Satoshi Hiramine

Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: A randomized trial

BACKGROUND & AIMS Early menopause in women with chronic hepatitis C virus (HCV) infection is associated with a low likelihood of a sustained virological response (SVR) in conjunction with their antiviral treatment. This is potentially related to their reduced estrogen secretion. The study was done to determine whether selective estrogen receptor modulator administration might improve the efficacy of the current standard of care (SOC) treatment, pegylated interferon (PegIFN) α2a plus ribavirin (RBV), for postmenopausal women. METHODS One hundred and twenty-three postmenopausal women with genotype 1b chronic hepatitis C were randomly assigned to one of two treatment groups: raloxifene hydrochloride (RLX) (60 mg/day) plus SOC (PegIFNα2a 180 μg/week and RBV 600-1,000 mg/day) (n=62) or SOC only (n=61). Genotyping was performed of the polymorphism in the interleukin-28B (IL28B) gene region (rs8099917) of DNA collected from each patient. RESULTS One RLX-treated patient discontinued RLX because of a systemic rash following 2 weeks of treatment. Twenty-four weeks after treatment, the SVR rate was significantly higher for RLX plus SOC patients (61.3%) than for SOC only patients (34.4%) (p=0.0051). Further, the SVR rate was significantly higher for RLX plus SOC patients with IL28B TT (72.5%) than for SOC only patients with IL28B TT (39.2%) (p=0.0014), but no such relationship was observed in patients carrying the minor IL28B allele. CONCLUSIONS RLX improved the efficacy of SOC in the treatment of postmenopausal women with chronic hepatitis C. RLX shows promise as an adjuvant to the standard antiviral treatment of such patients.

Glycated albumin as a diagnostic tool for diabetes in a general Japanese population

OBJECTIVE Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population.

Serum cholesterol and triglyceride reference ranges of twenty lipoprotein subclasses for healthy Japanese men and women.

AIM This epidemiological study was done to generate normal ranges for the cholesterol and triglyceride levels in serum lipoprotein subclasses isolated from healthy adults based on gender and menopausal status. METHODS Cholesterol and triglyceride levels in 20 lipoprotein subclasses as separated by high performance liquid chromatography were measured in serum obtained from 825 fasting healthy subjects (267 men, 558 women). RESULTS For serum cholesterol, 13.7% was found in very low density lipoprotein (VLDL) subclasses, 55.6% in low density lipoprotein (LDL) subclasses, and 30.4% in high density lipoprotein (HDL) subclasses. For serum triglycerides, these values were 52.1%, 27.9%, and 17.4%, respectively. Levels of cholesterol in some VLDL subclasses were inversely correlated with the levels of some HDL subclasses, while for triglycerides, elevated levels in any one subclass were generally strongly associated with elevated levels in all other subclasses. Men had significantly higher large VLDL-cholesterol levels than women (P < 0.05), while women had significantly higher small VLDL-cholesterol levels than men (P < 0.001). Women had significantly higher large LDL- and large and medium HDL-cholesterol levels than men (P < 0.001). Men had significantly higher chylomicron (CM), large and medium VLDL-, and small LDL-triglyceride levels than women (P < 0.001). Women had significantly higher very large and large HDL-triglyceride levels than men (P < 0.01). Postmenopausal women had significantly higher CM, all VLDL, and large, medium and small LDL-cholesterol levels, and significantly higher all VLDL, LDL, and HDL-triglyceride levels than premenopausal women (P < 0.001). CONCLUSIONS Our data document important gender and menopausal status differences in cholesterol and triglyceride subclass levels, as well as significant correlations between values in the various serum lipoprotein subclasses.

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

The kinetics of the hepatitis B surface antigen level after the initiation of antiretroviral therapy for hepatitis B virus and human immunodeficiency virus coinfected patients

BACKGROUND Hepatic flares (HF), which reflect hepatitis B virus (HBV)-related immune reconstitution inflammatory syndrome (IRIS), frequently occur in patients with HBV and human immunodeficiency virus (HIV) coinfection after the start of antiretoroviral therapy (ART). The rate of hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss is higher for patients with HF after the initiation of ART. METHODS We retrospectively examined the kinetics of the HBsAg and HBeAg levels of six HBV/HIV coinfected patients after the commencement of ART that included tenofovir. All were male and HBeAg positive. RESULTS Three patients developed HF after the initiation of ART. All subsequently lost HBeAg and one of them lost HBsAg after HF. None who did not experience HF lost HBeAg. The HBsAg and HBeAg levels remarkably decreased when HF occurred, but the decline of HBsAg was very slow in the periods before and after HF. The median decline of the HBsAg level at 48 weeks was 2.20 Log IU/mL for patients with HF, but only 1.00 Log IU/ml for patients without HF. Little decline was seen for either group in the median decline of the HBsAg level from 48 weeks to 96 weeks, 0.28 Log IU/mL in the HF group and 0.06 Log IU/mL in the non-HF group. CONCLUSION The immune reconstitution of a HBV/HIV coinfected patient plays an important role in the clearance of HBV. If HBsAg and HBeAg levels decrease rapidly when HF occurs, the hepatic flare would be due to HBV-related IRIS.

Efficacy and Tolerance of Interferon β Plus Ribavirin Treatment for Chronic Hepatitis C Patients with Depression or ThrombocytopeniaComparison with Pegylated Interferon α Plus Ribavirin Treatment

Objective: Limited data has been reported comparing natural human interferon β (nIFNβ) and pegylated IFN-α (PEG-IFNα) when Ribavirin (RBV) is combined. This case-control study was done to compare the efficacy and adverse effects of a combination treatment of nIFNβ or PEG-IFNα plus RBV for chronic hepatitis C patients. Methods: Sixty patients with chronic hepatitis C, 42 infected with hepatitis C virus (HCV) genotype 1 and 18 infected with genotype 2, were treated with nIFNβ plus RBV. Of them, 23 (38.3%) suffered pre-treatment severe depression. Their data was compared with 60 undepressed patients treated with a combination of PEG-IFNα plus RBV. nIFNβ was given intravenously and PEG-IFNα was injected subcutaneously. Results: Sustained virological response (undetectable HCV RNA at 24 weeks after the end of treatment) did not significantly differ between the nIFNβ and PEG-IFNα treated patients (genotype 1, 21.4% vs. 33.3%, P=0.328; genotype 2, 72.2% vs. 88.9%, respectively, P=0.402). None of the nIFNβ treated patients showed exacerbation of depression, while 7 (11.7%) of 60 PEG-IFNα treated patients developed severe depression or malaise. The platelet count of nIFNβ treated patients increased to higher than baseline after week 8, but the platelet count of PEG-IFNα treated patients decreased throughout the treatment. There were significant differences of the changes of platelet counts between the both groups throughout the treatment (all P<0.001). Conclusion: nIFNβ plus RBV treatment was well tolerated by chronic hepatitis C patients with depression or thrombpcytopenia.

Erratum to A thymine–adenine dinucleotide repeat polymorphism near IL28B is associated with spontaneous clearance of hepatitis C virus (J Gastroenterol, (2015), 50, (1069-1077), 10.1007/s00535-015-1056-1)

Please note that there are errors in the original article: In the paragraph with the heading ‘‘Association between spontaneous HCV clearance and the number of TA repeats in the African-American samples’’ in the Results section (p. 1073), the expression shown as ‘‘(20.0 vs. 60.9 %...)’’ in the third sentence should read ‘‘(20.0 vs. 59.4 %...)’’. The sentence should read as follows: ‘‘The rate of spontaneous clearance was significantly lower for persons in whom the TA repeats of both alleles were ten or shorter compared to those with no allele of ten or shorter (20.0 vs. 59.4 %, p = 0.001) and compared to those with at least one allele 11 or longer (20.0 vs. 53.6 %, p = 0.004).’’ Similarly, in the last sentence of the legend for Fig. 2, 60.9 %. should be 59.4 %. The sentence should read as follows: ‘‘The rate of spontaneous clearance was significantly lower for 10/10 (20.0 %) than for 11/11 (59.4 %) or the combined group of 11/11 and 10/11 (53.6 %).’’

Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C

AIM To investigate the efficacy of virological response (VR) to telaprevir (TVR)-based triple therapy in predicting treatment outcome of hepatitis C. METHODS This prospective, multicenter study consisted of 253 Japanese patients infected with hepatitis C virus (HCV) genotype 1b. All received 12 wk of TVR in combination with 24 wk of pegylated-interferon-α (IFN-α) and ribavirin. Serum HCV RNA was tested at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. VR was defined as undetectable serum HCV RNA. Sustained virological response (SVR) was VR at 24 wk after the end of treatment and was regarded as a successful outcome. RESULTS Of 253 patients, 207 (81.8%) achieved SVR. The positive predictive value of VR for SVR was 100% at week 2, after which it gradually decreased, and was over 85% to week 12. The negative predictive value (NPV) gradually increased, reaching 100% at week 12. The upslope of the NPV showed a large increase from week 4 (40.6%) to week 6 (82.4%). There was a moderate concordance between the SVR and VR at week 6 (kappa coefficient = 0.44), although other VRs had poor concordance to SVR. Multiple logistic regression analysis extracted VR at week 6 (P < 0.0001, OR = 63.8) as an independent factor contributing to SVR. In addition, the interleukin-28B single nucleotide polymorphism and response to previous pegylated-IFN-α and ribavirin therapy were identified as independent factors for SVR. CONCLUSION VR at week 6, but not at week 4, is an efficient predictor of both SVR and non-SVR to TVR-based triple therapy.

P711 A NOVEL GENETIC MAKER TO IMPROVE THE PREDICTION OF HCV SPONTANEOUS CLEARANCE: POLYMORPHISMS CONSISTING OF (TA)N DINUCLEOTIDE REPEAT NEAR IL28B GENE

irreversible CYP3A4 inhibitor, and inhibitor of multiple cellular uptake and efflux transporters. This study evaluated the interaction between ALV and methadone to assess potential clinical risks for methadone withdrawal or toxicity. Methods: Open-label screening (Part 1) and randomized, placebocontrolled, double blind (Part 2) investigation. Healthy subjects received a single 5mg dose of methadone before and after ALV (Part 1). Then, opioid-dependent patients on stable MMT (≤150mg daily) were randomized (2:1) to receive ALV 600mg BID or placebo for 7 days (Part 2). Safety assessments included daily vitals and 12lead ECGs, laboratory tests, and continuous pulse oximetry. Blood samples were collected for Rand S-methadone concentrations prior to and after dose administration on D1 (before ALV) and D8. Non-compartmental PK analysis was performed. Results: 16 healthy and 22 MMT subjects (14 active; 8 placebo) were enrolled. Two healthy and 2 MMT subjects withdrew consent before study completion. Dizziness (37.5%), headache (18.8%), and nausea (18.8%) were the most commonly reported AEs among healthy subjects; somnolence (30.8% vs. 25.0%), headache (30.8% vs. 12.5%), nausea (15.4% vs. 0%), and tremor (15.4% vs. 0%) among MMT subjects receiving ALV vs. placebo.