3 New HCV Abstracts

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Hepatology. 2011 Mar 7. doi: 10.1002/hep.24272. [Epub ahead of print]

Second phase HCV RNA decline during telaprevir based therapy increases with drug

effectiveness: Implications for treatment duration.

Guedj J, Perelson AS.

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos

87545, USA.

Abstract

Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a

rapid first phase followed by a slower second phase. The current understanding

of viral kinetics attributes the magnitude of the first phase decay to the

treatment effectiveness, whereas the second phase decay is attributed to the

progressive loss of infected cells. Here we analyzed data from 44 patients

treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic

model that accounts for the pharmacokinetics of telaprevir, we found that the

second phase slope of viral decline to be strongly correlated with the treatment

effectiveness and to be roughly four-fold more rapid than has been reported with

interferon-based therapies. Since telaprevir is not known to increase the death

rate of infected cells, our results suggest the second phase slope of viral

decline is driven not only by the death of infected cells but may also involve

other mechanisms, such as a treatment effectiveness-dependent degradation of

intracellular viral RNA. As a consequence of the enhanced viral decay caused by

the high antiviral effectiveness of telaprevir, we predict that if drug

resistance could be avoided by using an appropriate combination of antiviral

agents, treatment duration needed to clear HCV might be dramatically shortened.

Indeed, we predict that in 95% of fully compliant patients, the last virus

particle should be eliminated by week 7 of therapy. If the remaining infected

hepatocytes act as a potential reservoir for the renewal of infection, no more

than 10 weeks of treatment should be sufficient to clear the infection in 95% of

fully compliant patients. However, if patients miss doses, treatment duration

would need to be extended. (HEPATOLOGY 2011.).Copyright © 2011 American

Association for the Study of Liver Diseases.

PMID: 21384401 [PubMed - as supplied by publisher]

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12.

Hepatology. 2011 Mar 4. doi: 10.1002/hep.24285. [Epub ahead of print]

IL-32: A new proinflammatory cytokine involved in HCV-related liver inflammation

and fibrosis.

Moschen AR, Fritz T, Clouston AD, Rebhan I, Bauhofer O, Barrie HD, EE,

Kim SH, Dinarello CA, Bartenschlager R, Jonsson JR, Tilg H.

Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical

University, Innsbruck, Austria; Department of Internal Medicine II

(Gastroenterology and Hepatology), Innsbruck Medical University, Innsbruck,

Austria.

Abstract

Interleukin 32 (IL-32) is a recently described proinflammatory cytokine that

activates p38 MAPK and NF-êB, thereby inducing proinflammatory cytokines such as

IL-1â and TNF-á. We investigated the role of IL-32 in patients with chronic

hepatitis C virus (HCV) infection. Steady-state hepatic mRNA levels of IL-32

were determined in a cohort of 90 subjects; anti-IL-32 staining was used in a

second cohort of 132 consecutive untreated chronic HCV patients. Correlations

with histological features of steatosis, inflammation and fibrosis were made. In

vitro, endogenous IL-32 in monocytes and in the human hepatoma cell line Huh-7.5

were examined. The effects of IL-32-overexpression and IL-32-silencing on HCV

replication were studied using HCV luciferase reporter viruses. There were

highly significant positive associations between hepatic IL-32 mRNA expression

and liver steatosis, inflammation, fibrosis, smooth muscle actin (SMA) area, and

serum alanine aminotransferase (ALT) levels. IL-32 protein expression was

positively associated with portal inflammation, SMA area and ALT. In vitro,

IL-1â and TNF-á significantly induced IL-32 expression in human Huh-7.5 cells.

Alone, stimulation with IFNá did not induce IL-32 expression in Huh-7.5.

However, IFNá exerted a significant additive effect on TNF-á-induced but not

IL-1â-induced IL-32 expression, particularly in CD14(+) monocytes. This effect

was dependent both on NF-êB and Jak/STAT signaling. Viral infection of Huh-7.5

cells resulted in a significant (11-fold) induction of IL-32 mRNA expression.

However, modulation of IL-32 in Huh-7.5 cells by overexpression or silencing did

not influence HCV virus replication as determined by luciferase assays.

CONCLUSION: IL-32 is a novel proinflammatory cytokine involved in HCV-associated

liver inflammation/fibrosis. IL-32 is expressed by human hepatocytes and

hepatoma cells and its expression is regulated by proinflammatory stimuli. (269

words) (HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of

Liver Diseases.

PMID: 21381070 [PubMed - as supplied by publisher]

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13.

Hepatology. 2011 Mar 4. doi: 10.1002/hep.24284. [Epub ahead of print]

High predictive accuracy of an unbiased proteomic profile for sustained

virologic response in chronic hepatitis C patients.

Patel K, Lucas J, J, Dubois L, Tillmann H, A, Uzarski D,

Califf R, Moseley M, Ginsburg G, McHutchison J, McCarthy J; for MURDOCK Horizon

1 Study Team.

Duke Clinical Research Institute, Duke University, Durham, NC.

keyur.patel@....

Abstract

Chronic hepatitis C (CHC) infection is a leading cause of end-stage liver

disease. Current standard-of-care (SOC) interferon-based therapy results in

sustained virological response (SVR) in only one-half of patients, and is

associated with significant side-effects. Accurate host predictors of virologic

response are needed to individualize treatment regimens. We applied a label-free

LC-MS-based proteomics discovery platform to pre-treatment sera from a

well-characterized and matched training cohort of 55 CHC patients, and an

independent validation set of 41 CHC genotype 1 patients with characterized

IL28B genotype. Accurate mass and retention time methods aligned samples to

generate quantitative peptide data, with predictive modeling using Bayesian

sparse latent factor regression. We identified 105 proteins of interest with two

or more peptides, and a total of 3768 peptides. Regression modeling selected

three identified metaproteins, vitamin D binding protein, alpha 2 HS

glycoprotein, and Complement C5, with a high predictive AUROC of 0.90 for SVR in

the training cohort. A model averaging approach for identified peptides resulted

in AUROC of 0.86 in the validation cohort, and correctly identified virologic

response in 71% of patients without the favorable IL28B 'responder' genotype.

CONCLUSION: Our preliminary data indicates that a serum-based protein signature

can accurately predict treatment response to current SOC in most CHC patients.

(HEPATOLOGY 2011.).Copyright © 2011 American Association for the Study of Liver

Diseases.

PMID: 21381069 [PubMed - as supplied by publisher]