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Eiichi Ogawa,1 Norihiro Furusyo,1 Mindie H Nguyen2 1Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan; 2Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA Abstract: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has been approved for the treatment of chronic hepatitis B virus (HBV) infection. TAF has been shown to be a potent inhibitor of HBV replication at a low dose, with high intracellular concentration and more than 90% lower systemic TFV concentration than tenofovir disoproxil fumarate (TDF). In two randomized, double-blind, multinational, Phase 3, non-inferiority trials for hepatitis B e antigen (HBeAg)-positive and -negative patients (primary analysis: 48 weeks), TAF 25 mg orally once-daily was not inferior to TDF 300 mg in achieving an HBV DNA level

Background The Wisteria floribunda agglutinin-positive human Mac-2-binding protein ( WFA+-M2 BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA+-M2 BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. Aim To evaluate the diagnostic ability of WFA+-M2 BP for liver fibrosis in the clinical setting and the clinical utility of WFA+-M2 BP for predicting the efficacy of direct-acting anti-viral ( DAA) treatment for chronic hepatitis C patients. Methods The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA+-M2 BP and treatment efficacy was evaluated. Results The serum WFA+-M2 BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index ( COI) for WFA+-M2 BP for diagnosing advanced fibrosis. The sustained virological response ( SVR) rate was significantly, negatively correlated with the serum WFA+-M2 BP level. Multiple logistic regression analysis found a low serum WFA+-M2 BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA+-M2 BP level. Conclusion Serum WFA+-M2 BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients. [ABSTRACT FROM AUTHOR]

Objectives: The current standard of care for chronic hepatitis C patients is a pegylated interferon-α plus ribavirin combination treatment. This study was carried out to determine the relationship between ribavirin concentration in the later stages of treatment and virological relapse.Patients and Methods: Serum ribavirin concentration of 183 chronic hepatitis C patients (genotype 1) treated with pegylated interferon-α2b plus ribavirin for 48 weeks was prospectively measured by HPLC at weeks 4, 12, 24, 36 and 48. Patients with undetectable serum hepatitis C virus (HCV) RNA 24 weeks after the end of treatment were designated as having sustained virological response (SVR). Patients with undetectable HCV RNA during the treatment but with virological relapse after the end of treatment were designated relapse.Results: The mean ribavirin concentration at each testing point of patients with SVR (1401, 1725, 1803, 1811 and 1901 ng/mL) was significantly higher than that of relapse patients (998, 704, 607, 643 and 654 ng/mL) at weeks 4, 12, 24, 36 and 48, respectively (all P < 0.001). Multivariate regression analysis for relapse extracted ribavirin concentration at week 36, but not cumulative ribavirin dosage. The cut-off value by receiver operating curve analysis for predicting a relapse was 1503 and 1562 ng/mL at weeks 36 and 48, respectively.Conclusions: Ribavirin concentration in the later stages of treatment is an important marker of viral relapse. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is a major problem associated with hemodialysis. The extent of liver damage in hemodialysis patients with chronic HCV infection has not been thoroughly documented. The aim of this study was to evaluate liver damage of hemodialysis patients infected with HCV. A total of 233 hemodialysis patients were categorized into two groups at entry: group X, 80 positive for serum HCV RNA, and group Y, 153 negative for serum HCV RNA. All were tested for serum alanine aminotransferase (ALT) serially from 1989 to 1998, and serum hyaluronic acid (HA), serum type-IV collagen (IV-C), platelet counts, and ultrasonographic examination of the liver was done in 1998. In group X, 61.3% had continuously abnormal ALT levels for over six months followed by normal ALT levels. Of the group X patients, 11.3% had abnormal ALT levels in 1998, and in three, hepatocellular carcinoma occurred. Mean HA and IV-C levels in group X (648.8 and 188.7 ng/ml, respectively) were significantly higher than in group Y (213.1 and 165.5 ng/ml, respectively) (P < 0.05). Ultrasonographic findings significantly correlated with serum HA level and platelet counts and showed significantly more abnormalities in group X than in group Y (P < 0.05). From these findings, a combined examination with ultrasonography and serum fibrogenesis markers is useful for detection of liver damage in hemodialysis patients with HCV viremia. [ABSTRACT FROM AUTHOR]

TT virus (TTV) has been identified in patients with posttransfusion hepatitis of unknown etiology and is thought to be a new hepatitis virus. We determined the extent of TTV infection in the Japanese general population and the relationship between TTV DNA genotype and liver damage. In 1998, we tested 847 serum samples for TTV. TTV DNA was assayed by a nested polymerase chain reaction and classified into three different genotypes and eight subtypes. TTV DNA was detected in 25.3% and 32.4% of the inhabitants of the two areas studied, respectively. The genotype distribution was similar in both areas. G1, G2, and G3 were 60%, 20%, and 5%, respectively. Of the 20 subjects with TTV DNA alone and elevated serum ALT levels, 18 were G1, one was G2, and one was G3. TTV infection is endemic in the Japanese general population studied. The main TTV genotype, G1, may be related to the ensuing liver damage. [ABSTRACT FROM AUTHOR]

To determine the effects of interferon treatment, we studied 77 Japanese patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase (ALT). Of 77 patients, 37 were given natural interferon-alpha for 24 weeks, and 40 not given interferon acted as controls. Serum samples were tested for HCV RNA and genotypes by polymerase chain reaction (PCR). HCV RNA levels were measured by competitive PCR. Of 37 treated patients, 11 (29.7%) had sustained elimination throughout a six-month follow-up, while HCV RNA was not eliminated in any untreated patients. At 24 months, the number of patients with elevated ALT was not significantly different between treated (13.5%) and untreated patients (15%). Interferon eliminates HCV RNA in patients with normal ALT without severe side effects. The natural history of HCV infection should be clarified so that the interferon treatment regimen can be tailored to the needs of each patient. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine if HCV can be transmitted from patient to patient in psychiatric institutions and to determine possible routes of infection. We did a cross-sectional survey of 196 Japanese psychiatric patients tested for HCV and HBV markers and 400 age- and sex-matched controls. Anti-HCV was detected in 10.2% and antibody to hepatitis B core antigen was detected in 44.4% of the patients, a significantly higher prevalence than found among matched controls. A multiple regression logistic analysis was used to identify risk factors that could indicate the route of infection by HCV. Duration of hospitalization, age, razor sharing, and history of surgery proved to be statistically significant independent risk factors associated with positive anti-HCV results [odds ratio (OR), 4.00; 95% confidence interval (CI), CI, 1.74-9.19; OR, 2.19; 95% CI, 1.27-1.3.77; OR, 4.90; 95% CI, 1.29-18.86; OR, 3.35; 95% CI, 0.997-11.3, respectively]. These observations suggest that razor sharing played an important role in the spread of the HCV infection in the institutionalized psychiatric patients we studied. [ABSTRACT FROM AUTHOR]

To more accurately determine the seroprevalence of hepatitis G virus (HGV) infection, we surveyed antibody to HGV (anti-E2) by enzyme-linked immunosorbent assay (ELISA) and HGV RNA by nested polymerase chain reaction (PCR) in 298 residents of a hepatitis C virus (HCV)-endemic area of Japan and in 225 hemodialysis patients. We then compared these findings with known HCV and hepatitis B virus (HBV) infection prevalences. Anti-E2 and HGV RNA prevalences were 32 (10.7%) and 5 (1.7%) in the residents and 24 (10.7%) and 10 (4.4%) in the hemodialysis patients, respectively. Anti-E2 and HGV RNA concurrence was found in two of the hemodialysis patients. Total HGV marker (anti-E2 and/or HGV RNA) prevalences [37 (12.4%) in residents and 32 (14.2%) in hemodialysis patients], were significantly lower than the prevalences of antibody to HCV (anti-HCV) by ELISA [59 (19.8%) and 96 (42.7%)], and antibody to hepatitis B core antigen (anti-HBc) by radioimmunoassay (RIA) [87 (29.2%) and 101 (44.9%)] (P<0.05). The anti-HCV prevalence in subjects with total HGV marker was significantly higher than in those without total HGV marker. There was no significant difference in anti-HBc prevalence between those with and without total HGV marker. The viremic rate was highest in HCV infection (HCV RNA by PCR/anti-HCV) (83.2%), with HGV infection (HGV RNA/total HGV marker) (21.7%) intermediate, and HBV infection (hepatitis B surface antigen by RIA/anti-HBc) (5.3%) lowest (P<0.05). These findings indicate that HGV infection was less endemic than HCV and HBV. HGV was eliminated naturally more frequently than HCV infection and less frequently than HBV infection. [ABSTRACT FROM AUTHOR]

To compare virological, biochemical, and immune responses to human lymphoblastoid interferon (IFN-alpha) and human fibroblast interferon (IFN-beta) in patients with chronic hepatitis C virus (HCV) infection, 120 patients were randomly assigned to three groups (group A, 60 patients receiving IFN-alpha, 6 million units (MU) once a day, daily for one month and thrice weekly for five months; group B, 40 patients receiving 6 MU IFN-beta once a day daily for two months; and group C, 20 patients receiving 3 MU IFN-beta twice a day (6 MU/day) daily for two months). Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Patients with sustained clearance of serum HCV RNA detected by polymerase chain reaction (PCR) at six months after IFN treatment were defined as having complete response to IFN treatment. A low level of HCV RNA (< or = 10(4) copies/50 microl, measured by competitive PCR) and HCV RNA of genotype 2a were favorable factors for a complete response to both IFNs. Complete response in group A treatment was strongly associated with early HCV RNA clearance, in contrast with group B. A significantly higher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%), compared with groups A (41.6%) and B (27.5%). sIL-2R levels rose in each group during IFN administration. In group C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findings indicate that timing of serum HCV RNA negativity in sustained response differs between IFN-alpha and IFN-beta administrations and that early HCV RNA clearance was induced by twice-a-day IFN-beta treatment. [ABSTRACT FROM AUTHOR]

To determine the effects of hepatitis G virus (HGV) infection on chronic hepatitis C virus infection (HCV) and to evaluate HGV response to interferon, we investigated HGV RNA by polymerase chain reaction in 247 Japanese patients with chronic HCV infection (166 men and 81 women; 124 had chronic hepatitis and 26 cirrhosis, and 97 hepatocellular carcinoma). HGV RNA was detectable in 22 (8.9%) patients, among whom 21 were men: this male predominance was statistically significant (P < 0.01). There were no differences in age, aminotransferase level, stage of liver disease, HCV RNA level by competitive polymerase chain reaction, genotype, or interferon response to HCV RNA between patients with HCV infection alone or with HCV/HGV coinfection. Sustained elimination of HGV RNA was found in 28.6% of the 14 treated patients with HCV/HGV coinfection. In the 14 treated patients, sustained elimination of both viruses was seen in two, HCV alone was eliminated in two, and HGV alone was eliminated in two. Aminotransferase level improvement by interferon treatment was associated with clearance of HCV, but not of HGV. Thus, HGV infection had no apparent effects on HCV infection, and the sensitivity of HGV to interferon is comparable to but independent of HCV. [ABSTRACT FROM AUTHOR]

To determine the role of serum soluble interleukin-2 receptor (sIL-2R) in chronic hepatitis B virus (HBV) infection, the level of serum sIL-2R was measured in sera of 105 patients with chronic HBV infection and in 21 healthy controls, using enzyme-linked immunosorbent assay. Serum sIL-2R levels were significantly higher in chronic HBV-infected patients with chronic hepatitis (508+/-310 units/ml) and liver cirrhosis (543+/-283 units/ml) than in healthy controls (331+/-106 units/ml, P < 0.05). Moreover, serum sIL-2R levels were significantly higher in patients with chronic hepatitis or liver cirrhosis than in asymptomatic HBV carriers (341+/-150 units/ml, P < 0.01). There was no difference in serum sIL-2R levels between asymptomatic HBV carriers and healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significant relationship was found between serum sIL-2R and ALT levels (P < 0.05) in patients with chronic HBV infection, although there was no correlation between sIL-2R and HBV DNA levels. Serum sIL-2R levels in most patients decreased to the same level as asymptomatic HBV carriers and healthy controls at 48 weeks after the end of treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96 weeks. Thus, serum sIL-2R levels indicate the degree of liver damage among patients with chronic HBV infection. The serum sIL-2R levels one year after interferon administration may be a useful marker of determined at the effectiveness by this treatment. [ABSTRACT FROM AUTHOR]

To determine the routes of transmission of hepatitis G virus (HGV) and the relationship between HGV and hepatitis C virus (HCV) infections, we tested for HGV RNA by polymerase chain reaction and antibody to HCV (anti-HCV) in 494 hemodialysis patients, 638 inhabitants of two HCV endemic areas, and in 400 blood donors in Japan. HGV RNA was detected in 6.9% of hemodialysis patients, in 1.4% of inhabitants, and in 0.8% of donors, and anti-HCV was detected in 39.3%, 12.4%, and 1.8%, respectively. Of HGV RNA-positive hemodialysis patients, and HGV RNA-positive inhabitants, 64.7% and 11.1%, respectively, had been given blood transfusions. The prevalences of HGV RNA and anti-HCV significantly increased with the duration of hemodialysis. Of all HGV RNA positives, 74.4% were coinfected with HCV and subjects with HGV RNA alone had normal liver function. In conclusion, HGV is transmitted by blood transfusion and within the hemodialysis unit itself. HGV does not seem to injure hepatocytes. [ABSTRACT FROM AUTHOR]

To compare hepatitis C virus (HCV) RNA levels determined by branched DNA probe assay and by competitive polymerase chain reaction (PCR) as predictive markers of the response to interferon for treatment of patients with chronic HCV infection, we studied data on 140 patients treated for six months with natural interferon-alpha. Serum samples were tested for HCV RNA by PCR. HCV RNA was grouped into four genotypes by PCR with type-specific primers, and HCV RNA level was measured by branched DNA probe assay and by competitive PCR. HCV RNA was detected in all patients prior to initiation of the treatment. A complete response, sustained elimination of HCV RNA, occurred in 51 patients (36.4%). With multiple logistic regression analysis assessment, when using competitive PCR, a low level of HCV RNA (P < 0.0001), younger age (P = 0.0054) and genotype 2a and 2b (P < 0.0158) were significant predictive markers for a complete response to interferon treatment. When using branched DNA probe assay, a low level of HCV RNA (P < 0.0001) and age (P = 0.0089) were predictive markers, but genotype was not. The branched DNA probe assay had a narrower linear range for quantitation of HCV RNA level than competitive PCR. In conclusion, HCV RNA level determined by branched DNA probe assay proved to be useful for prediction of effects of interferon and it is cost effective as a marker of complete response to interferon treatment for patients with chronic HCV infection. [ABSTRACT FROM AUTHOR]