Yasunobu Kawakami

Hepatitis C virus infection in institutionalized psychiatric patients: Possible role of transmission by razor sharing

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.

Differences between interferon-α and -β treatment for patients with chronic hepatitis C virus infection

To compare virological, biochemical, and immuneresponses to human lymphoblastoid interferon(IFN-α) and human fibroblast interferon(IFN-β) in patients with chronic hepatitis C virus(HCV) infection, 120 patients were randomly assigned to threegroups (group A, 60 patients receiving IFN-α, 6million units (MU) once a day, daily for one month andthrice weekly for five months; group B, 40 patients receiving 6 MU IFN-β once a day daily fortwo months; and group C, 20 patients receiving 3 MUIFN-β 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 byenzyme-linked immunosorbent assay. Patients withsustained clearance of serum HCV RNA detected bypolymerase chain reaction (PCR) at six months after IFNtreatment were defined as having complete response to IFNtreatment. A low level of HCV RNA (≤10-4copies/50 mul, measured by competitive PCR) and HCV RNAof genotype 2a were favorable factors for a completeresponse to both IFNs. Complete response in group Atreatment was strongly associated with early HCV RNAclearance, in contrast with group B. A significantlyhigher 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-2Rlevels rose in each group during IFN administration. Ingroup C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findingsindicate that timing of serum HCV RNA negativity insustained response differs between IFN-α andIFN-β administrations and that early HCV RNAclearance was induced by twice-a-day IFN-βtreatment.

Human lymphoblastoid interferon treatment for patients with hepatitis C virus-related cirrhosis

To evaluate the efficacy and safety of human lymphoblastoid interferon treatment (interferon alfa) for patients with compensated cirrhosis caused by hepatitis C virus (HCV) infection, we randomly assigned 82 cirrhotic patients with chronic HCV infection (44 men, 38 women; mean age, 58.6 years) to two groups: 41 patients were treated with interferon alfa (480 million U over 6 months), and the other patients received no drug treatment. HCV RNA genotypes were determined by polymerase chain reaction (PCR) testing using type-specific primers. HCV RNA levels were measured by competitive PCR testing. No untreated patients eliminated HCV RNA from the serum or had a decrease in the level of alanine aminotransferase to normal during the observation period. Of the 34 patients who completed interferon alfa treatment, 6 (17.6%) who were considered complete responders eliminated HCV RNA from the serum by the end of treatment and sustained this elimination throughout a 6-month follow-up period. Complete responders constituted 6 (46.2%) of 13 patients with HCV RNA levels < or = 10(5) copies/50 microL, but none of the 21 patients with levels > 10(5) copies/50 microL were complete responders. Two (7.1%) of 28 patients with genotype 1b infection and 4 (66.7%) of 6 with genotype 2a were complete responders. Five patients withdrew because of interferon alfa-induced side effects (1 for thrombocytopenia, 3 for severe general malaise, and 1 for impotence), and 2 withdrew after being diagnosed with hepatocellular carcinoma. Hepatic failure did not occur in any treated patient in the present study. These findings indicate that interferon alfa treatment is useful for compensated cirrhosis caused by HCV infection if the HCV RNA levels are low and the infection is of genotype 2a.

Increased frequency of interferon-γ-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection

Increased frequency of interferon-γ-producing peripheral blood CD4 + T cells in chronic hepatitis C virus infection

Immunogenicity and safety of a novel AS03A-adjuvanted H1N1 2009 pandemic influenza vaccine in adults in Japan

We are grateful to the New York Medical College, New York for providing the vaccine virus strain and to the National Institute for Biological Standards and Control (NIBSC, UK) and the Therapeutic Goods Administration (TGA) from the Australian Government for providing the reference standards. The authors are indebted to the participating study volunteers, clinicians, nurses and laboratory technicians at the study sites as well as to the sponsor’s project staff for their support and contributions throughout the study. We are grateful to all teams of GSK Biologicals for their contribution to this study, especially Kazunori Yagi, Maki Matsuzaki, Kayoko Endo, Kenji Ishizuka, Shinobu Tamura, Hiroshi Tamura for clinical study management and site monitoring, Karl Walravens and Roger Bernhard from the clinical and serological laboratory teams, Liliana Manciu for preparation of the study protocol and related study documentation, Koen Ceulemans for global study management, Dorothy Slavin (Clinical Safety Representative), Edith Lépine for project management, and David Vaughn for project direction. The authors thank Avishek Pal (GlaxoSmithKline Biologicals) for medical writing and Dr Antoine Minne (Keyrus Biopharma) and Dr. Wendy Van Doorslaer (XPE Pharma & Science) for editorial assistance and manuscript coordination.

Comparison of HCV RNA levels by branched DNA probe assay and by competitive polymerase chain reaction to predict effectiveness of interferon treatment for patients with chronic hepatitis C virus

To compare hepatitis C virus (HCV) RNA levelsdetermined by branched DNA probe assay and bycompetitive polymerase chain reaction (PCR) aspredictive markers of the response to interferon fortreatment of patients with chronic HCV infection, westudied data on 140 patients treated for six months withnatural interferon-alpha. Serum samples were tested forHCV 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 probeassay and by competitive PCR. HCV RNA was detected inall patients prior to initiation of the treatment. A complete response, sustained elimination ofHCV RNA, occurred in 51 patients (36.4%). With multiplelogistic regression analysis assessment, when usingcompetitive 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 fora complete response to interferon treatment. When usingbranched DNA probe assay, a low level of HCV RNA (P < 0.0001) and age (P = 0.0089) werepredictive markers, but genotype was not. The branchedDNA probe assay had a narrower linear range forquantitation of HCV RNA level than competitive PCR. In conclusion, HCV RNA level determined bybranched DNA probe assay proved to be useful forprediction of effects of interferon and it is costeffective as a marker of complete response to interferontreatment for patients with chronic HCVinfection.

Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection.

OBJECTIVES:To determine the profile of cytokine secretion by CD4+ T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-γ and interleukin (IL)-4 producing cells from CD4+ T lymphocytes in peripheral blood obtained from patients chronically infected with HCV.METHODS:Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-γ and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA.RESULTS:The frequency of IFN-γ producing CD4+ cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls (p < 0.01, respectively). In contrast, the percentages of IL-4-producing CD4+ cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-γ-producing cells.CONCLUSIONS:In HCV infected subjects, both serum sIL-2R and IFN-γ are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.

Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response.

We investigated the timing of the disappearance and reappearance of serum hepatitis C viral (HCV) RNA in patients with chronic hepatitis C during interferon treatment and follow-up. Serum samples were tested for HCV RNA by polymerase chain reaction in 62 patients with chronic hepatitis C treated with interferon-alpha for 24 weeks. We found that 17 patients obtained complete response, with absence of serum HCV RNA for 6 months after the treatment. Twenty-nine patients had a partial response, with reappearance of serum HCV RNA within 6 months of follow-up, and 16 patients were nonresponders who were positive for serum HCV RNA throughout the observation period. HCV RNA disappeared within 2 weeks of treatment in 31 patients, including all 17 (100%) complete responders and 14 (48.3%) of the 29 partial responders. The patients remaining positive for HCV RNA at the second week were 15 (51.7%) of the 29 partial responders and the 16 nonresponders. In all of the 29 partial responders, viremia recurred within 1 month after the treatment. These results indicate that the status of HCV RNA at the second week of treatment is a useful predictor of effective treatment, whereas status at the first month after cessation of treatment is useful for assessing the effectiveness of interferon itself.

Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults

Background Long-term persistence of immune response and safety of two doses of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) administered 21 d apart was evaluated in Japanese adults [NCT00989612]. Methods One-hundred healthy subjects aged 20−64 y (stratified [1:1] into two age strata 20−40 y and 41−64 y) received 21 d apart, two doses of AS03-adjuvanted 3.75µg haemagglutinin (HA) H1N1 2009 vaccine. Immunogenicity data by haemagglutination inhibition (HI) assay six months after the first vaccine dose (Day 182) and microneutralization assay following each of the two vaccine doses (Days 21 and 42) and at Day 182 are reported here. Results Persistence of strong HI immune response was observed at Day 182 that met the US and European regulatory thresholds for pandemic influenza vaccines (seroprotection rate: 95%; seroconversion rate: 93%; geometric mean fold-rise: 20). The neutralizing antibody response against the A/Netherlands/602/2009 strain (antigenically similar to vaccine-strain) persisted for at least up to Day 182 (vaccine response rate: 76%; geometric mean titer: 114.4) and paralleled the HI immune response at all time points. No marked difference was observed in HI antibody persistence and neutralising antibody response between the two age strata. The vaccine had a clinically-acceptable safety profile. Conclusion Two priming doses of H1N1 2009 pandemic influenza vaccine induced an immune response persisting for at least six months after the first vaccine dose. This could be beneficial in evaluating the importance and effect of vaccination with this AS03-adjuvanted pandemic influenza vaccine.

Effectiveness of Interferon Treatment for Patients with Chronic Hepatitis C Virus Infection and Normal Aminotransferase Levels

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-α 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.