Evaluation of advanced fibrosis measured by transient elastography after hepatitis C virus protease inhibitor-based triple therapy

Abstract Purpose To evaluate the diagnostic efficacy of quantitative liver MR imaging using diffusion-weighted imaging (DWI) and normalized apparent diffusion coefficient (ADC) in diagnosis and staging of liver fibrosis and cirrhosis in egyptian patients with hepatitis C virus (HCV) infection and compare the results with transient elastography (FibroScan). Materials and Methods Twenty-five patients known to have hepatitis C virus were enrolled after fulfilling inclusion and exclusion criteria.. Quantification of liver, spleen and muscle ADC values was done using MRI DWI sequences using 4 different b-values (0, 200, 400, 800). Normalized ADC was calculated as the ratio of liver ADC to spleen ADC.. Post processing was performed using 3D synapse ADC viewer Tool. Results Liver ADC failed to distinguish different stages of fibrosis, except between stages 2 and 3 (p = 0.016). Normalized liver ADC distinguished between individual groups of fibrosis , with significant differences between mild stages (stage 0/1) and sever stages of fibrosis (stages 3) and between stages 0/1 and cirrhosis (stage 4). There were significant differences between stages 0–2 and 3–4 using normalized liver ADC. There was a statistically significant moderate correlation between fibrosis stage and normalized liver ADC (r = −0.403; p = 0.009). ROC analysis revealed higher performance using normalized liver ADC compared with liver ADC, with higher AUC, sensitivity, and specificity for detection of cirrhosis (stage 0 vs 4 and stages 0–3 vs 4), moderate-to-advanced fibrosis (stages 2–4), and advanced fibrosis and cirrhosis (stages 3–4), reaching significance for all comparisons except for diagnosis of stage 4 (cirrhosis). Conclusion Our results suggest that normalizing liver ADC with spleen ADC improves diagnostic accuracy for detection of liver fibrosis and cirrhosis in egyptian population when using breath-hold diffusion-weighted imaging.

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Development of autoantibodies against “rings and rods”-associated IMPDH2 in chronic hepatitis C genotype 1 infection during protease inhibitor based triple therapy in a “real life” cohort

Zeitschrift für Gastroenterologie ◽

10.1055/s-0036-1597391 ◽

2016 ◽

Vol 54 (12) ◽

pp. 1343-1404

Author(s):

W Dammermann ◽

S Polywka ◽

I Dettmann ◽

S Mindorf ◽

L Komorowski ◽

...

Keyword(s):

Chronic Hepatitis ◽

Hepatitis C ◽

Protease Inhibitor ◽

Triple Therapy ◽

Chronic Hepatitis C ◽

Real Life ◽

Genotype 1

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New Epidemiologic Data Regarding Hepatitis C Virus Infection in Romania

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.264.cvr ◽

2017 ◽

Vol 26 (4) ◽

pp. 381-386

Author(s):

Mircea Manuc ◽

Carmen M. Preda ◽

Corneliu P. Popescu ◽

Cristian Baicuș ◽

Theodor Voiosu ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Drug Users ◽

Antiviral Agent ◽

Virologic Response ◽

Advanced Fibrosis ◽

Direct Acting Antiviral ◽

Genotype 1B ◽

Direct Acting ◽

End Stage

Background & Aims: Literature data suggest that HCV genotype-1b is present in 93-99% of the Romanian patients infected with hepatitis C virus (HCV). We present the genotyping tests recently performed on patients with HCV and advanced fibrosis eligible for the Direct-Acting Antiviral (DAA) therapy, as well as the prevalence of these cases across Romania.Methods: The genotyping method was performed on 7,421 HCV patients with advanced fibrosis. The detection method was automatic real time PCR platform M2000 (Abbott). Every subject was introduced into a database including age, sex, county and address.Results: Genotype 1b was almost exclusively present: 7,392/7,421 (99.6%). Genotype 1b patients were 19.6% from Bucharest, 49% were males, with a median age of 60 years. Genotype non-1b was encountered in 29/7,421 subjects (0.4%), 62% were males, 69% from Bucharest and the median age was 52 years. Most of the subjects (75%) were in the 6th and 7th age decade. The prevalence of these cases varied significantly across Romanian counties: the highest was in Bucharest (61.3/105), Bihor (47/105), Iasi (46/105) and Constanța (43/105), and the lowest in Ilfov (2.8/105), Harghita (3.7/105), Covasna (5.4/105) and Maramureș (8.8/105) (p<0.001).Conclusions: Genotype 1b is encountered in 99.6% of patients with chronic hepatitis C and advanced fibrosis from Romania. The presence of genotypes non-1b is more common in Bucharest, in males and at a younger age. There are significant differences regarding the distribution of these cases across Romania: the highest rates are in Bucharest, Bihor, Iasi and Constanta.Abbreviations: BMI: body mass index; DAA: direct-acting antiviral agent; GT: genotype; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IDU: intravenous drug users; MELD: model for end stage liver disease; NASH: non-alcoholic steatohepatitis; SVR; sustained virologic response.

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Faculty Opinions recommendation of Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: a potential therapeutic agent for the treatment of hepatitis C infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046522.496495 ◽

2006 ◽

Author(s):

Andrew Combs

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitor ◽

Therapeutic Agent ◽

Hepatitis C Infection ◽

Potential Therapeutic Agent ◽

Orally Bioavailable ◽

Ns3 Protease

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Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

Bulletin of the National Research Centre ◽

10.1186/s42269-020-00467-w ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Stephen Ejeh ◽

Adamu Uzairu ◽

Gideon Adamu Shallangwa ◽

Stephen E. Abechi

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Binding Energy ◽

Protease Inhibitor ◽

Protease Inhibitors ◽

Antiviral Agents ◽

High Potency ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Direct Acting Antiviral Agents

Abstract Background Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. The conventional interferon-free treatment regimens are currently in use by a blend of direct-acting antiviral agents (DAAs) aiming at the viral NS3 protease. However, major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price. Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. This study aimed to use in-silico methods to identify high potent molecule as an NS3/4A protease inhibitor and investigating the binding energy of the identified molecule in comparison with approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) through molecular docking. Results The model obtained by in-silico method have the following statistical records, coefficient of determination (r2) of 0.7704, cross-validation (q2LOO = 0.6914); external test set (r2(pred) = 0.7049) and Y-randomization assessment (cR2p = 0.7025). The results from the model were used to identify 12 new potential human HCV NS3/4A protease inhibitors, and it was observed that the identified molecule is well-fixed when docked with the receptor and was found to have the lowest binding energy of − 10.7, compared to approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) with − 9.5, − 10.0, − 10.5 binding energy, respectively. Conclusion The binding affinity (− 10.7) of the newly identified molecule docked with 3D structures of HCV NS3/4a protease/helicase (PDB ID: 4A92) was found to be better than that of Telaprevir, Simeprevir, and Voxilaprevir (approved direct-acting antiviral agents) which are − 9.5, − 10.0, and − 10.5, respectively. Hence, a novel molecule was identified showing high potency as HCV NS3/4a protease inhibitors.

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Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00308-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3670-3681 ◽

Cited By ~ 84

Author(s):

Fiona McPhee ◽

Jacques Friborg ◽

Steven Levine ◽

Chaoqun Chen ◽

Paul Falk ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitor ◽

Clinical Studies ◽

Replication Capacity ◽

Replication Complex ◽

Hcv Genotype ◽

Genotype 1A ◽

Genotype 1B ◽

Ns3 Protease

ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

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