Tsunamasa Watanabe

Impact of resistance-associated variant dominancy on treatment in patients with HCV genotype 1b receiving daclatasvir/asunaprevir.

Sustained virological responses (SVR) by daclatasvir (DCV) and asunaprevir (ASV) therapy for genotype 1b hepatitis C virus (HCV) infected patients has been significantly affected by pre‐existence of Y93 H resistance‐associated variants (RAVs) in the non‐structural protein 5A (NS5A) region. The aim of this study was to elucidate the dominancy of naturally occurring RAVs in viral quasispecies on treatment outcomes in patients with HCV. In total, 138 patients were prospectively selected from 152 patients treated with DCV and ASV, where evaluation of treatment outcomes at 12 weeks post‐treatment was possible. Pre‐treatment RAVs in the non‐structural protein 3 and NS5A regions were detected by polymerase chain reaction (PCR)‐Invader assays, and the ratio of Y93H RAVs in viral quasispecies was measured by quantitative PCR‐Invader assay. Among 25 patients detected the Y93H RAV, the Y93H ratio was 1–25% in 5 patients, 26–75% in 7 patients, and ≥76% in 13 patients. Overall, SVR at 12 weeks after the completion of treatment (SVR12) was 91% (125/138), and those with Y93H ratios of <1%, 1–25%, 26–75%, and ≥76% were 99%, 100%, 71%, and 23%, respectively. Thus, the SVR12 decreased as the HCV Y93H ratio increased (P < 0.0001). The dominancy of pre‐treatment RAVs of DCV and ASV affected its treatment outcomes, suggesting that evaluating the dominancy of HCV RAVs could be required for every other direct‐acting antiviral agent treatments. J. Med. Virol. 89:99–105, 2017.

Real-world virological efficacy and safety of elbasvir and grazoprevir in patients with chronic hepatitis C virus genotype 1 infection in Japan

BackgroundThe real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1.MethodsThe rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics.ResultsOverall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment.ConclusionsThe EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

Relationship of hepatitis B virus infection to the recurrence of hepatocellular carcinoma after direct acting antivirals

Recently, two conflicting articles about recurrence of hepatocellular carcinoma (HCC) after direct acting antivirals (DAA) against hepatitis C virus (HCV) were published. We investigated the relationship between DAA and HCC recurrence. Eligible patients were (1) history of HCC and treated curatively with interventions, and (2) interferon-free DAA therapy was initiated after eradication of HCC. We analyzed contributing factor for HCC recurrence. Ten out of 23 participants (43%) encountered recurrence of HCC. Age, sex, diabetes mellitus, fibrosis score, chemistry, and alpha-fetoprotein did not differ between patients with recurrence and patients without recurrence. The patients with recurrence had significantly higher values of antibody to hepatitis B core antigen (anti-HBc) than the patients without recurrence, 6.06±3.75 vs. 0.91±2.43 (p=0.0019). The relative risk of HCC recurrence comparing anti-HBc positive to negative was 5.2 (95% confidence interval 1.40 to 19.32). Odds ratio was 22.0 (95% confidence interval 2.5 to 191.1). We conclude that anti-HBc positivity was a strong contributing factor for HCC recurrence after DAA therapy.

Virological characteristics of hepatitis B genotype G/A2 recombination virus in Japan

We identified four cases of infection with hepatitis B virus genotype G and A2 recombinant (HBV/G/A2) strains, which were initially overlooked by enzyme immunoassay‐based genotyping. The patients were all men who have sex with men (MSM) and inhabited several metropolitan areas of Japan, suggesting that the recombinant strains may be circulating among high‐risk groups such as MSM. Here, we investigated the genomic structure and virological properties of the HBV/G/A2 strains.

Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen: Effect on LDV/SOF ± RBV in prior DCV/ASV failures

The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor‐containing regimen is unclear.

Diagnostic Ability of Endoscopic Bile Cytology Using a Newly Designed Biliary Scraper for Biliary Strictures

BackgroundA new device with metallic wires for scrape cytology was developed.AimsTo compare the diagnostic performance of scrape cytology and conventional cytology during endoscopic retrograde cholangiopancreatography for biliary strictures.MethodsA total of 420 cases with biliary stricture underwent transpapillary bile cytology. Among them, there are 79 cases with scrape cytology using the new device (scrape group) and 341 cases with conventional cytology (control group). Seventy-two and 174 cases underwent biliary biopsy at the same time as bile cytology in the scrape and control group, respectively.ResultsThe sensitivity for malignancy of bile cytology in the scrape and control group was 41.2% [pancreatic cancer (PC): 23.1%, biliary cancer (BC): 52.5%] and 27.1% (PC: 16.3%, BC: 38.0%), respectively (P = 0.023). When analyzed PC and BC, respectively, there was no significant difference between the two groups. In the both groups, the sensitivity was significantly higher for BC than PC. In the scrape group, there was no difference in the sensitivity between cytology and biopsy [39.7% (PC: 17.4%, BC: 55.3%)], but in the control group, a significantly lower sensitivity was observed with cytology than biopsy (36.4% (PC: 19.7%, BC: 50.0%)) (P = 0.046). When analyzed PC and BC, respectively, there was no significant difference between cytology and biopsy. The sensitivity of combined cytology and biopsy was 55.6% (PC: 30.4%, BC: 71.1%) in the scrape group and 47.0% (PC: 24.6%, BC: 64.3%) in the control group.ConclusionScrape bile cytology for biliary strictures may be superior to conventional cytology.

Hemoglobin Decrease with Iron Deficiency Induced by Daclatasvir plus Asunaprevir Combination Therapy for Chronic Hepatitis C Virus Genotype 1b

Background Decreased hemoglobin (Hb) level has been supposed to be a relatively rare side effect of a combination therapy against hepatitis C virus that consists of the NS5A inhibitor daclatasvir (DCV) and the NS3/4A protease inhibitor asunaprevir (ASV). Methods The study was conducted in 75 patients with genotype 1b chronic hepatitis C virus infection who had started combination therapy with DCV and ASV at St. Marianna University School of Medicine Hospital between September 2014 and December 2014. Results Among the patients examined, decreased Hb level by ≥1.5 g/dL from the values at treatment initiation was observed in 11 individuals. This was accompanied by decreased mean corpuscular volume, and iron and ferritin levels. Conclusions These findings suggest that the mechanism of the phenomenon is caused by iron deficiency. The underlying mechanism and clinical impacts will need to be further examined.

Efficacy and safety of elbasvir/grazoprevir for Japanese patients with genotype 1b chronic hepatitis C complicated by chronic kidney disease, including those undergoing hemodialysis: A post-hoc analysis of a multicenter study.

This study aimed to evaluate the efficacy and safety of elbasvir/grazoprevir in genotype 1b chronic hepatitis C Japanese patients with chronic kidney disease (CKD), including those undergoing hemodialysis.

Daclatasvir and asunaprevir improves health-related quality of life in Japanese patients infected with hepatitis C virus: DCV/ASV improves HRQOL in HCV patients

Interferon‐free direct‐acting antiviral agent (DAA) regimens for chronic hepatitis C virus (HCV) patients have improved their health‐related quality of life (HRQOL). Currently, there are no published data assessing the impact of DAAs regimens without sofosbuvir on HRQOL. The aim of this study was to investigate the improvement of HRQOL in Japanese HCV patients treated with a protease inhibitor and a nonstructural protein 5A inhibitor.

Serum monomeric laminin‐γ2 as a novel biomarker for hepatocellular carcinoma

The diagnosis of hepatocellular carcinoma (HCC) in the early stages is important for successful clinical management. Laminin (Ln)‐γ2 expression has been reported in various types of malignant carcinomas. We recently developed a highly sensitive method to measure serum monomeric Ln‐γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). Using our CLIA, we evaluated its diagnostic value in sera from patients with chronic liver disease (CLD) and patients with hepatocellular carcinoma (HCC). Serum alpha‐fetoprotein (AFP) and des‐gamma‐carboxy prothrombin (DCP) were also examined in these subjects. Median levels of Ln‐γ2 were significantly higher in patients with HCC (173.2 pg/mL; range: 39.5–986 pg/mL) compared with patients with CLD (76.7 pg/mL; range: 38.7–215.9 pg/mL) and with healthy volunteers (41.1 pg/mL; range: 10.9–79.0 pg/mL). The optimal cutoff value for Ln‐γ2 that allowed us to distinguish between HCC and nonmalignant CLD was 116.6 pg/mL. Elevated Ln‐γ2 levels were observed in 0% of healthy volunteers, 17% of patients with CLD, and 63% of patients with HCC. The positivity rate in patients with HCC for the combination of Ln‐γ2 and DCP was 89.5%, which was better than that for either of the two markers alone (63% and 68%, respectively). Among patients with early‐stage HCC (T1 or T2), the positivity rates for monomeric Ln‐γ2, AFP and DCP were 61%, 39% and 57%, respectively. Serum Ln‐γ2 may be a potential biomarker for HCC surveillance. The combination of Ln‐γ2 and DCP may be more sensitive for laboratory diagnosis of HCC than the combination of AFP and DCP.