Yoshimasa Hashimoto

Clinical and virological effects of long-term (over 5 years) lamivudine therapy

Ideally, long‐term lamivudine therapy should not induce tyrosine–methionine–aspartate–aspartate (YMDD) mutants (reverse transcription [rt]; rt M204I/V) in patients with chronic hepatitis B. There is little or no information on the clinical features of patients who do not develop such mutants. We analyzed 368 patients who received lamivudine therapy for more than 6 months between 1995 and 2003. Among them, 98 patients were negative for YMDD mutants during 5‐year lamivudine therapy. Multivariate analysis identified hepatitis B e antigen (HBeAg) negativity, lack of cirrhosis, and high gamma glutamyltranspeptidase (GGTP) level as independent factors associated with lack of emergence of YMDD mutants during 5‐year treatment. In these 98 patients, 21 patients developed YMDD mutants in the 5‐year posttreatment follow‐up. Old age was identified as the only factor associated with the emergence of YMDD mutants during that period. For all patients, 53 showed no elevation of alanine aminotransferase (ALT) or viral load after emergence of YMDD mutants during 5 years. Short latency to emergence of YMDD mutants, mixed (tyrosine–isoleucine–aspartate–aspartate (YIDD) [rtM204I] + tyrosine–valine–aspartate–aspartate (YVDD) [rtM204V]) type, and low ALT level were identified as independent factors associated with elevation ALT or viral load. HBeAg negativity, lack of cirrhosis, and high GGTP level were associated with lack of emergence of YMDD mutants during 5‐year period. Young age protected against emergence of YMDD mutants over the 5‐year period. Moreover, after the emergence of YMDD mutants, short latency to the emergence of YMDD mutant, mixed type mutants, and low baseline ALT level were associated with elevation of ALT or viral load. J. Med. Virol. 82:684–691, 2010.

Zoledronic acid delays disease progression of bone metastases from hepatocellular carcinoma

Aim:  We conducted a retrospective cohort study to investigate the efficacy of combination therapy with radiotherapy (RT) and zoledronic acid for bone metastases from hepatocellular carcinoma (HCC). Additionally, we investigated the efficacy of zoledronic acid for non‐irradiated bone metastases.

Prediction of response to peginterferon‐alfa‐2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b

Variation at the IL‐28B locus was recently reported to be a significant predictive factor of viral response to pegylated‐interferon plus ribavirin combination therapy against chronic hepatitis C. Predictive factors for the effect of therapy, including IL‐28B polymorphism rs8099917 and viral and clinical factors were investigated. A total of 288 patients were enrolled who were chronically infected with hepatitis C virus (HCV) genotype 1b and treated with combination therapy. Among them, 87 patients completed 48 weeks of therapy without dose reduction or discontinuation. In multivariate regression analysis, the rs8099917 TT genotype was the only independent factor significantly associated with sustained viral response (P = 0.016, OR 61.5), whereas substitutions at amino acid 70 (aa 70) of the HCV core protein (P = 0.038, OR 5.9) and non‐TT genotypes (P = 0.002, OR 17.2) were associated with nonvirological response. Both factors were also associated with viral dynamics during the initial stage of the therapy. Correlation analysis revealed that rs8099917 genotype was correlated with γ‐glutamyl transpeptidase, hyaluronic acid, and HCV core aa 70. In conclusion, host (IL‐28B polymorphism) and viral (aa 70) factors independently affect response to combination therapy. J. Med. Virol. 83:981–988, 2011.

Prolongation of interferon therapy for recurrent hepatitis C after living donor liver transplantation: analysis of predictive factors of sustained virological response, including amino acid sequence of the core and NS5A regions of hepatitis C virus.

Abstract Objective. The aim of the present retrospective study was to evaluate the therapeutic efficacy and predictive factors of prolongation of treatment with peginterferon (PEGIFN) combined with ribavirin (RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT). Methods. Fifty-three patients underwent LDLT due to HCV-related end-stage liver disease. Sixteen patients were removed from the study as a result of early death (n = 14), no recurrence of HCV (n = 1) and refusal of antiviral therapy (n = 1). Therapy is ongoing in another 10 patients. The remaining 27 patients were available to establish the efficacy of IFN therapy. HCV genotype was 1b in 24 patients. All patients with genotype 1b were treated with IFN therapy for at least 48 weeks after HCV RNA levels had become undetectable. Amino acid substitutions in the HCV core region and NS5A region were analyzed by direct sequencing before LDLT. Results. The rate of sustained virological response (SVR) was 37.0% (10/27). SVR rate in patients with genotype 1 was 29.2% (7/24) and 100% (3/3) in patients with genotype 2. Most patients with genotype 1b whose HCV RNA reached undetectable levels achieved SVR (87.5%; 7/8). However, mutation of the HCV core region and number of ISDR mutations were not associated with SVR rate in LDLT in our study. Conclusions. Prolonged IFN therapy for more than 48 weeks after HCV RNA reached undetectable levels might prevent virological relapse of HCV.

Transcatheter chemoembolization for unresectable hepatocellular carcinoma and comparison of five staging systems

Aim:  We compared the ability of five staging system to predict survival in patients with hepatocellular carcinoma (HCC) treated with chemoembolization.

Percutaneous transhepatic sclerotherapy for recurrent bleeding ileal varices diagnosed by capsule endoscopy and computed tomography during percutaneous transhepatic venography

We report a case of acute uncontrolled gastrointestinal bleeding in a patient with liver cirrhosis. A 64‐year‐old man was admitted to our hospital for further investigation of blood in stools. Preliminary examination by computed tomography (CT) as well as upper and lower endoscopy could not detect the bleeding source. Exploratory laparotomy was considered difficult due to potential easy bleeding and adhesions caused by past abdominal surgery. The hemoglobin level was normalized by blood transfusion. Capsule endoscopy (CE) identified ileal varices. The top of these ileal varices was red, prompting their identification as the source of bleeding. Percutaneous transhepatic venography (PTV) confirmed the presence of many varices in the branch of the superior mesenteric vein, although the bleeding source could not be identified. CT during PTV identified varices protruding into the ileal lumen, which were managed subsequently by percutaneous transhepatic sclerotherapy (PTS). The procedure stopped the bleeding completely. CE proved less invasive and effective in detecting obscure gastrointestinal bleeding. CT during PTV followed by PTS is suitable for diagnosis and treatment of bleeding varices in patients with portal hypertension.

Clinical outcome of esophageal varices after hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with major portal vein tumor thrombus

Aim:  To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4).

Achievement of Sustained Viral Response after Switching Treatment from Pegylated Interferon α-2b to α-2a and Ribavirin in Patients with Recurrence of Hepatitis C Virus Genotype 1 Infection after Liver Transplantation: A Case Report

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.

Eradication of hepatitis C virus genotype 1 after liver transplantation by interferon therapy before surgery: Report of three patients with analysis of interleukin‐28 polymorphism, hepatitis C virus core region and interferon‐sensitivity determining region

The achievement of sustained viral response (SVR) with interferon (IFN) therapy before liver transplantation (LT) is difficult due to liver dysfunction, pancytopenia and frequent side‐effects. Here, we report eradication of hepatitis C virus (HCV) genotype 1 after LT in three patients by IFN therapy before surgery. All three patients achieved virological response (VR), namely, fall in serum HCV RNA titer below the detection limit of real‐time polymerase chain reaction (PCR) during IFN administration. However, HCV RNA rebound after cessation of treatment in all three patients; namely, they could not achieve SVR despite treatment with pegylated (PEG) IFN plus ribavirin. All three patients had wild‐type amino acids (a.a.) at either aa70 or aa91 in the core region. Genotyping of IL‐28 single nucleotide polymorphisms (rs8099917) showed TT genotype in two patients and TG genotype in one. All three patients developed multiple hepatocellular carcinomas during the clinical course, and requested living donor LT using liver grafts from their relatives. The patients were treated with IFN to immediately before LT, at which time they remained negative for HCV RNA in serum by real‐time PCR. The three patients were followed‐up for 14–15 months after LT, during which they remained negative for HCV RNA despite no further IFN therapy. In conclusion, it is possible to eradicate HCV after LT by inducing VR with continuous IFN therapy to before LT in spite of viral and host evidences reflecting low susceptibility to IFN treatment.