Viral hepatitis and liver transplantatation


Etiologies and Outcomes of Acute Liver Failure in HIV + Adults: Results from the ALFSG Registry

Heather N. Simpson1, Timothy J. Davern2, K. Rajender Reddy3, Adrian Reuben4, Valerie Durkalski4, William M. Lee5, Robert J. Fontana1

1Divison of Gastroenterology, Department of Internal Medicine, University of Michigan Hospital, Ann Arbor, MI; 2Hepatology California Pacific Medical Center, San Francisco, CA; 3Gastroenterology, University of Pennsylvania, Philadelphia, PA; 4Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC; 5Internal Medicine, Southwestern Medical Center, Dallas, TX

The etiologies and outcomes of acute liver failure (ALF) in HIV + pts are largely unknown. In addition, the long term outcomes of HIV + pts with ALF undergoing transplantation have not been described. The aim of this study is to describe the presenting features, risk factors, and outcomes of adult HIV + pts with ALF enrolled in the ALFSG. METHODS: Clinical outcomes at 3 weeks of consecutive adult ALF HIV + pts enrolled between 1998 and January 2013 were reviewed and a subgroup returned for a study visit at 1 or 2 years after enrollment. RESULTS: Thirty three of the 2264 ALF pts (1.3%) were HIV +, enrolled at 16 sites. Etiologies of ALF included DILI in 11(33%), acetaminophen (APAP) overdose in 9 (27%), and the remaining 13 (39%) were due to HBV (4), AIH (4), indeterminate (3), HAV (1), and ischemia (1). The age, gender, and racial distribution of our cohort was similar to that of HIV+ pts in the general US population (2010 CDC HIV Surveillance Report). Twenty two (67%) were male and their mean age was 39.3 +/- 12.8 yrs; 18 (54%) were Caucasian, 13 (39%) African-American, and 2 (6%) were of other ethnicities. Seven (21%) had HBV co-infection, 2 (6 %) had HCV co-infection, 6 % reported a recent history of alcohol abuse. None had a recent history of IDU; 19/33 (57%) were receiving an antiretroviral agent at study enrollment. RUCAM scores were performed on 14 suspect drugs in the 11 DILI cases that were categorized into: highly probable (1), probable (5), possible (4), and unlikely (4). Implicated agents in the DILI cases included 7 combination antiretroviral agents given for 5-30 days, 2 trimethoprim-sulfamethoxazole cases, and 5 due to other drugs including voriconazole (1), sulfadiazine (2), duloxetine (1), and clarithromycin (1). Twenty four (73%) were alive at 3 weeks including 6 (18%) who had undergone transplantation (2 APAP, 1 DILI, 1 AIH, 1 HBV, 1 HAV). Six of 9 pts that died at 3 weeks were due to DILI. The APAP pts had a 3-week spontaneous survival rate of 78% compared to only 36% in the DILI group. Nine pts were seen at a mean of 26 months after enrollment which included 5 LT recipients (1 APAP, 1 DILI, 3 Other) and 4 spontaneous survivors (2 APAP, 1 DILI, 1 Other). At follow-up,7 (78%) had normal liver biochemistries and none of the LT recipients had experienced rejection or alloimmune hepatitis. CONCLUSIONS: DILI is over-represented in HIV+ ALF patients in comparison to the overall ALFsg cohort (33% vs 10%), but is not limited to anti-retrovirals. The small number of ALF HIV + LT recipients have generally done well, indicating that LT can be offered to selected HIV+ ALF patients.


K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche, Merck, Janssen, Vertex, Gilead, BMS, Novartis, Idenix; Grant/Research Support: Genentech-Roche, Merck, BMS, Ikaria, Gilead, Hyperion, Janssen, AbbVie

William M. Lee - Consulting: Eli Lilly, Novartis; Grant/Research Support: Gilead, Roche, Vertex, BI, Anadys, BMS, merck; Speaking and Teaching: Merck

Robert J. Fontana - Consulting: GlaxoSmithKline, tibotec; Grant/Research Support: Gilead, vertex, Ocera

The following people have nothing to disclose: Heather N. Simpson, Timothy J. Davern, Adrian Reuben, Valerie Durkalski


Aspirin reduces liver fibrosis progression in hepatitis C recurrence after liver transplantation

Armelle Poujol-Robert1, Pierre-Yves Boëlle2, Filomena Conti3, Francois Durand4, Christophe Duvoux5, Dominique Wendum6, Valerie Paradis7, Vincent Mackiewicz8, Olivier Chazouillères1, Raoul Poupon1

1service d'hépatologie, Hôpital Saint-Antoine, APHP, Paris, France; 2unité de santé publique, Hôpital Saint-Antoine, APHP, Paris' France; 3cenfre de transplantation hépatique, Hôpital Saint-Antoine, APHP, Paris' France; 4service déhepatologie ef réanimation hépatodigestive, Hôpital Beaujon, APHP, Clichy France; 5service d'hépatogastroentérologie' Hôpital Henri Mondor, APHP, Créteil' France; 6service d'anafomie et cytologie pathologiques, Hôpital Saint-Antoine, APHP, Paris' France; 7Département d'anatomie pathologique, Hôpital Beaujon, APHP, Clichy, France; 8service de virologie, service de microbiologie, Hôpital Beaujon, APHP, Clichy, France

Background and aims: There is strong evidence for an association between thrombosis in the hepatic microcirculation and liver fibrosis. Anticoagulants and antiplatelet therapy decrease liver fibrous tissue deposition in different animal models. The aim of this study was to evaluate liver fibrosis progression to F≥2 in liver transplant recipients with recurrent hepatitis C virus receiving or not daily low dose aspirin (75 to 100mg/d) for preventing hepatic artery thrombosis. Patients and methods: All patients HCV+ with PCR HCV+ who had undergone liver transplantation (LT) between 2000 and 2010 in 4 French centers were included in this retrospective study. Exclusion criteria were the following: HIV or HBV coinfection, previous LT, death within the year following LT. Liver fibrosis was assessed by histological evaluation according to METAVIR classification. Data were censored at the time of antiviral therapy starting. Fibrosis progression was analysed with a multi states model with time dependant covariables. Results: 188 HCV+ patients (male 83%, mean age 52 +/-8 years) transplanted for cirrhosis were included. 109 patients received aspirin (group A) and 79 did not (group B). The mean duration to F≥2 was 4.6 years (3.5-6.3) in group A and 3.1 (1.0-9.3) in group B. There was no difference between group A and B for donor gender (83% vs 84% males), donor age (51 vs 53 years), cold ischemia time (8.2 vs 8.4 hours), episodes of acute rejection (39% vs 35%), biliary complications (20% vs 23%) and immunosuppressive therapy (calcineurin inhibitors (CNI) vs CNI + mycophenolate mofetil). By univariate analysis, older recipient age (HR 0.78, p=0.005), older donor age (HR 1.26, p<0.0001), male donor gender (HR 1.54, p=0.006), number of corticosteroids bolus received (HR 1.31, p=0.02) and aspirin intake (HR 0.74, p=0.03) were associated with fibrosis progression to stage F≥2.HCV genotype, preservation injury, cold ischemia time, post LT diabetes were not associated with fibrosis progression. Multivariate analysis showed that male donor gender (HR 1.7, p=0.002) and older donor age (HR 1.3, p=0.0001) were associated with rapid fibrosis progression whereas aspirin intake (HR 0.66 [0.47-0.91], p=0.01) and older recipient age (HR 0.8, p=0.02) were associated with slow fibrosis progression. After adjustment on immunosuppressive therapy, aspirin intake was still associated with decreased fibrosis progression (HR 0.71 [0.51-0.99], p=0.05). Conclusion: Low dose aspirin reduces liver fibrosis progression in HCV recurrence after liver transplantation. These results are in line with the concept of an association between thrombosis and liver fibrosis.


Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead

Christophe Duvoux - Advisory Committees or Review Panels: Novartis, Roche, Novartis, Roche, Novartis, Roche, Novartis, Roche; Speaking and Teaching: Astellas, Astellas, Astellas, Astellas

Vincent Mackiewicz - Speaking and Teaching: Abbott Diagnostics

The following people have nothing to disclose: Armelle Poujol-Robert, Pierre-Yves Boëlle, Filomena Conti, Dominique Wendum, Valerie Paradis, Olivier Chazouilleres, Raoul Poupon


Protease inhibitor-based triple therapy is highly effective in liver transplant recipients with genotype 1 hepatitis C recurrence: A Canadian multicentre experience

Nabiha Faisal1, Eberhard L. Renner1, Marc Bilodeau2, Eric M. Yoshida3, Philip Wong4, Mang M. Ma5, Kelly W. Burak6, Bandar Al-Judaibi7, Curtis Cooper8, Thomas Shaw-Stiffel9, Les Lilly1

1Hepatology Transplant Unit, University Health Network, Toronto, ON, Canada; 2Liver Transplant Program, University of Montreal, Montreal, QC, Canada; 3Liver Transplant Program, University of British Columbia, Vancouver, BC, Canada; 4Liver Transplant Program, McGill University, Montreal, QC, Canada; 5Liver Transplant Program, University of Alberta, Edmonton, AB, Canada; 6Liver Transplanf Clinic, University of Calgary, Calgary, AB, Canada; 7Liver Transplant Program, Western University, London, ON, Canada; 8Infectious Disease Clinic, University of Ottawa, Ottawa, ON, Canada; 9Hepatology Clinics, University of Ottawa, Ottawa, ON, Canada

Introduction and Aim: Hepatitis C (HCV) related liver disease and hepatoma continue as the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to PEG-IFN/Ribavirin (P/R) therapy of recurrent HCV in Genotype 1(G1) LT recipients have been disappointing (30-40%. Experience with triple therapy using protease inhibitors (PI; Boceprevir (BOC), Telaprevir (TPV)) in these patients is limited. This report summarizes the results in a large cohort of patients treated for recurrent HCV using triple therapy in 6 Canadian adult liver transplant centres. Methods: 76 pts (64 male, mean age 56y) were treated for G1 HCV (55 G1a) with either BOC (2/3) or TPV at a mean of 44.7 mo. post LT. 2/3 pts were either prior non-responders or relapsers; the rest were treatment naϊve. Two pts had fibrosing cholestatic HCV; the balance chronic disease with mean fibrosis stage 2.55 pts were on cyclosporine based immunotherapy; the remainder on tacrolimus or neither. All BOC and the majority of TPV pts had a P/R lead-in phase of 4-24wks. Results: 69/76 total pts have had viral load (VL) measured on triple therapy; 56 (81%) were undetectable. 39 pts remain on treatment, 90% with undetectable VL. Of 37 pts off therapy, 28 had undetectable VL at treatment end, with VL pending in two others. 13 pts discontinued all treatment early, 3 for non response and 10 for adverse events, which included intolerance, infection (with one death), myocardial infarction, and acute pancreatitis (2 pts). One episode of rejection on treatment was documented; antiviral treatment was not interrupted. In one pt severe rash prompted BOC discontinuation. To date, 7 pts have reached SVR-12, and only one post treatment relapse has occurred. Mean cyclosporine reduction was 2/3 and tacrolimus 80%; mean ribavirin dose reduction was 50%. 36 patients received erythropoietin; half have required transfusions. Summary: High rates of undetectable HCVRNA are achieved with triple therapy in G1 HCV infected liver transplant recipients, and relapse is uncommon. 10/76 patients initiated on treatment ended treatment early due to adverse events. Anemia requiring RBV dose reduction, erythropoietin and/or transfusions has been the most common side effect. Conclusions: A triple therapy regimen including a PI for recurrent G1 HCV in liver transplant recipients appears significantly more effective than treatment with P/R only, with projected SVR rates >60%.


Eberhard L. Renner - Advisory Committees or Review Panels: Vertex Canada, Novartis, Astellas Canada, Rcohe Canada, Gambro; Grant/Research Support: Novartis Canada; Speaking and Teaching: Novartis, Astellas Canada, Roche Canada

Marc Bilodeau - Grant/Research Support: Merck; Speaking and Teaching: Merck, Vertex

Eric M. Yoshida - Advisory Committees or Review Panels: Hoffman LaRoche, Gilead Sciences Inc, Vertex Inc; Grant/Research Support: Cangene Corporation, Hoffman LaRoche, Merck Inc/Schering Plough, Pfizer Inc, Norvartis Inc, Vertex Inc, Jannsen Inc, Gilead Sciences Inc, Boeringher Ingleheim Inc, Abbie (formerly Abbott Laboratories), Astellas; Speaking and Teaching: Gilead Sciences Inc, Cangene Corporation, Vertex Inc, Merck Inc

Philip Wong - Advisory Committees or Review Panels: gilead, gilead, gilead, gilead; Grant/Research Support: merck, roche, merck, roche, merck, roche, merck, roche

Kelly W. Burak - Advisory Committees or Review Panels: Gilead, Gilead, Gilead, Gilead, Janseen; Grant/Research Support: Bayer, Bristol Myers Squibb, Genentech, Bayer, Bristol Myers Squibb, Genentech, Bayer, Bristol Myers Squibb, Genentech, Bayer, Bristol Myers Squibb, Genentech, Boehrihnger Ingelheim; Speaking and Teaching: Gilead, Astellas, Merck, Roche, Gilead, Astellas, Merck, Roche, Gilead, Astellas, Merck, Roche, Gilead, Astellas, Merck, Roche

Curtis Cooper - Advisory Committees or Review Panels: Vertex, MERCK, Roche; Grant/Research Support: MERCK, Roche; Speaking and Teaching: Roche, MERCK

The following people have nothing to disclose: Nabiha Faisal, Mang M. Ma, Bandar Al-Judaibi, Thomas Shaw-Stiffel, Les Lilly


Ten-year follow-up of a randomized study comparing Lamivudine vs Lamivudine+HBIG for the prevention of Hepatitis B virus recurrence after liver transplantation

Maria Buti1, Antoni Mas2, Martin Prieto3, Fernando Casafont4, Antonio Gonzalez5, Manuel Miras6, Jose Ignacio Herrero7, Lluis Castells1, Rafael Esteban1

1Hepatology Service, Hospital General Universitari Vall d'Hebro and Ciberehd, Barcelona, Spain; 2Institut de Malaties Digestives, Hospital Clinic, Barcelona, Spain; 3Hepatology Unit, Hospital Universitario La Fe and Ciberehd, Valencia, Spain; 4Gastroenterology Service, Hospital Universitario Marques de Valdecilla, Santander, Spain; 5Gastroenterology Service, Hospital Universitario Ntra. Sra de la Candelaria, Tenerife, Spain; 6Gastroenterology Service, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; 7Liver Unit, Clinica Universitaria de Navarra, Pamplona, Spain

Background. The current standard of care for prophylaxis against hepatitis B virus (HBV) infection after HBV-related orthotopic liver transplantation (〇LT) is lamivudine (LMV) combined with hepatitis B immune globulin (HBIg). The aim of this study was to assess the long-term safety and efficacy of LMV after OLT for chronic hepatitis B (CHB) combined with or without HBIg Methods: This is a phase 4 randomized study that included 29 patients undergoing 〇 LT for CHB-related liver disease and with HBV DNA <105 cps/mL at the time of 〇 LT. After 1 month of LMV+HBIg, patients were randomized to receive either LMV 100 mg daily or LMV daily+HBIg im monthly until month 18.Then, the study was opened allowing patients to be treated with either lamivudine or combination therapy indefinitely. The primary efficacy end-point was the absence of HBsAg at month 18, at year 5 and 10.Results: Fifteen patients were randomized to receive HBIg+LMV and 14 LMV until month 18 and then 20 continued with LMV monotherapy and 9 with HBIg+ LMV. Five and 10 year survival rates were 90% and 76% respectively. Seven patients died (6 from causes unrelated to HBV between month 29 and 144 and 1 from acute rejection and HBV recurrence at month 24). HBsAg recurrence rate was 14%. Both groups have similar HBV recurrence rates, 15% for the combination and 11% for LMV alone. Four patients, 3 of whom were LMV noncompliant experienced HBV recurrence at month 23,24,44,48.HBV-DNA by PCR in absence of HBsAg was detected in 4 cases at month 18, in 6 cases at year 5 and in none in year 10.The tolerance to HBIg and/or LMV was excellent and no AEs related to prophylaxis were observed. Conclusions: In this population of patients with low levels of viremia before 〇 LT, the rate of HBV recurrence was low and similar between LMV and HIg and LMV after a short course of HBIg and LMV, if therapy compliance is good. No HBV recurrence was observed after 4 years of 〇 LT and at year 10, all patients have undetectable levels of HBVDNA.


Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen;

Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

Jose Ignacio Herrero - Speaking and Teaching: Roche, Astellas, Novartis; Stock Shareholder: Roche, Novartis, Abbott,


Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo, MSD, BMS, Novartis, Gilead, Glaxo, Janssen

The following people have nothing to disclose: Antoni Mas, Martin Prieto, Fernando Casafont, Antonio Gonzalez, Manuel Miras, Lluis Castells


Scavenger receptor B-I antagonist ITX5061 modulates early HCV kinetics in patients undergoing liver transplantation: results of a phase Ib clinical trial

Ian A. Rowe1,2, Matthew J. Armstrong1, 2, Richard Parker1,2, Kathy Guo1, Darren Barton1, Gene D. Morse3, Jeff McKelvy4, Flossie Wong-Staal4, David H. Adams1, Jane A. McKeating5, David J. Mutimer1, 2

1Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, United Kingdom; 2Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 3NYS Center of Excellence in Bioinformatics and Life Sciences, University of Buffalo, Buffalo, NY; 4iTherX, Inc., San Diego, CA; 5HCV Research Group, University of Birmingham, Birmingham, United Kingdom

Prevention of recurrent HCV infection after liver transplantation (LT) is a major unmet clinical need. ITX5061 is a small molecule antagonist of scavenger receptor B-I (SR-BI) that prevents HCV entry and infection in vitro. The aim of this phase Ib study was to determine safety and efficacy of ITX5061 to prevent HCV allograft infection. Phase Ib single centre prospective open label study including 23 consecutive patients (21 males) undergoing LT. The first 13 control patients did not receive study drug. The subsequent 10 patients received ITX5061 150mg orally immediately pre-LT, post-LT and daily for 1 week. Plasma HCV RNA was quantified at 13 defined timepoints during the first week and weekly thereafter for one month, allowing detailed viral kinetic analysis. ITX5061 plasma concentrations before and after LT were measured with liquid chromatography/mass spectrometry. Clinicaltrials. gov NCT01292824.The majority of recipients were infected with HCV G1 (13/23). All patients survived 1 month after LT. ITX5061 treatment was well tolerated with no difference in the nature or frequency of adverse events between treated and untreated subjects. Oral absorption of ITX5061 was demonstrated with measurable plasma concentrations before and daily for one week after LT. HCV RNA declined during the first 24 hours but remained detectable for all patients during treatment and follow-up. Compared with values measured during the anhepatic phase of surgery, the median reduction in HCV RNA was greater for treated patients at all time-points (approximately 1log10 difference during treatment). The maximal decline in HCV RNA was greater than 2log10 in 8/10 treated patients compared to 6/13 untreated patients (Figure). In G1 patients (n=6) 7 days treatment was associated with a sustained reduction in HCV RNA (all greater than 2log10) compared with the control group (n=7), none of whom achieved a 2log10 reduction at any time. Following treatment withdrawal HCV RNA increased in all patients. Treatment with ITX5061, an inhibitor of HCV entry, is safe and well tolerated in LT. ITX5061 influences HCV RNA kinetics and a significant reduction in HCV RNA titres during treatment was observed. These findings support further investigation into the efficacy of ITX5061 in HCV infected patients undergoing LT.



Matthew J. Armstrong - Grant/Research Support: novo nordisk Jeff McKelvy - Employment: iTherX Pharma Inc

Flossie Wong-Staal - Board Membership: United Biomedicals, Inc.; Management Position: iTherX Pharma, Inc.

David J. Mutimer - Advisory Committees or Review Panels: BMS, Janssen, MSD, Gilead

The following people have nothing to disclose: Ian A. Rowe, Richard Parker, Kathy Guo, Darren Barton, Gene D. Morse, David H. Adams, Jane A. McKeating


Guillain-Barré syndrome and hepatitis E virus infection

Suzan D. Pas1, Bianca van den Berg2, Richie G. Madden4,5, Jeremy G. Hunter4,5, Anne P. Tio-Gillen3, Harry Dalfon4,5, Annemiek A. van der Eijk1, Barf C. Jacobs2,3

1Viroscience, ErasmusMC, Rotterdam, Netherlands; 2Neurology ErasmusMC, Rotterdam, Netherlands; 3Immunology, ErasmusMC, Rotterdam, Netherlands; 4Cornwall Gastrointestinal Unit, Royal Cornwall Hospital Trust, Truro, United Kingdom; 5European Centre for the Environment and Human Health, University of Exeter Medical School, Truro, United Kingdom

<Background> Guillain-Barré syndrome (GBS) is a typical postinfectious polyradiculoneuropathy. Various infections may trigger GBS, but in about half of the patients the causative infection is unknown. Hepatitis E virus (HEV) is an emerging pathogen, sometimes complicated by a range of neurological disorders. Cases of GBS following HEV infection have been reported, but may represent chance findings. The aim of this case-control study was to determine if HEV infection is associated with GBS. <Methods> HEV infections were determined in a representative cohort of 201 GBS patients and 201 healthy controls, with a similar distribution of age and year of sampling (1994-2008). The GBS cohort was representative with respect to age (median 50 yrs, IQR 34-66), male: female ratio (114: 87), and presence of the most common types of infections related to GBS. Serum or EDTA-plasma samples from GBS patients were obtained in the acute phase before start of treatment. All samples were tested for the presence of anti-HEV IgM and IgG (Wantai). In the serologic positive GBS patients, serum/EDTA plasma, available stool and cerebrospinal fluid samples were tested for HEVRNA (quantitative real-time PCR). HEV-ORF1 sequences were used for genotyping. <Results> An increased ratio of anti-HEV IgM antibodies was found in 10 GBS patients (5%) compared to 1 healthy control (0.5%) (O R 10.5, CI 1.3-82.5; p = 0.010). HEV RNA was detected in serum from 3 of these patients and additionally in faeces from 1 patient. HEV-ORF1 phylogenetic analysis characterised two samples as non related genotype 3 strains. 70% of anti-HEV IgM positive patients had mildly increased ALT (median 70 IU/L), range 26-921). All CSF samples were negative for HEV RNA, excluding an infectious polyradiculoneuropathy. The presence of anti-HEV IgM in GBS patients was not related to age, gender, disease severity or out-come after 6 months. IgM anti-ganglioside GM1 antibodies were detected in one anti-HEV IgM positive patient. Anti-HEV IgG was demonstrated in 92 (46%) patients compared to 77 (38%) healthy controls (O R 1.4, CI 0.9-2.0; p=0.130). Patients with anti-HEV IgG antibodies were older (median age 60, IQR 44-69) than patients without these antibodies (median age 44, IQR 30-59) (p<0.001) and initially more severely affected (higher GBS disability score at entry) (p=0.003). <Conclusions> This study indicates that HEV may be a new type of infection preceding GBS. In the Netherlands, 5% of patients with GBS have associated acute hepatitis E. Further research is required to determine by what mechanism HEV may trigger GBS and if HEV infections also precede the onset of GBS in other geographical areas.


Suzan D. Pas - Grant/Research Support: the Virgo consortium, funded by the Dutch government (FES0908), the Netherlands Genomics Initiative (NGI) project number 050-060-452, the European Community Seventh Framework Programme (FP7/2007-2013) under project EMPERIE (grant agreement no. 223498)

Harry Dalton - Consulting: GSK, Wantai, Aptalis; Speaking and Teaching: Merck

The following people have nothing to disclose: Bianca van den Berg, Richie G. Madden, Jeremy G. Hunter, Anne P. Tio-Gillen, Annemiek A. van der Eijk, Bart C. Jacobs