Case report: Identification of recombinant HCV genotype 1b–2b by viral sequencing in two patients with treatment failure, who responded to re-treatment with sofosbuvir and daclatasvir

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

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Refractory eosinophilic fasciitis successfully treated with infliximab: A case report

Journal of Scleroderma and Related Disorders ◽

10.1177/23971983211004399 ◽

2021 ◽

pp. 239719832110043

Author(s):

Paulina Śmigielska ◽

Justyna Czarny ◽

Jacek Kowalski ◽

Aleksandra Wilkowska ◽

Roman J. Nowicki

Keyword(s):

Case Report ◽

Connective Tissue ◽

Treatment Failure ◽

Immunosuppressive Drugs ◽

Unknown Etiology ◽

High Dose ◽

Eosinophilic Fasciitis ◽

Line Treatment ◽

First Line ◽

First Line Treatment

Eosinophilic fasciitis is a rare connective tissue disease of unknown etiology. Therapeutic options include high-dose corticosteroids and other immunosuppressive drugs. We present a typical eosinophilic fasciitis case, which did not respond to first-line treatment, but improved remarkably after infliximab administration. This report demonstrates that in case of initial treatment failure, infliximab might be a relatively safe and effective way of eosinophilic fasciitis management.

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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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