested that altered plasma and brain BCAA/AAA ratios are implicated in the pathogenesis of HE in cirrhosis.86, 87

Malnutrition and outcome following liver transplantation 

The presence of malnutrition in patients awaiting liver transplantation, the only curative treatment for end-stage liver disease, is well recognized88, 89 and cirrhotic patients on the waiting list for liver transplantation often present with a spectrum of malnutrition disorders ranging from under-nutrition to obesity. The negative impact of malnutrition on liver transplantation had initially been reported in early retrospective studies90 and both preoperative hypermetabolism and body cell mass depletion was shown to be of prognostic value for transplantation outcome.17 However, while the presence of a poor nutritional status may generally be considered to be one of the predictive factors for increased morbidity and mortality rates after liver transplantation, hard evidence for this supposition continues to elude us. For example, while some studies found that malnutrition in transplant patients resulted in increases in operative blood loss, length of stay in the intensive care unit, mortality and total hospital costs,91, 92, 93 these observations were not confirmed by others.78, 94, 95

Malnutrition is known to lead to glycogen depletion, and this has been suggested to result in increased plasma lactate: pyruvate ratios during the an hepatic phase and to favor the development of a post-operative systemic inflammatory response syndrome and multi-organ failure in these patients.96 In a prospective study, Merli et al97 presented data suggesting that malnutrition should be taken into account as a factor that increases both costs and post-transplant complications. Moreover, they demonstrated that malnutrition was the only independent risk factor for the length of stay in the intensive care unit and the total number of days of hospitalization in these patients. Others reported that pre-transplant nutritional status has a serious impact on the incidence of post-transplant sepsis.98 In view of the rather discrepant findings from studies of the effects of malnutrition on post-transplant outcome, further assessments are required in order to make specific recommendations for nutritional management in cirrhotic patients awaiting transplantation.

In the post-transplant period, nutritional therapy has been shown to improve balance and decrease the incidence of viral infections with a trend to shortening length of stay in the intensive care unit and consequent lowering of costs.99, 100

There has been a dramatic increase in the prevalence of obesity in liver-transplant recipients. Obesity increases early morbidity and mortality at the time of transplantation101, 102 and patients with a BMI greater than 35, when compared with patients with a BMI below 30, manifest higher intra-operative blood loss, more frequent multi-organ failure, and higher risk of infections. Results of other studies suggest that obese patients have higher post-transplant complications, longer hospital stays and higher hospital costs.101, 102, 103, 104, 105, 106 Obesity may also exaggerate the negative impact of risk factors such as donor graft cold ischemia time.107 Patients with diabetes or coronary artery disease, both commonly associated with obesity, are approximately 40% more likely to die within 5 years of liver transplantation compared to non-diabetics or to patients without coronary artery disease.108, 109 Metabolic syndrome, a disorder in which obesity, insulin resistance, high blood pressure and dyslipidemia coexist, is highly prevalent in liver transplant patients110 and is predicted by alcoholic etiology of cirrhosis, excessive weight prior to transplantation, as well as reduced intakes of calcium, potassium, fiber and folate.110 Finally, in line with these observations, despite excellent graft function, many long-term liver transplant survivors manifest a sarcopenic obesity-phenotype characterized by increased body fat but low muscle mass.111

The impact of nutritional status on neurological complications following liver transplantation has recently been reviewed.10 Neurological complications post-liver transplantation are legion and include diffuse encephalopathy, seizures, intracranial hemorrhage and stroke, post-operative metabolic encephalopathy, fatal progressive neurological deterioration, peripheral nerve damage, central pontine myelinolysis, cerebral abscess, ataxia, non-encephalopathic psychosis and confabulation.112, 113, 114 The incidence of these complications is generally reported to be in the 25–75% range.112, 115, 116, 117, 118, 119, 120, 121 As mentioned above, some of these “complications” may be attributable to unrecognized pre-existing neural deficits related to malnutrition.

Assessment of nutritional status 

Accurate nutritional assessment remains a challenge in patients with cirrhosis since many of the traditionally-employed parameters of nutritional status vary with severity of liver disease and there are no methods currently considered to represent a gold standard. Commonly used methods including subjective global assessment (based on physical symptoms of malnutrition and a knowledge of nutritional history), anthropometrics and bio-impedance analysis are all influenced by liver disease per se.122, 123 Moreover, in a recent prospective study, a range of methods including subjective global assessment, anthropometry, handgrip dynamometry and associated biochemical tests were found to result in a wide variability of results and lack of a clear consensus.124

In one potentially interesting new development, Morgan et al125 validated a method whereby BMI and mid-arm muscle circumference were combined with details of dietary intake in a semi-structured algorithm construct to provide a sensitive and reproducible instrument for nutritional assessment in patients with chronic liver diseases. Use of this method has, however, not gained wide acceptance at this moment in time.

In another recent study, parameters such as the prognostic nutritional index (PNI) and controlling nutritional status (CONUT) were tested as nutritional assessment tools in patients with chronic liver disease.126 These are simple assessment constructs of only two or three biochemical examinations of (blood albumin, total lymphocyte count, and total cholesterol) that were shown to be associated with both the severity of chronic liver disease and anthropometric values leading the authors to propose that they represent simple effective tools for nutritional assessment in patients with chronic liver disease. However, the use of albumin, a visceral protein synthesized by the liver, in these equations is questionable since visceral proteins appear to correlate better with the severity of underlying liver disease rather than with malnutrition status.127 It has also been demonstrated that blood iron levels are significantly decreased in chronic liver disease patients suffering from malnutrition but is not altered in well-nourished chronic liver disease patients,128 a finding that could afford complementary information on nutritional status in these patients. At the present time, given the lack of a single indicator of malnutrition in liver disease, the subjective global assessment in conjunction with a combination of other tests is generally employed.129, 130, 131 Given the wide consensus that nutritional status should be routinely assessed in all patients with chronic liver disease in order to recognize malnutrition and prevent nutritional depletion, the development of a simple, well-validated and reproducible tool for the assessment of nutritional status in these patients is long overdue.

Nutritional recommendations

General Nutritional Recommendations in Cirrhosis

Nutritional recommendations for cirrhotic patients in general focus on suppression of hepatotoxic agents and the provision of optimal macronutrient supply in terms of energy, protein, carbohydrates and lipids together with micronutrients such as vitamins and minerals.15, 132 Energy, macro- and micronutrient supplies should be based on the results of individual nutritional assessments and adjusted for weight maintenance and/or repletion. General recommendations are summarized in Table 1.

Table 1. General recommendations for cirrhotic patients.

Nutriment Recommendation
Energy 30–50 kcal/kg body weight
Sufficient to restore/maintain nutritional status and enhance liver regeneration (adjust for obese patients)
Protein 1.0–1.8 g/kg body weight depending on the severity of malnutrition (adjust if renal disease present)
Carbohydrates 45–75% of caloric intake or 4–6 meals rich in carbohydrates per day
Lipids 20–30% of caloric intake (adjust if steatorrhea present)
Vitamins B group vitamin supplements
Particular attention to lipid-soluble vitamins
Correct specific deficiencies
Minerals Zinc, magnesium and selenium supplements
Correct specific deficiencies
Nutritional Recommendations for HE in Cirrhosis

Nutritional recommendations for cirrhotic patients with HE should follow ISHEN practice consensus recently published by Amodio et al.15 These recommendations, including specific pattern of dietary intake,133, 134 which should also be based on individual nutritional assessment, are summarized in Table 2.

Table 2. Nutritional recommendations for cirrhotic patients with HE.

Nutrient Recommendation
Energy Optimal daily energy intake; 30–40 kcal/kg body weight
Small meals evenly distributed throughout the day and late snack
a of complex carbohydrates; (adjust for obese patients)
Protein Optimal daily protein intake; 1.2–1.5 g/kg body weight
Encourage diet rich in vegetables and dairy protein
If patient intolerant to dietary protein, consider BCAA supplementation
b
Fiber 25–45 g/daily
Vitamins and minerals Multivitamin preparation in patients at increased risk of malnutrition; Correct specific deficiencies

aLate evening snacks allow cirrhotic patients to minimize gluconeogenesis, reduce protein utilization and favor a positive nitrogen balance.127, 128

bBCAAs, which are not metabolized by the liver, provide an alternative source of proteins.

Nutritional Recommendations Related to Liver Transplantation in Cirrhosis 

The interval between listing and transplantation provides a therapeutic window to establish nutritional management before the surgical procedure. The main goals of pre-transplant nutritional management are prevention of further energy and nutrient depletion and correction of macro- and micronutrient deficiencies. Nutrient supply should include adequate calories, proteins, vitamins, minerals and trace elements. Determining the extent of nutritional supplementation requires calculation of the individual patient's energy needs.

Preoperative malnutrition, surgical stress, post-interventional complications and post-operative protein catabolism suggest the need for early nutritional support following liver transplantation. Early post-transplant nutritional intervention improves a number of surrogates of nutritional status in liver-transplant patients. Pre-transplant nutritional assessment and nutritional intervention followed by post-surgical monitoring and follow-up after recovery are required. Additional well-designed and controlled studies are needed in order to elaborate precise nutritional recommendations for these patients.

Future research 

Several issues relating to the impact of malnutrition and outcomes in chronic liver disease remain to be addressed. Firstly, a well-designed, validated, accurate, simple and reproducible tool for nutritional assessment is needed. Secondly, there has been little focus on the prevalence, impact, consequences, and mechanistic targets or therapy for sarcopenia in cirrhosis. Studies for the identification of signaling pathways responsible for regulation of muscle mass in cirrhosis, including sarcopenic obesity, are required. Another important issue relates to nutritional recommendations for obese cirrhotic patients. In addition, the impact of vitamin A hepatotoxicity as well as vitamin E, riboflavin and zinc deficiencies on the progression of cirrhosis and its complications require further investigation. Finally, the important issue of nutritional recommendations in liver-transplant patients remain to be comprehensively formulated. Figure 1 summarizes important issues relating to nutrition and chronic liver disease.

PIIS0973688313005550_gr1_lrg

Figure 1  Impact of nutritional management on outcome in cirrhotic patients.
Conclusion

In summary, malnutrition is common in chronic liver diseases and may impact negatively on disease outcome, on the incidence and severity of complications and on outcome following liver transplantation. The pathogenesis of malnutrition in chronic liver disease is multifactorial. Malnutrition in liver transplanted patients is one of the predictive factors for increased morbidity and mortality. The incidence of complications of liver disease per se and of liver transplantation increases with malnutrition and the impact of nutritional intervention on outcomes in cirrhotic patients may vary with the etiology and severity of the disease. Nutritional status in cirrhotic patients should be precisely and accurately assessed in order to design a nutritional intervention adapted to the needs of the individual patient. Early identification and treatment of malnutrition has the potential to lead to better disease outcome, prevention of complications of the disease and improved post-transplant outcomes.

Conflicts of interest 

All authors have none to declare.

References 

Source