Haruya Ishiguro

New Proposal for Response-Guided Peg-Interferon- Plus-Ribavirin Combination Therapy for Chronic Hepatitis C Virus Genotype 2 Infection

This study aimed to determine the most suitable duration of pegylated‐interferon (Peg‐IFN)‐plus‐ribavirin combination therapy in patients infected with hepatitis C virus (HCV) genotype 2 who had not achieved rapid virological response (serum HCV RNA disappearance after 4 weeks of therapy). HCV genotype 2 patients (n = 182) with a high viral load received >80% of the standard Peg‐IFN‐plus‐ribavirin dose for at least 24 weeks, and their final virological responses were studied. Patients were classified into “rapid virological response” and “non‐rapid virological response” groups. The non‐rapid virological response group was further divided into a “virological response at 8 weeks” (serum HCV RNA disappearance after 8 weeks of therapy) and a “non‐virological response at 8 weeks” group. Factors related to rapid virological response and optimal therapy duration in the non‐rapid virological response group were evaluated. Multivariate logistic regression analysis showed that subtype HCV genotype 2a (P = 0.0015) and low concentration of pretreatment serum HCV RNA (P = 0.0058) were independent factors in a rapid virological response. In the virological response at 8 weeks group, the sustained virological response rate after 24 weeks of therapy was significantly lower than after 36 weeks (P = 0.044) or after 48 weeks (P = 0.006), and was similar for 36‐ and 48‐weeks. The cost for achieving (CAS) one sustained virological response was lowest with 36‐week therapy. Prolongation of Peg‐IFN‐plus‐ribavirin combination therapy to 36 weeks is suitable for achieving virological response at 8 weeks, given the high, sustained virological response rate and cost benefit. J. Med. Virol. 85:1523–1533, 2013.

Serum Apolipoprotein B-100 Concentration Predicts the Virological Response to Pegylated Interferon Plus Ribavirin Combination Therapy in Patients Infected With Chronic Hepatitis C Virus Genotype 1b

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg‐IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity‐determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg‐IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b‐infected patients to investigate whether the response to Peg‐IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B‐100 (apoB‐100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB‐100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046–2.456), alpha‐fetoprotein (OR, 0.764; 95% CI, 0.610–0.958), non‐wild‐type ISDR (OR, 5.617; 95% CI, 1.274–24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225–114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3‐log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB‐100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB‐100 concentrations could predict virological response to Peg‐IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. J. Med. Virol. 85:1180–1190, 2013.

Assessment of the features of serum apolipoprotein profiles in chronic HCV infection: difference between HCV genotypes 1b and 2

BackgroundThe life cycle of hepatitis C virus (HCV) is tightly associated with host lipoprotein metabolic pathways. Apolipoprotein is present on the outer surface of lipoprotein particles and plays an important role in lipoprotein metabolism. We aimed to elucidate the influence of chronic HCV infection on serum apolipoprotein profiles.MethodsFasting serum apolipoprotein profiles of 310 subjects with active or cleared HCV infection were examined. Subsequently, the association between chronic HCV infection and serum apolipoprotein levels was determined using multiple regression analysis.ResultsActive HCV infection was associated with high serum levels of apo A-II and low serum levels of apo C-II and C-III. HCV infection with both genotype 1b (G1b) and genotype 2 (G2) was associated with low serum levels of either apo C-II and C-III, whereas only HCV G1b infections caused elevated levels of apo A II and E. Among active HCV infections, HCV G1b was associated with an elevation in the serum apo E levels. Furthermore, IL28B non-major genotype (rs8099917 TG/GG) was associated with low levels of serum apo B and high levels of apoA-II, and advanced fibrosis was associated with low levels of apo B and C-II in G1b infection.ConclusionsActive HCV infection is distinctively associated with characteristic serum apolipoprotein profiles. The influence on apolipoprotein profiles varies with different HCV genotypes. Moreover, the genotype of IL28B and hepatic fibrosis affected serum apolipoproteins in G1b infection. Abnormalities in serum apolipoproteins may provide a clue to the elucidation of complex interactions between active HCV infection and lipid metabolism.

Esophageal Capsule Endoscopy for Screening Esophageal Varices among Japanese Patients with Liver Cirrhosis

Purpose. Although esophageal capsule endoscopy (ECE) is reportedly useful in the diagnosis of esophageal varices (EV), few reports have described the benefits of this technique in Asian countries. The present paper evaluates the usefulness of ECE for diagnosing EV in Japanese patients with cirrhosis. Methods. We examined 29 patients with cirrhosis (20 males and 9 females; mean age 60 years; Child-Pugh classification A/B/C; 14/14/1) using ECE followed by esophagogastroduodenoscopy (EGD). High-risk EV were defined as F2 and/or RC2 and above. Results. The sensitivity and specificity of ECE for the diagnosis of high-risk EV were 92% and 80%, respectively. Conclusions. The findings showed that ECE is a highly sensitive method of diagnosing high-risk EV that requires endoscopic or pharmacological therapy. Thus, ECE might be a useful method for the screening and followup of EV in patients with cirrhosis.

Effect of Oral Rehydration Solution on Fatigue during Outdoor Work in a Hot Environment: A Randomized Crossover Study

Effect of Oral Rehydration Solution on Fatigue during Outdoor Work in a Hot Environment: A Randomized Crossover Study: Tomohisa Ishikawa, et al. Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine

Serum lipoprotein profiles and response to pegylated interferon plus ribavirin combination therapy in patients with chronic HCV genotype 1b infection.

Background Abnormal serum lipid profiles have been noted in patients with chronic hepatitis C virus (HCV) infection. Moreover, many reports suggest that serum lipoprotein profiles are more profoundly distorted in patients with HCV G1b infection who have an unfavorable response to pegylated interferon (peg-IFN) plus ribavirin (RBV) combination therapy. However, after the discovery of single nucleotide polymorphisms near the IL28B gene (rs8099917 and rs12979860) as potent predictive factors affecting the response to peg-IFN plus RBV, lipid factors are thought to be confounding factors. Objectives To re-examine the significance of lipoprotein profiles on virological response to peg-IFN plus RBV combination therapy in patients with chronic HCV G1b infection, we examined cholesterol and triglyceride concentrations in each lipoprotein fraction separated by high performance liquid chromatography. Patients and Methods Lipoprotein profiles were examined using fasting sera from 108 patients infected with HCV G1b who had chronic hepatitis, as determined by liver biopsy. Results of lipoprotein profiles and clinical data, including IL28B genotype and amino acid substitution at aa70 of HCV G1b, were compared between patients with a sustained virological response (SVR) and non-SVR or a non-virological response (NVR) and virological responses other than NVR (non-NVR). In addition, significant predictive factors independently associated with virological response to peg-IFNα-2b plus RBV were determined by logistic regression analysis. Results An increased ratio of cholesterol/triglyceride in very low-density lipoprotein (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.01-9.44) along with a major genotype of rs8099917 (OR 9.09; 95% CI 2.94-33.33), were independent predictive factors for SVR. In contrast, lipid factors were not elucidated as independent predictive factors for NVR. Conclusions Examination of the fasting lipid profile has clinical importance in predicting the efficacy of peg-IFN-α-2b plus RBV combination therapy for patients with HCV G1b even after the discovery of the IL28 genotype as a potent predictive factor.

Early syphilitic hepatitis concomitant with nephrotic syndrome followed by acute kidney injury

Although acute hepatitis and nephrotic syndrome are commonly reported as complications of tertiary syphilis, nephrotic syndrome concomitant with hepatitis in early-stage syphilis is rare. Here, we describe the case of a 46-year-old male who was diagnosed with acute liver dysfunction and nephrotic syndrome after presenting with general malaise, and who subsequently developed acute kidney injury. Laboratory examination showed alkaline phosphatase had a greater magnitude of elevation compared to alanine aminotransferase, suggesting the possibility of syphilitic hepatitis. The rapid plasmin regain test and Treponema pallidum hemagglutination assay were positive, supporting the presence of a syphilis infection. Additionally, liver biopsy examination showed infiltration of inflammatory cells into the portal area and epithelioid cell granulomas. Moreover, kidney biopsy examination by both optical and electron microscopy showed a congestion of neutrophils in the capillary vessels, structural collapse of the tubules, and subepithelial deposits under the epithelium of the glomerular endothelial cells. These pathological changes were consistent with those reported previously for early syphilitic hepatitis and nephrotic syndrome in early-stage syphilis. All the symptoms, including liver and renal dysfunction, resolved after benzyl penicillin treatment was initiated. Hence, we believe early-stage syphilis should be included in the differential diagnosis of unknown liver damage and/or nephrosis.

Dyslipoproteinemia in Chronic HCV Infection

Hepatitis C virus (HCV) is a unique virus whose life cycle is closely associated with lipoprotein metabolism [1, 2, 3]. Assembly of HCV particles, formation of HCV-virions, is closely connected to the formation of lipid droplets in hepatic cells that may serve as an assembly platform [1, 4]. In addition, the production of HCV particles is tightly linked to the very low-density lipoprotein (VLDL) production pathway [5, 6]. HCV particles circulating in the blood during chronic HCV infection form lipo-viral particles (LVP) that are rich in triglycerides (TG), apoB-100 and apoE, with physiochemical similarity to VLDL particles and are highly infectious [7, 8]. In contrast, denser HCV particles are less infectious. These data strongly suggest that both viral particles and VLDL are integral components of LVPs with high infective capability. Although LVPs are thought to be assembled in liver cells by association with host lipoproteins prior to secretion, association between HCV and VLDL in the circulation after secretion from the liver cannot be ruled out.

Interferon-λ3 polymorphisms in pegylated-interferon-α plus ribavirin therapy for genotype-2 chronic hepatitis C.

AIM To evaluate interferon-λ3 (IFNL3) polymorphisms in response-guided pegylated interferon-α plus ribavirin (Peg-IFNα/RBV) therapy for genotype 2 (G2) chronic hepatitis C. METHODS Between January 2006 and June 2012, a total of 180 patients with chronic infections of G2 hepatitis C virus (HCV) were treated with response-guided Peg-IFNα/RBV therapy. The treatment duration was 24 wk for patients who achieved rapid virologic response (RVR), and 36 or 48 wk for patients who did not. Then, the impact of the IFNL3 single nucleotide polymorphism genotype (TT/non-TT at rs8099917) on treatment outcomes was evaluated in the 180 patients, and between patients infected with either HCV sub-genotype 2a or 2b. RESULTS Of the 180 patients evaluated, 111 achieved RVR, while the remaining 69 patients did not. In RVR patients, the sustained virologic response (SVR) rate was 96.4%, and the IFNL3 genotype did not influence the SVR rate (96.6% vs 95.8% in IFNL3 genotype TT vs non-TT). However, in non-RVR patients, the SVR rate decreased to 72.5% (P < 0.0001), and this rate was significantly different between the IFNL3 genotype TT and non-TT groups (80.0% vs 42.9%, P = 0.0146). Multivariate regression analysis in non-RVR patients identified the IFNL3 genotype TT as the only baseline-significant factor associated with SVR (OR = 5.39, 95%CI: 1.29-22.62; P = 0.0189). In analysis according to HCV sub-genotype, no significant difference in the SVR rate was found between HCV sub-genotypes 2a and 2b. CONCLUSION In response-guided Peg-IFNα/RBV combination therapy for chronically HCV G2-infected patients, the impact of the IFNL3 genotype on SVR was limited to non-RVR patients.

Elevation in Serum Concentration of Bone-Specific Alkaline Phosphatase without Elevation in Serum Creatinine Concentration Secondary to Adefovir Dipivoxil Therapy in Chronic Hepatitis BVirus Infection

Of 168 patients with chronic hepatitis B virus (HBV) infection-related liver disease, 20 patients who had received 100 mg of lamivudine plus 10 mg/day of adefovir dipivoxil (ADV) (ADV group) and 124 patients who had received 0.5 mg/day of entecavir or 100 mg/day of lamivudine (non-ADV group) for >1 year were enrolled. For comparative analyses, 19 well-matched pairs were obtained from the groups by propensity scores. At the time of enrollment, serum creatinine and phosphate concentrations were similar between the ADV and non-ADV groups; however, urinary phosphate (P = 0.0424) and serum bone-specific alkaline phosphatase (BAP) (P = 0.0228) concentrations were significantly higher in the ADV group than in the non-ADV group. Serum BAP was significantly higher at the time of enrollment than before ADV administration in the ADV group (P = 0.0001), although there was no significant change in serum BAP concentration in the non-ADV group. There was a significant positive correlation between the period of ADV therapy and ΔBAP (R 2 = 0.2959, P = 0.0160). Serum BAP concentration increased before increase in serum creatinine concentration and was useful for early detection of adverse events and for developing adequate measures for continuing ADV for chronic HBV infection-related liver disease.