Journal of Hepatology: "Myocardial injury in patients with chronic hepatitis C infection"

Abstract entitled "Myocardial injury in patients with chronic hepatitis C infection" posted online 8/13/12 in Journal of Hepatology.eu. A compelling study from Japan that definitely warrants further research into this phenomena and may add to the long list of extra-hepatic manifestations of having active, replicating Hepatitis C virus in the human body. This particular study found a link between myocardial perfusion and HCV.  Patients who achieved an SVR garnered better severity scores (SS) than prior to therapy. Relapsers saw improved SS scores while on therapy, but the scores worsened with the reappearance of virus.  If these results are confirmed, it adds to a growing base of evidence that dictates treating earlier instead of later. 

Article in Press

Myocardial injury in patients with chronic hepatitis C infection

Shigeo Maruyama, Masahiko Koda, Nobuyuki Oyake, Hidetoshi Sato, Yasuyoshi Fujii, Yutaka Horie, Yoshikazu Murawaki

Received 4 April 2012; received in revised form 13 July 2012; accepted 31 July 2012. published online 13 August 2012.

Accepted Manuscript

Abstract

Background & aims
The existence of a direct pathogenic link between hepatitis C virus (HCV) infection and myocardial injury has not been confirmed. We investigated the association between myocardial conditions and HCV in patients with HCV-related chronic hepatitis using thallium-201 myocardial scintigraphy.

Methods
In 217 consecutive cases of chronic HCV infection without overt heart disease, we performed electrocardiography (ECG), echocardiography, serum tests on myocardial injury and thallium-201 myocardial scintigraphy. Myocardial injury was confirmed by severity score (SS), which was calculated as the sum of thallium-201 perfusion defect scores. SS was followed prior to and after interferon (IFN) therapy in 200 patients with chronic hepatitis C.

Results
An abnormal ECG was found in 9% of the patients with chronic hepatitis C. Abnormal SS was found in 87% of chronic hepatitis C patients. Independent factors related to higher pretreatment SS were histology activity index score, serum HCV RNA titer and indocyanine green disappearance rate. After IFN therapy, SS was improved in patients with sustained virologic response. Among relapsers, the SS improved at the initial disappearance of HCV RNA, but SS worsened with reappearance of HCV RNA. The SS in non-viral responders did not change with IFN therapy.

Conclusions
Myocardial perfusion defects were found in 87% of the patients with chronic hepatitis C and improved with viral eradication from IFN therapy.

Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C...

Article-In-Press published online 5-28-12 on the Journal of Hepatology website.  Interesting study that finds higher insulin resistance in non-diabetic HCV-subjects that have the T/T and T/C-allele than their CC allele counterparts. IR, along with fibrosis and steatosis, have been established predictors of response to PEG + Ribavirin therapy - Insulin resistance could be one factor that explains the the difficulty in treating HCV patients with IL28B TT and TC genotypes. 

Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C

Albert Friedrich Stättermayer, Karoline Rutter, Sandra Beinhardt, Thomas-Matthias Scherzer, Andreas Stadlmayr, Harald Hofer, Fritz Wrba, Petra Steindl-Munda, Michael Krebs, Christian Datz, Michael Trauner, Peter Ferenci

Received 29 December 2011; received in revised form 20 March 2012; accepted 5 April 2012. published online 28 May 2012.
Accepted Manuscript

Abstract
Background /aims
Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance in treatment-naïve patients with chronic hepatitis C.

Methods
202 non-diabetic CHC patients (GT1: 181, GT4: 21; m=126, f=76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis and genetic data were analyzed.

Results
Insulin resistance (HOMA-IR3.0) was associated with the rs12979860 genotype, presence of advanced fibrosis and higher BMI. HOMA-IR in CC and in TC/TT was 2.08±1.61 (mean±SD) and 2.94±2.89 (P=.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92±3.15; F0-2: 2.38±2.38; P=.004). The percentage of steatotic hepatocytes was greater in patients with advanced fibrosis (21.3±21.5 vs. 9.1±14.2; P<.001), HOMA-IR3.0 (17.7±17.8 vs. 8.8±15.4%; P<.001) and BMI>25.0kg/m2 (14.7±17.0 vs. 9.1±16.1; P<.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95%CI: 1.344-5.917; P=.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; P=.007) as independent risk factors for insulin resistance.

Conclusion
Insulin resistance is more common in carriers of the T-allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.

Abbreviations: CHC, chronic hepatitis C, HCV, hepatitis C virus, HOMA, homeostasis model of assessment, IR, insulin resistance, IL28B, interleukin 28 B, PNPLA3, patatin like phospholipase domain-containing 3, SVR, sustained virologic response, SNP, single nucleotide polymorphism, T2DM, type 2 diabetes mellitus

TMC435 activity in HCV genotypes 2-6...

For your comments - Posted on 2/12/12 in the 'Articles in Press' section of the Journal of Hepatology. From the results of the Phase IIa study,Janssen's TMC435 HCV protease inhibitor appears to have activity in HCV genotypes 2,4,5 & 6, with potency being most apparent in 6,4,2 in that order. TMC435 seems to share the lack of activity in genotype 3 HCV with it's predecessors Telaprevir and Boceprevir. 

Article in Press
Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2 to 6: TMC435-C202, a phase IIa, open-label study

Journal of Hepatology Feb 12 2012

Background & Aims

TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2 to 6.

Methods

The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from Day 8 with a follow-up period up to Days 37–42.

Results

Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary endpoint at Day 8, the mean (±standard error) change in plasma HCV ribonucleic acid (log10 IU/mL) from baseline was greatest for genotypes 6 (-4.35±0.29) and 4 (-3.52±0.43), followed by genotypes 2 (-2.73±0.71) and 5 (-2.19±0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.

Conclusions

The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.