8 New Hepatitis C Abstracts

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Am J Gastroenterol. 2011 Oct 4. doi: 10.1038/ajg.2011.341. [Epub ahead of print]

Comparison of Transient Elastography and Acoustic Radiation Force Impulse for

Non-Invasive Staging of Liver Fibrosis in Patients With Chronic Hepatitis C.

Rizzo L, Calvaruso V, Cacopardo B, Alessi N, Attanasio M, Petta S, Fatuzzo F,

Montineri A, Mazzola A, L'abbate L, Nunnari G, Bronte F, Di Marco V, Craxì A,

Cammà C.

Source

Unità Operative di Malattie Infettive, Ospedale Garibaldi Nesima e Ferrarotto,

Catania, Italy.

Abstract

OBJECTIVES:

Transient elastography (TE) is adequate for a diagnosis of cirrhosis, but its

accuracy for milder stages of fibrosis is much less satisfactory. The objective

of this study was to compare the performance and the discordance rate of

acoustic radiation force impulse (ARFI) and TE with liver biopsy in a cohort of

chronic hepatitis C (CHC) patients.

METHODS:

One hundred thirty-nine consecutive patients with CHC were enrolled in two

tertiary centers, and evaluated for histological (Metavir score) and biochemical

features. All patients underwent TE and ARFI.

RESULTS:

TE was unreliable in nine patients (6.5%), while in no cases (0%) were ARFI

invalid measurements recorded (P=0.029). By area under receiver operating

characteristic curve (AUROC), the best cutoff values for TE and ARFI for

significant fibrosis (≥F2) were ≥6.5 kPa (AUROC: 0.78) and ≥1.3 m/s

(AUROC: 0.86), respectively. For severe fibrosis (F3-F4), these cutoff values

were 8.8 kPa (AUROC: 0.83) for TE and 1.7 m/s (AUROC: 0.94) for ARFI. For

cirrhosis, TE had its best cutoff at ≥11 kPa (AUROC: 0.80) and ARFI at

≥2.0 m/s (AUROC: 0.89). By pairwise comparison of AUROC, ARFI was

significantly more accurate than TE for a diagnosis of significant and severe

fibrosis (P=0.024 and P=0.002, respectively), while this difference was only

marginal for cirrhosis (P=0.09). By partial AUROC analysis, ARFI performance

results significantly higher for all three stages of fibrosis. The average

concordance rates of TE and ARFI vs. liver biopsy were 45.4 and 54.7%,

respectively. By multivariate analysis, ARFI was not associated with alanine

aminotransferase (ALT), body mass index, Metavir grade, and liver steatosis,

while TE was significantly correlated with the ALT value (P=0.027).

CONCLUSIONS:

In a cohort of patients with CHC, ARFI imaging was more accurate than TE for the

non-invasive staging of both significant and severe classes of liver fibrosis.Am

J Gastroenterol advance online publication, 4 October 2011;

doi:10.1038/ajg.2011.341.

PMID: 21971536 [PubMed - as supplied by publisher]

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Eur J Gastroenterol Hepatol. 2011 Nov;23(11):990-6.

The early on-treatment perihepatic lymph node response predicts sustained viral

response of anti-hepatitis C virus therapy.

Lin YM, Sheu MJ, Kuo HT, Feng IC, Sun CS, Koay LB, Lin CY.

Source

aDepartment of Internal Medicine, Division of Hepatogastroenterology, Chi-Mei

Medical Center bDepartment of Senior Citizen Service Management, Chia Nan

Univerisity of Pharmacy & Science, Tainan, Taiwan.

Abstract

BACKGROUND AND AIMS:

In chronic hepatitis C, the change of perihepatic lymph nodal size after

antiviral therapy could be a marker of virologic response. Whether the

on-treatment nodal manifestations predict virologic responses is unknown.

METHODS:

Patients (n=88) with biopsy-proven chronic hepatitis C received standard doses

of bi-therapy for 24 weeks; sequential changes of the perihepatic lymph nodes

were evaluated prospectively by ultrasound. Pretreatment and on-treatment

factors were analyzed and correlated with sustained virologic response, focusing

on early on-treatment nodal changes (12 weeks).

RESULTS:

Perihepatic lymph nodes were prevalent in 75% of the patients; 72 patients

(81.8%) achieved sustained viral response. Before treatment, no factor was

significantly associated with the nodal prevalence or size. The pretreatment

nodal width (mean 5.3 vs. 3.6 mm; P=0.023) and the on-treatment nodal

manifestations including a reduction in nodal width at 12 weeks of antiviral

treatment (median; 1.05 vs. 0 mm, P=0.029) and a reduction of nodal volume at

the end of treatment (24 weeks; median 0.62 vs. -0.01 ml, P=0.015) were

significantly correlated with the sustained virologic response. A reduction of

nodal width greater than 2.5 mm at 12 weeks always predicts sustained virologic

response (100 vs. 77%; P=0.019).

CONCLUSION:

Results confirm the high prevalence of perihepatic lymphadenopathy in patients

with chronic hepatitis C. The use of the nodal width measurement in routine

ultrasound follow-up may be a simpler early predictor of sustained virologic

response during standard bi-therapy.

PMID: 21975695 [PubMed - in process]

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Eur J Gastroenterol Hepatol. 2011 Oct 1. [Epub ahead of print]

The study of relationship between neutropenia and infection during treatment

with peginterferon α and ribavirin for chronic hepatitis C.

Yu JW, Sun LJ, Zhao YH, Kang P, Yan BZ.

Source

Department of Infectious Diseases, Second Affiliated Hospital, Harbin Medical

University, Harbin, China.

Abstract

OBJECTIVE:

Neutropenia is frequent during treatment of chronic hepatitis C (CHC) with

peginterferon and ribavirin. It remains unclear whether neutropenia is

associated with infection in CHC. The aim was to study the relationship between

neutropenia and infection during treatment with peginterferon and ribavirin for

CHC.

METHODS:

A retrospective cohort on 399 patients treated with peginterferon α and

ribavirin derived from our hospital database was conducted. The occurrence of

infections and their relationship to neutropenia were investigated. Potential

risk factors for infection were identified by multivariate analysis.

RESULTS:

During treatment, neutropenia [absolute neutrophil counts (ANC) <1.5×10/l]

occurred in 251 patients, mild neutropenia [ANC (0.75-1.5)×10/l] occurred in

132 patients, moderate neutropenia [ANC (0.50-0.75)×10/l] occurred in 103

patients, and severe neutropenia (ANC<0.50×10/l) occurred in 16 patients.

Eighty infections (20.1%) occurred, 14 infections (17.5%) were defined as

severe. There was no significant difference in infection rate between patients

with and without moderate and severe neutropenia (21.0%, 25/119 vs. 19.6%,

55/280; χ=0.097, P=0.755). There was no significant difference in infection

rate between patients with and without peginterferon dose modifications (21.5%,

31/144 vs. 19.2%, 49/255; χ=0.307, P=0.580). In multivariate logistic

regression analysis, the independent factors associated with infection were age

(P=0.021), diabetes (P=0.004), and cirrhosis (P=0.012).

CONCLUSION:

Infections during treatment with peginterferon α and ribavirin for CHC are not

associated with neutropenia. The independent factors associated with infection

are age, diabetes, and cirrhosis.

PMID: 21971375 [PubMed - as supplied by publisher]

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Hepatology. 2011 Jul;54(1):20-7. doi: 10.1002/hep.24443.

Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus.

Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X.

Source

Clinical Trials and Medical Information, Vertex Pharmaceuticals Inc., Cambridge,

MA 02139, USA. medicalinfo@...

Abstract

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the

enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine

and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study

assessed the effect of telaprevir coadministration on the pharmacokinetics of a

single dose of either cyclosporine or tacrolimus in two separate panels of 10

healthy volunteers each. In Part A, cyclosporine was administered alone as a

single 100-mg oral dose, followed by a minimum 8-day washout period, and

subsequent coadministration of a single 10-mg oral dose of cyclosporine with

either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750

mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a

single 2-mg oral dose, followed by a minimum 14-day washout period, and

subsequent coadministration of a single 0.5-mg dose of tacrolimus with

steady-state telaprevir (750 mg q8h). Coadministration with steady-state

telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞))

by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by

approximately 70-fold. Coadministration with telaprevir increased the terminal

elimination half-life (t(½)) of cyclosporine from a mean (standard deviation

[sD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a

mean (SD) of 40.7 (5.85) hours to 196 (159) hours. CONCLUSION: In this study,

telaprevir increased the blood concentrations of both cyclosporine and

tacrolimus significantly, which could lead to serious or life-threatening

adverse events. Telaprevir has not been studied in organ transplant patients;

its use in these patients is not recommended because the required studies have

not been completed to understand appropriate dose adjustments needed for safe

coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory

approval has not been obtained.

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

Comment in

Hepatology. 2011 Jul;54(1):3-5.

PMID: 21618566 [PubMed - indexed for MEDLINE]

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J Hepatol. 2011 Sep 27. [Epub ahead of print]

Immunosuppression and HCV Recurrence after Liver Transplantation.

Samonakis DN, Germani G, Burroughs AK.

Source

The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery

Royal Free Hospital and UCL, London, UK.

Abstract

HCV related liver disease is the most common indication for liver

transplantation. Recurrence of HCV infection is universal and has a substantial

impact on patient and graft survival. Immunosuppression is a major factor

responsible for the accelerated recurrence and compressed natural history of

recurrent HCV infection. Accumulating experience has provided data to support

certain strategies for immunosuppressive regimens. From the available evidence

more severe recurrence results from repeated bolus corticosteroid therapy and

antilymphocyte antibodies used to treat rejection. Low dose and slow tapering of

steroids are better than high dose maintenance and/or rapid tapering. Recent

meta-analyses favour steroid free regimens but these are complicated to

interpret as the absence of steroids may simply represent less immunopotency.

There is no difference in HCV recurrence between tacrolimus and cyclosporine

regimens, but tacrolimus increases graft and patient survival in HCV

transplanted patients. There may be a beneficial effect of maintenance

azathioprine given for 6 months or longer. There is no conclusive evidence for

benefit of mycophenolate and Interleukin-2 receptor blockers. Few data are

available for mTOR inhibitors. Better evidence is needed to establish the

optimal immunosuppressive regimen for HCV recipients and more randomized trials

should be performed.

Copyright © 2011. Published by Elsevier B.V.

PMID: 21963518 [PubMed - as supplied by publisher]

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J Virol. 2011 Oct 5. [Epub ahead of print]

ISG56 and IFITM1 proteins inhibit hepatitis C virus replication.

Raychoudhuri A, Shrivastava S, Steele R, Kim H, Ray R, Ray RB.

Source

Departments of Pathology.

Abstract

Hepatitis C virus (HCV) often leads to persistent infection. Interferon (IFN)

and IFN stimulated genes (ISGs) are amplified during HCV infection, but fail to

eliminate virus from liver in a large number of infected patients. We have

previously observed that HCV infection induces IFN-β production in immortalized

human hepatocytes (IHH) as early as 24 h after infection, although virus

replication is not inhibited. To gain insights on possible countermeasures of

virus for suppression of host antiviral response, the cellular transcriptional

profile of ISGs were examined upon various treatments of IHH. A majority of ISGs

were up-regulated in IFN treated IHH as compared to mock-treated cells. However,

comparison of ISG expression in IFN treated, and IFN pretreated-HCV genotype 2a

infected IHH indicated that virus infection suppresses up-regulation of a subset

of effector molecules, including ISG56 and IFITM1. Similar results were observed

from HCV infected Huh7 cells. Subsequent study suggested that exogenous

expression of ISG56 or IFITM1 inhibits HCV replication in IHH or Huh7 cells, and

knockdown of these genes enhanced HCV replication. Further characterization

revealed that overexpression of these ISGs does not block HCV pseudotype entry

into Huh7 cells. Together, our results demonstrated that ISG56 and IFITM1 serve

as important molecules to restrict HCV infection, and may have implications in

development of therapeutic modalities.

PMID: 21976647 [PubMed - as supplied by publisher]

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J Virol. 2011 Sep 28. [Epub ahead of print]

A GENETIC INTERACTION BETWEEN THE CORE AND NS3 PROTEINS OF HEPATITIS C VIRUS IS

ESSENTIAL FOR PRODUCTION OF INFECTIOUS VIRUS.

DM, Atoom AM, Zhang X, Kottilil S, RS.

Source

Immunology and Infectious Diseases, Faculty of Medicine, Memorial University of

Newfoundland, St. 's, Newfoundland, Canada, A1B 3V6.

Abstract

By analogy to other members of the Flaviviridae family, the hepatitis C virus

(HCV) core protein is presumed to oligomerize to form the viral nucleocapsid,

which encloses the single-stranded RNA genome. Core protein is directed to lipid

droplets (LDs) by Domain 2 (D2) of the protein and this process is critical for

virus production. Domain 1 (D1) of core is also important for infectious

particle morphogenesis, although its precise contribution to this process is

poorly understood. In this study, we mutated amino acids 64-75 within D1 of core

and examined the ability of these mutants to produce infectious virus. We found

that residues 64-66 are critical for generation of infectious progeny, whereas

67-75 were dispensable for this process. Further investigation of the defective

64-66 mutant (termed JFH1(T)-64-66) revealed it to be incapable of producing

infectious intracellular virions, suggesting a fault during HCV assembly.

Furthermore, isopycnic gradient analyses revealed that JFH1(T)-64-66 assembled

dense intracellular species of core, presumably representing nucleocapsids.

Thus, amino acids 64-66 are seemingly not involved in core

oligomerization/nucleocapsid assembly. Passaging of JFH1(T)-64-66 led to the

emergence of a single compensatory mutation (K1302R) within the helicase domain

of NS3 that completely rescued its ability to produce infectious virus.

Importantly, the same NS3 mutation abrogated virus production in the context of

wild-type core protein. Together, our results suggest that residues 64-66 of

core D1 form a highly specific interaction with the NS3 helicase that is

essential for the generation of infectious HCV particles at a stage downstream

of nucleocapsid assembly.

PMID: 21957313 [PubMed - as supplied by publisher]

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J Virol. 2011 Sep 28. [Epub ahead of print]

HCV Nucleotide Inhibitors PSI-352938 and PSI-353661 Exhibit a Novel Mechanism of

Resistance Requiring Multiple Mutations within Replicon RNA.

Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Zennou V, Otto MJ, Furman

PA.

Source

Pharmasset, Inc. 303A College Road East, Princeton, New Jersey 08540.

Abstract

PSI-352938, a cyclic phosphate nucleotide, and PSI-353661, a phosphoramidate

nucleotide, are prodrugs of β-d-2' -deoxy-2' -α-fluoro-2'

-β-C-methylguanosine-5' -monophosphate. Both compounds are metabolized to the

same active 5' -triphosphate, PSI-352666, which serves as an alternative

substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV

replication. PSI-352938 and PSI-353661 retained full activity against replicons

containing the S282T substitution that confers resistance to certain 2'

-substituted nucleoside/tide analogs. PSI-352666 was also similarly active

against both wild-type and S282T NS5B polymerases. In order to determine the

mechanism of resistance for these compounds, in vitro selection studies were

performed using HCV replicon cells. While no resistant genotype 1a or 1b

replicons could be selected, cells containing genotype 2a JFH-1 replicons

cultured in the presence of PSI-352938 or PSI-353661 developed resistance to

both compounds. Sequencing of the NS5B region identified a number of amino acid

changes, including S15G, R222Q, C223Y/H, L320I and V321I. Phenotypic evaluation

of these mutations indicated that single amino acid changes were not sufficient

to significantly reduce the activity of PSI-352938 and PSI-353661. Instead, a

combination of three amino acid changes, S15G/C223H/V321I, was required to

confer a high level of resistance. No cross resistance exists between the 2'

-F-2' -C-methylguanosine prodrugs and other classes of HCV inhibitors including

2' -modified nucleoside/tide analogs such as PSI-6130, PSI-7977, INX-08189 and

IDX-184. Finally, we determined that in genotype 1b replicons the C223Y/H

mutation failed to support replication, and although the A15G/C223H/V321I triple

mutant did confer resistance to PSI-352938 and PSI-353661, it replicated at only

about 10% efficiency compared to that of wild-type.

PMID: 21957306 [PubMed - as supplied by publisher]

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