Impact of viral amino acid substitutions and host IL28B polymorphism on replication and susceptibility to interferon of hepatitis C virus.

[Guest guest]

Dig Dis Sci. 2011 Jun 2. [Epub ahead of print]

Retreatment of Hepatitis C with Consensus Interferon and Ribavirin After

Nonresponse or Relapse to Pegylated Interferon and Ribavirin: A National VA

Clinical Practice Study.

Yee HS, Currie SL, Tortorice K, Cozen M, Shen H, Chapman S, Cunningham F, Monto

A.

Source

Gastroenterology Section, Department of Veterans Affairs Medical Center (VAMC),

4150 Clement Street (111B), San Francisco, CA, 94121, USA.

Abstract

BACKGROUND:

Studies of the retreatment with consensus interferon (CIFN) and ribavirin (RBV)

of hepatitis C virus (HCV)-infected patients who failed prior pegylated

interferon alfa/ribavirin (PEG-IFN/RBV) have found quite variable efficacy and

tolerability of this therapy. As such, CIFN/RBV use and efficacy in clinical

practice were evaluated within the Department of Veterans Affairs (VA), the

largest national, integrated system for HCV care.

AIMS:

The purpose of this study was to determine rates of sustained virologic response

(SVR) and patterns of CIFN/RBV use in the VA. Methods included retrospective

review of national VA data in HCV-infected patients who had previously failed

≥12 weeks of PEG-IFN/RBV and were prescribed CIFN/RBV between October 1, 2003

and September 30, 2006.

RESULTS:

A total of 597 patients met the study criteria. CIFN was primarily dosed as 15

mcg subcutaneously daily combined with standard doses of RBV. Mean treatment

duration was 21 weeks; CIFN was discontinued within 4 weeks in 24%.

Hematological growth factors were used in 49%. Post-treatment viral loads were

available in 385 patients. SVR to CIFN/RBV was achieved in 11%, and was

significantly higher in prior PEG-IFN/RBV relapsers compared with nonresponders

(31% vs. 6%, respectively; P < 0.0001). A 2-log(10) or greater drop in HCV RNA

after 24 weeks of PEG-IFN/RBV was a predictor of subsequent SVR to CIFN/RBV.

CONCLUSIONS:

CIFN/RBV was used frequently in clinical practice for retreatment of

PEG-IFN/RBV. In this setting, early treatment discontinuation was common.

Overall SVR was low, although response was significantly better in prior

PEG-IFN/RBV relapsers and those who had a 2-log(10) or greater decline than in

nonresponders.

PMID: 21633833 [PubMed - as supplied by publisher]

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Eur J Gastroenterol Hepatol. 2011 May 26. [Epub ahead of print]

Usefulness of a novel serum proteome-derived index FI-PRO (fibrosis-protein) in

the prediction of fibrosis in chronic hepatitis C.

Cheung KJ, Tilleman K, Deforce D, Colle I, Moreno C, Gustot T, Van Vlierberghe

H.

Source

aDepartment of Gastroenterology and Hepatology, Ghent University Hospital

bLaboratory for Pharmaceutical Biotechnology, Faculty of Pharmaceutical

Sciences, Ghent University, Ghent cDepartment of Gastroenterology and

Hepatopancreatology dLaboratory of Experimental Gastroenterology, Erasme

Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Abstract

BACKGROUND:

Liver biopsy is an imperfect standard for the assessment of chronic hepatitis C

liver fibrosis. In this study, the diagnostic role of proteome-derived protein

markers and the usefulness of a protein-based index were assessed.

METHODS:

Characteristics, clinical biochemistry, and protein markers of patients with

chronic hepatitis C from a study (n=62) and validation group (n=73) were

statistically assessed according to fibrosis severity. Multivariate models were

built using linear discriminant analysis for the prediction of minor fibrosis

(F0-F1), moderate fibrosis (F2-F3), and cirrhosis (F4). The best model was

validated and diagnostic performance was compared with the aspartate

aminotransferase-to-platelet ratio index based on their receiver operator

characteristic curves.

RESULTS:

Statistical analysis resulted in significant outcomes for both clinical and

protein markers. The best multivariate model was based on four protein markers:

α-2-macroglobulin (A2M), haptoglobin, hemopexin, and galectin-3-binding

protein. A2M and hemopexin were the primary predictors according to this model.

A novel index A2M/hemopexin [fibrosis-protein (FI-PRO) index] showed a

diagnostic performance rate of 0.80-0.92 for the detection of significant

fibrosis (F2-F4) and advanced fibrosis (F3-F4) in the validation group, which

was better compared with aspartate aminotransferase-to-platelet ratio index.

FI-PRO had an overall positive predictive value of 86% for significant fibrosis

and a negative predictive value of at least 90% for advanced fibrosis.

CONCLUSION:

Proteome-derived protein markers were successfully implemented in clinical

diagnosis of hepatitis C fibrosis, which resulted in the FI-PRO index. The

efficiency and usability of FI-PRO should be validated in large-scale,

prospective studies.

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Hepatology. 2011 May 26. doi: 10.1002/hep.24453. [Epub ahead of print]

Impact of viral amino acid substitutions and host IL28B polymorphism on

replication and susceptibility to interferon of hepatitis C virus.

Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, CN, Ochi H, Tateno C,

Yoshizato K, Nakamura Y, Kamatani N, ma K.

Source

Department of Medicine and Molecular Science, Division of Frontier Medical

Science, Programs for Biomedical Research, Graduate School of Biomedical

Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center,

Hiroshima University, Hiroshima, Japan.

Abstract

Amino acid (aa) substitutions of core 70 and 91 and in the NS5A interferon

sensitivity determining region (ISDR) as well as genetic polymorphisms in the

host IL28B locus affect outcome of interferon (IFN)-based therapies for chronic

hepatitis C patients. The combination of these factors and the quasispecies

nature of the virus complicate understanding of the underlying mechanism. Using

infectious hepatitis C virus (HCV) genotype 1b clone HCV-KT9, we introduced

substitutions at both core aa70 (Arg to Gln) and aa91 (Leu to Met). We also

introduced four and nine ISDR aa substitutions into core mutant HCV-KT9. Using

human hepatocyte chimeric mice with different IL28B genotypes, we examined the

infectivity, replication ability and susceptibility to IFN of these clones.

While aa substitutions in the ISDR significantly impaired infectivity and

replication ability of the virus, core aa70 and 91 substitutions did not. The

effect of IFN treatment was similar in core wild-type and mutant viruses.

Interestingly, virus titer was significantly higher in mice with the favorable

IL28B allele (rs8099917TT and rs12979860CC) in the transplanted hepatocytes than

in mice with hepatocytes from rs8099917TG and rs12979860TT donors (P<0.001).

However, the effect of IFN was significantly greater, and intrahepatic

expression levels of IFN-stimulated genes were significantly higher in mice with

the favorable IL28B allele. Conclusion: Our data suggests that HCV replication

levels and response to IFN are affected by human hepatocyte IL28B SNP genotype

and mutations in the ISDR. The mechanism underlying the clinically observed

association of wild-type core protein in eradication-favorable host cells should

be investigated further. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID: 21618576 [PubMed - as supplied by publisher]