Resistance-Associated NS5A Variants of Hepatitis C Virus Are Susceptible to Interferon-Based Therapy.

The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p<0.001).Y93H RAV is more susceptible to interferon-based therapy than the Y93 wild type

Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein as a Screening Tool for Significant Liver Fibrosis in Health Checkup

Chronic liver disease is generally widespread, and a test for screening fibrotic subjects in a large population is needed. The ability of Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP) to detect significant fibrosis was investigated in health checkup subjects in this research. Of 2021 health checkup subjects enrolled in this prospective cross-sectional study, those with WFA+-M2BP ≥ 1.0 were defined as high risk. Liver fibrosis was evaluated using magnetic resonance elastography (MRE) in subjects with high risk. The primary outcome was the positive predictive value (PPV) of WFA+-M2BP for significant fibrosis (liver stiffness ≥ 2.97 kPa by MRE). This trial was registered with the UMIN clinical trial registry, UMIN000036175. WFA+-M2BP ≥ 1.0 was observed in 5.3% of the 2021 subjects. The PPV for significant fibrosis with the threshold of WFA+-M2BP at ≥1.0, ≥1.1, ≥1.2, ≥1.3, ≥1.4, and ≥1.5 was 29.2%, 36.4%, 43.5%, 42.9%, 62.5%, and 71.4%, respectively. A WFA+-M2BP of 1.2 was selected as the optimal threshold for significant fibrosis among high-risk subjects, and the PPV, negative predictive value, sensitivity, and specificity for significant fibrosis were 43.5%, 84.0%, 71.4%, and 61.8%, respectively. WFA+-M2BP ≥ 1.2 was significantly associated with significant fibrosis, with an odds ratio (OR) of 4.04 (95% confidence interval (CI): 1.1-16, p = 0.04), but not FIB-4 ≥ 2.67 (OR: 2.40, 95%CI: 0.7-8.6, p-value = 0.2). In conclusion, WFA+-M2BP is associated with significant fibrosis and could narrow down potential subjects with liver fibrosis. The strategy of narrowing down fibrosis subjects using WFA+-M2BP may be used to screen for fibrotic subjects in a large population

HCV RNA reduction of Y93H RAV versus the Y93 wild type during SMV/PR therapy.

<p>Reduction of HCV RNA from baseline to an early time point during SMV/PR therapy was determined for Y93H RAV and the Y93 wild type. Within 7 days of the initiation of therapy, HCV RNA reduction was significantly greater for Y93H RAV (-3.7 ± 1.3 logIU/mL/day) than the Y93 wild type (-3.4 ± 1.0 logIU/mL/day) (p<0.001).</p

Detection of Y93H RAV by direct sequencing at baseline and during SMV/PR therapy.

<p>BT, breakthrough;</p><p>SVR, sustained virological response</p><p>*within 7 days of the initiation of treatment, when HCV RNA was still detectable,</p><p>**at least 3 months after the end of treatment</p><p>Detection of Y93H RAV by direct sequencing at baseline and during SMV/PR therapy.</p

Changes in the proportion of Y93H RAV within each individual.

<p>The proportion of Y93H RAV over the Y93 wild type within each patient was determined by deep sequencing at baseline and at an early time point during SMV/PR therapy (within 7 days). The mean proportion of Y93H RAV was 52.7% at baseline and 29.7% during therapy (p = 0.023). The proportion of Y93H was reduced in 21 of 29 cases (72.4%, solid lines). In contrast, Y93H percentages increased in 8 cases (27.6%, broken lines).</p

Changes in the proportion of Y93H RAV in 4cases with breakthrough or relapse.

<p>Deep sequencing was performed in 4 patients with relapse (a) or breakthrough (b, c, d) to quantify the proportion of Y93H RAV against the Y93 wild type. In two cases, PR therapy was continued up to 24 wks after stopping SMV (b and c). The proportion of Y93H RAV decreased during SMV/PR therapy and at the time of breakthrough/relapse compared to baseline but recovered to the baseline level at follow up. PR therapy; pegylated interferon plus ribavirin therapy, SMV/PR therapy; Simeprevir plus pegylated interferon / ribavirin therapy</p

Baseline characteristics.

<p>AST, aspartate aminotransferase’</p><p>ALT, alanine aminotransferase’</p><p>AFP, alpha-fetoprotein’</p><p>PR therapy, pegylated interferon plus ribavirin therapy’</p><p>RAV, resistance-associated variants’</p><p>SMV/PR therapy; Simeprevir plus pegylated interferon / ribavirin therapy’</p><p>TVR, telaprevir,</p><p>SVR; sustained virological response</p><p>Baseline characteristics.</p