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Conference Reports

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DDW Conference - May 19-22, 2002 - San Francisco, CA

Alan Franciscus
Editor-in-Chief, HCV Advocate

The Digestive Disease Weekly Conference is being held in San Francisco from May 19 – 22, 2002. This report begins the HCV Advocate’s daily coverage of clinical data related to hepatitis C. These reports will focus on live plenary presentations with a summary of posters and abstracts to follow upon completion of this daily conference coverage.

May 19, 2002

Impact of High Serum Glucose on Liver Fibrosis in Chronic Hepatitis C
Vlad D. Ratziu, Mona Munteanu, Frederic Charlotte, Luminita Bonyhay, Thierry Poynard, Paris, France

Overweight, especially when associated with diabetes accounts for most cases of cryptogenic cirrhosis and thus might contribute to the development of fibrosis in CHC. Overweight and diabetes are risk factors of liver fibrosis in patients with NASH.

The aim of this study is to study the impact of overweight, diabetes and related metabolic complications on fibrosis progression in CHC.

710 patients with CHC were retrospectively studied. The inclusion/exclusion criteria were as follows:

Inclusion Criteria Exclusion Criteria
Chronic HCV by PCR HBV or HIV coinfection
Transmitted by IDU or transfusion Organ transplant recipients
Known duration of infection Current or past use of immunosuppressive drugs (including chemotherapy)
Liver biopsy available  

55% of patients had no or minimal fibrosis (Metavir F0 or F1) and 45% had septal fibrosis (F2, F3 or F4). Independent risk factors of septal fibrosis were:age (p<10-3), daily alcohol(p<10-3), serum glucose (p=0.003), anti-HBc (p=0.04) and male sex (p= 0.04). BMI(p<10-3; r=0.26), serum triglycerides (p=0.002; r= 0.12), serum ferritin(p<10-3; r= 0.18) and steatosis(p<10-3; r= 0.16), were associated with serum glucose but did not independently predict septal fibrosis. After adjustment for the duration of infection, patients with serum glucose >6.1 mmol/l had a faster progression to septal fibrosis than those with normalserum glucose (p<10-3by log rank test). Multivariate analysis by the Cox model showed that age at infection >30yrs. (p<10-3), male sex(p<10-3), daily alcohol >50 g (p= 0.02) and serum glucose >6.1 mmol/l(p<0.05) were independently associated with septal fibrosis. A separate, per fibrosis stage showed that serum glucose >6.1 mmol/l was associated with intermediate (F3) and advanced (F4) but not with early (F2) fibrosis stages.

Independent variables associated with late fibrogenesis F4 (logistic regression)
Variable Relative Risk (CI 95%) p-value
Age = 50 years 3.7 (2-7) <0.001
Glycemia = 6.1 mmol/l 4.1 (2.2 – 7.6) <0.001
Daily alcohol = 50g 3.2 (1.5 – 6.7) 0.002
BMI = 28 kg/m2 2.6 (1.3 – 5.4) <0.01
Male sex 1.9 (1 – 3.6) <0.05
Ferritin = 300µg/l 0.8 (0.4 – 1.8) N.S (0.7)
Presence of anti-HBc 1 (0.5 -= 1.9) N.S (0.9)

Features of the polymetabolic syndrome in patients with high and low serum glucose
Variable Gly < 6.1(%) Gly = 6.1 (%) p-value
BMI = 25 kg/m2 29 46 0.002
BMI = 28 kg/m2 11 24 0.001
TG = 1.7 mmol/l 12 23 0.02
Steatosis = 10% 38 51 0.03
Liver iron score = 3 24 19 N.S (0.3)
Ferritin = 300µg/l 26 37 N.S (0.08)
Daily alcohol = 50g 15 17 N.S (0.6)

Conclusions:

  1. Overweight and especially high serum glucose are independent cofactors of liver fibrosis in patients with chronic hepatitis C
  2. The impact of high serum glucose on liver fibrosis occurs at intermediate and late stages of fibrogenesis
  3. The role of insulin resistance and fibrogenesis deserves further exploration
  4. These findings might have potentially important therapeutic implications

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Fatigue Is Associated with High Circulating Leptin Levels in Chronic Hepatitis C
Piche Thierry, Gelsi Eve, Hebuterne Xavier, Rampal Patrick, Tran Albert, Nice, France

Fatigue is a frequent and disabling symptom reported by patients with chronic hepatitis C (CHC). Its mechanism is poorly understood. Recent attention has focused on the role of leptin and energy expenditure in CHC. Our aims were to analyze fatigue in CHC and to determine its relationships with disease activity, resting energy expenditure (REE), circulating leptin, and TNF alpha.

Seventy-eight CHC patients, 22 healthy controls and 13 primary biliary cirrhosis (PBC) patients underwent measurements of REE, body composition, leptin, and TNF-a. All subjects completed the Fatigue Impact Scale (FIS) questionnaire. A liver biopsy and viral load measurements were performed in all patients.

38 of the 78 CHC patients considered fatigue the worst or initial symptom of their disease. The fatigue score of the patients was significantly higher than that of the controls (53.2 +/- 40.1 vs. 17.7 +/- 16.9; p < 0.0001) and was more pronounced in females (p = 0.003). Leptin was increased significantly in CHC patients compared to controls (15.4 +/- 20.7 vs. 6.4 +/- 4.1 ng/mL; p < 0.05). In CHC patients, the fatigue score correlated significantly with leptin corrected for fat mass (r = 0.30, p = 0.01). This correlation increased when the physical domain of fatigue was concerned (r = 0.39, p = 0.0009). Furthermore, a similar positive correlation was found in PBC patients (r = 0.56, p = 0.04). No correlation was found between fatigue and age, REE, liver function tests, viral load or the METAVIR score in CHC patients.

In summary, fatigue is present in CHC patients and is more pronounced in females. The FIS questionnaire is clinically relevant and may be useful for future therapeutic trials aimed at reducing fatigue. Fatigue may be partly mediated by leptin.

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Does High Body Mass Index Affect Hepatic Fibrosis, Steatosis and Inflammation in Patients with Chronic Hepatitis C?
Mohamed A. Metwally, Claudia O. Zein, Nizar N. Zein, Rochester, MN

It has been reported that high body mass index (BMI) may have a negative impact on the rate of fibrosis progression in HCV patients. Steatosis is a common histopathological finding in liver biopsy of chronic HCV patients, but hepatic fibrosis is the responsible factor for the complication of chronic hepatitis C. Body mass index is a well known to be associated with hepatic steatosis in obese and diabetic patients and the lowering of BMI may potentially decrease hepatic steatosis in these patients. The impact of high BMI on hepatic fibrosis, steatosis and inflammatory activity in patients with chronic HCV is still under investigation.

The aim of this study is to assess the potential association between body mass index and stage of hepatic fibrosis in HCV patients.

209 consecutive previously untreated chronic HCV patients were enrolled. Chronic HCV was confirmed by serological, virological and histological investigations. Other confounding liver diseases were excluded. Liver biopsies were reviewed for stage of fibrosis, degree of inflammation and degree of steatosis. Laboratory and demographic data at time of liver biopsy including alcohol intake and diabetes mellitus were collected. Univariate analysis was used to compare mean BMI against levels of hepatic fibrosis, inflammatory activity, and steatosis. Demographic data were compared also against levels of hepatic fibrosis, inflammatory activity, and steatosis. T test for continuous data chi-square test or Fishers exact test for categorical data was used for the analysis. Multivariate analysis against level of hepatic fibrosis was done to control for confounding variables including diabetes mellitus and alcohol intake.

Higher BMI values were associated with more advanced hepatic fibrosis (Stage III/IV) in unvariate analysis (P=0.02) and was still significant after controlling for alcohol intake and diabetes in multivariate analysis (P=0.04). High BMI was also associated with hepatic steatosis (P=0.03), although there was no statistically significant association between steatosis and fibrosis stages suggesting that the association between BMI and fibrosis is independent of that of BMI and steatosis. BMI was not associated with hepatic inflammatory activity (P=0.6). There was no significant association between hepatic steatosis and alcohol intake (p=0.5) nor diabetes mellitus (p=0.6). There was no significant association between stage of hepatic fibrosis and degree of steatosis.

In summary, higher BMI values were associated with more severe hepatic fibrosis in patients with chronic HCV infection. Whether high BMI in HCV patients contribute directly to progression of hepatic fibrosis and whether dietary lowering of BMI will slow the progression of HCV associated liver disease remains to be determined.

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Latinos with Hepatitis C Display More Severe Laboratory Changes Compared to Other Ethnic Groups
Maurizio Bonacini, Anne Celona, Tim Kuo, Manish Prakash, Los Angeles, CA

Latinos (Hispanics) may have faster hepatic fibrosis progression than other ethnic groups (Am J Gastroenterol 2001;96:2438-41).

The aim of this study is to address ethnic differences in a large cohort of patients with antibodies to hepatitis C attending the L.A. County hepatitis clinic.

We surveyed clinic cards of patients seen from 1993 to the present, for demographics and laboratory data. IDU alone or in combination with other risks was the most commonly reported risk factor, 48% of the entire cohort.

The risk factors were as follows: Asians were the least likely to report IDU or transfusions (32%) while Caucasians and Hispanics were most likely to report these two risks (74% and 70% respectively). Transfusion was reported less frequently in African Americans (85) and Caucasian men (9%) than in Latinos (19%)p<0.01. Women are significantly more likely to report transfusions than men in all ethnic groups except Caucasians. 1271 patients were categorized into 4 major ethnic groups, 95 patients were Asian (A), 232 African-American (AA), 323 Caucasian (C), 621 Latino or Hispanic (L). The A group was significantly older than all other groups (p=0.0001) and were more commonly coinfected with HBV than AA or L. Caucasians were also more likely to be HBV-positive than L (p= 0.02). The AA group had a lower percentage of female patients than either A(p<0.0001), C (p=0.0003), or L (p= 0.01). Latinos, both men and women were significantly more likely to report transfusion as a risk factor than C or AA. In all groups except C, men reported IDU more frequently than women. Latinos had higher serum bilirubin and ALTlevels (P<0.001) and lower serum albumin levels compared to AA and C(p<0.01). Prothrombin times were not statistically different across ethnic groups.

  A=95 AA=232 C=323 L=621
% of group 7% 18% 25% 49%
Age (mean) 54.5 45.7 41.8 44.7
Female (%) 48% 25% 39% 35%
ALT # 40 IU/L 5% 19% 22% 11%
Mean ALT* 92 81 83 104
Mean TB* 0.8 0.8 0.7 0.9
Mean Albumin* 4.1 4.1 4.2 4.0
% HbsAg +ve 11% 4% 6% 2%
* geometric mean

In summary, Latinos presented with more significant biochemical abnormalities than the other groups. Latinos were the group with the highest transaminase and bilirubin values and then lowest albumin levels. Asians were the least likely to report IDU or transfusion as a risk factor, which Caucasians and Hispanics were most likely to report as risks. Asians were most likely to have HBV coinfection.

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Viral Kinetics of Hepatitis C Virus (HCV) Genotype 3 Is Faster Than Genotype 1 HCV: Effect of Different Treatment Schedules
Jose E. M. Medeiros-Filho, Joao R. R. Pinho, Avidan U. Neumann, Isabel M. V. G. C. Mello, Marcilio F. Lemos, Luiz C. Da Silva, Antonio A. Laudanna, Flair J. Carrilho, São Paulo, Brazil; Ramat Gan, Israel

Patients infected with HCV of genotype 2 and 3 have a better EOT response to IFN treatment (with or without RBV) than patients infected with genotype 1. The early kinetics of HCV decline during various treatment forms of interferon alpha therapy was extensively studied for genotype 1. A comparison of early kinetics with frequent sampling was done only between genotype 1 and 2 (Neumann et al, JID 2000) and has indeed shown more rapid decline with genotype 2. However, little is known about the kinetics of HCV in genotype 3. Here we compare the early kinetics of HCV genotype 1 and 3.

Thirty-three patients (10 genotype 3 and 23 genotype 1 patients) were treated with IFN 9MU at first day, followed by IFN 3 MU daily or every other day plus ribavirin (RBV) for 14 days after randomization. After this period, all them received IFN 3MU every other day for 12 months. HCV RNA was determined by COBAS Amplicor V2 daily during 14 days, then monthly.

Mean viral load (VL) decline for genotype 3 patients 24h after first dose was 1.78 + 0.5 log IU/ml, significantly higher than genotype 1 patients ( 0,93 + 0,4 log IU/ml;p<0.001). Mean baseline VL was similar (6.03 vs. 5.99 log IU/ml) in both groups. Genotype 3 patients presented a second phase slope faster when compared to genotype 1 patients, independently of use of IFN daily (-0.299/day vs. -0.1/day; p=0.02) or each other day (-0.26/day vs. -0.068/day; p=0.003). No significant difference was observed in genotype 3 patients second phase slope between IFN daily or each other day (-0.299/day vs. -0.26/day; p=0.7). A higher proportion of genotype 3 patients were HCVRNA negative at week 4 (8/10) and at week 12 (9/10) compared to genotype 1 patients (2/23 and 10/23).

In summary, genotype 3 infected patients have more rapid early viral decline than genotype 1 infected patients. Genotype 3 kinetic results are comparable to genotype 2 data (Neumann et al, JID 2000) which can be related to better effectiveness of IFN alpha in blocking genotype 3 virion production and/or a possible better immune response in genotype 3 infected patients as this effect was detected in the 2 phases of response. Since pre-treatment viral loads are similar between patients infected with these two genotypes in our population it is possible to assume that also the replication rate is faster for genotype 3. However, more studies evaluating genotype 2 and 3 viral replication after acute infection or treatment relapse are still needed to directly evaluate viral replication rates.

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