Steroids Do Not Influence the Severity of Hepatitis C Recurrence in the First Year After Liver Transplantation

L. Baiocchi1 G. Tisone2 A. Petrolati 1, S. Battista3, G. Palmieri3, M. Angelico1.

1University of Rome Tor Vergata’, Faculty of Medicine Gastment. Dept., Rome, Italy2; University of Rome Tor Vergata’, Faculty of Medicine Dept.of Surgery, Rome, Italy; 3 of Rome ‘Tor Vergata’, Faculty of Medicine Dept. of Pathology, Rome, Italy

 

Background

Hepatitis C recurrence is a major concern in patients transplanted for HCV-related liver disease. It has been suggested that immunosuppression may favour the severity of disease but current evidence seems to indicate that the use of less steroids and/or the early steroid withdrawal are associated with more aggressive disease recurrence.

 

Aim

To evaluate whether the short-term use vs. the non-use of steroids after OLT affects the frequency/severity of recurrent HCV-disease at year 1 after transplant.

 

Methods

Fifty HCV-infected OLT recipients transplanted at our Center were retrospectively divided in two groups according to the use or non use of prednisone: group A comprised 27 patients (23 MJ4F age 51.1±6.6) who received prednisone (20mg/day in the first 3 months) in addition to conventional cyclosporine A microemulsion; group B comprised 23 patients (16M/7F age 55.1±5.8) who received cyclosporine A microemul sion alone. All patients underwent monthly ALT determinations and had a liver biopsy performed at year 1 after transplant, which was scored for necro-inflammation and fibrosis according to Ishak.

 

Results

At year 1: persistently abnormal ALT values were found in 48% of patients in group A and in 57% of group B (n.s.); the mean histological grading score was 3.1±1.9 and 3.1±1.7. respectively (n.s.); the mean histological staging score was 1±0.4 and 1.4±0.8, respectively (n.s.).

 

Conclusion

The short-term use of steroids following liver transplantation is unrelated to the biochemical and histological severity of recurrent hepatitis C at year 1 after surgery.

 

Safety, Pharmacokinetics and Pharmacodynamic Results of Higher Dose of Albuferon in a Phase I/II Single and Double Dose-Escalation Study in the Treatment Experienced Subjects with Chronic Hepatitis C

V. Balan1 M. Sulkowski2 ,D. Nelson 3, G. Everson R. Dickson 5, L. Lambiase 6,A. Post R 7,  Redfield R 8, Wiesner J.9, Recta10, B. Osborn 10, L. Novello10, W. Freimuth10, M. Subramanian10.

1Mayo Clinic, Phoenix AZ, USA; 2 Hopkins University, Baltimore MD, USA; 3 University of Florida, Gainesville FL, USA; 4University of Colorado, Denver CO. USA; 5 Clinic, Jacksonville FL, USA; 6University of Florida At Jacksonville, Jacksonville FL, USA; 7 Hospitals of Cleveland, Cleveland OH, USA; 8 of Maryland, Baltimore MD, USA; 9 Clinic, Rochester MN, USA; 10Human Genome Sciences, Inc., Rockville MD, USA

 

Introduction

Albuferon is a novel recombinant protein Consisting of IFN alfa genetically fused to human serum albumin. The phase 1/2, dose escalation study is conducted in HCV subjects who had previously failed IFN alfa containing regimens.

 

Methods

Subjects were enrolled sequentially to receive 1 or 2 subcutaneous injections of Albuferon up to 80 mcg. Further dose escalation included single injection cohorts up to 600 mcg. Double injection dose cohorts up to 600 mcg (400 mcg. 500 mcg and 600 mcg) on Day 1 and 14 will also be evaluated.

 

Results

Eighty-one subjects are currently enrolled. 97% were infected with HCV genotype 1, with a mean prior therapy duration of 68 weeks. Albuferon was well tolerated. Adverse events were transient, most were mild to mod erate, and did not show dose related increases. No subjects developed anti Albuferon antibodies. Cmax following single injection doses was dose- proportional.

 

Preliminary analyses suggest a median terminal half-life of 143 hours at the two highest single injection cohorts (500 and 600 mcg). The magnitude and duration of viral reduction in the 2 cohorts combined were statistically significant (P-value <0.02) at Day 1 through Day 21. Antiviral response (>0.5 log reduction) was observed in 62.5% (25/40) of subjects in the single injection cohorts (120-600 mcg). cDNA array analysis demonstrated a molecular profile consistent with drug response.

 

Conclusions

Albuferon was safe and well tolerated. Dosing every 2-4 weeks is supported by the pharmacokinetics. Anti-viral response was ob served in the higher single dose cohorts.

 

Percentage of HCV infection Hepatocytes Is A Better Predictive Factor of Response to the Peg-IFN-A Plus Ribavirin Therapy Than Serum HCV-RNA Concentrations

J. Bartolome E. Rodriguez-Inigo, J.M. Lapez-Alcorocho, N. Ortiz-Movilla. M. Pardo. P. Rey, V. Carreno.

Fundacion Estudio Hepatitis Virales, Madrid, Spain

 

Introduction

We studied whether the percentage of infected hepatocytes in the pre treatment liver biopsy (determined by in situ hybridization) predicts better than serum HCV-RNA concentration, the response to the PEG-IFN-alpha plus Ribavirin therapy.

 

Methods

Ninety-seven patients (62 men and 35 women) with chronic hepatitis C (all infected by the HCV lb genotype) treated with PEG-IFN-alpha plus ribavirin were analyzed. Of them. 38 (39%) were long-term responders and 59 (61%) were non-responders. No differences (p=0.445) in the pretreatment serum HCV-RNA concentration were found between responders (I .7xlOE6 ± 4.4x10E5 IU/mL) and non- responders (l.3xlOE6 ± 2.4xl0E5 IU/mL).

 

Results

By contrast the percentage of infected hepatocytes was statistically lower (p= 0.000034) in responders (6.8% ± 0.73%) than in non-responders (13.4% ± 1.3%). Fifty four patients had an HCV-RNA concentration in serum <800000 IU/mi and of them 21(38.8%) were responders and 33 (61.2%) non-responders. On the other hand, thirty three patients had <5% of infected hepatocytes and of them 19 (57.6%) were responders and 14 (42.4%) non-responders.

 

In a logistic regression analysis considering gender, ALT, necroinflammatory activity, fibrosis score etc, the only independent factors associated with the response were the percentage of infected hepatocytes (p= 0.0005; OR:2.1825; 95% CI: 1.4079-3.3833) and age (p= 0.013; OR; 1.0643; 95% CI:1.0134-1.1178) but not the serum HCV-RNA concentration.

 

Conclusion

The percentage of infected hepatocytes in the pretreatment liver biopsy is a better predictive factor of response than the serum HCV-RNA concentration.

 

Correlation Between Liver Elasticity Measured By Transient Elastography and Liver Fibrosis Assessed By Morphometry in Patients with HCV Chronic Hepatitis C

M. Ziol1,2 N. Barget3 L. Sandrin4 C. Foumier F. Mal3 F. Kazemi3, A. Kettaneh5 , M. Beaugrand5

1EA 3406, Univertisy Paris 13, Paris, France; 2 Pathologie Department, Hopital Jean Verdier; Bondy, France; 3 Unit, Hopital Jean Verdier Bondy, France; 4 Paris,

France; 5 Medicine Department, Hopital Jean Verdier Bondy

 

Introduction

Liver fibrosis (LF) evaluation by non-invasive techniques is a major challenge. FibroScan® a new non-invasive system based on transient elastography measures liver elasticity. A previous prospective study in 220 patients with chronic hepatitis showed that liver elasticity could be used to predict fibrosis stage (FS) assessed by Metavir scoring system.

 

Method

This prospective study was designed to further study the correlation between liver elasticity and fibrosis in 69 patients with chronic HCV hepatitis using fibrosis area fraction (FAF) measured on liver biopsies. All patients had a liver biopsy providing a large sample suitable for morphometric analysis and a liver elasticity measurement within less than 4 months. FS was evaluated by Metavir score and FAF by quantitative image analysis of 5 micrometers thick picrosirius stained sections. The FAF was assessed using interactive thresholding of greyscale converted digital image of 10 to 20 consecutive fields (x 200) for each liver biopsy.

 

Results

Within the studied population (20 Fl, 21 F2, 5 F3 and 23 F4 patients), FAF was 6.3 ± 6.2 (range 0.3 - 28.8) and highly correlated to FS (Spearman correlation r = 0.66. p < 0.0001). The correlation coefficients were r = 0.65 and r = 0.74 (both p < 0.0001) between liver elasticity and FAF or FS, respectively.

 

Conclusion

Liver elasticity accurately reflects hepatic fibrosis area in patients with chronic HCV hepatitis and thus appears to be a reliable non-invasive tool to measure liver fibrosis.

 

Interferon (IFN) Therapy Has Little Effect on Progression of Portal Hypertension in Hepatitis C Virus (HCV) Related Cirrhosis

L. Benvegnu F. Pasin, M. Gios, A. Ferrari, A. Alberti.

Dpt. of Clinical and Experimental Medicine - University of Padova, Padova, Italy

 

Introduction

The effect of IFN therapy on complications of HCV-related cirrhosis is not fully understood. There are data indicating that hepatocellular carcinoma (HCC) might be prevented or delayed, while much less clear is the effect on portal hypertension and esophageal varices.

 

Aim/Method

We have conducted along- term follow-up study of 380 consecutive patients with compensated HCV related cirrhosis. 185 patients were treated with one or more courses of IFN therapy, while 195 remained untreated. All patients were followed-up with periodical (every 6 months) evaluation and abdominal ultrasound and with periodical (every 12-24 months) esophagogastroduodenoscopy.

 

Results

During a mean follow-up period of 88.8 ± 42.0 months, 15.1% of IFN treated and 22.6% of untreated patients developed HCC, 19.8% of treated and 24.8% of untreated showed esophageal varices appearance or worsening, 11.9% of treated and 19.5% of untreated developed ascites, 3.8% of treated and 5.6% of untreated had variceal bleeding, 1.1% of treated and 3.1% of untreated developed portal-systemic encephalopathy and 11.9% of treated and 20.9% of untreated patients dead from liver-related causes. By the Kaplan-Meier method and the log-rank test IFN treated patients showed a significantly lower incidence of HCC (p = 0.028), of ascites (p = 0.020), and of liver-related death (p = 0.003).

 

No significant difference was observed on varices appearance of worsening, variceal bleeding and portal-systemic encephalopathy occurrence.

 

Conclusion

Our results indicate that one or more courses of IFN therapy may delay HCC development and improve survival in patients with compensated HCV-cirrhosis, while seem to have a trivial effect on portal hypertension-related complications.

 

HCV Genotype and Pediatric HCV Infection

F. Bortolotti 1 M, Resti2 G. Verucchi 2 G. Nebbia 2  R. Giacchino2 ,MG. Marazzi 2 ,M. Marcellini 2 , C. Barbera G. Maggiore 2 , S. Bartolacci 1, M. Guido 3

1Clin Medico 5, University, Padua, Italy; 2 Observatory For HCV Infection In Childhood, Padua, Italy; 3 Pathology, University, Padua, Italy

 

Introduction

Pediatric HCV infection, with its peculiar aspects (perinatal exposure, lack of liver damage cofactors, histologically mild disease) is an interesting model to investigate the clinical significance of HCV genotypes.

 

Methods

373 consecutive HCV RNA+, otherwise healthy, children from 15 observatory centers were studied (InnoLipa).

 

Results

The following patterns were recorded:

  • la=73 cases (20%. median age at entry=54 mo. maternal infection=56%);
  • lb=154 cases (41%, age=72 mo, maternal infection=44%);
  • 2=63 cases (17%, age 102 mo, maternal infection=40%);
  • 3=54 cases, (14%, age 17 mo; maternal infection=83%);
  • 4=19 (5%. age 24 mo, maternal infection=l00%);
  • other types=3%.

 

The table shows the rates of sustained (=>2 years) HCV RNA clearance in treated and untreated children (mean follow- up: 5.0±3.1 years). Persistent viremia with normal ALT was recorded in 37% children with genotype 2.

 

Conclusions

Genotype 3 is significantly associated with spontaneous viremia clearance early in life; children with genotype 2 have often a biochemically mild disease; both types 2 and 3 are predictors of sustained response to IFN.

 

Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis:  A Multicenter Case-Control Study Using MRI and Neuropsychological Tests

M. Casato1, D. Saadoun 2 A. Marchetti 1, C. Picq2 , P. Pantano2, D. Dormont 2,M.C. Piatella2 ,Duhaut R. Ciancil1, M. Fiorilli1, J.C. Piette2, P. Cacoub2

1Dept. of Clinical Medicine, La Spienza Hosp., Roma, Italy; 2 Dept. of Internal Medicine, Hôpital Pitie-Salpetrière, Paris, France

 

Introduction / Objective

Clinical evaluation (neuropsychological tests) and cerebral magnetic resonance imaging (MRI) study in HCV-MC vasculitis patients.

 

Patients & Methods

This prospective study included 40 patients with MC vasculitis and chronic active HCV infection (HCV RNA+). A battery of 10 standardized neuropsychological tests was administered by one experienced neuropsychiatrist. All patients underwent cerebral MRI investigation and their results were compared to those of 36 healthy volunteers, matched for sex and age.

 

Results

The mean duration of cryoglobulinemic disease was 11.2 ± 8 years (range 2-45 years). The mean cryoglobulin serum level was 1.08 ± 1.49 g/L. The most common HCV genotype was one (19 of 37 patients, 51%) and the mean HCV RNA level was 7.7 ± 18.6 million Eq/mi.

 

Among HCV-MC patients. 33 out of 40(82%) patients had received or were receiving interferon alpha at the time of inclusion. Thirty two of the 34 evaluated HCV-MC patients (94%) had a deficiency in one or more of the 10 cognitive domains examined.

 

The most commonly involved domains were those of attention (68%), executive functions (41%), and visual construction and visual spatial functions (35%).

 

MRI analysis showed that patients had a higher mean number of total (7.03 ± 9.9 vs. 2.03 ± 3.1, p=0.007) and pen- ventricular (2.4 ± 3.0 vs. 0.8 ± 1.4, p=0.007) white matter high intensity signals than controls.

 

Conclusion

The high frequency of impaired cognitive function and the extent of MRI brain abnormalities in patients with HCV-associated mixed cryoglobulinemia vasculitis strongly suggest specific inflammatory involvement of the CNS.

 

A Phase II, Placebo-Controlled Study of Merimepodib (VX-497), in Combination with Pegylated Interferon-Alfa, and Ribavirin in Patients with Chronic Hepatitis C Non-Responsive to Previous Therapy with Interferon-Alfa and Ribavirin

P. Marcellin1 ,Y. Horsmans F2 ,Nevens3, J.D.Grange4 ,J.P.,Bronowicki5, D. Vetter6 ,R. Kauffman7 ,S. Knox L. McNair7 ,S. Moseley7 ,J. Alam7

1Service D ‘Hepatologie, Hopital Beaujon, Clichy, France; 23 Dept of Gastroentemlogy, UCL, Brussels, Belgium; 3 of Hepatology, KUL, Leuven, Belgium; 4 D ‘Hepatogastroentemlgie, Hopital Tenon, Paris, France; 5 D ‘Hepatogastroenterolgie, Vandoevre Les Nancy. Nancy, France; 6 D’Hepatogastroenterolgie, Hopital Civil, Strasbourg, France; 7 Phannaceuticals, Cambridge MA, USA

 

Introduction

Merimepodib (MPB) (VX-497) is a novel, selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the HCV replicon system, MPB shows potent anti-viral effects. As monotherapy for 28 days MPH reduces serum transaminase levels, and in a 28-day dual combination modestly enhances the antiviral effect of interferon alfa in patients with chronic hepatitis C (CHC).

 

Aim

In this study we evaluated the addition of MPB to pegylated (Peg) IFN and ribavirin (RBV), in patients who were non- responders to IFN and RBV

 

Methods

Thirty-one patients with genotype 1 CHC who had not responded to prior IFN and RBV therapy were randomized to receive MPH, 25 or 50 mg q12h or placebo orally, in combination with Peg-IFN and RBV for 24 weeks. Patients with no detectable virus at 24 weeks received the same treatment for an additional 24 weeks then were followed post- treatment to ascertain sustained response.

 

Results

The three treatment groups were similar in baseline HCV-RNA and ALT. The combination of Peg-IFNIRBVIMPB was well tolerated.

 

  • HCV-RNA undetectable at any time <24 wks:

 

    • Peg-IFN/RBV/Placebo, 3/10(30%);
    • Peg-IFN/RBV/IMPB 25 mg, 2/10(20%);
    • Peg-IFN/RBV/MPB 50 mg, 8/11(73%),

p=0.O2* .

 

  • HCV-RNA undetectable at 24 wks:
    • Peg IFN/RBV/Placebo, 3/9 (33%);
    • Peg-IFN/RBV/MPB 25 mg, 2/6 (33%);
    • Peg-IFN/RBV/MPB 50 mg, 6/7 (86%),

p=O.3*

 

(*JonckheereTerpstra test for increasing dose response)

 

Conclusion:

The addition of MPB at a dose of 50 mg, to Peg-IFN and RBV was well tolerated and showed an enhanced anti-viral effect at 24 weeks in an IFN-RBV non-responder population.

 

Prophylactic Prescribing of Anti-Depressants to Patients Treated for Hepatitis C in a US Healthcare Plan

J.S. Markowitz1 , EM. Gutterman1, W. Klaskala2

1Health Data Analytics, Princeton Junction NJ, USA; 2 Laboratories mc, Nutley, NJ, USA

 

Introduction

Prophylactic prescribing of antidepressants may reduce depression, an adverse reaction associated with interferon (INF) treatment for hepatitis C viral (HCV) infection, which can lead to premature treatment discontinuation. This study evaluates prophylactic antidepressant prescribing prior to INF therapy for HCV.

 

Methods

We used a nested case-control design in a 20% random sample in a public healthcare plan in California between January 1996 and June 2002. Eligible patients had >2 claims with an HCV diagnosis and 12 months of plan coverage prior to the first HCV claim.

 

Cases were prescribed INF following HCV diagnosis. For each case, two controls, who received no INF, were randomly selected. The study ended the day prior to INF prescription for cases and after a matched follow-up period for controls.

 

Antidepressant prescribing up to 90-days preceding the initiation of INF therapy was considered “prophylactic.”

 

Results

In the 1587 HCV diagnosed, antidepressant prescribing was 57.3% in cases and 47.2% in controls (p<0.001). Respective rates of prophylactic prescribing in cases and controls limited to the subgroup (n=802) utilizing antidepressants were:

  • 40.9% vs. 40.3% (p=0.857) in 30 days,
  • 54.5% vs. 56.1% (p=0.647) in 60 days and,
  • 61.4% vs. 63.9% (p=0.470) in 90 days.

 

Conclusions

In this cohort, there is no evidence of prophylactic antidepressant prescribing prior to starting INF treatment. As suggested by antidepressant rates exceeding 50%, physicians appear willing to introduce interferon therapy to HCV patients with prior depressive conditions. Because some patients may benefit from prophylactic antidepressant therapy, more systematic evaluation of this issue is recommended.

 

Lack of Evidence of Sexual Transmission of Hepatitis C Among Monogamous Couples:  Results of a Ten-Year Prospective Follow-Up Study

C. Vandelli1 ,F. Renzo1 ,L. Romano2 S. Tisminetzky3 ,M. De Palma4  , T. Stroffolini5 ,E. Ventura1, A. Zanetti2

1Department of Internal Medicine, Policiinico of Modena, Modena, Italy; 2 of Virology, University of Milano, Milano, Italy; 3 Trieste, Italy; 4 Bank, Policlinico of Modena, Modena, Italy; 5 Department, S. Giacomo Hospital, Roma, Italy

 

Introduction

We have evaluated the risk of sexual transmission of hepatitis C virus (HCV) infection among 895 monogamous heterosexual partners of HCV chronically infected individuals in a long-term prospective study.

 

Methods / Results

The follow up period was 8060 person-years; 776 (86.7%) spouses were followed up for ten years. corresponding to 7760 person-years of observation and 119(13.3%) spouses (69 whose infected partners cleared the virus following treatment and 50 who ended their relationship or were lost at follow- up) contributed for additional 300 person-years.

 

During the follow-up three HCV infections were observed corresponding to an incidence rate of 0.37 per 1,000 person-years. However, in one case the infecting HCV genotype in a spouse was different from that of the partner ((2a, 1b), likely excluding a sexual route of transmission. Despite the remaining two couples had concordant genotypes, sequence analysis of the NS5b region of the HCV genome, coupled with a phylogenetic analysis showed that the corresponding partners carried different viral isolates, again excluding the possibility of intraspousal transmission of HCV.

 

Conclusion

These findings indicate an extremely low or even null risk of HCV transmission within heterosexual monogamous couples.

 

Treatment Practices Regarding Management of Patients with Hepatitis C Infection Non-Responders to Antiviral Therapy

M. Maynard1, C. Deguerry1, P. Pradat1, C. Trepo1 and Norevic;

1 Hotel-Dieu, Lyon, France; 2 Multicenter - NOREVIC Group, France

 

Introduction/Aim

To explore through a National French prospective survey, treatment practices regarding HCV patients non-responders (NR) to antiviral therapy.

Patients and Methods

HCV patients NR to at least one antiviral treatment and consecutively observed in 27 French Hepatology Centres were recruited. A standardised questionnaire regarding clinical history and treatment was used for each patient.

 

Results

Three hundred eighty nine NR patients were included from May 2002 to October 2003. Sixty percent of them were males and the mean age was 52 years. Eighty percent had a genotype 1 and the median duration of infection was 23 years. At inclusion, 52% of the patients were under treatment. The main reason for not being treated was medical decision in 67% of cases, patient refusal in 14%, and another reason in 19% (the majority were waiting for inclusion in a clinical trial). Cessation of treatment was mostly due to lack of response (38%), therapeutic window (28%) and intolerance (26%).

 

Among patients starting a new therapy at inclusion, 54% were enrolled into a clinical trial. Among patients under treatment, 30% were treated by bitherapy (83% by PEG-IFN/ribavirin), 28% by tritherapy (77% by PEG-IFN/ribavirin/amantadine), 28% by monotherapy (mostly by PEG IFN(61%), while 15% had another therapy.

 

Fifty-one percent of patients with cirrhosis had no treatment. Among treated cirrhotic patients 47% were treated by monotherapy (71% by IFN, 29% by ribavirin), 28% had a PEG IFN/ribavirin bitherapy.

 

Conclusion

Maintenance therapy is widely used in France although 50% of cirrhotic patients remain untreated.

 

Reversibility of Cirrhosis is Associated with a Decrease of Liver-Related Complications

J. Serpaggi1,P. Lebray1, B. Nalpas1,A. Vallet-Pichard1, E. Morales1, N. Youssef 2, F. Carno3, H. Fontaine1, P. Bedossa4, S.Pol1.

1 Unit and INSERM U-370, 2 of Pathology, Necker-Enfants-Malades Hospital, Paris; 3 Dept. of Pathology, Georges Pompidou Hospital, Paris; 4 Dept. of Pathology, Kremlin Bicêtre Hospital, Paris, France

 

Aim

To assess the impact of cirrhosis reversibility on survival and occurrence of cirrhosis complications.

 

Methods

Retrospective analysis of patients with biopsy-proven cirrhosis and post-treatment biopsy (January 1980 - may 2003). Cirrhosis reversibility was defined as a decrease of the Metavir fibrosis score 2 after two independent blinded analysis. Cirrhosis-related complications included variceal bleeding, ascitis, spontaneous bacterial peritonitis, hepatocellular carcinoma and hepatic encephalopathy.

 

Results

Twenty-two (14/101 HCV-, 3/16 HBV-, 5/10 autoimmune- and 0/9 alcohol-related. all Child-Pugh A) of the 136 cirrhotic patients (16.17%) showed reversibility of cirrhosis.

 

The mean decrease of activity scores by METAVIR was 1.35 ± 1.04 for patients with and 0.50 ± 1.06 for patients without reversibility (pc 0.005). Among the 17 patients with regressive viral cirrhosis, 15 were sustained virologic responders (37.7% of the total of complete responders) and 2 biochemical responders. After a mean follow-up of 7 ± 3 years, there were significantly less cirrhosis-related complications (0% vs 25.4%, p= 0.004) and a decrease in mortality (0% vs 17.5%, p= 0.04) in patients with reversibility. Among responders to treatment, liver-related complications were less frequent in patients with than without reversibility: 0% vs 21.1% (p= 0.04).

 

Conclusions

Complete regression of cirrhosis may be associated with a suppression of the necro-inflammation and result in a disappearance of liver-related morbidity and mortality, improving survival. In the absence of cirrhosis reversibility, a close monitoring should be maintained since sustained response does not exclude the risk of complication.

 

Higher Meld Scores Pre Liver Transplantation Have No Influence on the Long Term Survival of the Liver Transplant Patient

E. Nagler1, H. Van Vlierberghe1,  R. Troisi2,  I. Colle1, M. De Vos1, B. de Hemptinne2.

1Dpt of Gastroenterology, Ghent University Hospital, Gent,Belgium; 2 Dpt of Hepatobiliary Surgery and Liver Transplantation, Ghent University Hospital, Gent, Belgium.

 

Introduction

Since the implementation of the MELD score in the USA as a score to allocate livers to patients on the liver transplant waiting list, fewer patients died or were removed from this waiting list. However, if the principle ‘sickest patient first’ could result in a worse long term survival is unknown. We examined the influence of the MELD score on the long term survival of liver transplant patients.

 

Materials and Methods

By a search through the files of Belgian adult patients transplanted for a non fulminant liver failure in the period between January 1991 and December 2001, we included 121 patients. MELD score was calculated by using variables taken as close as possible prior to liver transplantation. Log rank testing and Kaplan Meier survival curves were performed using different cut off levels for the MELD score (15, 18, 20 and 25).

 

Results
Indications for transplantation were mainly alcoholic (38%) or HCV (26.4%). Gender distribution was male: 62% versus female 38%. Mean age was 54 years ± 10 years. Mean MELD score was 16 ± 6. The follow up time was 5.38 years (range: 1.6-12.3 years). By using different MELD cut off levels, no difference in survival at different time points was noted. Discussion. Using the MELD score as an allocation tool, has no influence on the long term survival of the liver transplant patient. Together with the better selection of the patients on the waiting list, the MELD score seems to be a superior allocation system.

 

Liver Transplantation in HIV-HCV Co-Infected Patients: Five Case Reports

G. Vennarecci1, G.M. Ettorre1, M. Antonini1, M. Maritti1, L. Giovannelli1, G. D’Offizi2, P. Narciso2, P. Noto2, E. Boumis2, P. DeLongis2, P. Nasta4, G.P. Carosi4, F. Del Nonno1, L. Perracchio1,G.P. Palmieri3, R. Santoro1, G. Visco1, E. Santoro1.

1Department of Surgical Oncology and Liver Transplantation, Regina Elena Cancer Institute, Rome, Italy; 2Institute For Infectious Disease LazzaroSpallanzani, Rome, Italy; 3 Department 3of Patology, University of TorVergata, Rome, Italy.

 

Aim

The aim of the study was to evaluate the feasibility of LT in HIV-HCV co-infected patients in Italy.

 

Methods

Five patients (5 M, mean age 42 years) underwent LT from September 2002 to August 2003 under an Italian multicentric trial coordinated by the National Transplant Center. These were the first five LT in HIV+ patients in Italy. All patients were HIV-HCV positive (1 HBV and 1 HBV plus a small HCC). Pre-LT plasma HIV 1-RNA levels was undetectable and CD4+ T-cell count was >200 cells/mL for 3 months in all patients. Two patients received HAART before LT. LT was performed following the piggy-back technique.

 

Results

Immunosuppression was an association of tacrolimus-steroids-MMF. All patients are alive and mean follow-up is 8 months (4-15). All patients have not yet resumed HAART and despite this all have low level of HIV RNA, CD4+T-cell count increased after LT and no opportunistic infections were observed. Two patients who received HAART till the procedure had a severe form of liver dysfunction early after LT. Three patients developed early recurrence of hepatitis C (1 fibrosing cholestatic hepatitis) requiring combination therapy of interferon plus ribavirin. None developed acute rejection. One patient 8 months after LT developed an unexplained thrombosis of the right portal vein which resulted in atrophy of the right liver. Significant improvement of quality of life was observed in 3/5 patients.

 

Conclusion

Liver transplantation in HIV-HCV coinfected patients is feasible and results in the short and medium term are good. Early and severe HCV recurrence occurred after liver transplantation.

 

First Clinical Results for a Novel Antiviral Treatment for Hepatitis C: a Phase I/II Dose Escalation Trial Assessing Tolerance, Pharmacokinetics, and Antiviral Activity of NM 238

E. Godofsky1, N. Afdhal2, V. Rustgi3, L. Shick4, L. Duncan5, X.J. Zhou6, G. Chao6, C. Fang6, B. Fielman6, M. Myers6, N.A. Brown6

1Bach and Godofsky, Bradenton FL, USA; 2Beth Israel Deaconess Medical Center, Boston MA, USA; 3University MedicalCenter, Washington DC, USA; 4University of Massachusetts Health Center, Worcester MA, USA; 5Northwest Medical Specialties, TacomaWA, USA; 6Idenix Pharmaceuticals, Cambridge MA, USA.

 

Background

NM283, a novel candidate HCV RNA polymerase inhibitor, has anti-flavivirus activity that is highly synergistic with interferon-alpha in vitro, and suppresses viremia in chimpanzees chronically infected with human-derived HCV-1 (Standring, EASL2003). Here we report the first clinical data for NM283 in humans.

 

Methods

A Phase I/II dose escalation trial is investigating NM283 in the range 50-800 mg/day. Subjects are treatment-naïve or experienced adults with HCV-1 associated chronic hepatitis C, with baseline serum HCV RNA >5 log10. For each dose, 12-patient cohorts are randomized 10:2 to receive NM283 or placebo for 15 days with 14 days of follow-up.

 

Results

Dosing cohorts of 50, 100, 200, and 400 mg/day, involving 48 patients, have been completed with once-daily oral dosing. Dose-related decreases in serum HCV RNA were observed during treatment, ranging from a mean 0.15 log10 at the lowest dose (50 mg/day) to 0.73 log10 at 400 mg/day, half the anticipated maximal dosing in this ongoing trial. Tolerance of study treatment has been satisfactory, with no serious adverse events, dose-limiting toxicities, or pattern of laboratory abnormalities. At 400 mg/day, some NM283-treated patients experienced transient mild nausea (5/10) or vomiting (2/10) on Day 1, but all patients completed treatment without modification. NM283 is well-absorbed, with dose-proportional plasma drug levels. Final data, including higher NM283 doses, will be reported.

 

Conclusions

NM283 exhibits consistent antiviral activity with satisfactory tolerance and linear pharmacokinetics in HCV-1 infected chronic hepatitis C patients. Expanded testing of NM283, alone and in combination with peg-interferon, is anticipated.

 

Hepatitis C Virus Infection After Liver Transplantation-Early and Dose Escalating Antiviral Therapy with Interferon Alpha and Ribavirin Increases Tolerability Without Losing Effectiveness

M. Schuchmann 1, G. Greif-Higer1, M. Wunsch2, C. Mönch2, A.P. Barreiros1, B. Elke1, W.O. Böcher1, S. Kanzler1, P.R. Galle1, A.W. Lohse1, G. Otto2.

1 Department of Medicine, 2Department of Transplantation Surgery, University of Mainz, Mainz, Germany.

 

Background

Due to inevitable re-infection of the graft, survival of patients with HCV after LTX is worse compared to HCV negative patients.

 

Methods

From 1997-8/2003 206 patients (55 HCV pos) underwent liver transplantation at our center. From July 2000, patients with HCV re-infection - proven by transaminases and liver biopsy - were treated as early as possible (4-12 weeks after LTX): A 4-week period of monotherapy with low dose interferon alpha (IFN alpha) was followed from week 5 on by a dose escalation according to body weight and additional treatment with Ribavirin.

 

Results

HCV pos. patients had a worse survival after liver transplantation compared to HCV neg. patients (60 vs. 79% two-years-survival; p<0.059). Re-infection was proven in 50% of the patients within 150 days after LTX and survival among this group was significantly worse (p<0.02). Up to now we treated 21 patients with an antiviral therapy with IFN alpha and Ribavirin. 8 patients are still under treatment - 4 of them show virological response. Among the other 13 patients, 2 had a sustained viral response, 2 patients had to stop therapy due to side effects, 4 were non-responders and 5 patients died before completing the therapy.

 

Conclusion

HCV pos. recipients have a worse survival after liver transplantation compared to HCV neg. patients. Our preliminary experience with an early onset, dose escalating and therefore better tolerated regimen of therapy with IFN alpha and Ribavirin demonstrates that complete viral response can be achieved and merits to be tested in a randomized trial.