Koichi Takaguchi

Daclatasvir Plus Asunaprevir for Chronic HCV Genotype 1b Infection

All‐oral combinations of direct‐acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin‐based regimens. In this open‐label, phase 3 study, 135 interferon‐ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24). This study is registered with ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon‐ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non‐CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol‐defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. Conclusion: Interferon‐free, ribavirin‐free all‐oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon‐based therapy. (Hepatology 2014;59:2083–2091)

Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection.

BACKGROUND & AIMS To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients. METHODS One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples. RESULTS After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset. CONCLUSIONS Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.

Tolvaptan for improvement of hepatic edema: A phase 3, multicenter, randomized, double‐blind, placebo‐controlled trial

Hepatic edema is manifested by ascites, lower limb edema and intolerable symptoms. Some patients insufficiently respond to the conventional diuretic therapy. Therefore, a novel therapeutic option is required. We conducted a phase 3 study to confirm therapeutic effect of tolvaptan on hepatic edema associated with liver cirrhosis.

Efficacy and safety of double filtration plasmapheresis in combination with interferon therapy for chronic hepatitis C

Aim:  Efficacy and safety of double filtration plasmapheresis (DFPP) for chronic hepatitis C were prospectively analyzed in Japanese clinical settings.

Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B

BACKGROUND & AIMS Anti-hepatitis C virus (HCV) therapy by interferon (IFN)-free regimen with oral direct-acting antiviral drugs are tolerable in aged patients, with fewer adverse effects than IFN-based therapies. We investigated the efficacy and tolerability of an IFN-free anti-HCV therapy in extremely aged patients, as well as the survival benefit of sustained virologic response (SVR). METHODS Following IFN-free therapy with daclatasvir and asunaprevir, tolerability and SVR rate were compared between 115 HCV genotype 1-infected patients aged 80years or older, 151 patients in their 70s (⩾70 and <80years), and 115 patients under the age of 70. One-year mortality and morbidity in patients aged ⩾80years were compared between SVR patients and propensity score-matched patients with persistent HCV infection. RESULTS The SVR rate was 96.5% in patients ⩾80years, comparable to that in patients aged ⩾70 and <80years (95.4%) and patients aged <70years (93.9%). There were no differences in treatment discontinuation rate (2.6%, 1.3%, and 0.9%, respectively). One-year mortality was significantly lower in SVR patients (2.7%) than in patients with persistent HCV infection (15.3%, p=0.0016). Whereas 1-year mortality due to liver-related diseases was 8.1% in patients with persistent HCV infection who were aged ⩾80years, no SVR patients died from liver diseases within 1-year after the end of therapy. CONCLUSIONS IFN-free therapy for HCV infection was associated with high tolerability and antiviral efficacy, even in patients aged ⩾80years. In addition, there seemed to be a survival benefit from the eradication of HCV in this population. LAY SUMMARY IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged ⩾80years as in younger patients (patients aged ⩾70 and <80years and patients aged <70years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged ⩾80years.

Clinical Evaluation of Sofosbuvir/Ledipasvir in Chronic Hepatitis C Genotype 1 with and without Prior Daclatasvir/Asnaprevir Therapy.

This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy.

Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy

This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy.

Characteristics and Prognosis of Hepatocellular Carcinoma Detected in Patients with Chronic Hepatitis C after the Eradication of Hepatitis C Virus: a Multicenter Study from Japan

We investigated the characteristics and prognosis of patients with hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) to antiviral therapy for chronic hepatitis C virus (HCV) infection, namely, the eradication of HCV, according to surveillance status after SVR.

Significance of a reduction in HCV RNA levels at 4 and 12 weeks in patients infected with HCV genotype 1b for the prediction of the outcome of combination therapy with peginterferon and ribavirin

BackgroundThe importance of the reduction in hepatitis C virus (HCV) RNA levels 4 and 12 weeks after starting peginterferon (PEG-IFN) and ribavirin combination therapy has been reported to predict a sustained virologic response (SVR) in patients infected with HCV genotype 1. We conducted a multicenter study to validate this importance along with baseline predictive factors in this patient subpopulation.MethodsA total of 516 patients with HCV genotype 1 and pretreatment HCV RNA levels ≥5.0 log10 IU/mL who completed response-guided therapy according to the AASLD guidelines were enrolled. The reduction in serum HCV RNA levels 4 and 12 weeks after starting therapy was measured using real-time PCR, and its value in predicting the likelihood of SVR was evaluated.ResultsThe area under the receiver operating characteristics (ROC) curve was 0.852 for 4-week reduction and 0.826 for 12-week reduction of HCV RNA levels, respectively. When the cut-off is fixed at a 2.8-log10 reduction at 4 weeks and a 4.9-log10 reduction at 12 weeks on the basis of ROC analysis, the sensitivity and specificity for SVR were 80.9% and 77.9% at 4 weeks and were 89.0% and 67.2% at 12 weeks, respectively. These variables were independent factors associated with SVR in multivariate analysis. Among 99 patients who showed a delayed virologic response and completed 72-week extended regimen, the area under ROC curve was low: 0.516 for 4-week reduction and 0.482 for 12-week reduction of HCV RNA levels, respectively.ConclusionsThe reduction in HCV RNA levels 4 and 12 weeks after starting combination therapy is a strong independent predictor for SVR overall. These variables were not useful for predicting SVR in patients who showed a slow virologic response and experienced 72-week extended regimen.

Effects of branched-chain amino acid granules on serum albumin level and prognosis are dependent on treatment adherence in patients with liver cirrhosis

To test if the treatment adherence to branched‐chain amino acid (BCAA) granules influences the serum albumin level and prognosis in prospective 2984 patients with decompensated liver cirrhosis who were prescribed BCAA granules containing 952 mg of L‐isoleucine, 1904 mg of L‐leucine and 1144 mg of L‐valine at 4.15 g/sachet three times a day after meals.