AASLD/Abstract Preview/ LT/Cirrhosis/Halt C and More

Click Here To See Some Of The Abstracts That Will Be Presented At : The AASLD Covering The Several new anti-viral medications that are currently in development.

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A Few Highlights of What Will Be Presented At The : AASLD Oct 29-Nov 2

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Genotype

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A Phase IIa, open-label study to assess the antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6 m

C. Moreno1; T. Berg2; T. Tanwandee3; S. Thongsawat4; H. Van Vlierberghe5; S. Zeuzem6; O. Lenz7; M. Peeters7; V. J. Sekar8; G. . De Smedt7 1. Department of Gastroenterology and Hepatopancreatology, Erasme Hospital, Brussels, Germany. 2. Medizinische Klinik m. S. Hepatologie und Gastroenterologie Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany. 3. Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. 4. Chiang Mai University, Chiang Mai, Thailand. 5. Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium. 6. Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany. 7. Tibotec BVBA, Mechelen, Belgium. 8. Tibotec Inc., Titusville, NJ, United States.
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Aim:

TMC435, an inhibitor of the HCV NS3/4A protease, has demonstrated potent antiviral activity in both treatment-naïve and treatment-experienced patients infected with HCV genotype 1 (GT 1). We report here the results of a Phase IIa, open-label, proof-of-concept study (TMC435-C202) to assess the antiviral activity and safety of TMC435 200 mg once-daily (QD) in patients infected with HCV GT 2–6.

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Methods:

Treatment-naïve patients infected with HCV (GT 2–6) were included in five cohorts by genotype and received seven consecutive days of monotherapy with oral TMC435 200 mg QD. The primary endpoint was change from baseline in HCV RNA at Day 8; plasma HCV RNA was determined using the COBAS Taqman HCV v2 assay. Secondary endpoints included safety and tolerability. Patients could start treatment with pegylated interferon and ribavirin from Day 8 onwards.

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Results:

In total, 37 patients were enrolled (GT 2: n=6; GT 3: n=8; GT 4: n=8; GT 5: n=7; GT 6: n=8), recruited in Belgium, Germany and Thailand. At Day 3 of TMC435 monotherapy, the mean (range) change from baseline in plasma HCV RNA (log10 IU/mL) was -2.02 (-3.6; -0.3) for GT 2, 0.16 (-0.7; 1.8) for GT 3, -3.43 (-3.9; 2.6) for GT 4, -2.71 (-4.0; -1.5) for GT 5 and -3.57 (-4.2; -2.7) for GT 6. For the primary endpoint at Day 8, the mean (range) change from baseline in plasma HCV RNA (log10 IU/mL ) was -2.73 (-4.9; -0.4) for GT 2, -0.04 (-1.2; 1.0) for GT 3, -3.52 (-4.8; -1.4) for GT 4, -2.19 (-3.1; -0.3) for GT 5 and -4.35 (-5.2; -2.8) for GT 6. Four patients (GT 4: n=2; GT 6: n=2) achieved HCV RNA levels less then 25>

Type and incidence of AEs (all grade 1–2) was similar across cohorts and the most common adverse events (AEs) were influenza-like illness and headache. There were no discontinuations and no serious AEs during the 7-day TMC435 monotherapy period. Conclusions:Monotherapy with oral TMC435 200 mg QD for 7 days showed potent antiviral activity, with highest antiviral activity against GT 4 and GT 6, followed by GT 5 and GT 2. No antiviral activity was seen against GT 3. All AEs were mild to moderate, with no discontinuations during the 7-day monotherapy period.

Length of Peginterferon-Ribavirin Therapy According to HCV Genotype and Rapid Virological Response in HIV/HCV Coinfected Patients: The EXTENT Trial

P. Barreiro1; P. Tuma1; A. Rivero2; M. Cervantes3; I. Santos4; A. M. Camacho2; E. Vispo1; V. Asensi5; V. Soriano1 1. Hospital Carlos III, Madrid, Spain. 2. Hospital Reina Sofía, Córdoba, Spain. 3. Hospital Parc Taulí, Barcelona, Spain. 4. Hospital La Princesa, Madrid, Spain. 5. Hospital Central de Asturias, Oviedo, Spain.

Background:

Treatment of chronic hepatitis C is less effective and associated with more complications in HIV-HCV coinfected patients. HCV G2/3 and RVR are good predictors of SVR in this population, and following the steps of HCV monoinfection, the length of therapy might be individualized accordingly.

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Methods:

The efficacy of pegIFN alfa2b plus weight-based RBV was examined in HIV/HCV coinfected patients randomized to different lengths of therapy as follows: 6 mo. for G2/3 with RVR, 12 mo. for G1/4 with RVR or G2/3 without RVR, and 15 mo. for G1/4 without RVR. Definition of RVR and SVR was serum HCV-RNA less then 10>

Mean age 43 years-old, 75% males, 89% former IDUs, 85% under HAART and mean CD4 count 570±266 cells/µL. Mean HCV-RNA 6.1±0.9 IU/mL, 73% >500,000 IU/mL, and 67% HCV G1/4. Liver fibrosis by METAVIR was 32% F0F1, 25% F2, 28% F3 and 15% F4. RVR was recognized in 17 (16%) patients with G1/4 and in 27 (49%) with G2/3 (p more then 0.001). p="0.9);">

Among HCV G2/3 patients, SVR was seen in 12 (60%) patients with RVR treated for 6 mo. and in 17 (77%) patients without RVR treated for 12 mo. (p=0.3); and only 1 (17%) patient without RVR treated for 6 mo. attained SVR (p=0.01).

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Conclusion:

In HIV/HCV coinfected patients, extension of HCV therapy to 15 months improves the chances of SVR in G1/4 carriers without RVR. Likewise, shortening the length of therapy to 6 months may be offered to G2/3 patients with RVR.

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Predictors of relapse in genotype 3 infected chronic HCV patients who achieve rapid virologic response

S. R. Shah1; P. Marcellin2; G. R. Foster3; M. P. Manns4; K. Patel5; S. Kottilil6; E. Pulkstenis7; M. Subramanian7; D. R. Nelson8; S. Zeuzem9 1. Jaslok Hospital and Research Centre and Breach Candy Hospital, Mumbai, Maharashtra, India. 2. Hopital Beaujon, Clichy, France. 3. The Royal London Hospital, London, United Kingdom. 4. Medizinische Hochschule Hannover (MHH), Hannover, Germany. 5. Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, United States. 6. National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States. 7. Human Genome Sciences, Inc., Rockville, MD, United States. 8. University of Florida, Gainsville, FL, United States. 9. Medizinischen Klink I. Klinikum der Johann Wolfgang Goethe-Universitaet Hospital, Frankfurt Main, Germany.
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Background:

Current recommendation for chronic hepatitis C (CHC) patients with genotype 3 is treatment duration of 24-weeks. Rapid virologic response at week 4 (RVR) has a high predictive value for sustained virologic response (SVR), though not all subjects with RVR achieve SVR. It is therefore important to identify patients who may require longer duration of therapy.

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Methods:

505 genotype 3 infected CHC patients who received 24-weeks of treatment with either albinterferon alfa-2b or peginterferon alfa-2a with oral ribavirin 800 mg/d in a phase 3 trial were analyzed. In the 402 patients who achieved RVR (HCV RNA less then 43 or="3.0;" p="0.003)," or="2.5;" p="0.04)," or="2.2;" p="0.04)," or="2.2;" p="0.02),">ULN (OR=2.1; p=0.03). SVR rates in RVR patients with low viral load and no steatosis (n=118) was 98% compared with 79% in RVR patients with high viral load and steatosis (n=148). Furthermore, in a multivariate model for predictors of steatosis, HCV RNA ≥ 400k was the strongest independent predictor of steatosis (OR= 6.3; p<0.0001).

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Conclusions:

Viral load is highly associated with steatosis in genotype 3 patients who achieve RVR. Both viral load and steatosis are independent predictors of relapse in this patient population. Studies are warranted to explore the biological mechanisms, and to consider longer treatment duration in RVR patients with these risk factors.

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Patients with genotype 4 HCV infection respond worse to 48week combination therapy with peginterferon α plus ribavirin when compared to patients with genotype 1: the Greek experience

S. Savvidou1; I. Goulis1; D. Chrysagis2; G. V. Papatheodoridis3; S. Manolakopoulos4; C. K. Triantos5; E. Akriviadis1 1. 4th Department of Internal Medicine, Medical School of Aristotle University, Hippocration General Hospital of Thessaloniki, Thessaloniki, Greece. 2. Department of Internal Medicine, Infectious Diseases Hospital of Thessaloniki, Thessaloniki, Greece. 3. 2nd Department of Internal Medicine, Athens University Medical School, Hippocration General Hospital of Athens, Athens, Greece. 4. Department of Gastroenterology, Polyclinic General Hospital of Athens, Athens, Greece. 5. Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece.
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Background & Aims:

Prevalence estimation for genotype 4 chronic hepatitis C (CHC) in Greece is approximately 15%. Genotype 4 response to current combination treatment with peginterferon α plus ribavirin is still in debate. Reports from Middle East showed favourable treatment outcome, while reports from Southern Europe showed the contrary.

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Aim of this study was to compare sustained virological response (SVR) rates between genotype 4 and genotype 1, the two most difficult genotypes to treat.

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Patients & Methods:

Demographic, virological and histological data from 467 consecutive CHC patients from 5 Greek centers of follow-up were recorded. All patients received standard combination therapy with peginterferon α-2a(180μg/w) or -2b(1.5μg/kg/w), plus weight-based ribavirin. Only genotype 1 and 4 patients were included in statistical analysis to identify possible differences in treatment outcome and in SVR determinants.

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Results:

Genotype distribution was: 202(43.3%), 30(6.4%), 136(30.2%), 82(17.6%) and 17(3.6%) for genotypes 1, 2, 3, 4 and undefined genotypes, respectively. A total of 39 patients (8.4%) were excluded because either they did not complete post-treatment follow-up or they had discontinued therapy due to severe side-effects. Further subgroup analysis was performed only in genotype 1 and 4 patients who satisfied inclusion criteria. Baseline patient characteristics were: 144(56.5%) male, aged 47.1±13.1 years-old, 54(21.2%) former intravenous drug users, 29(11.4%) heavy alcohol drinkers, mean BMI 23.3±3.8kg/m2, 48(18.8%) high baseline viral load, 38(14.9%) had advanced fibrosis, 13(5.1%) severe necro-inflammatory activity and 83(32.6%) evidence of hepatic steatosis in pretreatment liver biopsy, 38(14.9%) had previously been subjected to IFN therapy, and median treatment duration was 40.2 months.

SVR was achieved in 144(56.5%) patients, while comparison between genotype 1 and 4 revealed a statistical significant difference in SVR rate (62% vs. 39.7% respectively, Fisher’s exact test, p=0.002). No difference related to any of the demographic, virological or histological variable was recorded between the two genotypes in order to explain their significant difference in treatment response. In multiple regression analysis, non-response was independently associated with genotype 4 (OR 4.04, p<0.001), p="0.018)," p="0.027)">

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Women

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Hepatitis C recurrence in female recipients have a worse treatment outcome: An Italian Multicenter Study

V. Giannelli1; M. Giusto1; M. Pompili2; R. Viganò3; M. Marino4; M. F. Donato5; M. Rendina6; P. Toniutto7; M. Morelli9; M. Angelico12; P. Burra10; L. Miglioresi11; A. Gasbarrini2; S. Fagiuoli8; M. Merli1 1. Dept Clinical Medicine, University of Rome "La Sapienza", Rome, Italy. 2. Catholic University of Rome, Rome, Italy. 3. Niguarda Hospital, Milan, Italy. 4. Univesity of Modena, Modena, Italy. 5. Maggiore Hospital, Milan, Italy. 6. University of Bari, Bari, Italy. 7. University of Udine, Udine, Italy. 8. Ospedali Riuniti of Bergamo, Bergamo, Italy. 9. S.Orsola-Malpighi Hospital, Bologna, Italy. 10. University of Padova, Padova, Italy. 11. S.Camillo-Spallanzani Hospital, Rome, Italy. 12. Tor Vergata University , Rome, Italy.

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Background and Aim

It has been recently proposed that female gender may increase the risk of graft loss after liver transplantation (LT) in HCV patients, particularly in female recipients receiving an older graft (≥ 60 years). It has not been investigated whether gender may influence HCV treatment outcome after LT. Aim of the study was to assess differences in gender regarding treatment outcome of HCV recurrence in liver transplant recipients.

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Methods:

A retrospective analysis was performed in HCV liver recipients who underwent interferon (IFN) or pegylated-IFN plus ribavirin (RBV) therapy from 1999 to 2008 in 12 Italian experienced liver transplant centres.

Combined antiviral treatment was scheduled for at least 48 weeks. Difference in gender was analyzed by using Chi-Square test. For independent and continuous variables we used the Wilcoxon test or the Mann-Whitney U test as appropriate.

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Results:

In our series of 452 patients (mean age 53 + 8 years) males were 74% and females 26%.Males and females were similar for age, distance from LT, donor age, HBV coinfection, previous HCV-treatment, diabetes, body mass index, distance between therapy and LT, baseline HCV-RNA viral load , baseline fibrosis, type of immunosuppressive therapy, and ribavirin and IFN dose per kg.Sustained Virological Response (SVR) was lower in females than in males (25% vs 39%; p=0.005).

Genotype-1 was more frequent in female than in male recipients (84 vs 72% ; p=0.01), however when only patients infected with genotype 1 were considered SVR was lower in females than in males (15,6 vs 27.7%;p=0.01).

Mean length of therapy in females and males was respectively 37.4 ± 25.1 vs 42.3 ± 25.4 weeks ; p=0.03. Only 53% of females completed at least 80% of therapy vs 66% of males; p=0.01.Discussion:Our study demonstrates a lower response to antiviral treatment in women liver recipients with HCV recurrence. Female patients who underwent antiviral therapy had a lower mean duration of therapy and an higher rate of therapy discontinuation.

Menopause is Associated with Relapse in Chronic Hepatitis C Patients Treated with Pegylated Interferon Plus Ribavirin. C.

Stern1; M. Martinot-Peignoux1; M. Ripault1; N. Boyer1; A. Cardoso1; A. El Ray1; T. Asselah1; D. Valla1; P. Marcellin1 1. Service d'Hépatologie, Hôpital Beaujon, Clichy, France.
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BACKGROUND/AIMS:

Relapse after treatment of chronic hepatitis C (CHC) patients with the combination of pegylated interferon (PEG-IFN)-α and ribavirin (RBV) is observed in 30% of patients with end of therapy (EOT) response. Factors associated with relapse are not well known. The aim of this study was to evaluate the factors related to relapse in CHC patients, particularly in female patients, treated with PEG-IFN in combination with RBV.

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METHODS:

A total of 249 consecutive naive CHC patients treated with PEG-IFN-α-2a or -2b plus RBV (800 to 1200 mg/day) and with EOT response were included. Among these, 84 (34%) patients were female. Duration of therapy was defined according to the current guidelines. Clinical, biological, virological and histological data were collected. Type of PEG-IFN, initial doses and modifications of therapy were analyzed. The efficacy of treatment was evaluated with a sensitive qualitative HCV RNA assay (<15>

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RESULTS:

Relapse was observed in 34% of patients; 50% received PEG-IFN-α2a. Overall population presented the following characteristics: mean age 47±11, obesity (BMI ≥30) in 10%, genotype 1 in 33%, advanced fibrosis (≥F3) in 24% and marked steatosis (≥30%) in 27%. In the logistic regression, factors related to relapse in overall population were: obesity (p=0.011), genotype 1 (p=0.001), marked steatosis (p=0.006) and PEG-IFN dose reduction (p<0.001).>

Therefore, to confirm a possible impact of menopause on relapse in CHC female patients, we compared patients under and older than 50 years according to gender. In males (n=165), relapse was present in 22% and 28% of patients under 50 years and older than 50 years (p=0.38), respectively. When relapse rates were analyzed in females (n=84), a statistically difference related to age was observed (14% vs 37%, p=0.023).

Among female patients, factors associated with relapse were: menopause (p=0.006), obesity (p=0.031), high viral load (≥400,000 IU/mL) (p=0.014), genotype 1 (p=0.034) and necro-inflammatory activity ≥A2 (p=0.043). In the logistic regression, only menopause was independently associated with relapse in CHC female patients (p=0.007, 95% CI 1.66 - 24.47).

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CONCLUSION:

CHC patients infected with genotype 1 and presenting obesity and marked steatosis have higher rates of relapse. PEG-IFN reduction, but not ribavirin reduction, is associated with relapse. In female patients, menopause has a negative impact on SVR rates.

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HALT-C

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Maintenance peginterferon (pegIFN) therapy to prevent hepatocellular carcinoma (HCC) in patients (pts) with advanced chronic hepatitis C (CHC): extended follow-up results from the HALT-C Trial

A. S. Lok1; J. E. Everhart2; E. C. Wright2; T. R. Morgan3; A. M. Di Bisceglie4; H. Kim5 1. Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI, United States. 2. NIDDK, NIH, Bethesda, MD, United States. 3. VA Med Ctr, Long Beach, CA, United States. 4. Saint Louis Univ, Saint Louis, MO, United States. 5. NERI, Watertown, MA, United States.
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Background:

IFN has been reported to decrease the incidence of HCC in pts with CHC. Earlier reports of the HALT-C trial found that maintenance pegIFN did not reduce clinical outcomes during the first 4 yr but the follow-up may have been too short to observe a chemopreventive effect on HCC. Aim: To determine whether pegIFN decreased the incidence of HCC in the HALT-C cohort with longer follow-up.

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Methods:

1050 pts with CHC and Ishak fibrosis ≥3, who failed to achieve SVR after pegIFN and ribavirin therapy, were randomized to receive pegIFN 90 μg/wk x 3.5 yrs or no treatment. Pts were followed q 3 mos x 3.5 yrs then q 6 mos until the end of the study.Results: After a median follow-up of 6.1 yrs (max 8.7), 88 (68 definite and 20 presumed) pts met predefined criteria of HCC: 37/515 (7.2%) pegIFN-treated and 51/533 (9.6%) control pts (p=0.24). PegIFN was associated with a significantly lower incidence of HCC among pts with cirrhosis at baseline but not those with fibrosis; cumulative incidence at 8 yrs was 11% vs. 24.2%, HR 0.45 (95% CI 0.24-0.83, p=0.01) for pts with cirrhosis, and 10.1% vs. 9.8%; HR 1.44 (95% CI 0.77-2.69, p=0.26) for those with fibrosis. Among pts with cirrhosis at baseline, the cumulative rate of HCC in the two treatment groups did not diverge until after yr 4. A beneficial effect of pegIFN among pts with cirrhosis at baseline persisted when presumed HCC cases were excluded and when the analysis was limited to pts at risk after yr 4. Treated pts who had a decrease in histologic activity index (HAI) by ≥2 points on follow-up biopsy had a lower incidence of HCC than those with unchanged or increase in HAI: 2.9% vs. 9.4% (p=0.03).

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Conclusions:

Extended follow-up of the HALT-C cohort showed a modest benefit of long-term pegIFN in decreasing the incidence of HCC. This effect was mainly observed in pts with established cirrhosis and took several yrs to become apparent.

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Elderly Patients
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Sustained Virological Response of Antiviral Therapy and Clinical Outcomes in Elderly Patients with Compensated HCV-related Cirrhosis

P. Charatcharoenwitthaya1; R. Sermsathanasawadi1; S. Chainuvati1; N. Pausawasdi 1; S. Nimanong 1; V. Prachayakul1; S. Pongprasobchai 1; S. Leelakusolvong1; S. Manatsathit1; U. Kachintorn1; T. Tanwandee 1 1. Medicine, Gastroenterology Division, Siriraj Hospital, Bangkoknoi, Bangkok, Thailand.
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Background & Aims:

The clinical utility of antiviral therapy in elderly patients with HCV-related cirrhosis has not been elucidated. The aims of this retrospective study were 1) to evaluate whether antiviral therapy had similar benefits between patients with HCV-related cirrhosis aged ≥ 60 years and those aged less then 60

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Methods:

This study analyzed data on 194 consecutive patients with compensated HCV-related cirrhosis who received more than 1 year periodic medical screening from 1997 through 2009.

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Results:

A total of 159 cirrhotic patients (85 female and 74 male; mean age, 53.7±8.1 years) were treated with a combination of conventional interferon or peginterferon and ribavirin; 36 of them (23%) were 60 years of age or older.

The cohorts aged ≥ 60 years had a median model of end-stage liver disease (MELD) score of 7 (range: 6-19); a median pretreatment viral load of 5.9 log10IU/L; and 61% were infected with HCV genotype 3. Clinical, hematologic, biochemical, and virological features were not different between patients aged ≥ 60 years and those aged < p=".0002)" p=".02)">

During a median follow-up of 56.5 months (range: 17-139), none of 17 elderly responders developed liver failure or died whereas 4 of 19 elderly nonresponders had liver failure and one of them died of cirrhotic complication. The annual incidence of HCC was 4.7% in elderly responders and 7.6% in elderly nonresponders.

Comparison with patients aged ≥ 60 years who have never received antiviral therapy (n=35), SVR was found to be associated with a significant reduction in the risk of liver-related death (p=.04) and liver failure (p=.0008) but was not associated with a reduction in the risk of HCC development (p=.1) among elderly cirrhotic patients.

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Conclusion:

Although the efficacy of antiviral therapy among elderly patients with compensated HCV-related cirrhosis was inferior to that of young patients, achieving SVR in this population was associated with improved clinical outcomes, particularly prevention of decompensation of cirrhosis.

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Peginterferon α Plus Ribavirin for Chronic Hepatitis C in the Era of the Aging Society

Y. Komorizono1; K. Sako1; Y. Goto1; T. Shibatou1 1. Hepatology, Nanpuh Hospital, Kagoshima, Japan.
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Background and Aim:

Today, the majority of patients with chronic hepatitis C are characterized by aging. However, the debate regarding combination therapy of peginterferon α and ribavirin for elderly patients with chronic hepatitis C remains unresolved. This study aimed to evaluate the effects of age on combination therapy with peginterferon α and ribavirin for chronic hepatitis C. Patients and

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Methods:

We retrospectively reviewed the medical records of 222 chronic hepatitis C patients (95 males and 127 females aged 23-77 years; mean age, 59.5 years) who were treated with peginterferon α-2a or α-2b plus ribavirin. Patients with HCV genotype 1 received peginterferon α-2b at a dose of 1.5 µg/kg or peginterferon α-2a at a dose of 180 µg/body weekly plus ribavirin at 600-800 mg/day for 48 weeks. Patients with HCV genotype 2 received peginterferon α-2b at a dose of 1.5 µg/kg weekly plus ribavirin at 600-800 mg/day for 24 weeks. We compared the tolerability and efficacy between older patients (≥65 yr, n=74) and younger patients (<65 n="148)">

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Results:

The proportion of 70/70/70 adherence was significantly lower in older patients than in younger patients (45% vs. 63%, P=0.01). The SVR rate was also significantly lower in older patients than in younger patients (38% vs. 57%, P=0.008). Among the patients with HCV genotype 1, the SVR rate was significantly lower in older patients than in younger patients (31% vs. 52%, P=0.006). In contrast, the older and younger patients with HCV genotype 2 had similar SVR rates (80% vs. 77%, P=0.842).

Multiple regression analyses in all patients indicated that a rapid virologic response (odds ratio (OR), 6.2; 95% confidence interval (CI), 2.0-19.2; P=0.002) and 70/70/70 adherence (OR, 10.0; 95%CI, 4.8-20.8; P<0.001)>

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Conclusions:

Treatment adherence was the most important factor associated with treatment success.

Older patients with HCV genotype 1 had poorer treatment adherence leading to inferior treatment efficacy, while patients with HCV genotype 2 should be considered for peginterferon α plus ribavirin therapy regardless of their age.

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Older age increases the risk of relapse in Genotype-1 Chronic Hepatitis C patients showing complete early virologic response during peginterferon and ribavirin therapy

G. Borroni1; M. Andreoletti2; A. Bortoli3; M. Casiraghi4; M. Cazzaniga5; R. Ceriani6; P. Guerzoni7; G. Mandelli8; B. Omazzi3; M. L. Pich6; A. Prada3; G. Spinzi8; N. M. Terreni8 1. ASL Provincia di Milano 1, Abbiategrasso, Italy. 2. Ospedale A. Manzoni, Lecco, Italy. 3. Azienda Ospedaliera G. Salvini, Rho, Italy. 4. Ospedale Civile di Legnano, Legnano, Italy. 5. Università degli Studi, IRCCS Policlinico S. Donato, S. Donato Milanese, Italy. 6. IRCCS Istituto Clinico Humanitas, Rozzano, Italy. 7. Ospedale di Varese, Varese, Italy. 8. Ospedale Valduce, Como, Italy.
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Background.

A variable proportion of patients with chronic hepatitis C (CHC) attained a complete early virological response (c-EVR) during treatment but fail to achieve a sustained virological response (SVR). The ability to identify such patients during treatment and the possibility to tailor therapy to individual patients may allow us to convert potential relapsers into sustained responders. This study therefore, investigated predictors of relapse in genotype-1 patients showing c-EVR during treatment with peginterferon (PegIFN) plus ribavirin (RBV).

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Methods.

The ongoing study included 280 genotype-1 CHC patients consecutively treated with PegIFN plus RBV in 7 non-tertiary centres from October 2004 to January 2008. Patients treated for less than 80% of the 48-weeks scheduled time (56 patients, 20%) and those who still had detectable HCV-RNA at week 12 (96 patients, 34.3%) were excluded from the analysis. Patients non responders to previous interferon-based treatment or co-infected with HBV or HIV were also excluded. Data were analyzed by logistic regression.

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Results.

A total of 128 (45.7%) patients (M/F 80/48, mean age 45.6 years) achieved c-EVR, of whom 16.9% had liver cirrhosis and 44.1% showed high pre-treatment viral load (>800000 UI/mL).

The prevalence of co-morbidities was 11.8% and 21% of patients were relapser o non-tolerant to a previous IFN-based treatment. 72 patients (56%) were treated with PegIFN α-2b (mean starting dose: 1.32±0.02 µg/Kg/week) and 56 patients (44%) were treated with PegIFN α-2a (mean starting dose 180 µg/week). Mean RBV starting dose was 14.3±1.9 mg/Kg/day.

The rates of SVR and relapse after stopping therapy were 79% and 21% respectively. At univariate analysis, factors that predicted relapse after completion of treatment were: presence of liver cirrhosis (OR:3.70; 95%CI=1.35-10.16; p=0.011), low platelet count (OR:0.99; 95%CI=0.98-0.99; p=0.03) and older age (OR:1.07; 95%CI=1.03-1.11; p=0.0001).

Multiple logistic regression analysis identified older age as the sole independent predictor of the likelihood of relapse (OR:1.05; 95%CI=1.01-1.09; p=0.008). Conclusions. Older age is the sole predictor of relapse in genotype-1 CHC patients who attained undetectable HCV RNA after 12 weeks of treatment.

Long-term evaluation of neurocognitive performance in patients with chronic hepatitis C infection and peginterferon-alfa-based therapy

A. Schaefer1; G. Teuber2; S. Wollschläger3; M. Scheurlen1; M. R. Kraus4, 1 1. Med. Klinik u. Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. 2. IFS Stresemannallee, Frankfurt/Main, Germany. 3. Krankenhaus Dresden-Friedrichstadt, Dresden, Germany. 4. Kreiskliniken Altötting-Burghausen, Burghausen, Germany.

Background and Aims:

Neurocognitive symptoms are widely discussed in the context of chronic hepatitis C virus (HCV) infection. We assessed the long-term course of neurocognitive parameters in HCV patients with and without virus elimination and the significance of these changes for the patients’ everyday life situations.Patients and

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Methods:

In a tricenter prospective longitudinal study, we enrolled a cohort of 168 hepatitis C outpatients treated antivirally with peginterferon alfa and ribavirin. In a repeated measures design, neurocognitive performance was longitudinally assessed using the TAP (Test Battery for Attentional Performance; subtasks alertness, divided attention [optical and acoustic subtasks], vigilance, and working memory). Evaluation time points were prior to IFN therapy (baseline), at weeks 12 and 24 of IFN treatment, as well as 4 weeks and 12 months after antiviral treatment (long term follow-up evaluation).

Main outcome measure was neurocognitive performance at the time of long-term follow-up, compared with baseline values and stratified for sustained virological response (SVR, defined as HCV virus RNA negativity 6 months after the end of antiviral combination treatment).

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Results:

In the total study sample, neurocognitive performance was significantly impaired during antiviral treatment, which was reflected by increased reaction times for all assessed TAP subdomains (P < n =" 116" n =" 52">

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Conclusions:

We could demonstrate a clear and significant positive long-term effect of virus eradication on relevant aspects of attentional and neurocognitive performance in patients with chronic hepatitis C infection. This SVR-associated improvement of neurocognitive function points towards considering a broader therapy indication also for HCV patients without advanced liver disease but with symptoms of infection-associated neurocognitive decline.

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Cirrhosis

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Fatigue in patients with liver cirrhosis: the impact of hormonal abnormalities and the effect of liver transplantation

E. Kalaitzakis1; A. Josefsson1; M. Castedal2; E. Bjornsson1 1. Institute of Internal Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 2. Transplantation Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

Fatigue is considered to be common in chronic liver disease and may influence health-related quality of life(QoL). Although there are several reports on fatigue in patients with cholestatic liver disease, data on fatigue and its possible association with mood disorders and QoL in liver cirrhosis(LC) are scarce.

Also, limited data exist on the effect of liver transplantation on fatigue in these patients. Last, thyroid and adrenal hormones as well as testosterone levels are often abnormal in LC but their relation to fatigue is unexplored.

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Methods

A total of 111 consecutive patients with LC(mean age 53(SD10); 36F; 26 with viral, 24 with alcoholic and 22 with cholestatic LC; Child-Pugh score 9(2); MELD 15(6); 20 with HCC) under pretransplant evaluation were prospectively included. Three validated questionnaires were used to measure fatigue(Fatigue Impact Scale-FIS), anxiety and depression (Hospital Anxiety and Depression-HAD) and QoL(SF-36).

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Results were compared with those obtained from a random sample from the general population(n=858, age range 25-75yr, 420F). Serum thyrotropin, free 3-(T3) and 4-(T4) iodothyronine, cortisol, testosterone and dehydroepiandrosterone levels were measured. Hepatic encephalopathy was assessed clinically and with the number connection tests A&B. Transplant recipients(n=70) were followed up one year post-transplant.

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Results

Cirrhotics had, compared to controls from the general population, more pronounced fatigue expressed as total FIS score (67(41) vs 48(38), p<0.001) r="-0.54," r="-0.68,">

The total FIS score of transplant recipients improved significantly one year post-transplant(41(40); p<0.001>0.05 vs controls). In all 15% had significant depression and 13% anxiety according to HAD, 35% had low T3, 5% increased thyrotropin, 16% low cortisol and 21% low testosterone at baseline. In multivariate analysis the pre-transplant total FIS score was related to the HAD depression score(beta=0.59, p<0.001), beta="0.33," beta="0.19," p="0.03)">

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Conclusions

In cirrhosis fatigue is common and associated with impaired QoL. Liver transplantation dramatically improves fatigue in these patients. Depression, severity of cirrhosis and low cortisol levels are important determinants of fatigue in cirrhosis.

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Hepatic encephalopathy: treat or teach?

E. Amato1; S. Facchini1; S. Schiff1; A. Gatta1; P. Amodio1; S. Montagnese1 1. Department of Clinical and Experimental Medicine, University of Padova, Padova , Italy.
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A good understanding of hepatic encephalopathy (HE), compliance with anti-HE treatment and avoidance of precipitating factors are crucial to reduce HE recurrence and HE-related hospitalisations. The aim of this study was to assess the degree of understanding of HE and its treatment in a group of patients with cirrhosis and their caregivers.

Thirty cirrhotic patients with a history of HE were enrolled (8 were on lactulose, four on rifaximin, 17 on both and one on probiotics). Where available (n=27), the patients’ caregivers were also enrolled. Patients underwent evaluation of their neuropsychiatric status (clinical, electroencephalography [EEG], paper-and-pencil and computerised psychometry), quality of life (SF36) and understanding of HE and its treatment based on an ad hoc questionnaire.

Caregivers underwent the same questionnaire plus the Caregiver Burden Inventory (CBI).Seven patients (23%) were neuropsychiatrically unimpaired, 7 (23%) were qualified as having minimal (EEG and/or psychometric abnormalities) and 16 (53%) as having mild overt HE. Of the patients, 11 (37%) were aware of previous HE, 10 (33%) of being on anti-HE treatment, 9 (30%) had adequate understanding of the expected treatment effects and 5 (17%) of disease overall. Of the caregivers, 14 (52%) were aware of previous HE, 10 (37%) of their relative being on anti-HE treatment, 10 (37%) had adequate understanding of the expected treatment effects and 9 (33%) of disease overall. Of the patients on lactulose, 11 (44%) were taking an adequate amount, 10 (40%) too little and 4 (16%) too much. No significant differences in SF36 scores were observed between patients with and without HE on the day of study. In contrast, CBI scores were significantly higher in the caregivers of patients with HE (21±17 vs. 6±5, p=0.04) and correlations were observed between the caregivers’ CBI scores and the patients’ HE indices (i.e. EEG theta power: R=0.5, p<0.03).>

No association was observed between the presence of HE on the day of study and the patients’ understanding of disease or treatment. In contrast, caregivers of patients with HE on the day of study had better understanding of both disease and treatment than caregivers of patients with no HE on the day of study (p<0.05).

HE significantly affects the quality of life of caregivers. Understanding of HE is poor in both patients and their caregivers. However, caregivers seem to learn from previous HE experience, while patients do not, suggesting that educational interventions should be directed to the former.

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Six minute walk test as a predictor of survival in cirrhosis.

I. Garcia-Juarez1; A. Chavez-Ayala1; A. Duarte-Rojo1; J. Morales-Blanhir2; A. Torre-Delgadillo1; E. Lopez1; J. F. Sanchez-Avila1; M. Uribe-Esquivel1 1. Gastroenterology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico. 2. Pneumology Department, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico DF, Mexico.
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Introduction.

Liver cirrhosis is one of the most common causes of death in adults worldwide. Portopulmonary hypertension (PPHTN) and hepatopulmonary syndrome (HPS) are distinct clinical entities that may accompany liver disease and worsen survival. In patients with primary heart or lung disease, six-minute walk test (6MWT) has been validated as a prognosis factor of survival but there is little evidence of its role in patients with liver cirrhosis.

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Objective.

To determine the utility of the 6MWT as a predictor of mortality in cirrhotic patients with or without hepatopulmonary complications (HPC).

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Materials and Methods.

We conducted a prospective study between January 2006 and July 2009. All cirrhotic patients without primary heart or lung disease were considered to be enrolled. Previous informed consent was obtained and lung function test, arterial blood gases, contrast-enhanced transthoracic echocardiogram (CE-TTE) with saline microbubbles and 6MWT were performed in all patients. Six-Minute Walk Test was done according to previously established criteria for adults in Mexico City. Child Pugh and MELD score were also calculated. Survival analysis was done with Kaplan-Meir and log-rank test and a p value ≤ 0.05 was considered statistically significant.

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Results:

Fifty-two cirrhotic patients (female 61.5%; 51.4±15.2 yrs) agewere included and median follow-up was 32.5 months. Thirty-eight subjects were diagnosed with HPC (21 PPHTN, 5 with HPS and 12 both). Variables associated to better survival in all patients were: Abnormal 6MWT (p=0.013), previous TIPS (p=0.015) and presence of ascites (0.036). Serum albumin levels were lower in patients who died (2.7±0.62 vs 3.18±0.619, p=0.017). Survival analysis showed a better survival in patients with normal 6MWT compared to patients with abnormal 6MWT (86.5 vs 40.9%, p=0.009) but no difference was observed in patients without HPC (44.4 vs 60%, p=0.654).

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Conclusion.

The 6MWK is a good prognostic factor of survival in cirrhotic patients, especially in those with hepatopulmonary complications.

Kidney Disease in Patients with Cirrhosis

N. Sirjani1; J. A. Cuthbert1; R. Bhore2; D. C. Rockey1 1. Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, United States. 2. Biostatistics, University of Texas Southwestern Medical Center, Dallas, TX, United States.
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Background:

In this study we hypothesized that renal dysfunction would be prevalent in patients admitted with cirrhosis, and moreover that acute kidney injury (AKI) would be the most common type of renal insufficiency in these patients.

Further we reasoned that many patients would also have underlying chronic kidney disease (CKD) and that specific clinical variables might affect outcome in patients with cirrhosis and renal dysfunction. Aims:To determine the prevalence, cause, and outcome of AKI and CKD in patients with cirrhosis, and to investigate specific clinical and laboratory features of patients with cirrhosis and elevated creatinine.

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Methods:

This retrospective analysis examined hospital records of 152 consecutive patients with cirrhosis admitted to the hospital over a 3-year period with creatinine levels of 1.5 mg/dl or greater. Multiple clinical and laboratory variables were abstracted for each subject; precise definitions were used to define cirrhosis, and kidney disease (i.e., AKI, CKD). Specific causes of renal dysfunction were identified and univariate and multivariable logistic regression analyses were performed to identify markers with prognostic value for predicting hospital mortality. Results: The most common type of renal dysfunction was AKI (70%), followed by AKI plus CKD (17%) and CKD alone (13%). Among those with AKI, prerenal azotemia was the most common cause (69%), often occurring secondary to gastrointestinal (GI) hemorrhage.

The overall mortality for the cohort was 31%, (95% CI: [24%, 39%]) with the highest mortality occurring in patients with type I hepatorenal syndrome (HRS) (see Table).

We were unable to identify any patient with HRS II. In regression analysis the presence of upper GI bleeding, bacteremia, or HRS I, were strong predictors of in-hospital mortality.

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Conclusions:

AKI is the most common cause of renal dysfunction in patients with cirrhosis and is usually a result of simple volume depletion. CKD is also prevalent in cirrhosis, typically presenting as nephrotic syndromes.

Further, since HRS II was not identified, our data raise questions about whether this disorder truly exists in hospitalized patients. GI bleeding and bacteremia appear to be important co-variates of adverse outcome in hospitalized cirrhotics with renal dysfunction.

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Liver Transplant

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Early prediction of Liver Related Events (LRE) in patients with established HCV recurrent disease after liver transplantation by Liver Stiffness Measurement

(LSM) M. Rendina1; N. Castellaneta1; M. Zappimbulso1; R. Bringiotti1; L. Lupo2; S. F. Rizzi1; A. Francavilla1; A. Di Leo1 1. Emergency and organ transplant, Gastroenterology, University of Bari, Bari, Italy. 2. Emergency and Organ transplant, Liver transplant Center, University of bari, Bari, Italy.
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Background:

The recurrence of HCV hepatitis after LT is universal and, following very accelerated fibrosis progression steps, once cirrhosis is established, up to 40% of patients are decompensated within 1 year. Identification of early predictors of poor outcome in this “high risk” population is urgently required. “Liver Stiffness Measurements” by Fibroscan (Echosens, Paris) is considered accurate in predicting severe fibrosis and cirrhosis also in the setting of HCV transplanted patients1.

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Aim of the Study :

To identify early predictors of liver-related morbidity and mortality (Liver Related Events, LRE) during F-up of pts with established HCV disease. Patients and methods: Of 423 liver transplant pts followed up in our Institution over 25 yrs, 203 were transplanted for HCV indications. Among them, 72 well defined HCV recurrent pts with a mean post-transplant F-up of 60 months were analyzed. These pts had undergone at least one satisfactory (good SR and IQR)1 LSM. Male/female ratio: 59/13; mean age 60±8 yrs. Genotype 1 and high peri-transplant viral load: 83.3% and 90%, respectively. Cox’s proportional hazards model was used. The occurrence of LRE was defined in presence of: ascites, large esophageal varices and/or bleeding, encephalopathy, re-OLT and death. Dates of first available stiffness measurements during F-up served as baseline.

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Results:

Fourteen patients (19.4%) developed LRE events after a median follow up from baseline of 47±18 months. Types of decompensations: ascites (57%), large esophageal varices (28.5%) and encephalopathy (25%). Eight pts died during follow up; only 1 had undergone re-OLT. Univariate analyses showed the risk of LRE was significantly correlated with LSM, the other significant risk factors were Meld, Child, transaminases and INR. At risk analysis, the probability of the occurrence of LRE was maximum with a 9 kPA LSM cut-off (HR 21.04; p<>

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Conclusion:

This study has shown that stiffness measurement by Fibroscan is associated with the risk of graft failure and decompensation in patients with established HCV disease of the graft and, therefore, could be a useful tool helping to individualize the therapy and address follow up strategy in this high risk population.1. Rigamonti C et al. Gut 2008; 57:821-827

The Impact of Donor Race on Recurrent Hepatitis C after Liver Transplantation

M. J. Moeller1; A. Zalawadia1; A. Alrayes1; G. Divine1; K. Brown1; D. Moonka1 1. Gastroenterology and Hepatology , Henry Ford Hospital, Detroit, MI, United States.
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Background:

Several studies have demonstrated mixed results on the influence of donor race on patient and graft survival in patients infected with hepatitis C (HCV) after liver transplant. However, few studies have looked at the impact of donor race on recurrent HCV. The current study is a retrospective analysis of the influence of patient and donor race on the severity of recurrent HCV at a single center.

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Methods:

Of patients transplanted at our center between 2000 and 2006, 222 were infected with HCV. Of these, 165 were eligible to be evaluated for recurrent HCV after transplant. We excluded those with graft loss within one year not related to recurrent HCV, advanced fibrosis from other causes, and lack of follow-up.

Patients were given a recurrent HCV score of 1, 2 or 3. A score of 1 was assigned if no more than mild portal fibrosis was present at year 1 and no bridging fibrosis at any point. A score of 2 was defined as moderate portal fibrosis or focal bridging fibrosis at 1 year or bridging fibrosis or cirrhosis after three years. A score of 3 was defined as bridging fibrosis, cirrhosis, or graft loss from HCV within 3 years.

Several baseline characteristics were recorded. Analysis was performed using ordinal multivariate logistic regression modeling.

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Results:

Of the 165 patients with a recurrent HCV score, 105 (64%) had a score of 1, 29 patients (18%) had a score of 2 and 31 patients (19%) had a score of 3. 132 (80%) recipients had white donors and 26 (16%) recipients had black donors. 115 (70%) patients were white and 40 (24%) were black.

The mean recurrent HCV score for the patient donor/recipient race combinations are as follows: white donor/white recipient was 1.54, white donor/black recipient was 1.89, black donor/white recipient was 1.18, and black donor/black recipient was 1.23. Having a white donor was also significantly associated with a higher recurrent HCV score regardless of recipient race (OR 2.93, p=0.044). In black patients, having a white donor had an OR of 4.62 (p=0.046). Having a white donor was also associated with a higher recurrent HCV score (4.48, p=0.0275) on multivariable analysis. Using all 222 patients, donor race was not associated with overall patient and graft survival.

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Conclusion:

Patients receiving white donor grafts had significantly worse recurrent HCV than those receiving grafts from black donors regardless of recipient race. This difference was especially marked in black recipients and persisted on multivariate analysis. This data suggests a graft from a white donor is potentially one more important variable in identifying patients at risk for more aggressive recurrent HCV after OLT.

Rapid Virological Response is Highly Predictive of Sustained Virological Response in Patients Treated for Hepatitis C following Liver Transplantation

. L. B. Lilly1; A. H. Albenmousa1; G. Therapondos1; N. Selzner1; G. A. Levy1; E. L. Renner1 1. Multi Organ Transplant, University Health Network, Toronto, ON, Canada.

Background:

Antiviral treatment of recurrent hepatitis C virus (HCV) following liver transplantation continues to be associated with poorer results than in non-transplant HCV patients, with sustained virological response (SVR) rates typically in the 30-40% range. Rapid virological response (RVR), defined as an undetectable serum HCVRNA after four weeks of treatment, has been shown to be predictive of SVR in non-transplant patients, irrespective of genotype (G), but has not been assessed in transplant recipients. Aim: To investigate the role of RVR in predicting SVR in patients treated for HCV after liver transplantation.

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Patients and Methods:

Two hundred and fifty patients have been treated for recurrent HCV in our program (67% G1, 20% G 2 or 3). Of these, 63 had serum HCVRNA measured after 4 weeks of interferon treatment. 14 of these patients remain on treatment; 49 have completed therapy and are therefore included in this analysis. Results: 70% of these patients were G1. 17 of 49 patients (35%) achieved RVR. Of these 17 patients, 5 (29%) were G1, and 9 (53%) were G2 or G3. Sixteen patients with RVR went on to SVR, yielding a predictive value of 94%. The remaining patient relapsed following an end-of-treatment response.

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Conclusions:

In this preliminary analysis, it would appear that RVR is predictive of SVR, although it occurs less frequently in G1 patients than in G2 or G3 transplant recipients treated for HCV. This predictive result may be independent of viral genotype, similar to the non-transplant HCV population.

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These findings may have implications in determining drug dosing or appropriate duration of antiviral treatment in this challenging patient population, and could give the treating physician and patient additional incentive in continuation of treatment in the face of potentially debilitating side effects or cytotoxicities.

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A large Italian multicenter retrospective study on antiviral treatment in liver transplanted patients with recurrent hepatitis C: early vs late timing of treatment correlates with outcome

M. F. Donato1; C. Rigamonti1; E. Arosio1; S. Fagiuoli2; F. Ponziani3; A. Gasbarrini3; M. Marino4; L. Belli5; M. Rendina6; P. Toniutto7; M. Morelli8; P. Burra9; L. Miglioresi10; M. Merli11; M. Angelico12; M. Colombo1 1. First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 2. Ospedali Riuniti of Bergamo, Bergamo, Italy. 3. Internal Medicine, Catholic University of Rome, Rome, Italy. 4. University of Modena, Modena, Italy. 5. Hepatology Unit, Niguarda Hospital, Milan, Italy. 6. University of Bari, Bari, Italy. 7. University of Udine, Udine, Italy. 8. S. Orsola-Malpighi Hospital, Bologna, Italy. 9. University of Padua, Padua, Italy. 10. San Camillo-Spallanzani Hospital, Rome, Italy. 11. Sapienza University, Rome, Italy. 12. Tor Vergata University, Rome, Italy.
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Background/aims:

Interferon (IFN) plus ribavirin (Rbv) based-therapy is the standard of care treatment for recurrent hepatitis C virus infection (HCV) following liver transplantation (OLT), however the best timing of therapy balancing the potential benefits against the risks is still debated. We evaluated whether timing of antiviral treatment has an impact on outcome of patients transplanted for end-stage HCV.

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Methods:

In this retrospective multicenter study we investigated 464 patients transplanted for end-stage HCV from 1989 to 2008 who underwent antiviral treatment after OLT in 12 Italian Liver Transplant Unit (75% males; 74% genotype 1-4; median recipients age 55 yrs, range 19-68 yrs; median donor age 49 yrs, range 12-99 yrs). Sustained virological response (SVR) was HCV-RNA undetectable at month 6 after end of treatment. Immunosuppression was CSA-based in 39% of patients, FK506-based in 57%, sirolimus or everolimus in monotherapy in 3%.

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Results:

The majority of recipients (94%) were treated with IFN+Rbv combination therapy (76% PEG-IFN+Rbv) after a median time from OLT of 24 months (1-199). Overall SVR was obtained in 161 patients (34%), 23% in HCV genotype 1-4 and 70% in genotype 2-3 (p<0.0001). n="47," n="58," n="108,">12 months after OLT (n=251, SVR 38%, deaths 14% at a median time of 69 months following transplant). Rate of death was significantly higher when patients were treated early after OLT <3 p="0.001).">

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Conclusions:

Early antiviral treatment in patients with recurrent hepatitis C after OLT seems to be associated with low SVR rate and worse short term outcome.

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Antiviral treatment of HCV recurrence after liver transplantation: impact on costs and quality of life C.

Logge1; E. Vettorazzi2; B. Nashan1; M. R. Sterneck1 1. Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 2. Department of Medical Biometry and Epidemiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
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Introduction:

Within 5 to 10 years after OLT 20 to 40% of HCV patients (pts) develop cirrhosis with rapid decompensation and graft loss. Response to antiviral therapy with pegylated interferon-α (pegIFN) and ribavirin can stop disease progression. Aim of our analysis was to determine cost-effectiveness of antiviral treatment for HCV recurrence post OLT.

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Methods:

A markov model was constructed to simulate disease progression of recurrent HCV until graft loss (= death).

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Outcome and cost-effectiveness of treatment strategies in genotype 1/4 and 2/3 pts were analysed: Pts with HCV genotype 1/4 received pegIFN/ribavirin for 48 weeks and stopped treatment in case of EVR (negative HCV PCR after 12 w). Pts with genotype 2/3 received treatment for 48 or 24 w and also stopped treatment in case of EVR.

Based on literature data a 40% EVR and 21% SVR was assumed for genotype 1/4 and a 90% EVR with a 75% or 73% SVR in the 48- and 24-week strategy for genotype 2/3 pts, respectively. Health-state utilities to assess quality of life and health-state costs were based on literature estimates. A societal perspective was used and a 3% annual discount rate applied. Results: The probability of organ loss/death 10, 20 and 30 years post OLT was 0.41, 0.79 and 0.93 in the no treatment and 0.34, 0.65 and 0.78 in the treatment strategy for genotype 1/4 pts, 0.18, 0.35 and 0.45 in the 48 w and 0.19, 0.36 and 0.46 in the 24 w treatment strategy of genotype 2/3 pts. In genotype 1/4 pts treatment resulted in a mean life-time cost increase of € 40,393.- and a gain of 1.23 QUALYs.

In genotype 2/3 pts the 48- and 24-w treatment strategies resulted in a mean life-time cost increase of € 103,427.- and € 87,344.- and a gain of 4.42 and 4.3 QUALYs, respectively. The ICER was € 32,860/QUALY in pts with genotype 1/4 and € 23,385/QUALY and € 20,316/QUALY in pts with genotype 2/3 treated for 48- and 24-weeks, respectively. Therefore all treatments undercut the German limit of cost-effectiveness of € 50,000/QUALY. In a two-way sensitivity analysis costs of potential future antiviral therapies for genotype 1/4 pts improving EVR and SVR were calculated. Costs per QUALY will not exceed the ones of the EVR strategy (ICER € 32,860/QUALY) if additional drug costs are not higher than € 3,708.- per 10% improvement of EVR. Based of an ICER of €50,000/QUALY drug costs must not exceed € 27,249.- per 10% EVR improvement.

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Conclusion:

In all pts treatment with pegIFN/ribavirin gains QUALYs and is cost-effective. Potential future more effective antiviral therapies in pts with genotype 1/4 remain on the same level cost effective if additional costs do not exceed € 3,708 per 10% EVR gain.

Silibinin monotherapy prevents graft infection after orthotopic liver transplantation in a patient with chronic hepatitis C.

S. Beinhardt1; S. Rasoul-Rockenschaub2; T. Scherzer1; R. Strassl3; A. Stättermayer1; K. Rutter1; K. Zinober1; H. Hofer1; P. E. Steindl-Munda1; P. Ferenci1 1. Internal Medicine III, Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria, Austria. 2. Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria. 3. Clinical Virology, Medical University of Vienna, Vienna, Austria.

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Chronic hepatitis C (CHC) is the most common reason for orthotopic liver transplantation (OLT). Almost all patients have recurrence of HCV after transplantation. Combination therapy with pegylated interferon and ribavirin, started before OLT, with the objective of achievement HCV-RNA-negativity is mostly not well tolerated in patients with de-compensated liver disease. Intravenous silibinin (Legalon SIL®) is a potent direct inhibitor of HCV RNA-dependent RNA polymerase. Aim of this case-report is to elevate efficacy of silibinin mono-therapy, initiated pre-OLT, as an interferon-free therapy-alternative.

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Patient&Methods:

A 46-year-old male patient with beta-thalassemia and chronic hepatitis C (GT 1a/4) was listed for OLT because of decompensated liver cirrhosis with hepatocellular carcinoma in 2009. In 1998 treatment with interferon-alfa2b (5 MU 3 times weekly) and weight based ribavirin was unsuccessful (HCV-RNA positive after 24 weeks). Pre and post OLT HCV-RNA levels were quantified at baseline (BL) by real-time PCR COBAS TaqMan HCV Test, Roche Diagnostics (lower limit of detection: 15 IU/ml) at several time points during therapy.Results: Intravenous silibinin mono-therapy (20 mg/kgBW/day) was initiated 15 days before OLT. Baseline virus load was 28.800 IU/ml and declined to 43 IU/ml till day of OLT. Intravenous silibinin was continued for further 22 days. HCV-RNA became unquantifiable (<15>

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Conclusion:

This is the first report on successful eradication of HCV and consecutive prevention of viral recurrence by silibinin intravenous mono-therapy initiated before OLT. Silibinin as an interferon-free treatment should be prospectively evaluated to prevent graft infection in patients with HCV-associated liver cirrhosis.

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