Natural History of CHB : Role of Antiviral Therapy for Hepatitis B: pros

( Kazuaki Chayama ) 대한간학회 2004 Clinical and Molecular Hepatology(대한간학회지) Vol.10 No.1(S)

Baseline RAS Test: Clinical Practice

( Kazuaki Chayama ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

With the advent of direct-acting antiviral agents, including NS3 protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors, the success rate of eradication of hepatitis C virus has improved dramatically. However, the efficacy of DAA therapy may be compromised by selection for viral mutations within the DAA target regions. Resistance-associated variants (RAVs) such as NS3 D168A/V and NS5A Y93H and L31M may be present prior to therapy or may emerge de novo following exposure to the agents, leading to failure of the drugs to eradicate the virus. DAA therapy with daclatasvir, an NS5A inhibitor, and asunaprevir, an NS3 protease inhibitor, has been approved and used successfully in several Asian countries. However, NS5A inhibitors such as daclatasvir are particularly susceptible to RAVs. Two phase III clinical studies conducted in Japan showed that the eradication rates of patients with RAVs were only 43 and 35% in patients with NS5A Y93H RAVs compared to 91% and 98% in patients with wild type. Therefore, it is clearly necessary to consider the presence of Y93H RAVs when selecting patients to be treated with daclatasvir plus asunaprevir combination therapy. We developed an assay to determine the frequency of Y93H and L31M/V variants using the Invader assay. The assay is able to quantitatively detect variants with a level of accuracy comparable to that of deep sequencing. Using this assay, we have been able to screen patients prior to therapy and have tried to avoid treating patients with high levels of resistant strain with this combination therapy. We treated 310 patients with genotype 1 infection with daclatasvir plus asunaprevir combination therapy. The frequency of Y93H and/or L31M/V variants was <1% in 233 (87.6%) patients and ≥1% in the remaining 33 (12.4%) patients. The sustained viral response rate (SVR) was 94% in patients without RAVs (<1%) but slightly lower at 91% in patients with RAVs. The SVR rate declined as the RAV frequency increased. The overall SVR was 94%, which is comparable to rates obtained with more recent combination therapies such as sofosbuvir (NS5B polymerase inhibitor) plus ledipasvir (NS5A inhibitor). These results showed that RAV screening is valuable as a means to minimize treatment failure and prevent further selection for resistant strains. Whereas RAVs affecting the NS3 protein tend to have poor fitness and are often out-competed by wild-type when treatment is discontinued, NS5A RAVs tend to have higher fitness and are maintained at stable frequencies in the absence of the drug as well as in patients who have never been exposed to DAA agents. Given the low cost of the Invader assay (less than $US 100 dollars) compared to the cost of a course of DAA therapy and the potential costs and uncertainty associated with re-treatment in the case of viral breakthrough, RAV pre-screening should be considered as an effective way to improve treatment outcomes and reduce costs.

An Integrated Analysis of the Efficacy of Glecaparevir/ Pibrentasvir by Geographical Region

( Edward Gane ),( Kazuaki Chayama ),( Mudra Kapoor ),( Stuart K Roberts ),( Jeong Heo ),( Jia-horng Kao ),( Thomas Berg ),( Philippe J Zamor ),( Brian Conway ),( James Park ),( Sandra S Lovell ),( Rak 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The pangenotypic direct-acting antiviral (DAA) regimen glecaprevir (developed by AbbVie and Enanta) coformulated with pibrentasvir (G/P) is approved in the US, EU, and Japan to treat chronic HCV genotype (GT) 1-6 infection. In the US and EU, G/P is indicated for treatment-naïve, HCV genotype (GT) 1-6-infected patients without and with compensated cirrhosis for 8-week and 12-week treatment durations, respectively, and achieved SVR12 rates ≥95% across all six major GTs. In clinical studies, G/P exposures were similar across ethnicities; an integrated analysis of the efficacy of G/P by geographical region was conducted to assess the impact of geography and ethnicity on SVR12. Methods: Data were pooled from 9 phase 2 and 3 clinical studies; data from 2 additional phase 3 clinical studies conducted in Japan were pooled separately. Patients had HCV GT1-6 infection with or without compensated cirrhosis and were either HCV treatment-naïve or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV), sofosbuvir and RBV with or without pegIFN, or NS5A- and/or protease inhibitor-containing regimens. G/P (300 mg/120 mg) was orally dosed once-daily for 8, 12, or 16 weeks. The primary efficacy endpoint in all studies was SVR12. Safety and tolerability were assessed in all patients. Data from all 11 studies will be pooled for presentation. Results: In total, 2369 patients were included in the integrated analysis: 964 (41%) were enrolled in North America, 891 (38%) in Europe, and 514 (22%) enrolled and pooled from Taiwan, Korea, Australia, New Zealand, Chile, Israel, and South Africa; 332 additional patients were enrolled in Japan. The SVR12 results by region were 97% (935/964; 95% CI 95.9-98.1), 98% (876/891; 95% CI 97.5-99.1), and 96% (496/514; 95% CI 94.9-98.1) for patients enrolled in North America, Europe, and the other pooled countries, respectively. Patients enrolled in Japan achieved a 98% (325/332; 95% CI 95.7-99.0) SVR12 rate. Less than 1% of all patients had virologic failure. G/P was well-tolerated with a favorable safety profile; treatment discontinuations due to adverse events and cases of drug-induced liver injury were rare (<1%). Conclusions: G/P efficacy, safety and tolerability were consistently favorable regardless of baseline characteristics, suggesting that recently updated HCV treatment guidelines for the use of G/P in clinical practice can be applied to all ethnicities and geographical regions, without need for modification.

Characteristics and Early Diagnosis of Gastric Cancer Discovered after Helicobacter pylori Eradication

( Masanori Ito ),( Shinji Tanaka ),( Kazuaki Chayama ) 대한간학회 2021 Gut and Liver Vol.15 No.3

The prevalence of gastric cancer after eradication (GCAE) is increasing dramatically in Japan. GCAE has characteristic features, and we must understand these features in endoscopic examinations. Differentiated cancer types were frequently found after eradication and included characteristic endoscopic features such as reddish depression (RD). However, benign RD can be difficult to distinguish from gastric cancer because of histological alterations in the surface structures (nonneoplastic epithelium or epithelium with low-grade atypia [ELA]) as well as multiple appearances of RD. Recently, we clarified similar alterations in genetic mutations between ELA and gastric cancer, suggesting that ELA is derived from gastric cancer. Clinically, submucosal invasive cancer was frequently found in patients after eradication therapy even if they received annual endoscopic surveillance. We can improve the diagnostic ability using image-enhanced endoscopy with magnified observation. (Gut Liver 2021;15:338-345)

Endoscopic Assessment of Colorectal Cancer with Superficial or Deep Submucosal Invasion Using Magnifying Colonoscopy

Shinji Tanaka,Nana Hayashi,Shiro Oka,Kazuaki Chayama 대한소화기내시경학회 2013 Clinical Endoscopy Vol.46 No.2

Among early colorectal carcinoma, endoscopic treatment is generally indicative for cases with intramucosal to submucosal (SM) super-ficial invasion, because cases with SM deep invasion should be treated surgically due to the risk of lymph node metastasis. It is impor-tant, therefore, to distinguish between superficial and deep SM invasion in early colorectal carcinoma prior to treatment. In this review we assessed the clinical usefulness and knack of pit pattern and narrow band imaging (NBI) diagnosis using magnifying observation. VN type pit pattern, type C3 in NBI Hiroshima classification and NBI type 3 in NBI international colorectal endoscopic (NICE) classification are useful predictors of SM deep invasion. In NBI magnifying observation evaluation of both the vascular pattern and surface pattern are important. We have to use pit pattern diagnosis and NBI magnifying diagnosis as the situation demands with the knowledge of both advantage and disadvantage in each diagnostic method.

Clinical Usefulness of Dual Red Imaging in Gastric Endoscopic Submucosal Dissection: A Pilot Study

Naoki Yorita,Shiro Oka,Shinji Tanaka,Takahiro Kotachi,Naoko Nagasaki,Kosaku Hata,Kazutaka Kuroki,Kazuhiko Masuda,Mio Kurihara,Mariko Kiso,Tomoyuki Boda,Masanori Ito,Kazuaki Chayama 대한소화기내시경학회 2020 Clinical Endoscopy Vol.53 No.1

Background/Aims: Dual red imaging (DRI) is a new, image-enhanced endoscopy technique. There are few reports about the usefulnessof DRI during gastric endoscopic submucosal dissection (ESD). We aimed to examine the usefulness of DRI in endoscopic hemostasisduring gastric ESD. Methods: We enrolled a total of 20 consecutive patients who underwent gastric ESD. Five endoscopists compared DRI with white lightimaging (WLI) for the visibility of blood vessels and bleeding points while performing endoscopic hemostasis. Results: The visibility of blood vessels was increased in 56% (19/34) of the cases, and the visibility of bleeding points was improved in55% (11/20) of the cases with the use of DRI compared with the use of WLI. Conclusions: DRI improved the visibility of blood vessels and bleeding points in cases with oozing bleeding, blood pooling around thebleeding points, and multiple bleeding points.