C.M. Fernandez-Rodriguez1, P. Lopez Serrano1, M.L. Gutierrez1, S. Alonso1, M. Nevado2, J.L. Lledo1
1Gastroenterology and Hepatology Unit, Fundacion Hospital Alcorcon, Madrid, Spain 2Pathology Unit, Fundacion Hospital Alcorcon, Madrid, Spain
Hepatic steatosis associated to genotype 3 HCV is associated to low serum cholesterol and may be mediated by a protein-core direct cytopathic effect. Reversal of this lipid metabolic disturbance in long-term virological sustained responders is less-well known.
To examine the serum colesterol levels of HCV patients infected with genotype-3 chronic, its relationship with liver steatosis and the long-term effect of sustained virological response (SVR) on hypocholesterolemia as compared with non-responders and with patients with genotype-1.
Two hundred and fifteen consecutive untreated patients with chronic hepatitis C referred to our institution for assessing antiviral treatment have been studied (genotype 1, n = 158; genotype 2, n =4; genotype 3, n =41 and genotypes 4 y 5, n=12). Data on virological response 6 months after the end of treatment were available in 160 patients.
Patients infected by genotype 3 showed lower age-adjusted serum cholesterol levels and more frequent moderate to severe hepatic steatosis than those infected by non-3 genotypes (P<0.001). There was an inverse correlation between the degree of steatosis and serum cholesterol in patients with genotype-3 (p>0.01) but not in patients with genotype 1. In patients with genotype-3 and SVR, serum cholesterol raised from 140 mg/dl (IC 120-151) to 185 mg/dl (IC 171-199) six months after the end of treatment (p: 0. 0001). By contrast, serum cholesterol did not change in non-responders: 143 mg/dl (IC 99-187) to 140 mg/dl(IC 111-169). In patients infected with genotype 1, regardless of virological sustained response, serum cholesterol remained unchanged: From 196 mg/dl (181-211) to 204 (193-215) in SVR and from 180 (167-192) to 170 (160-181) in non-responders.
In addition to cause hepatic steatosis, genotype-3 of HCV, but not other genotypes, decreases serum cholesterol which was inversely proportional to the degree of hepatic steatosis. This interference with the metabolic lipid pathway is reversible with sustained virological response.
G. Venezia1, O. Lo Iacono1, S. Petta1, M. Amato2, V. Rodolico3, A. Mattina2, C. Giordano2, V. Di Marco1, C. Mineo1, S. De Lisi1, P. Almasio1, A. Craxì1
1Gastroenterology, University of Palermo, Palermo, Italy 2Endocrinology, University of Palermo, Palermo, Italy 3Pathological Anatony, University of Palermo, Palermo, Italy
Steatosis is commonly present in chronic hepatitis C (CHC); however the pathophysiology and metabolic association of steatosis and its role in disease progression have not been established. Leptin “resistance” and low levels of adiponectin play a role in the pathogenesis of hepatic steatosis and insulin resistance.
To evaluate the presence of insulin resistance, levels of leptin, adiponectin and resistin and their possible relationship with steatosis and fibrosis in CHC.
We studied fifty-five naïve patients with biopsy-proven CHC (age: 51 ± 12 years; gender: 33M/22F). METAVIR and Brunt classifications and the ATP III metabolic syndrome definition were applied. BMI, fasting glucose, insulin, C-peptide, resistin, leptin, adiponectin, lipoprotein, apo-β was performed.
Thirty-three (60%) patients had genotype 1b and 4 (8%) genotype 3a; 20 (36%) had histological steatosis with grade 2 or 3 (>33% hepatocytes involved). Patients with CHC and steatosis grade 2 or 3 were older (p=0.018), had higher staging (p=0.047). Metabolic syndrome was present in 7/20 (35%) pts with steatosis and in 4/35 (11%) without (p= 0.036). BMI (25.1±3.1 vs 28.0±5.1; p=0.034), serum triglycerides concentration (91±41 vs 128±74; p=0.018), insulin level (11.6±11.4 vs 13.8±5.0 p=0.014), HOMA (3.0±3.6 vs 3.3±1.4; p=0.016), fasting glucose insulin ratio (11.7±7.4 vs 7.9±3.0 p= 0.034), leptin (14.7±10.1 vs 25.6±11.3 p=0.003) and leptin/adiponectin ratio (0.6±0.4 vs 1.3±08 p= 0.002) were statistical associated with steatosis. No statistical association was found for grading, ALT, GGT, glucose, cholesterol and HDL concentration, lipoprotein, apo-β and adiponectin, resistin and C-peptide. However no statistical correlation was found between fibrosis and leptin, adiponectin and its ratio.
In HCV infected patients high serum levels of leptin and ratio leptin/adiponectin are related to severe steatosis, but not with liver fibrosis; reflect their potential role in insulin resistance and the importance of antisteatotic regulatory mechanisms
M. Berenguer1, V. Aguilera1, M. Prieto1, F. San Juan2, S. Benlloch1, J.M. Rayón3, J. Berenguer1
1Hepatogastroenterology Department Hospital Universitario La Fe, Valencia, Spain 2Liver Unit, Surgery Department, Hospital Universitario La Fe, Valencia, Spain 3Pathology Department Hospital Universitario La Fe, Valencia, Spain
Recurrent HCV-cirrhosis occurs in a substantial proportion of recipients, with higher rates reported in patients transplanted recently. Both the aging of the donors and over-immunosuppression have been implicated in this worse outcome. In addition, controversial results have been reported with regards to the role of specific calcineurin-inhibitors.
To determine (1) whether the implementation of specific measures aimed at reducing or avoiding the negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C; (2) whether there are differences in outcome based on the induction immunosuppression (tacrolimus vs cyclosporine-based).
Comparative study between a cohort of patients transplanted recently (2001-2003) and a control group of HCV-infected patients transplanted before the implementation of three simple measures (1999-2000): (i) use dual immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) Slow steroid tapering; and (iii) selection, whenever possible, of organs from younger donors for HCV-candidates; (2) Prospective randomized trial comparing fibrosis progression and rate of HCV-related severe disease (F3, F4, cholestatic hepatitis) between tacrolimus and cyclosporine-based immunosuppressed using the most recent cohort. Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study.
Severe disease (defined as bridging fibrosis, cirrhosis, or fibrosing cholestatic hepatitis in the first two years) was significantly lower in this cohort compared to the control group (13/42, 31 % vs 26/47, 50%; p=.02). While the age of the donor had not changed significantly between the two cohorts, the proportion of patients on triple-quadriple regimes was lower and the duration of prednisone therapy longer in patients transplanted more recently. Cyclosporine (n=26) and tacrolimus (n=16) patients were similar with regards to demographics, donor age and sex, duration of prednisone, rejection, methyl-prednisolone boluses, surgical-related variables and follow-up. The percentage of patients developing severe disease was not statistically different between the cyclosporine and tacrolimus groups (27% vs 37.5%).
Improving the outcome of recurrent hepatitis C might be achieved by reducing overall immunosuppression and avoiding abrupt changes in immunosuppression.
Liver Transplantation – Special Populations - Children
F. Lacaille1, Y. Revillon1, D. Jan1, J. Pawlowska2, M. Marcellini3
1Hôpital Necker-Enfants Malades, paris, France 2Centrum Zdrowia Dziecka, Warsaw, Poland 3Ospedale Bambino Gesu, Rome, Italy
The prevention of long term complications is a major concern in children after liver transplantation (LT).
To evaluate the medium term results, we studied 53 children (20 boys), who survived more than 5 years after LT. Patients : they are 6 to 24 year-old, the median follow-up is 7.5 y (5-14.5). They received LT at a mean age of 3.5 y (11 m-14.5 y), for chronic cholestasis in 41. Two were retransplanted (1 primary non-function, 1 biliary complications). Graft was living-related in 37, a reduced liver in 6, a split liver in 2, a whole liver in 10.
2 children died, 5 y (cystic fibrosis), and 10 y (awaiting retransplantation) after LT. All others have a normal daily function. The 6 older ones are students or employed, the other ones attend school, only 2 being backward. Immunosuppression is ciclosporine in 39, tacrolimus in 14, 32 off prednisone. Height is > 85% mean for age except in 2 (Alagille, propionic acidemia). One child only weighs more than 125% of mean weight for height. Liver tests are abnormal in 13. Two patients have hepatitis B and 3 hepatitis C. One has arterial thrombosis and chronic biliary problems. Biliary stenosis necessitated surgery 2 to 7 y after LT in 4. Liver biopsy was performed in 29, and is normal only in 2 : lesions are ductular proliferation (3), rejection (19, mild in 18), related to hepatitis C (3). The immunosuppression was changed in 10 after the biopsy. Renal clearance was controlled in 24 : it is > 70 ml/mn/1.73 m2 in 18, 60-70 in 4, < 60 in 2. Five are treated for high blood pressure. Blood lipids are normal in all. Cardiac ultrasonography is normal in 13/15.
The medium term functional results of LT are good, the patients leading a near-normal life. Growth is satisfactory, overweight is not a major problem. However liver histology is seldom normal. Kidney function is already borderline in some patients and could be improved by a change of immunosuppression. Heart function should be followed, due to complications of hypertension, tacrolimus toxicity, or hypercholesterolemia.
G. Nicolini1, F. Gentili1, A. Onetti Muda3, A. De Santis1, S. Ginanni Corradini1, O. Riggio1, S. Natalizi3, M. Iappelli2, M. Rossi2, A.F. Attili1, M. Merli1
1II Gastroenterologia, Università di Roma 'La Sapienza', Rome, Italy 2II Clinica Chirurgica, Università di Roma 'La Sapienza', Rome, Italy 3Anatomia Patologica, Università di Roma 'La Sapienza', Rome, Italy
Hepatic steatosis has been described after liver transplantation (LT) and mostly associated with hepatitis C reinfection. Other factors, often present in transplanted patients, are associated with steatosis: overweight/obesity, diabetes, hypertension, hypertrigliceridemia, alcohol consumption. Moreover, donor characteristics and liver perfusion may contribute to the occurrence of post-LT steatosis.
Our study was aimed at defining the prevalence and factors associated to post-LT steatosis.
Among 107 consecutive patients transplanted at our University from January 2001 to January 2004, forty-two (29M/13F;mean age:55±8years) performed one or more liver biopsies, during follow-up. The main indication for biopsies was alteration in liver enzymes, but also protocol biopsies were included. Sixty-seven percent of patients were HCV-RNA positive. Steatosis was defined as mild-moderate (involving<60% of hepatocytes) or severe (>/=60%).
The overall prevalence of steatosis was 60%, while severe steatosis was present in 6 patients (14%). Patients’ characteristics at time of biopsy are reported in Table. Post-LT steatosis is related to hepatitis C recurrence; severe steatosis was associated with genotype 3. BMI, diabetes, hypertension, hypertrigliceridemia and donor steatosis were not associated with post-LT steatosis. A decreased arterial blood flow in the allograft seems to contribute to post-LT steatosis.
G.R. Silberhumer1, H. Hetz2, S. Rockenschaub1, B.A. Berlakovich1, R. Steininger1, F. Muehlbacher1
1Medical University Vienna, Department for Transplantsurgery, Vienna, Austria 2Medical University Vienna, Department for Anesthesiology, Vienna, Austria
Model for End-stage Liver Disease (MELD) score has emerged as a useful tool in predicting mortality in patients awaiting liver transplantation. There is still the discussion, if further parameters could improve the sensitivity and specificity of the MELD score.
From 1997 to 2003 622 adult patients with End Stage Liver Disease were listed for orthotopic liver transplantation (OLT). 388 patients were transplanted, 131 died on list, 55 were removed from the waiting list due to tumor progression (n=11), poor condition (n=6), non compliance (n=7), clinical improvement (n=28) or technical reasons (n=3). 48 patients are still awaiting OLT. All patients were categorized according to the MELD Score.
Patients who died on list showed a significant increase of their MELD score during waiting time (On list MELD: 21±7 vs. Off list MELD: 28±9) as well as a significant higher MELD score at listing compared to patients who were transplanted (On list MELD: 16±5 vs. Off list MELD: 17±7) or removed (On list MELD: 16±6 vs. Off list MELD: 12±3). Multivariate analysis (Cox Model) identified MELD score at listing (p<0,001), ascites (p<0,001) and spontaneous bacterial infection (p=0,003) as independent risk factors for death on the waiting list. Patient survival estimated by Kaplan Meier method was similar at 3, 6 and 12 months after transplantation regardless of the MELD Score. However, patients with a MELD Score >=25 showed a trend towards a lower survival at 3 years (62% versus 80%, p=0.08). A further detail of interest in this analysis was the fact that patients with MELD Score <11 showed a higher risk for death after OLT (89% survival) than on waiting list (98% survival) at three months.
Our study demonstrated that MELD Score is a strong predictor for death on the waiting list. It enables listing patients depending on their disease severity and uses only routine blood tests without any subjective parameters. Additionally we evaluated refractory ascites and recurrent infection as independent risk factors, too. These complications of portal hypertension have to be treated adequately, especially in patients with lower MELD Scores.
N. Yilmaz1, M.L. Shiffman1, R.T. Stravitz1, R.K. Sterling1, V.A. Luketic1, A.J. Sanyal1, M.J. Contos2, A.S. Mills2, A. Cotterell3, D. Maluf3, M.P. Posner3, R.A. Fisher3
1Hepatology Section, VCU Medical Center, Virginia Commonwealth University Medical Center, Richmond VA, USA 2Department of Pathology, VCU Medical Center, Virginia Commonwealth University Medical Center, Richmond VA, USA 3Division of Transplant Surgery, VCU Medical Center, Richmond VA, USA
It has been suggested that patients with HCV who underwent LT in recent years had reduced survival and this was secondary to more aggressive recurrent disease, especially in those patients who received and older donor organ.
To determine the impact of donor age on LT survival and disease recurrence in patients with chronic HCV.
222 patients underwent LT for HCV cirrhosis between 1991-2004; mean age 50 years; 75% male; 84% Caucasian. 30% had received interferon (IFN) prior to LT. Immunosuppression varied considerably over 13 years and included, OKT3(14%), ATG(2%), cyclosporine/Neoral(55%), tacrolimus(12%), azathioprine(14%), MMF(85%), sirolimus(41%) and prednisone(100%). Donor age ranged from 6-76 years; 10% were >60 years. All patients underwent protocol liver biopsy (LBX) 6 months after LT and at 1-2 year intervals thereafter. Rejection was always confirmed by LBX.
Patient survival at 1, 3 and 5 years was 86%, 82% and 74% when LT was performed between 1991-00; graft survival was 83%, 79% and 70%. In contrast, a significant (p<0.001) decline in patient and graft survival was observed when LT was performed between 2001-03; 81%, 68% and 50% and 80%, 66% and 48% at 1, 2 and 3 years respectively. Between 1991-00 the use of donor organs >60 years was <7% compared to 15% during 2001-03 (p<0.01). The 5 year patient and graft survival after LT when the donor was <60 years was 69% and 64% respectively versus only 42% when donor age was >60 years (p<0.001). In contrast, increasing donor age was not associated with more severe recurrent HCV. After 5 years 23% of grafts from donors <20 years had developed bridging fibrosis or cirrhosis compared to 25% from donors >60 years. No specific immunosuppression medication, acute rejection (20-30% over the 13 years) or treatment with IFN prior to LT appeared to affect patient or graft survival.
A significant decline in patient and graft survival was observed in patients who underwent LT after 2000. This was strongly associated with the increased use of organs from donors age >60 years. However, this decline in survival was not secondary to more severe recurrence of HCV.
R.G. Gish1, D. Nelson2, S. Arora3, M.W. Fried4, K.R. Reddy5, Y. Xu6, B. Murphy6, Study Group6
1California Pacific Medical Center, San Francisco CA, USA 2University of Florida, Gainesville FL, USA 3University of New Mexico, Albuquerque NM, USA 4University of North Carolina, Chapel Hill NC, USA 5Hospital of the University of Pennsylvania, Philadelphia PA, USA 6Valeant Pharmaceuticals International, Costa Mesa CA, USA
Dose-limiting anemia can be a prominent adverse event of therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting prodrug of ribavirin, may be a safer alternative when used in combination with pegylated interferon alfa-2a (PEG-IFN).
Of 180 HCV therapy-naive patients enrolled in the study, 171 patients received full-dose viramidine (400 mg: n = 47; 600 mg: n = 43; 800 mg: n = 44) versus ribavirin 1000-1200 mg/d (n = 37) in combination with PEG-IFN 180 µg/wk SC. Patients were predominantly male (64%), Caucasian (76%), and genotype 1 (72%), with a median HCV RNA of 6.5 log10 copies/mL. Analyses assessed the incidence of anemia (hemoglobin <10 g/dL) and HCV RNA levels (Bayer TMA assay; sensitivity to 5 IU/mL) among patients without dose reduction due to anemia to evaluate the intrinsic activity of viramidine versus ribavirin without the confounder of dose modification.
Among patients with no dose modification due to anemia at end of treatment (EOT), no significant differences were noted between viramidine (400, 600, and 800 mg BID) versus ribavirin in the proportion of patients with undetectable HCV RNA levels (55%, 63%, 55%, and 62%, respectively). Rates of anemia at EOT for the viramidine 400, 600, and 800 mg groups were 0%, 2%, and 11%, respectively, versus 27% for the ribavirin arm. Based on evaluable patients at EOT experiencing a decline in hemoglobin of at least 25%, the rate in the ribavirin group (48%) was higher versus the rate in the viramidine groups (400 mg: 14%; 600 mg: 18%; 800 mg: 15%). Other types of adverse events were similar between treatment arms.
At EOT in this Phase 2 study, viramidine demonstrated antiviral activity comparable to that of ribavirin when used in combination with pegylated interferon alfa-2a among patients with no dose modification due to anemia. Patients in the viramidine arms also showed a significantly lower incidence of anemia.
N. Afdhal1, M. Rodriguez-Torres2, E. Lawitz3, E. Godofsky4, G. Chao5, B. Fielman5, S. Knox5, N. Brown5
1Department of Medicine, Beth Israel Deaconess Medical Center, Boston MA, USA 2Fundacion de Investigacion de Diego, Santurce PR, USA 3Alamo Medical Research, San Antonio TX, USA 4Bach & Godofsky, Bradenton FL, USA 5Idenix Pharmaceuticals, Cambridge MA, USA
Only 40-50% of HCV-1 infected hepatitis C patients respond to pegylated interferon (peg-IFNα) plus ribavirin therapy. NM283 is a novel nucleoside analog that as monotherapy reduced serum HCV RNA by a mean 1.2 log10 (94%) in a recent 15-day trial in HCV-1 patients, most of whom had previously failed antiviral therapy for HCV infection. NM107, the parent compound of NM283, and interferon alfa exhibit synergistic antiviral effects against BVDV models in vitro, prompting the current investigation of NM283 combined with peg-IFNα in treatment naïve patients with chronic hepatitis C.
A multicenter, open-label phase IIa trial is evaluating whether NM283 plus peg-IFNα-2b has enhanced antiviral activity compared to NM283 alone in HCV-1 infected patients. Key entry criteria are: HCV RNA >5 log10 IU/mL, ALT <5 xULN, compensated liver disease, treatment naïve. Eligible patients are randomized 2:3 to NM283 or peg-IFNα + NM283 (combinationRx). NM283 is dosed orally QD for 24 weeks in both groups, escalating to 800 mg/day over the first week and then continuing at that dose. The group randomized to combinationRx receives peg-IFNα-2b (1.0 μg/kg weekly) starting on Day 8.
Presently 19 of 30 planned patients (age 22-65, 68% males) are enrolled and have received 10 or 12 weeks of treatment. Tolerance of both treatments has been satisfactory. Mean HCV RNA reductions (log10 IU/mL) from baseline to the last patient visit are 1.0 for the NM283 monotherapy group and 3.2 for the combinationRx group. Eleven of twelve combinationRx patients treated for at least 10 weeks have had substantial HCV RNA reductions (range 1.2-6.2 log10), and 8 of 12 patients have achieved >2 log10 decrease in HCV RNA, which has been associated with sustained response to current standard Rx. Presently 4 patients are PCR-negative (<10 IU/mL). 12-week early virological response data will be presented at the meeting.
NM283 combined with peg-IFNα shows consistent, rapid and marked anti-HCV activity in patients with HCV-1 infection, a historically difficult-to-treat group. Initial EVR rates with combinationRx are encouraging and support continued investigation of NM283 and NM283 + peg-IFNα, which may offer improved efficacy and tolerability for patients with HCV-1 infection.
C. Mussini1, V. Borghi1, S. Bellelli2, C. Angeletti2, F. Sabbatini1, F. Prati1, N. Mongiardo1, R. Esposito1
1Clinic of Infectious Diseases, Azienda Policlinico, Modena, Italy 2National Institute of Infectious Diseases L. Spallanzani, Rome, Italy
In HIV/HCV co-infected patients receiving antiretroviral therapy (ARV), the development of steatosis seems to be an important factor for the progression of HCV infection.
Consecutive liver biopsies from HIV/HCV co-infected patients were studied. Necro-inflammatory activity, fibrosis according to Ishak index and steatosis (scored as: grade 0, none; 1, fat involving <5% of hepatocytes; 2, 5 to <30%; 3, 30% to 60%; 4, >60%) were evaluated. Statistical analysis was performed by using SPSS.
106 patient were analyzed, 67.9% males, 91.5% intravenous drug user, median age 36 years (IQR 33-39). Median duration of HCV infection was 12 years (IQR 9-14); median CD4+ nadir count was 271 cells/uL (IQR 141-468). At biopsy, median CD4+ count value was 609 cells/uL (IQR 437-850) and median plasma HIV viremia was 388 copies/ml (IQR 50 – 3300). Concerning HCV genotype, 44.3% of patients had genotype 1 and 35.8% genotype 3, while median HCV viremia was 7.9 MU/ml (IQR 3.3-19.2). Severe hepatic fibrosis (>grading 3) was observed in 21 patients (19.7%), steatosis with grade >2 in 17 (16%). 38 patients (35.8%) did not received any previous ARV, 13 were treated with nucleoside analogues (NRTIs) (12.3%), 15 with 2 NRTIs and 1 non-nucleoside analogues (NNRTIs) (14.2%), 29 with 2 NRTIs and 1 protease inhibitor (PI) (27.4%), the remaining patients received different therapeutic associations. A steatosis of grade >2 was observed in 31% of patients receiving PIs, in 20% in NNRTIs and in 10.5% of those never treated. Severe steatosis was associated with HCV 3 genotype in 31.6% of the patients. By using a multivariate logistic regression, a significant association was found between steatosis and the use of 2 NRTIs+PI (OR 3.98, 95% CI 1.00-15.87; p= 0.05), and the presence of HCV 3 genotype (OR 3.5; 95% CI 1.04-11.76; p=0.04). The use of 2 NRTIs+NNRTI was not significantly associated with steatosis (OR 2.58, CI 0.45 - 14.69; p=0.29).
In HIV/HCV co-infected patients, infection with the HCV genotype 3 and the use of the ARV including PI worsens steatosis and thus fibrosis.