EASL 2007 Abstracts -- Type II Diabetes and Treatment

Data for the VX-950 presentation everyone is waiting doesn't look like it will be released until Sunday afternoon. Other abstracts are available on the EASL site. I'll try posting some I think relevant, but the more help the merrier, so please search and post whatever you seem interesting.

First abstract that caught my attention shows the relationship between treatment and Type II Diabetes. When I saw my liver specialist after treatment, he warned me that the treatment drugs could cause a worsening of the metabolic syndrome, including type 2 diabetes. I've posted previous studies on this before, but here is the 2007 EASL abstract. Folks, SOC treatment can save lives, but it isn't without a cost and therefore one should really ask the question -- of self and doctors -- do I really need to treat now?

The conclusion of abstract reads:

"Conclusions: This study revealed that the current treatment for HCV with Peginterferon and Ribavirin is associated with an increased risk to develop T2DM. The underlined mechanism is not clear."


Cont...

[jmjm530]

THERAPY OF CHRONIC HEPATITIS C WITH INTERFERON AND RIBAVIRIN

[jmjm530]

Sorry, forgot to post link to EASL 2007 Search page:

http://www.easl.ch/liver-meeting/Program/search.asp

[jmjm530]

I can't seem to link the page, but if you to to the search engine in the link, mentioned (http://www.easl.ch/liver-meeting/Program/search.asp) and insert "Hepatitis" in the "text search" box and then check
"Abstract Title" , then "search", you will get 248 abstract title links.

-- Jim

[Upbeat]

Great post.  Thanks.  After this study I would think anyone with either hep-c caused Diabetes or Diabetes from natural causes should avoid Tx at all costs.  I mean really if treatment can cause Diabetes just think what the affect would be with someone who already has it.

                                                                                                     Ron

[jmjm530]

CANNABIS USE AS AN INDEPENDENT PREDICTOR OF SEVERE STEATOSIS DURING CHRONIC HEPATITIS C

C. Hezode 1,2, E.S. Zafrani 3, F. Roudot-Thoraval 2,4, C. Costentin 1, A. Hessami 3, J.M. Pawlotsky 2,5, S. Lotersztajn 6, A. Mallat 1,6
1 Department Of Hepatology, Hopital Henri Mondor, Creteil, France; 2 INSERM U635, Hopital Henri Mondor, Creteil, France; 3 Department Of Patology, Hopital Henri Mondor, Creteil, France; 4 Department Of Public Health, Hopital Henri Mondor, Creteil, France; 5 Department Of Virology, Hopital Henri Mondor, Creteil, France; 6 INSERM U581, Hopital Henri Mondor, Creteil, France

We recently found a significant relationship between daily cannabis use and fibrosis severity in chronic hepatitis C (CHC). Cannabis Sativa binds two receptors, CB1 and CB2, and recent experimental data suggest that activation of CB1 receptors increases steatogenesis (Osei-Hyiaman et al, J Clin Invest 2005). The aim of the present study was therefore to evaluate the impact of cannabis use on steatosis severity during CHC.
311 consecutive na

[jmjm530]

Don't know if I'd go that far, but definitely something to take into serious consideration, esp if you don't have significant liver damage.

-- Jim

[jmjm530]

Conclusions: Treatment of chronic hepatitis C with combination therapy was comparably effective between patients aged = 60 years and those aged < 60 years in the same grade of hepatitis, although the ribavirin discontinuation rate was higher among the older patients than among the younger patients.
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EFFICACY OF RIBAVIRIN PLUS INTERFERON-ALFA IN ELDERLY PATIENTS WITH CHRONIC HEPATITIS C

T. Honda 1, Y. Katano 1, F. Urano 2, K. Hayashi 1, M. Ishigami 1, I. Nakano 1, K. Yoshioka 3, H. Toyoda 4, T. Kumada 4, H. Goto 1
1 Department Of Gastroenterology, Nagoya University School Of Medicine, Nagoya, Japan; 2 Department Of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Japan; 3 Division Of Liver And Biliary Diseases, Department Of Internal Medicine, Fujita Health University, Toyoake, Aichi, Japan; 4 Department Of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan

Background and aims: In Japan, patients with hepatitis C virus (HCV)-associated liver disease are getting older, and thus the number of deaths due to such disease is increasing. The efficacy of combination therapy with ribavirin and interferon for chronic HCV infection in elderly patients has not been fully clarified. The aim of this study was to evaluate the efficacy and tolerability of combination therapy in such patients. Methods: Two hundred twenty consecutive patients with chronic hepatitis C were treated with combination therapy. These patients were divided into two groups according to age: patients = 60 years (n = 66) and patients < 60 years (n = 154). Clinical characteristics, the sustained virologic response (SVR) rate obtained by intention-to-treat analysis, and the rate of reduction or discontinuation of ribavirin were compared between the two groups. Results: The hemoglobin level was significantly lower in patients aged = 60 years than in patients aged < 60 years (p = 0.0056). Creatinine clearance in patients aged = 60 years was worse than that in patients aged < 60 years (P < 0.0001). However other clinical characteristics of patients were not significantly difference between two groups. The ribavirin discontinuation rate was significantly higher in the patients aged = 60 years than in the patients aged < 60 years. However, the SVR rates did not differ significantly between patients aged = 60 years and those aged < 60 years (31.8% vs 38.3% by intention-to-treat analysis). According to multivariate analysis, genotype and HCV viral load were significantly associated with SVR while patient age did not affect SVR. Conclusions: Treatment of chronic hepatitis C with combination therapy was comparably effective between patients aged = 60 years and those aged < 60 years in the same grade of hepatitis, although the ribavirin discontinuation rate was higher among the older patients than among the younger patients.

[drofi]

How did the treated and not-treated groups differ in grading and staging / fibrosis? What was the reason to treat or not? Sorry, if I missed something. It is known that HCV itself can cause Diabetes and many other extrahepatic manifestations. We should know more factors of group mastching than age and gender.

[jmjm530]

Something else to show your doctor before he tries to reduce your riba dose.

Conclusion:
Adjuvant therapy with Epo and GCSF as an alternative to dose reduction of peginterferon or ribavirin achieved an SVR of 89% for genotype 2/3 and 55% for genotype 1 in treatment na

[jmjm530]

I was told to take Losartan (Cozaar) for high blood pressure on treatment. I've since gone off it. This study is interesting and if I do go on BP meds again, I might choose Losartan. In any event, something to discuss with your doctor if and when the BP issue comes up.
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LARGE POPULATION STUDY IN LIVER STIFFNESS MEASUREMENT: PREVALENCE OF SIGNIFICANT FIBROSIS AND CORRELATION WITH LIVER BIOCHEMISTRY IN CHRONIC HEPATITIS B

J. Fung 1, C.L. Lai 1, J.C. Yuen 1, D.K. Wong 1, C.T. Cheng 1, D.Y. But 1, M.F. Yuen 1
1 Department Of Medicine, Queen Mary Hospital, University Of Hong Kong, Hong Kong, Hong Kong-S.A.R., China

Background and Aim: The prevalence of fibrosis in a large population of chronic hepatitis B (CHB) patients is not known. The aim of this study was to investigate the prevalence of significant fibrosis in a Chinese population with CHB by liver stiffness measurement (LSM), and its correlation with liver biochemistry and demographic factors.

Methods: All CHB patients seen at Hepatitis Clinic, Queen Mary Hospital, Hong Kong for CHB between January to July 2006 with LSM by transient elastography were included.

Results: Of the 898 patients included with a median age of 44, 323 (36%) had significant fibrosis as defined by LSM of >8.1 kPa. Males had a higher median liver stiffness measurement (MLSM) than females (7.3 vs 5.9 kPa, p<0.001), and those positive for HBeAg had higher MLSM than HBeAg-negative patients (7.3 and 6.4 kPa respectively, p=0.017). In patients =25, 26-35, 36-45, 46-55, 56-65, and >65 years of age, the MLSM was 6.0, 6.0, 6.4, 7.6, 8.7and 11.6 kPa respectively (p<0.001), with 56% of those aged over 55 years having significant fibrosis. LSM scores correlated well with serum bilirubin, ALT, AFP, and albumin levels (all p<0.001). In patients with ALT<0.5 upper limit of normal (ULN), 0.5-1xULN, 1-2xULN, 2-5xULN and >5xULN, the MLSM was 5.7, 6.7, 8.4, 11.7 and 19.1 kPa respectively (p<0.001). After multivariate analysis, age, bilirubin, ALT, albumin and gender remained significant factors associated with significant fibrosis. Using a combination of serum ALT, bilirubin and albumin levels to predict the presence of significant fibrosis, the sensitivity and specificity were 19% and 98% respectively, with positive predictive value of 84% and negative predictive value of 96%.

Conclusion: The prevalence of significant fibrosis in Chinese CHB patients was high, affecting more than half of the patients over the age of 55 years. LSM correlated well with known factors associated with more severe disease, including older age, male sex, higher bilirubin and ALT, and lower albumin. The combination of serum bilirubin, ALT and albumin levels may be used to predict significant underlying fibrosis.

[jmjm530]

Drofi: How did the treated and not-treated groups differ in grading and staging / fibrosis? What was the reason to treat or not? Sorry, if I missed something. It is known that HCV itself can cause Diabetes and many other extrahepatic manifestations. We should know more factors of group mastching than age and gender.
-------------
The author's of the study acknowledged the fact that previous studies suggested HCV itself can cause diabetes, therefore I assume they factored in some of the variables you discuss in their conclusion. Maybe the complete article will be available online at some point, or you might want to email the authors with your questions after the meeting.

-- Jim

[jmjm530]

Interesting abstract on declining liver stiffness via Fibroscan for RVRs.

EVOLUTION OF LIVER STIFFNESS MEASUREMENT DURING ANTIVIRAL THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C

C. Hezode 1, I. Rosa 2, L. Castera 3, D. Roulot 4, V. Leroy 5, M. Bouvier-Alias 1, F. Roudot-Thoraval 1, C. Douvin 1, A. Mallat 1, J-M. Pawlotsky 1
1 Hopital Henri Mondor, Creteil, France; 2 Centre Hospitalier Intercommunal, Creteil, France; 3 Hopital Haut Leveque, Pessac, France; 4 Hopital Avicenne, Bobigny, France; 5 Hopital A. Michallon, Grenoble, France

Liver stiffness measurement with the Fibroscan is a non invasive method that assesses the severity of chronic liver disease, in particular fibrosis, in patients with chronic hepatitis C. Whether or not the virologic response to antiviral therapy is associated with concomitant changes in liver stiffness remains unknown. OBJECTIVE: To assess the dynamics of liver stiffness relative to the dynamics of the virologic response during the first 24 weeks of antiviral therapy in patients with chronic hepatitis C. METHODS: 78 patients (57 men, 21 women, mean age: 52+12 years, HCV genotype 1: 47.5%) with significant fibrosis defined by a liver stiffness measurement > 7 kPa were included. 68 patients were treated with the combination of pegylated interferon and ribavirin at the standard doses, whereas 10 untreated patients served as the control group. Liver stiffness and the HCV RNA level were determined at day 0 and at weeks 4, 8, 12, 18 and 24 of therapy. The rapid virologic response (n=40) was defined by a viral load < 615 IU/mL at week 4. The slow virologic response (n=17) was defined by a viral load > 615 IU/mL at week 4 but < 615 IU/mL at week 24. The nonresponse (n=11) was defined by an HCV RNA > 615 IU/mL at week 24. RESULTS: Liver stiffness at baseline did not differ between the treated and non treated patients. Liver stiffness at baseline was higher in the nonresponders than in the slow and rapid responders, but the difference did not reach significance due to the small number of nonresponders. Liver stiffness did not change significantly in the control group, in the non responders and in the slow responders. In contrast, it decreased significantly in the rapid responders (13.9 to 12.3, p=0.028). CONCLUSION: the rapid virologic response to pegylated IFN and ribavirin therapy is associated with a rapid improvement in liver stiffness as measured by the Fibroscan in patients with chronic hepatitis C.

[jmjm530]

THE VALUE OF PEGINTERFERON ALFA-2A THERAPY FOR CHRONIC C HEPATITIS IN HEMODIALISED PATIENTS

F. Ionita-Radu 1, P. Nuta 1, F. Fanea 1, L. Petrescu 2, C. Klein 2, D. Popescu 1, I. Nicolescu 1, T. Nicolaie 1, A. Rotaru 1, R. Ionescu 3
1 Department Of Internal Medicine 2, Gastroenterology Unit, Central Clinical Emergency Military Hospital

[jmjm530]

INJURY WITH HEPATITIS C (HCV)-CONTAMINATED NEEDLES IN HEALTH CARE WORKERS: WHAT IS THE TRUE RATE OF SEROCONVERSION?

A. Kubitschke 1, C. Bader 2, M.P. Manns 1, S. Kuhn 2, H. Wedemeyer 1
1 Department Of Gastroenterology, Hepatology And Endocrinology, Hannover Medical School, Hannover, Germany; 2 Betriebs

[jmjm530]

TELAPREVIR (VX-950) IS A POTENT INHIBITOR OF HCV NS3 PROTEASES DERIVED FROM GENOTYPE NON-1 HCV-INFECTED PATIENTS

C. Lin 1, B.L. Hanzelka 1, U. Muh 1, L. Kovari 1, D.J. Bartels 1, A.M. Tigges 1, J. Miller 1, B.G. Rao 1, A.D. Kwong 1
1 Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA

Background: Telaprevir (TVR, VX-950) is a highly selective HCV NS3

[NYCMark]

Jim, thanks, these are great. Here is the abstract for the losartan article (Dr. D put me on losartan even before I started treatment)

LONG-TERM TREATMENT WITH LOSARTAN REDUCES THE INFLAMMATORY ACTIVITY AND THE EXPRESSION OF KEY GENES INVOLVED IN LIVER FIBROGENESIS IN PATIENTS WITH CHRONIC HEPATITIS C


J. Colmenero 1, R. Bataller 1, X. Forns 1, P. Sancho-Bru 1, M. Bruguera 1, M. Dominguez 1, M. Moreno 1, V. Arroyo 1, D.A. Brenner 2, P. Gin

[jmjm530]

RESULTS OF AN INTERIM ANALYSIS OF A PHASE 2 STUDY OF TELAPREVIR (VX-950) WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PREVIOUSLY UNTREATED SUBJECTS WITH HEPATITIS C

J.G. McHutchison 1, G.T. Everson 2, S. Gordon 3, I. Jacobson 4, R. Kauffman 5, L. McNair 6, A. Muir 7
1 Division of Gastroenterology, Duke University and Duke Clinical Research Institute, Durham, NC, USA; 2 Department of Hepatology, University of Colorado Health Sciences Center, Denver, CO, USA; 3 Henry Ford Health System, Detroit, MI, USA; 4 Division of Gastroenterology and Hepatology, Weill Medical College of Cornell, New York, NY, USA; 5 Vertex Pharmaceuticals, Cambridge, MA, USA; 6 Vertex Pharmaceuticals, Cambridge, MA, USA; 7 Division of Gastroenterology, Duke University and Duke Clinical Research Institute, Durham, NC, USA

Background: The VX05-950-104 study (PROVE1) is a randomized, placebo-controlled Phase 2 study of telaprevir (TVR), in combination with peginterferon alfa-2a (Peg-IFN-2a) and ribavirin (RBV), in naive subjects with genotype 1 hepatitis C infection. We report the results of a planned interim safety and data analysis. A total of 250 subjects received study drug.
Methods: Subjects were randomized into 4 groups; 3 groups were randomized to receive TVR 750 mg q8h, Peg-IFN-2a 180 ug/week, and RBV 1000-1200 mg/day for 12 weeks followed by 0, 12 or 36 weeks of Peg-IFN-2a and RBV (TVR/PR groups). The control group was randomized to receive up to 48 weeks of Peg-IFN-2a/RBV, with TVR-matched placebo for the first 12 weeks. This planned interim analysis was performed when the first 80 enrolled subjects had completed 12 weeks of dosing. All subjects in the TVR groups received the same treatment through Week 12; these groups were pooled for this analysis.
Results: The total incidence of adverse events was similar in the control and TVR/PR groups (75% vs. 80%). Discontinuations due to adverse events were more frequent in the TVR/PR group (9% vs. 3%). Rashes were more common and some were more severe, and gastrointestinal (GI) events were more common, in the TVR/PR group. In subjects for whom results were available at Week 12, the proportion of subjects with undetectable HCV RNA at Week 12 was 88% in the TVR/PR group, and 52% in the control group (p=0.0001). (Taqman assay: LOD 10 IU/mL).
Conclusions: TVR/PR produced a higher frequency of HCV RNA undetectability than Peg-IFN-2a/RBV alone, in this 12-week interim analysis. The adverse event profile was similar in type of events, but rash and GI events were more common in the TVR/PR group. The Independent Data Monitoring Committee reviewed the data and recommended no changes to the study. An interim analysis, including data up to 12 weeks on-study in all subjects, as well as SVR12 data in subjects who have stopped all treatment at 12 weeks or earlier, will occur in March.
* PROVE1 Publication Committee, for the study team.

[jmjm530]

RESULTS OF AN INTERIM ANALYSIS OF A PHASE 2 STUDY OF TELAPREVIR (VX-950) WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN PREVIOUSLY UNTREATED SUBJECTS WITH HEPATITIS C

J.G. McHutchison 1, G.T. Everson 2, S. Gordon 3, I. Jacobson 4, R. Kauffman 5, L. McNair 6, A. Muir 7
1 Division of Gastroenterology, Duke University and Duke Clinical Research Institute, Durham, NC, USA; 2 Department of Hepatology, University of Colorado Health Sciences Center, Denver, CO, USA; 3 Henry Ford Health System, Detroit, MI, USA; 4 Division of Gastroenterology and Hepatology, Weill Medical College of Cornell, New York, NY, USA; 5 Vertex Pharmaceuticals, Cambridge, MA, USA; 6 Vertex Pharmaceuticals, Cambridge, MA, USA; 7 Division of Gastroenterology, Duke University and Duke Clinical Research Institute, Durham, NC, USA

Background: The VX05-950-104 study (PROVE1) is a randomized, placebo-controlled Phase 2 study of telaprevir (TVR), in combination with peginterferon alfa-2a (Peg-IFN-2a) and ribavirin (RBV), in naive subjects with genotype 1 hepatitis C infection. We report the results of a planned interim safety and data analysis. A total of 250 subjects received study drug.
Methods: Subjects were randomized into 4 groups; 3 groups were randomized to receive TVR 750 mg q8h, Peg-IFN-2a 180 ug/week, and RBV 1000-1200 mg/day for 12 weeks followed by 0, 12 or 36 weeks of Peg-IFN-2a and RBV (TVR/PR groups). The control group was randomized to receive up to 48 weeks of Peg-IFN-2a/RBV, with TVR-matched placebo for the first 12 weeks. This planned interim analysis was performed when the first 80 enrolled subjects had completed 12 weeks of dosing. All subjects in the TVR groups received the same treatment through Week 12; these groups were pooled for this analysis.
Results: The total incidence of adverse events was similar in the control and TVR/PR groups (75% vs. 80%). Discontinuations due to adverse events were more frequent in the TVR/PR group (9% vs. 3%). Rashes were more common and some were more severe, and gastrointestinal (GI) events were more common, in the TVR/PR group. In subjects for whom results were available at Week 12, the proportion of subjects with undetectable HCV RNA at Week 12 was 88% in the TVR/PR group, and 52% in the control group (p=0.0001). (Taqman assay: LOD 10 IU/mL).
Conclusions: TVR/PR produced a higher frequency of HCV RNA undetectability than Peg-IFN-2a/RBV alone, in this 12-week interim analysis. The adverse event profile was similar in type of events, but rash and GI events were more common in the TVR/PR group. The Independent Data Monitoring Committee reviewed the data and recommended no changes to the study. An interim analysis, including data up to 12 weeks on-study in all subjects, as well as SVR12 data in subjects who have stopped all treatment at 12 weeks or earlier, will occur in March.
* PROVE1 Publication Committee, for the study team.

[jmjm530]

Did you have high bp, or for liver-related reasons per study? If for high bp, what was your bp before and after Losartan, what dose did he put you on, and are you still on it. Any side effects? Also, did you take Losartan by itself or with a water pill. The water pill/Cozaar combo is called "Hyzaar".

-- Jim

[jmjm530]

NOVEL MODE OF VIRAL DECLINE DURING TELAPREVIR (VX-950) AND PEG-IFN COMBINATION TREATMENT PREDICTED BY A NEW COMBINED INTRACELLULAR AND CELLULAR HEPATITIS C VIRAL DYNAMICS MODEL

A.U. Neumann 1, L. Rozenberg 1, H.W. Reesink 2, S. Zeuzem 3, H.M. Chu 4
1 Faculty Of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; 2 Academic Medical Center, Amsterdam, The Netherlands; 3 Saarland University Hospital, Homburg-Saar, Germany; 4 Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA

Background: HCV decline during telaprevir and Peg-IFN combined dosing shows rapid second phase slope (>1.2 log/wk) in CHC genotype 1 patients. The biological interpretation with current HCV dynamics models is a short infected cell half-life (t1/2<1.5d) in 90% of patients, which contradicts (P<0.001) established data (median t1/2=4.2d; range 1.5-70d; >7d in 30% of patients). A new model incorporating HCV intracellular replication dynamics into the current model is used to better understand viral kinetics during direct anti-HCV treatment.

Methods: Viral kinetics during 14 days treatment with telaprevir (750mg/q8h) and Peg-IFN-a2a (180ug/qw) were quantified (COBAS Taqman, Roche) in 8 patients (Reesink et al., EASL 2006) and fitted using a new mathematical model combining the Neumann 1998 model with intracellular replication dynamics. Intracellular RNA (ICR) is used to create replication units (RU), thus producing more ICR that is packaged and secreted as virions. The anti-viral effect (epsilon%) of telaprevir is assumed to be the blocking of ICR production by RU. Other free parameters are: RU loss rate (gamma), ICR loss rate (sigma), virion clearance rate (c), and infected cell loss rate (delta).

Results: In 7 patients with more than 3-log 1st phase decline (mean epsilon=99.93%), the second phase slope is primarily determined by RU loss rate, gamma (half-life 1.6-1.8 days), rather than by infected cell loss rate, delta (half-life 1.9-13.9 days), as in previous model. In 1 patient with a lower effectiveness (99.6%) the second phase is slower and determined by the loss rate of infected cells, delta (half-life 8.7 days). A critical effectiveness threshold to allow the rapid gamma-mode second phase decline can be determined as a function of intracellular dynamics parameters.

Conclusions: We predict a new mode of second phase HCV decline representing the turnover rate of intracellular replication units (gamma) rather than infected cells (delta). This gamma-mode is rapid and uniform in patients with potent enough anti-viral effect, as in most patients treated with telaprevir and Peg-IFN. This model supports further investigation of the potential for complete hepatic clearance of HCV RNA with shorter duration treatment. Further analysis is needed to ascertain the effect of viral evolution.

[missy60051]

Yes I totally agree.  

Thank you so much for the information.
Like I've said before, you're a god sent.

[jmjm530]

ULTRASOUND EVALUATION OF PERIHEPATIC LYMPH NODES DURING ANTIVIRAL THERAPY WITH THE PROTEASE INHIBITOR TELAPREVIR (VX-950) IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION

M. Friedrich-Rust 1, N. Forestier 1, C. Sarrazin 1, H.W. Reesink 2, E. Herrmann 1, S. Zeuzem 1
1 Department Of Internal Medicine, Saarland University Hospital, Homburg-Saar, Germany; 2 Academic Medical Center, University Of Amsterdam, Amsterdam, The Netherlands

Background and aims. Previous studies have shown that the total perihepatic lymph node (PLN) volume is associated with the extent of inflammatory activity in the liver and changes according to the antiviral response in patients receiving interferon-based therapy for chronic hepatitis C infection. The aim of this prospective pilot study was to examine whether the total PLN volume similarly changes in patients receiving antiviral monotherapy with the protease inhibitor telaprevir. In contrast to interferons, protease inhibitors do not have direct immunomodulatory activity, although indirect mechanisms have been discussed.
Methods. The study was conducted in a subgroup of 19 patients with chronic hepatitis C genotype-1 infection treated with the protease inhibitor telaprevir (3 dosing groups ranging from 1350-2400 mg/day) or with placebo in a double-blind, randomised placebo-controlled Phase Ib clinical trial over a period of 14 days. The ultrasound examination was performed by an experienced investigator, blinded to all clinical data. The total PLN volume was assessed before initiation of antiviral therapy, at the end of treatment, and at follow-up. Number and size of all detectable PLN were determined, the individual PLN volume was calculated assuming a rotating ellipsoid, and the individual PLN volume was then summarized as total PLN volume.
Results. Treatment with telaprevir resulted in a significant reduction of plasma HCV-RNA in all patients at the end of 14 days of treatment. In patients receiving telaprevir the total PLN volume decreased significantly at the end of 14 days of treatment compared to pre-treatment size (1.26ml to 0.76ml, p= 0.01). In contrast, no significant difference was seen in patients receiving placebo.
Conclusions. Since protease inhibitors have no direct effects on the immune system the mechanism of perihepatic lymphadenopathy according to our results appears to be primarily related to viral replication and inflammation in the liver. Therefore, changes in PLN size are a strong surrogate indicator, that the protease inhibitor telaprevir not only decreases viremia and aminotransferases, but may also reduce histological inflammatory activity in the liver.

[jmjm530]

THE INFLUENCE OF OBESITY AND DIABETES ON CLINICAL AND THERAPEUTICAL OUTCOME IN HCV RELATED CHRONIC HEPATITIS: AN ITALIAN NATIONWIDE SURVEY STUDY (PROBE GROUP).

M. Persico 1, M. Masarone 1, L. Cimino 2, B. Fimiani 2, N. Passariello 3, C. Coppola 4, G. Raimondo 5, F. Resta 6, P. Del Poggio 7, A. Orani 8, M. Sarracino 9, A. Alberti 10
1 General Medicine Department, Second University Of Napoli, Napoli, Italy; 2 Gastroenterology Department, University Of Napoli, Napoli, Italy; 3 Internal Medicine Department, Policlinico Of Napoli, Napoli, Italy; 4 Hepatology Department, San Leonardo Hospital, Castellammare, NA, Italy; 5 Internal Medicine And Hepatology Department, Policlinico Of Messina, Messina, Italy; 6 Infectious Diseases Department, Moscati Hospital, Taranto, Italy; 7 Internal Medicine Department, Treviglio Hospital, Treviglio, BG, Italy; 8 Infectious Diseases Department, Manzoni Hospital, Lecco, Italy; 9 Roche Monza, Monza, Italy; 10 Clinic Of Internal Medcine, University Of Padova, Padova, Italy

Background: The insulin-resistance seem influencing the clinical outcome of HCV infected patients. Aim of the present study was to assess the influence of obesity and diabetes on a large Italian population of patients with HCV related chronic hepatitis (CH-HCV). Methods:A retrospective study, representative of all Italian population, was designed. Centres participating to the study were asked to enroll the last 25 consecutive patients treated with PEG-INF and Ribavirin during the last year previous the start of the study. Epidemiological, clinical, biochemical and histological (METAVIR Score) parameters as well as obesity (BMI>30) and diabetes were recorded. Univariate, multivariate and/or comparative analysis between groups were performed. Results: 3025 patients were enrolled in the study and of these 385 (12.72%) were obese and/or diabetics. Prevalence of obesity among HCV patients was not different from that reported in the Italian general population. Age, sex, viral load were not statistically different in patients with and without cofactors whereas fibrosis stage was higher in obese/diabetic patients than non obese/non diabetic subjects (F3

[jmjm530]

INSULIN RESISTANCE IN VIRAL HEPATITIS B AND C AND NON VIRUS RELATED CHRONIC HEPATITIS

M. Montagnani 1, F. Lodato 1, F. Azzaroli 1, M.R. Tame 1, A. Colecchia 1, P. Cecinato 1, R. Muratori 1, D. Festi 1, G. Mazzella 1
1 Department Of Internal Medicine And Gastroenterology, University Of Bologna, Bologna, Italy

Background/Aims Insulin resistance (IR) is the background of many cryptogenetic liver diseases. In genotype 1 and 2 HCV chronic hepatitis (CH-C) the virus seems to induce insulin resistance (IR). In HBV chronic hepatitis (CH-B) the virus role in steatosis and IR is to be clarified. Aim of our study is to evaluate IR and the relationship with disease severity, in patients with CH-C, CH-B or with non-virus related hypertransaminasemia (NV-H).
Methods Twenty-eight outpatients with NV-H and 50 outpatients in follow-up for CH-B (n=23) or CH-C (n=27) were consecutively enrolled between January and May 2006. Patients with alcohol consumption >10 gr/day were excluded. Abdominal circumference (AC), BMI, fasting blood glucose (FBG) insulinemia, OGTT, HOMA-r and liver ultrasonography were evaluated. ANOVA, Mann-Whithney test and c2 were used for statistical analysis. Data are expressed as mean

[jmjm530]

ALFA-LIPOIC ACID ENHANCES CHOLINE DEFICIENT DIET-INDUCED FATTY LIVER AND STEATOHEPATITIS, AND PROMOTES THE GROWTH OF PRENEOPLASTIC LESIONS IN RAT LIVER

A. Perra 1, G. Simbula 1, M. Pibiri 1, P. Sulas 1, G.M. Ledda-Columbano 1, A. Columbano 1
1 Unit Of Oncology And Molecular Pathology, Department Of Toxicology, University Of Cagliari, Cagliari, Italy

Background and Aims: a-lipoic acid (a-LA) is a thiol containing antioxidant widely used in a number of conditions related to liver diseases, including alcohol-induced damage, mushroom poisoning, metal intoxication, CCl4 poisoning, and hyperdynamic circulation in biliary cirrhosis. However, little is known about its effect on the hepatocarcinogenic process. Herein, we investigated the effect of a-LA on the development of rat preneoplastic enzyme-altered foci generated by a model of hepatocarcinogenesis Methods: Initiation of rat hepatocytes was achieved by treatment with a single dose of diethylnitrosamine and promotion by feeding a choline-methionine deficient (CMD) diet, with or without a-LA. Preneoplastic lesions were identified by their positivity to the placental form of glutathione S-transferase (SGTP). consisting of initiation with a single dose of diethylnitrosamine (DENA) and promotion by feeding a choline-methionine deficient (CMD) diet. Results: The results showed that a-LA administered in drinking water at concentration of 0.05, 0.1 and 0.2% for 6 weeks significantly increased the number of preneoplastic foci positive for the placental form of glutathione S-transferase (GSTP). Further experiments where a-LA was administered in the diet at the final concentration of 0.2% for 6 weeks or 10 weeks showed a much higher number of GSTP-positive foci as compared to rats fed a CMD diet alone (94/cm2 vs 13/cm2), and a strong increase in the mean foci area and the percentage of GSTP-positive liver tissue. Very few GSTP-positive foci were observed in DENA-treated rats fed a choline supplemented (CS) diet with or without a-LA. The increased number and size of preneoplastic lesions caused by a-LA was associated with enhanced fatty accumulation, liver damage and regeneration, as shown by histological analysis, increased expression of CYP2E1 and COX-2, activation of JNK, elevated levels of serum transaminases and enhanced bromodeoxyuridine incorporation, indicating that a-LA addition to CMD diet aggravates, rather than ameliorating the hepatic accumulation of triglycerides and liver injury caused by the CMD diet. Conclusions: these results show that a-LA acts as a strong co-promoting agent in the process of liver carcinogenesis, and suggest extreme caution in the use of a-LA for conditions associated with liver damage.

[jmjm530]

LONGTERM TREATMENT WITH PEG-IFN-ALFA2B REDUCES HEPATOCELLULAR INCIDENCE AND PREVENTS CLINICAL COMPLICATIONS IN HEPATITIS C CIRRHOSIS - AN INTERIM ANALYSIS OF A MULTICENTER TRIAL

A. Erhardt 1, U. Heinzel-Pleines 1, W. Boecher 2, H. Wedemeyer 3, M.M. Dollinger 5, F.W. Albert 6, T. Witthoeft 4, D. Haeussinger 1
1 Universitaetsklinik Duesseldorf, Duesseldorf, Germany; 2 Universitaetsklinik Mainz, Mainz, Germany; 3 Medizininische Hochschule Hannover, Hannover, Germany; 4 Universitaetsklinik Schleswig-Holstein, Schleswig-Holstein, Germany; 5 Universitaetsklinik Halle, Halle, Germany; 6 Westpfalzklinik Kaiserslautern, Kaiserslautern, Germany

Background and aims: Interferons has been shown to inhibit fibrosis progression. This multicenter, randomized, prospective trial investigated the efficacy of low-dose pegylated interferon-alpha 2b (0,35-1

[jmjm530]

HYPERHOMOCYSTEINEMIA (high levels of homocystene in blood) IN CHRONIC HEPATITIS C : ROLE IN STEATOSIS, FIBROGENESIS AND RESPONSE TO ANTIVIRAL TREATMENT

X. Roblin 1, V. Ducros 2, M.N. Hilleret 1, N. Sturm 3, A. Plages 1, J.P. Zarski 1, V. Leroy 1
1 Departement DHepato-Gastroent

[NYCMark]

Jim, I'm on Hyzaar. I was put on it for BP reasons (but now that I see it has antifibrotic properties, I suspect he chose that one for a reason. I'm always surprised how methodical he is, though you would never know from his demeanor!). I really can't recall my pressures but they were never much more than 140/90. They tend to be lower now, in the 120/80 range.
Mark

[jmjm530]

Can you tell me what dose of "Hyzaar" you're on, and if you're getting any side effects. Thanks.

-- Jim

[jmjm530]

The following suggests multiple Fibroscan probe locations as also suggested by HR, remember HR? :) Anyway, this differs from the U.S. trial protocol where they  only use one probe location but do the mean of ten different probes at that one location. It's unclear whether this study used the mean of ten different probes or not and that may account for the difference. I'll certainly bring this paper with me if I decide to have another Fibroscan.

CAN FIBROSCAN OVERCOME THE SAMPLING ERROR OF LIVER BIOPSY?

H. Yeshua 1,4, S. Zelber-Sagi 1, Y. Luria 1, S. Levitt 1, E. Brazovski 2, Y. Kovalev 1, A. Kessler 3, M. Webb 1, L. Blendis 1, R. Bruck 1, Z. Halpern 1, R. Oren 1
1 Department Of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 2 Department Of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 3 Department Of Radiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; 4 Clalit Health Services, Tel-Aviv, Israel

Background: Liver biopsy is considered the gold standard to assess the stage of liver fibrosis. Nevertheless, liver biopsy is an invasive procedure limiting its acceptance by patients. In addition, sampling variability can be found in 15-30% of biopsies, probably reflecting the heterogeneity of the distribution of fibrotic features throughout the liver.
Transient elastography (Fibroscan) is a new rapid noninvasive technique to assess liver fibrosis, by measuring liver stiffness.
Aim: To find out whether the measurement of liver stiffness can vary according to the probe location.
Methods: A total of 174 patients with chronic liver diseases (135 with hepatitis C, 39 with various aetiologies for chronic liver diseases) underwent 3 successive series of fibroscan examination in 3 different sites in the RUQ. All measurements were taken by the same operator. Histopathology stage was assessed according to Batts and Ludwig.
Results: In 144 patients (82.7%) there was no significant difference between the three successive series of fibroscan measurement. In these patients a significant correlation to the stage of liver biopsy was found (p<0.0001, r=0.85). In 30 patients, a difference of at least one stage was found between the measurements (discordance rate of 17.2%).
Conclusions: Assessment of liver fibrosis by both liver biopsy and fibroscan demonstrate stage variability. While repeated liver biopsy is rarely recommended, fibroscan should be performed from various liver sites and thus overcome the problem of sampling variability. It is yet to be determined which measurement is to be adopted: the worst, the best or the average of the three measurements?

[jmjm530]

META-ANALYSIS OF THE PERFORMANCE OF FIBROSCAN FOR THE STAGING OF LIVER FIBROSIS

M. Friedrich-Rust 1, M.F. Ong 2, S. Martens 2, C. Sarrazin 1, S. Zeuzem 1, E. Herrmann 2
1 Department Of Internal Medicine, Saarland University Hospital, Homburg-Saar, Germany; 2 Department Of Internal Medicine, Saarland University, Homburg-Saar, Germany

Background. Liver biopsy is the reference standard for the staging of liver fibrosis with a never negligible sampling variability. Therefore, non-invasive markers and methods for the assessment of liver fibrosis have been frequently evaluated. Transient Elastography (FibroScan, Echosens, France) has recently been studied in a multitude of liver diseases.
Methods. A systematic review and meta-analysis was conducted to evaluate the performance of FibroScan for the staging of liver fibrosis. The meta-analysis was performed using the DerSimonian and Laird estimator (DLE) in a Random Effect Model for AUROC.
Results. The literature search yielded 18 full papers, 5 corresponding letters/editorials, and 76 abstracts. Thirty-six studies (9 full papers and 27 abstracts) were included in the analysis. Heterogeneity between the studies was statistically significant. The DLE of AUROC for diagnosis of Metavir stage F = 2 (significant fibrosis), F = 3 (severe fibrosis) and F = 4 (cirrhosis) was 0.842

[goldyn]

Thanks for all the info..i have been on blood pressure meds since getting off tx. im going to ask my doc about the blood pressure med. you were on.. im also now watching my sugar last test fasting was 108, doc just watchin it now....

[NYCMark]

Jim - I'm on Hyzaar (losartan/hctz) 50/12.5
I hadn't noticed any side effects except perhaps increased frequency of urination. But now that I'm on combo treatment, and drinking tons of water, it's hard to sort out which side effects are due to what.
Mark

[chcnme]

Jim, you just don't know how much you are appreciated.   Or maybe you do, but I gotta say -- da** if you can't pump out some info on Hep C like I have never seen  (GOOD info, too - and sound solid advice), and I wonder if you realize how important it is to some of us and how much your hard work is appreciated.  I'm going back to reading now.  While I'm here, hello to everyone.  

[jmjm530]

The increased urination is from the hydrochlorothiazide part of the pill. hydrochlorothiazide is a diuretic, and sometimes is used by itself to control blood pressure. In my case, I'd probably start with Cozaar first, which is Hyzaar minus the diuretic, and then add the diuretic if not happy with the results. My home BP monitor is on the fritz so don't know what's happening these days but with the squats and dead lifts I'm doing in the gym, maybe time to get a new one. Felt a little dizzy this afternoon but I did do 4 sets of 20 barbell squats each, plus two additionals sets of 20 "Hindu" squats and another couple of sets of Hindu pushups and then some ellipse machine. You know, maybe I'd better look for that Hyzaar now. LOL.

Be well,

-- Jim

[returntosender]

Thanks - very hopeful stuff on many levels.  I also developed high blood pressure as well as metabolic syndrome after completing treatment.  Blood pressure shot up to 210 over 130 at one point.  Started on Altace 5mg then to Altace 10 then added Norvasc 5mg and now on Norvasc 10mg.  Finally got the pressure down to normal levels.  I am stictly watching the diet - lost about 20 pounds so far - and added cardio as well.  Must say that the blood pressure got my attention.  

Notwithstanding all of these issues I must say that I feel really great approaching my 1 year anniversary of completing treatment.  Lots of energy.  Lots of optimism.  Motivated and all that.   All in all, I would say it was worth it - although it really took a good part of a year to get over treatment.  Seeing a new liver doc on the 1st of May - probably get viral load done then.  Last bridge to cross on this journey.  Congrats on your SVR.  

[jmjm530]

MOLECULAR BASIS FOR VX-950 RESISTANCE

C. Welsch 1,2, F.S. Domingues 2, I. Antes 2, S. Susser 1, M. Albrecht 2, C. Hartmann 2, C. Sarrazin 1, T. Lengauer 2, S. Zeuzem 1
1 Department Of Internal Medicine II, Saarland University Hospital, Homburg-Saar, Germany; 2 Max Planck Institute For Informatics, Computational Biology And Applied Algorithmics, Saarbrucken, Germany

Background and aims: A recent phase 1b clinical trial of the peptidomimetic HCV NS3 protease inhibitor (PI) VX-950 in genotype 1 infected patients, revealed four sites with amino acid mutations conferring varying degrees of drug resistance. The molecular basis of drug resistance for mutations in the binding pocket was already investigated. Nevertheless, the effect of two additional resistance mutations has not yet been interpreted. These two mutations (at V36 and T54) are located in the protein interior and not in the peptide binding site and catalytic triad. Interestingly, they have been linked to clinical resistance during viral breakthrough, associated with low to intermediate levels of viral resistance, together with an only intermediate reduction of viral replicative fitness.

Methods: Available experimental structure information from X-ray and NMR, provided by the Protein Data Bank, has been used to study the HCV NS3 protease and its ligands. Structural superposition of alternative experimental models of the same protein binding to different ligands and corresponding maps of non-covalent bondings were applied to investigate the interaction mode of different peptidomimetics, in order to understand the molecular basis for VX-950 drug resistance.

Results: Our results indicate that the cyclopropyl group in VX-950 is oriented towards a small hydrophobic pocket on the protein surface. This pocket undergoes induced-fit upon binding of PI. Both mutational sites, V36 and T54, were located spatially close to that hydrophobic pocket, with T54 opposite to V36 and next to a loop structure directly involved in the surface pocket. In particular mutations in these two residues are expected to significantly change the conformation of the cyclopropyl binding pocket. For T54 mutations, an immediate effect on adjacent secondary structure elements involved in the surface pocket can be expected.

Conclusions: Our results indicate that the cyclopropyl binding pocket is involved in resistance to VX-950. Mutations at V36 and/or T54 result in impaired interaction or complete loss of interaction at that site, which would explain the development of viral breakthrough variants. Complementary PI inhibitors, not using the hydrophobic pocket described, may prevent cross-resistance.

[mikesimon]

Thanks Jim. Mike

[DoubleDose]

Jim,

Thanks for making it easy to read all the relevant abstracts and presentations from the liver conference.  It sure is nice not to have to follow links or search for the information.

As far as the study you displayed regarding development of Type II Diabetes after interferon therapy....all I can say is: Finally.... they are looking honestly at the consequences of therapy.  I think we will see a LOT more in coming years, as thousands of post-treatment patients are followed by doctors and researchers.  Many of us are experiencing the progression toward diabetes, high blood pressure, metabolic syndrome, erectile dysfunction, autoimmune effects, etc.all stemming from doing lengthy rounds of interferon.  We need SOLUTIONS to these problems, not people or doctors who stick their heads in the sand and claim that none of these problems are (yet) proven to result from tx.  Well now we are finally getting studies linking therapy to serious medical problems...as we all knew from our own experiences already.

The reason I am so adamant about this issue is that without acknowledging the real consequences of tx, the medical community will be slow to find ways to ameliorate these problems, or to treat them aggressively in post tx individuals.  I am finally seeking serious medical advice on all these problems, and am beginning medications for BP, changing diet, having hormonal and endocrine studies done, as well as pre-diabetes intervention.  To those who say all these problems are just 'old age', or coincidence....just read the studies!  We must deal 'head on' with these problems, or our post-tx life will be as difficult and risk laden as our  pre-tx lives.  Let's keep the pressure on the medical community to study the problems, and develop solutions.

Thanks again Jim.  I hope you are feeling great.

DoubleDose

[jmjm530]

Not to be cynical, but realistically I don't think our issues will get much attention other than the recognition we are already seeing such as in the study posted. "Attention" in medicine often involves dollars and the dollars in HCV are in finding new, shorter and less toxic cures. Of course that's wonderful for those treating in the future, but for those of left with interferon-related post treatment problems, I think we will be somewhat on our own for at least sometime. Hope I'm wrong but just don't see a whole lot of interest in our group of SVRs other than follow up studies in regard to long term virus suppression, liver histology and HCC. Still, studies like this at least show recognition, and that in itself is a start.

As to what we can do now regarding many of our drift toward metabolic syndrome, type II diabetes, etc -- I guess we must forcifully deal with it as those who have it for reasons other than HCV inteferon therapy. Be it with drugs, lifestyle changes or alternative medicine, and mind/body 'exercises' such as meditation, yoga, Tai Chi, etc. I have already stepped up my exercise program, working on diet (so very difficult), thinking about TCM, and looking into taking a Tai Chi class. Didn't need this recent article to convince me, but it did have a catalytic effect. Article describes the positive effect of Tai Chi on Shingles and the immune system. In fact, Tai Chi proved as effective against Shingles as the vaccine they tested it against. Very impressive.
http://www.post-gazette.com/pg/07101/776733-114.stm

Be well,

-- Jim

[Eisbein]

Good job Jim, thanks for providing this thread.

Ina