3 New Hepatitis Abstracts

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J Hepatol. 2011 Jun 30. [Epub ahead of print]

Activation of Unfolded Protein Response and autophagy during HCV infection

modulates innate immune response.

Estrabaud E, De Muynck S, Asselah T.

Source

Service d'Hépatologie and INSERM U773 CRB3, Beaujon Hospital, University Paris

VII France.

Abstract

Autophagy, a process for catabolizing cytoplasmic components, has been

implicated in the modulation of interactions between RNA viruses and their host.

However, the mechanism underlying the functional role of autophagy in the viral

life cycle still remains unclear. Hepatitis C virus (HCV) is a single-stranded,

positive-sense, membrane-enveloped RNA virus that can cause chronic liver

disease. Here we report that HCV induces the unfolded protein response (UPR),

which in turn activates the autophagic pathway to promote HCV RNA replication in

human hepatoma cells. Further analysis revealed that the entire autophagic

process through to complete autolysosome maturation was required to promote HCV

RNA replication and that it did so by suppressing innate antiviral immunity.

Gene silencing or activation of the UPR-autophagy pathway activated or

repressed, respectively, IFN-β activation mediated by an HCV-derived

pathogen-associated molecular pattern (PAMP). Similar results were achieved with

a PAMP derived from Dengue virus (DEV), indicating that HCV and DEV may both

exploit the UPR-autophagy pathway to escape the innate immune response. Taken

together, these results not only define the physiological significance of

HCV-induced autophagy, but also shed light on the knowledge of host cellular

responses upon HCV infection as well as on exploration of therapeutic targets

for controlling HCV infection.

Copyright © 2011. Published by Elsevier B.V.

PMID: 21723841 [PubMed - as supplied by publisher]

Related citations

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J Hepatol. 2011 Jun 30. [Epub ahead of print]

A sprint to increase response to HCV treatment: expectancies but caution.

Asselah T.

Source

Service d'hépatologie, Hôpital Beaujon, Clichy, France and INSERM, U773,

Centre de Recherche Bichat-Beaujon CRB3, and University Paris Diderot.

Abstract

BACKGROUND:

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who

do not have a sustained response to therapy with peginterferon-ribavirin,

outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that

binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an

additional treatment.

METHODS:

To assess the effect of the combination of boceprevir and

peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1

infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three

groups. In all three groups, peginterferon alfa-2b and ribavirin were

administered for 4 weeks (the lead-in period). Subsequently, group 1 (control

group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2

received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with

a detectable HCV RNA level at week 8 received placebo plus

peginterferon-ribavirin for an additional 12 weeks; and group 3 received

boceprevir plus peginterferon-ribavirin for 44 weeks.

RESULTS:

A total of 403 patients were treated. The rate of sustained virologic response

was significantly higher in the two boceprevir groups (group 2, 59%; group 3,

66%) than in the control group (21%, P<0.001). Among patients with an

undetectable HCV RNA level at week 8, the rate of sustained virologic response

was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple

therapy. Among the 102 patients with a decrease in the HCV RNA level of less

than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained

virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively.

Anemia was significantly more common in the boceprevir groups than in the

control group, and erythropoietin was administered in 41 to 46% of

boceprevir-treated patients and 21% of controls.

CONCLUSIONS:

The addition of boceprevir to peginterferon-ribavirin resulted in significantly

higher rates of sustained virologic response in previously treated patients with

chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin

alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov

number, NCT00708500).

Copyright © 2011. Published by Elsevier B.V.

PMID: 21723840 [PubMed - as supplied by publisher]

Related citations

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Scand J Infect Dis. 2011 Jul 5. [Epub ahead of print]

Correlates of spontaneous clearance of hepatitis C virus in a Danish human

immunodeficiency virus type 1 cohort.

Clausen LN, Weis N, Schønning K, Fenger M, Krarup H, Bukh J, Benfield T.

Source

Department of Infectious Diseases, Copenhagen University Hospital , Hvidovre.

Abstract

Abstract Background: Around a quarter of individuals infected with hepatitis C

virus (HCV) are spontaneously able to clear the virus. Correlates of spontaneous

HCV clearance are not well established and the aim of this study was to

characterize factors associated with spontaneous HCV clearance in a human

immunodeficiency virus (HIV)-co-infected cohort. Methods: We analyzed 327

anti-HCV-positive HIV-1-infected patients using multivariate logistic

regression. HCV clearance was defined as the presence of anti-HCV with

undetectable HCV RNA from at least 2 measurements more than 6 months apart.

Results: We included 327 HIV-1-infected individuals, predominantly of Caucasian

race; 112 (34%) were females, 258 (79%) were injecting drug users (IDU), 25 (8%)

were men who have sex with men (MSM), and 20 (6%) were hepatitis B surface

antigen (HBsAg)-positive. Seventy-six (23%; 95% confidence interval (CI) 18-28)

had cleared their HCV infection and 251 (77%; 95% CI 72-82) had a chronic

infection. The clearance rate in HBsAg-positive individuals was 65%. Being

female, HBsAg-positive, or belonging to HIV exposure groups IDU and MSM

predicted higher HCV clearance rates (adjusted odds ratio (aOR) 1.8, 95% CI

1-3.2; aOR 7.6, 95% CI 2.7-21; aOR 5.2, 1.2-23.5; and aOR 10.2, 95% CI 1.8-58,

respectively). Race, acquired immunodeficiency syndrome (AIDS), and

antiretroviral therapy were not associated with HCV clearance. Conclusions: The

HCV clearance rate in this HIV-1 cohort was 23%. MSM and IDUs may have higher

clearance rates due to their repeated exposure to low-dose HCV, leading to

immune memory. Our data suggest an interaction of hepatitis B virus and HCV that

influences the outcome of acute HCV infection.

PMID: 21728744 [PubMed - as supplied by publisher]