5 New Hepatitis C Pub Med Abstracts

[Guest guest]

Am J Gastroenterol. 2011 Sep 20. doi: 10.1038/ajg.2011.312. [Epub ahead of

print]

Frequency of Elevated Hepatocellular Carcinoma (HCC) Biomarkers in Patients With

Advanced Hepatitis C.

Sterling RK, EC, TR, Seeff LB, Hoefs JC, Di Bisceglie AM, Dienstag

JL, Lok AS.

Source

Hepatology Section, Virginia Commonwealth University Medical Center, Richmond,

Virginia, USA.

Abstract

OBJECTIVES:

Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in

patients with advanced hepatitis C are lacking. The aim of this study was to

determine the frequencies and performance of elevated α-fetoprotein (AFP),

AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in

advanced hepatitis C.

METHODS:

Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening

ultrasound was performed every 12 months. Levels of biomarkers were compared in

patients in whom HCC did or did not develop.

RESULTS:

In all, 855 patients were evaluated; HCC developed in 46. Among patients without

HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and

199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP

consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had

at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once

in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with

elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the

biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had

the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml

had the highest sensitivity (76%), but specificity was ≤58%. Independent

predictors of elevated AFP were gender (female), race (Black), more advanced

disease, and HCC. Elevated DCP was associated with more advanced disease and

HCC.

CONCLUSIONS:

Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently

in patients with chronic hepatitis C and advanced fibrosis, are related to

factors other than HCC, and are poor predictors of HCC.Am J Gastroenterol

advance online publication, 20 September 2011; doi:10.1038/ajg.2011.312.

PMID: 21931376 [PubMed - as supplied by publisher]

-------------------------------------------------

Gastroenterology. 2011 Sep 14. [Epub ahead of print]

Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127,

and Ribavirin in Patients with Chronic HCV infection.

Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Müllhaupt B, Gane E,

Schuchmann M, Lohse A, Pol S, Bronowicki JP, S, Arasteh K, Zoulim F,

Heim M, Stern JO, Kukolj G, Nehmiz G, Haefner C, Boecher WO.

Source

J.W. Goethe University Hospital, furt, Germany.

Abstract

BACKGROUNDS & AIMS:

Therapeutic regimens are being developed for patients with hepatitis C virus

(HCV) infection that do not include the combination of peginterferon alfa and

ribavirin. We investigated the antiviral effect and safety of BI 201335 (an

inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B

non-nucleoside polymerase) with ribavirin.

METHODS:

Thirty-two treatment-naïve patients with chronic HCV genotype-1 infection were

randomly assigned to groups that were given 400 mg or 600 mg BI 207127, 3 times

each day (TID), plus 120 mg BI 201335 once daily and 1000-1200 mg ribavirin per

day for 4 weeks. The primary efficacy endpoint was virological response (HCV RNA

<25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4

weeks of assigned combination therapy.

RESULTS:

In the group given BI 207127 400 mg TID, the rates of virologic response were

47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed

in patients with genotype-1b, compared with genotype-1a infections. In the group

given BI 207127 600 mg TID, the rates of virologic response were 82%, 100%, and

100%, respectively, and did not differ among genotypes. One patient in the group

given 400 mg TID had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at

day 22. The most frequent adverse events were mild gastrointestinal disorders,

rash, and photosensitivity. There were no severe or serious adverse events; no

patients discontinued therapy prematurely.

CONCLUSIONS:

The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI

207127, and ribavirin has rapid and strong activity against HCV genotype-1 and

does not cause serious adverse events.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21925126 [PubMed - as supplied by publisher]

Related citations

--------------------------------------------------------

Gut. 2011 Sep 19. [Epub ahead of print]

Impact of hepatitis C triple therapy availability upon the number of patients to

be treated and associated costs in France: a model-based analysis.

Deuffic-Burban S, Mathurin P, Pol S, Larsen C, Roudot-Thoraval F, Desenclos JC,

Dhumeaux D, Yazdanpanah Y.

Source

Université Lille Nord de France, Lille, France.

Abstract

ObjectiveThe combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and

a protease inhibitor (PI) has been approved in summer 2011 for the treatment of

genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially

improved efficacy. The aim of this study was to estimate the number of G1

patients to be treated in France in 2012 and associated costs.MethodsA published

model of HCV and data on PEG-IFN sales were used to estimate patients needing

treatment using three scenarios. (1) HCV screening rate unchanged versus 2010;

proportion of treated F0-F1 patients unchanged, proportion of treated F2-F4

patients increased to the current proportion of treated F2-F4 G2/3 patients. (2)

Scenario 1 but the proportion of treated F0-F1 patients increased to the current

proportion of treated F0-F1 G2/3 patients. (3) Scenario 2 but a 5% increase in

the HCV screening rate. To estimate cost, treatment duration was multiplied by

drug unit cost. Probabilities corresponding to treatment duration were estimated

based on liver fibrosis stage, treatment-naive or experienced status of the

patient and virological response kinetics on treatment.ResultsCompared with the

5100 G1 patients treated in 2010, the number of G1 patients receiving treatment

in 2012 would be 15 000 in scenario 1, 18 300 in scenario 2 and 19 400 in

scenario 3, among whom 2.5-3.7% may receive PEG-IFN/RBV and 96.3-97.5%

PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638

million Euros.ConclusionThese model-based estimates indicate that new anti-HCV

treatments may result in a three- to fourfold increase in the number of G1

patients to be treated in France in 2012.

PMID: 21930731 [PubMed - as supplied by publisher]

Related citations

------------------------------------------------------------------

Hepatology. 2011 Sep 19. doi: 10.1002/hep.24683. [Epub ahead of print]

An IL28B polymorphism predicts pegylated interferon plus ribavirin treatment

outcome in chronic hepatitis c genotype 4.

De Nicola S, Aghemo A, Rumi MG, Galmozzi E, Valenti L, Soffredini R, De

Francesco R, Prati GM, D'Ambrosio R, Cheroni C, Donato MF, Colombo M.

Source

Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione

IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi

di Milano.

Abstract

BACKGROUND:

Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region

are the strongest baseline predictors of a sustained virologic response (SVR) to

Peg-Interferon (PegIFN) and Ribavirin (Rbv) in patients with hepatitis C virus

(HCV) genotype 1 infection. Whether this holds true for HCV-4 patients too, is

unknown. Aim To investigate the predictive power of the rs12979860 IL28B SNP for

a response to Peg-IFN and Rbv in HCV-4 patients.

METHODS:

All HCV-4 patients consecutively treated between September 2004 and June 2010

with PegIFN and Rbv at two liver Centers at the Maggiore Hospital Milan (Italy)

underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype.

RESULTS:

Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis)

103 were included in the final analysis, since 5 discontinued treatment for non

virologic reasons and 4 did not consent to genetic testing. Twenty four (23%)

were genotype CC, 65 (63%) CT and 14 (14%) TT. Overall 50 (49%) achieved an SVR,

21 (88%) CC patients vs 29 (37%) CT/TT (p<0.0001). CC patients more often had a

rapid virologic response (RVR) than CT/TT patients (12, 50% vs 23, 29% p =

0.08), while also showing lower relapse rates [0% (0/21) vs 36% (16/45)

p=0.0013]. In non-RVR patients, SVR rated were higher in CC than CT/TT patients

[9(75%) vs. 13(23%)p=0.001]. By logistic regression, the IL28B rs12979860 CC

genotype was an independent predictor of SVR with an odds ratio of 11.1 (95%

confidence interval 3.04 - 40.57 (p <0.0001).

CONCLUSIONS:

The IL28B rs12979860 SNP may have an added value in the treatment algorithm of

HCV-4 patients, since it is the strongest predictor of an SVR to PegIFN/ Rbv

therapy. (HEPATOLOGY 2011.).

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

PMID: 21932415 [PubMed - as supplied by publisher]

Related citations

----------------------------------------------------

Hepatology. 2011 Sep 19. doi: 10.1002/hep.24686. [Epub ahead of print]

CD59 incorporation protects hepatitis C virus against complement-mediated

destruction.

Amet T, Ghabril M, Chalasani N, Byrd D, Hu N, Grantham A, Liu Z, Qin X, He JJ,

Yu Q.

Source

Department of Microbiology and Immunology, Indiana University School of

Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202.

Abstract

Several enveloped viruses including HIV-1, CMV, HSV-1, Ebola virus, vaccinia

virus, and influenza virus have been found to incorporate host regulators of

complement activation (RCA) into their viral envelopes and, as a result, escape

antibody-dependent complement-mediated lysis (ADCML). HCV is an enveloped virus

of the family Flaviviridae and incorporates more than 10 host lipoproteins.

Patients chronically infected with HCV develop high-titer and cross-reactive

neutralizing antibodies (nAbs) yet fail to clear the virus, raising the

possibility that HCV may also use the similar strategy of RCA incorporation to

escape ADCML. The current study was therefore undertaken to determine whether

HCV virions incorporate biologically functional CD59, a key member of RCA. Our

experiments provided several lines of evidence demonstrating that CD59 was

associated with the external membrane of HCV particles derived from either

Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV

particles were captured by CD59-specific Abs. Second, CD59 was detected in

purified HCV particles by immunoblot analysis and in the cell-free supernatant

from HCV-infected Huh7.5.1 cells, but not from uninfected or Ad5 (a nonenveloped

cytolytic virus)-infected Huh7.5.1 cells by ELISA. Last, abrogation of CD59

function with its blockers increased the sensitivity of HCV virions to ADCML,

resulting in a significant reduction of HCV infectivity. Additionally, direct

addition of CD59 blockers into plasma samples from HCV-infected patients

increased autologous virolysis. CONCLUSION: our study, for the first time,

demonstrates that CD59 is incorporated into both cell line-derived and plasma

primary HCV virions at levels that protect against ADCML. This is also the first

report to show that direct addition of RCA blockers into plasma from

HCV-infected patients renders endogenous plasma virions sensitive to ADCML.

(HEPATOLOGY 2011.).

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

PMID: 21932413 [PubMed - as supplied by publisher]

[Guest guest]

Am J Gastroenterol. 2011 Sep 20. doi: 10.1038/ajg.2011.312. [Epub ahead of

print]

Frequency of Elevated Hepatocellular Carcinoma (HCC) Biomarkers in Patients With

Advanced Hepatitis C.

Sterling RK, EC, TR, Seeff LB, Hoefs JC, Di Bisceglie AM, Dienstag

JL, Lok AS.

Source

Hepatology Section, Virginia Commonwealth University Medical Center, Richmond,

Virginia, USA.

Abstract

OBJECTIVES:

Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in

patients with advanced hepatitis C are lacking. The aim of this study was to

determine the frequencies and performance of elevated α-fetoprotein (AFP),

AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in

advanced hepatitis C.

METHODS:

Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening

ultrasound was performed every 12 months. Levels of biomarkers were compared in

patients in whom HCC did or did not develop.

RESULTS:

In all, 855 patients were evaluated; HCC developed in 46. Among patients without

HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and

199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP

consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had

at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once

in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with

elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the

biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had

the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml

had the highest sensitivity (76%), but specificity was ≤58%. Independent

predictors of elevated AFP were gender (female), race (Black), more advanced

disease, and HCC. Elevated DCP was associated with more advanced disease and

HCC.

CONCLUSIONS:

Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently

in patients with chronic hepatitis C and advanced fibrosis, are related to

factors other than HCC, and are poor predictors of HCC.Am J Gastroenterol

advance online publication, 20 September 2011; doi:10.1038/ajg.2011.312.

PMID: 21931376 [PubMed - as supplied by publisher]

-------------------------------------------------

Gastroenterology. 2011 Sep 14. [Epub ahead of print]

Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127,

and Ribavirin in Patients with Chronic HCV infection.

Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Müllhaupt B, Gane E,

Schuchmann M, Lohse A, Pol S, Bronowicki JP, S, Arasteh K, Zoulim F,

Heim M, Stern JO, Kukolj G, Nehmiz G, Haefner C, Boecher WO.

Source

J.W. Goethe University Hospital, furt, Germany.

Abstract

BACKGROUNDS & AIMS:

Therapeutic regimens are being developed for patients with hepatitis C virus

(HCV) infection that do not include the combination of peginterferon alfa and

ribavirin. We investigated the antiviral effect and safety of BI 201335 (an

inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B

non-nucleoside polymerase) with ribavirin.

METHODS:

Thirty-two treatment-naïve patients with chronic HCV genotype-1 infection were

randomly assigned to groups that were given 400 mg or 600 mg BI 207127, 3 times

each day (TID), plus 120 mg BI 201335 once daily and 1000-1200 mg ribavirin per

day for 4 weeks. The primary efficacy endpoint was virological response (HCV RNA

<25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4

weeks of assigned combination therapy.

RESULTS:

In the group given BI 207127 400 mg TID, the rates of virologic response were

47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed

in patients with genotype-1b, compared with genotype-1a infections. In the group

given BI 207127 600 mg TID, the rates of virologic response were 82%, 100%, and

100%, respectively, and did not differ among genotypes. One patient in the group

given 400 mg TID had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at

day 22. The most frequent adverse events were mild gastrointestinal disorders,

rash, and photosensitivity. There were no severe or serious adverse events; no

patients discontinued therapy prematurely.

CONCLUSIONS:

The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI

207127, and ribavirin has rapid and strong activity against HCV genotype-1 and

does not cause serious adverse events.

Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID: 21925126 [PubMed - as supplied by publisher]

Related citations

--------------------------------------------------------

Gut. 2011 Sep 19. [Epub ahead of print]

Impact of hepatitis C triple therapy availability upon the number of patients to

be treated and associated costs in France: a model-based analysis.

Deuffic-Burban S, Mathurin P, Pol S, Larsen C, Roudot-Thoraval F, Desenclos JC,

Dhumeaux D, Yazdanpanah Y.

Source

Université Lille Nord de France, Lille, France.

Abstract

ObjectiveThe combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and

a protease inhibitor (PI) has been approved in summer 2011 for the treatment of

genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially

improved efficacy. The aim of this study was to estimate the number of G1

patients to be treated in France in 2012 and associated costs.MethodsA published

model of HCV and data on PEG-IFN sales were used to estimate patients needing

treatment using three scenarios. (1) HCV screening rate unchanged versus 2010;

proportion of treated F0-F1 patients unchanged, proportion of treated F2-F4

patients increased to the current proportion of treated F2-F4 G2/3 patients. (2)

Scenario 1 but the proportion of treated F0-F1 patients increased to the current

proportion of treated F0-F1 G2/3 patients. (3) Scenario 2 but a 5% increase in

the HCV screening rate. To estimate cost, treatment duration was multiplied by

drug unit cost. Probabilities corresponding to treatment duration were estimated

based on liver fibrosis stage, treatment-naive or experienced status of the

patient and virological response kinetics on treatment.ResultsCompared with the

5100 G1 patients treated in 2010, the number of G1 patients receiving treatment

in 2012 would be 15 000 in scenario 1, 18 300 in scenario 2 and 19 400 in

scenario 3, among whom 2.5-3.7% may receive PEG-IFN/RBV and 96.3-97.5%

PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638

million Euros.ConclusionThese model-based estimates indicate that new anti-HCV

treatments may result in a three- to fourfold increase in the number of G1

patients to be treated in France in 2012.

PMID: 21930731 [PubMed - as supplied by publisher]

Related citations

------------------------------------------------------------------

Hepatology. 2011 Sep 19. doi: 10.1002/hep.24683. [Epub ahead of print]

An IL28B polymorphism predicts pegylated interferon plus ribavirin treatment

outcome in chronic hepatitis c genotype 4.

De Nicola S, Aghemo A, Rumi MG, Galmozzi E, Valenti L, Soffredini R, De

Francesco R, Prati GM, D'Ambrosio R, Cheroni C, Donato MF, Colombo M.

Source

Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione

IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi

di Milano.

Abstract

BACKGROUND:

Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region

are the strongest baseline predictors of a sustained virologic response (SVR) to

Peg-Interferon (PegIFN) and Ribavirin (Rbv) in patients with hepatitis C virus

(HCV) genotype 1 infection. Whether this holds true for HCV-4 patients too, is

unknown. Aim To investigate the predictive power of the rs12979860 IL28B SNP for

a response to Peg-IFN and Rbv in HCV-4 patients.

METHODS:

All HCV-4 patients consecutively treated between September 2004 and June 2010

with PegIFN and Rbv at two liver Centers at the Maggiore Hospital Milan (Italy)

underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype.

RESULTS:

Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis)

103 were included in the final analysis, since 5 discontinued treatment for non

virologic reasons and 4 did not consent to genetic testing. Twenty four (23%)

were genotype CC, 65 (63%) CT and 14 (14%) TT. Overall 50 (49%) achieved an SVR,

21 (88%) CC patients vs 29 (37%) CT/TT (p<0.0001). CC patients more often had a

rapid virologic response (RVR) than CT/TT patients (12, 50% vs 23, 29% p =

0.08), while also showing lower relapse rates [0% (0/21) vs 36% (16/45)

p=0.0013]. In non-RVR patients, SVR rated were higher in CC than CT/TT patients

[9(75%) vs. 13(23%)p=0.001]. By logistic regression, the IL28B rs12979860 CC

genotype was an independent predictor of SVR with an odds ratio of 11.1 (95%

confidence interval 3.04 - 40.57 (p <0.0001).

CONCLUSIONS:

The IL28B rs12979860 SNP may have an added value in the treatment algorithm of

HCV-4 patients, since it is the strongest predictor of an SVR to PegIFN/ Rbv

therapy. (HEPATOLOGY 2011.).

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

PMID: 21932415 [PubMed - as supplied by publisher]

Related citations

----------------------------------------------------

Hepatology. 2011 Sep 19. doi: 10.1002/hep.24686. [Epub ahead of print]

CD59 incorporation protects hepatitis C virus against complement-mediated

destruction.

Amet T, Ghabril M, Chalasani N, Byrd D, Hu N, Grantham A, Liu Z, Qin X, He JJ,

Yu Q.

Source

Department of Microbiology and Immunology, Indiana University School of

Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202.

Abstract

Several enveloped viruses including HIV-1, CMV, HSV-1, Ebola virus, vaccinia

virus, and influenza virus have been found to incorporate host regulators of

complement activation (RCA) into their viral envelopes and, as a result, escape

antibody-dependent complement-mediated lysis (ADCML). HCV is an enveloped virus

of the family Flaviviridae and incorporates more than 10 host lipoproteins.

Patients chronically infected with HCV develop high-titer and cross-reactive

neutralizing antibodies (nAbs) yet fail to clear the virus, raising the

possibility that HCV may also use the similar strategy of RCA incorporation to

escape ADCML. The current study was therefore undertaken to determine whether

HCV virions incorporate biologically functional CD59, a key member of RCA. Our

experiments provided several lines of evidence demonstrating that CD59 was

associated with the external membrane of HCV particles derived from either

Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV

particles were captured by CD59-specific Abs. Second, CD59 was detected in

purified HCV particles by immunoblot analysis and in the cell-free supernatant

from HCV-infected Huh7.5.1 cells, but not from uninfected or Ad5 (a nonenveloped

cytolytic virus)-infected Huh7.5.1 cells by ELISA. Last, abrogation of CD59

function with its blockers increased the sensitivity of HCV virions to ADCML,

resulting in a significant reduction of HCV infectivity. Additionally, direct

addition of CD59 blockers into plasma samples from HCV-infected patients

increased autologous virolysis. CONCLUSION: our study, for the first time,

demonstrates that CD59 is incorporated into both cell line-derived and plasma

primary HCV virions at levels that protect against ADCML. This is also the first

report to show that direct addition of RCA blockers into plasma from

HCV-infected patients renders endogenous plasma virions sensitive to ADCML.

(HEPATOLOGY 2011.).

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

PMID: 21932413 [PubMed - as supplied by publisher]