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
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.
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.
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.
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.).
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.
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
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.
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.
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.
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.
J. Bartolome E. Rodriguez-Inigo, J.M. Lapez-Alcorocho, N. Ortiz-Movilla. M. Pardo. P. Rey, V. Carreno.
Fundacion Estudio Hepatitis Virales, Madrid, Spain
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.
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).
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.
The percentage of infected hepatocytes in the pretreatment liver biopsy is a better predictive factor of response than the serum HCV-RNA concentration.
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
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.
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.
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.
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.
L. Benvegnu F. Pasin, M. Gios, A. Ferrari, A. Alberti.
Dpt. of Clinical and Experimental Medicine - University of Padova, Padova, Italy
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.
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.
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.
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.
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
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.
373 consecutive HCV RNA+, otherwise healthy, children from 15 observatory centers were studied (InnoLipa).
The following patterns were recorded:
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.
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.
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.
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.
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.
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
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).
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
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.
The three treatment groups were similar in baseline HCV-RNA and ALT. The combination of Peg-IFNIRBVIMPB was well tolerated.
(*JonckheereTerpstra test for increasing dose response)
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.
J.S. Markowitz1 , EM. Gutterman1, W. Klaskala2
1Health Data Analytics, Princeton Junction NJ, USA; 2 Laboratories mc, Nutley, NJ, USA
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.
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.”
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:
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.
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
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.
These findings indicate an extremely low or even null risk of HCV transmission within heterosexual monogamous couples.
M. Maynard1, C. Deguerry1, P. Pradat1, C. Trepo1 and Norevic;
1 Hotel-Dieu, Lyon, France; 2 Multicenter - NOREVIC Group, France
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.
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.
Maintenance therapy is widely used in France although 50% of cirrhotic patients remain untreated.
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
To assess the impact of cirrhosis reversibility on survival and occurrence of cirrhosis complications.
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 independent blinded analysis. Cirrhosis-related complications included variceal bleeding, ascitis, spontaneous bacterial peritonitis, hepatocellular carcinoma and hepatic encephalopathy.
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).
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.
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.
Since the implementation of the MELD score
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).
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.
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.
The aim of the study was to evaluate the
feasibility of LT in HIV-HCV co-infected patients in
Five patients (5 M, mean age 42 years)
underwent LT from September 2002 to August 2003 under an Italian multicentric trial coordinated by the
Immunosuppression was an association of tacrolimus-steroids-
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.
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.
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.
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.
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.
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.
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.
Due to inevitable re-infection of the graft, survival of patients with HCV after LTX is worse compared to HCV negative patients.
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.
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.
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.