Efficacy and safety of glecaprevir and pibrentasvir in Japanese patients with hepatitis C virus infection aged 75 years or older.

BACKGROUND: It is estimated that approximately 50% of patients with hepatitis C virus (HCV) infection in Japan are currently over 75 years old. However, patients aged ≥ 75 years are typically underrepresented in clinical trials of direct-acting antivirals. This study aimed to evaluate the efficacy and safety of glecaprevir and pibrentasvir (G/P) treatment in Japanese patients with HCV infection aged ≥ 75 years. METHODS: This multicenter, retrospective study included 271 Japanese patients with HCV infection from 12 centers in Miyazaki Prefecture, Japan. Demographic, clinical, virological, and adverse events (AEs) data obtained during and after G/P treatment were collected from medical records. The patients were divided into two groups: younger (n = 199, aged < 75 years) and older (n = 72, aged ≥ 75 years). Virological data and AEs were analyzed according to the age group. RESULTS: In intention-to-treat (ITT) and per-protocol analyses, the overall sustained virological response 12 (SVR12) rates were 93% and 98.8%, respectively. Two patients in the older group and 14 patients in the younger group dropped out before SVR12 assessment. Although patients in the older group tended to have liver cirrhosis, 95.8% in the older group and 92% in the younger group achieved SVR12 in the ITT analysis (P = 0.404). In total, 48 (17.7%) patients experienced treatment-related AEs. Common AEs during treatment included pruritus, headache, and fatigue. The AEs were not significantly different between the two groups. CONCLUSIONS: Compared with younger patients, older patients showed similar virological response and tolerance to G/P treatment.

Monocyte-derived fibrocytes elimination had little contribution on liver fibrosis.

BACKGROUND: Monocyte-derived fibrocytes play an important role in the progression of fibrosis in the skin, lungs, heart and kidney. However, the contribution of fibrocytes to liver fibrosis is unclear. The aim of this study was to investigate whether fibrocytes contributed to fibrosis progression in the livers of carbon tetrachloride (CCl4)-treated mice. METHODS: C57BL/6J mice were divided into 4 groups: normal control group, CCl4-treated group, CCl4 + control liposome-treated group, and CCl4 + clodronate liposome-treated group. For the elimination of systemic monocyte and monocyte-derived fibrocyte, one group was treated with clodronate liposome, and another group with control liposome as a control. After 4 weeks of treatment, hepatic mononuclear cells were subjected to immunofluorescent (IF) staining and fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes. Measurement of collagen-positive Sirius red stained area and collagen-I mRNA expression in the liver were performed to evaluate the degree of liver fibrosis quantitatively. RESULTS: In the liver of the CCl4-treated and CCl4 + control liposome-treated groups, the number of fibrocytes, the area positive for Sirius red staining and collagen-I mRNA expression significantly increased compared with those in the normal control group. In the liver of the CCl4 + clodronate liposome-treated group, few fibrocytes was observed as in the normal control group, but Sirius red staining positive area and collagen-I mRNA expression were increased and equivalent to the CCl4-treated and CCl4 + control liposome-treated groups. CONCLUSION: Monocyte-derived fibrocytes play a minimal role in CCl4-induced liver fibrosis. Cells other than fibrocytes such as hepatic stellate cells play a central role in liver fibrosis.

[Two cases of acute hepatitis E infected with descendant strains of hepatitis E virus genotype 3 strain isolated from swine herd in Miyazaki Prefecture 12 years ago - one case had acute facial paralysis].

We experienced two cases of acute hepatitis E in Miyazaki Prefecture in the same period. The patients were unknown to each other and did not have any clear causes or common risk factors of hepatitis E virus (HEV) infection. Nucleotide sequences of the HEV isolates revealed that the two isolates were closely related but with different HEV genotype 3 strains. The two cases appeared to be infected from unknown and different sources. Molecular phylogenetic analysis indicated that the strains were probably descendants of the strains which had been isolated from swine herd in Miyazaki Prefecture 12 years previously. This result indicates that the strains persisted in pig farms, in wild life, or in the natural environment in this region. The source should be identified, and efforts should be made to prevent of the spread of the infection. One of the cases had acute facial paralysis, which might be an extra-hepatic manifestation of HEV infection.

Impact of a single nucleotide polymorphism upstream of the IL28B gene in patients positive for anti-HCV antibody in an HCV hyperendemic area in Japan.

The influence of genetic variation at the interleukin-28B (IL28B) locus on the natural course of hepatitis C virus (HCV) infection has not been fully investigated. The goal of this study was to examine whether an IL28B polymorphism (rs8099917) is associated with natural clearance of HCV and with disease parameters of HCV infection in an HCV hyperendemic area of Japan. The patients were 502 anti-HCV antibody-positive residents who participated in liver disease screening program from 2002 to 2004. Patients who underwent interferon-based therapy or had hepatocellular carcinoma were excluded. Of these patients, 149 were negative for HCV RNA (prior infection) and 353 were positive for HCV RNA or HCV core antigen (HCV carriers). In multivariate analysis, the IL28B TT genotype was a predictor for prior HCV infection. In addition, nine of the patients with prior HCV infection were positive for anti-HCV antibody with positive for HCV core antigen or HCV RNA before 2001, and these nine patients all had the IL28B TT genotype. Furthermore, the IL28B TT genotype was associated independently with higher HCV core antigen levels in HCV carriers. In contrast, the IL28B genotype did not affect the biochemical markers, such as alanine aminotransferase, hepatic fibrosis markers, and α-fetoprotein, and the degree of hepatic fibrosis assessed by transient elastography in HCV carriers. We concluded that IL28B polymorphism (TT genotype) is associated with spontaneous clearance of HCV and conversely with high viral loads in HCV carriers. In contrast, the IL28B genotype does not affect disease progression such as hepatic fibrosis.

Impact of antibody to hepatitis B core antigen on the clinical course of hepatitis C virus carriers in a hyperendemic area in Japan: A community-based cohort study.

AIM: Subjects positive for antibody to hepatitis B core antigen (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are considered to have occult hepatitis B virus (HBV) infection. The aim of this study was to determine the impact of occult HBV infection on aggravation of the clinical course in hepatitis C virus (HCV) carriers. METHODS: A prospective cohort study was performed in 400 subjects who were positive for anti-HCV antibody and negative for HBsAg. Among these subjects, 263 were HCV core antigen positive or HCV RNA positive (HCV carriers). We examined whether the presence of HBcAb affected the clinical course in these HCV carriers from 1996-2005. RESULTS: The HBcAb positive rates were 53.6% and 52.6% in HCV carriers and HCV RNA negative subjects, respectively. There were no differences in the incidence of hepatocellular carcinoma (HCC) and cumulative mortality associated with liver-related death between HCV carriers who were positive and negative for HBcAb. In multivariate analysis, age (≥65 years) and alanine aminotransferase level (≥31 IU/L) emerged as independent risk factors for HCC development and liver-related death, but the HBcAb status was not a risk factor. In addition, increased serum hepatic fibrosis markers (measured from 2001-2004) were not associated with HBcAb status. CONCLUSION: In our cohort study, the presence of HBcAb had no impact on HCC development, liver-related death and hepatic fibrosis markers in HCV carriers. Thus, our results indicate that occult HBV infection has no impact on the clinical course in HCV carriers.

MRI diffusion-weighted imaging detects a fresh portal vein thrombus as a high intensity lesion in a patient with a liver transplant: A case report.

Portal vein thrombosis is one of the most serious complications after liver transplantation. It is important to determine the age of the thrombus for management of portal vein thrombosis. We present a case report of histologically confirmed heterogenous fresh portal vein thrombus which was depicted heterogenous high signal intensity on magnetic resonance diffusion weighted imaging. The sequence may be a useful imaging tool for detecting fresh thrombus components in the portal vein thrombosis.

Frailty Status Predicts New Long-term Care Insurance Certification in Hepatitis C Patients Receiving Antiviral Therapy.

BACKGROUND/AIM: Direct-acting antiviral (DAA) therapies for patients with hepatitis C virus (HCV) infection deliver higher cure rates and lower frequencies of adverse events than existing therapies, though DAA treatment costs $45,000-64,000 in Japan. The prognosis of patients who require new long-term care insurance (LTCI) certification is inferior to that of patients who do not. Here, we clarify the factors associated with new LTCI certification in elderly patients with HCV infection who undergo DAA therapy. PATIENTS AND METHODS: We retrospectively surveyed 53 patients aged ≥70 years who were treated with DAAs, and evaluated the factors associated with new LTCI certification. RESULTS: Of 53 patients, 10 required new LTCI certification. Age ≥85 years and a modified Japanese Cardiovascular Health Study index ≥2 were independently associated with new LTCI certification. CONCLUSION: In elderly HCV patients, poor frailty status strongly predicted new LTCI certification after DAA therapy.

Increased rate of death related to presence of viremia among hepatitis C virus antibody-positive subjects in a community-based cohort study.

UNLABELLED: The overall mortality of patients infected with hepatitis C virus (HCV) has not been fully elucidated. This study analyzed mortality in subjects positive for antibody to HCV (anti-HCV) in a community-based, prospective cohort study conducted in an HCV hyperendemic area of Japan. During a 10-year period beginning in 1995, 1125 anti-HCV-seropositive residents of Town C were enrolled into the study and were followed for mortality through 2005. Cause of death was assessed by death certificates. Subjects with detectable HCV core antigen (HCVcAg) or HCV RNA were considered as having hepatitis C viremia and were classified as HCV carriers; subjects who were negative for both HCVcAg and HCV RNA (i.e., viremia-negative) were considered as having had a prior HCV infection and were classified as HCV noncarriers. Among the anti-HCV-positive subjects included in the analysis, 758 (67.4%) were HCV carriers, and 367 were noncarriers. A total of 231 deaths occurred in these subjects over a mean follow-up of 8.2 years: 176 deaths in the HCV carrier group and 55 in the noncarrier group. The overall mortality rate was higher in HCV carriers than in noncarriers, adjusted for age and sex (hazard ratio, 1.53; 95% confidence interval, 1.13-2.07). Although liver-related deaths occurred more frequently among the HCV carriers (hazard ratio, 5.94; 95% confidence interval, 2.58-13.7), the rates of other causes of death did not differ between HCV carriers and noncarriers. Among HCV carriers, a higher level of HCVcAg (>or=100 pg/mL) and persistently elevated alanine aminotransferase levels were important predictors of liver-related mortality. CONCLUSION: The presence of viremia increases the rate of mortality, primarily due to liver-related death, among anti-HCV-seropositive persons in Japan.

Therapeutic response of immunoglobulin 4-related aortitis and pancreatitis demonstrated by diffusion-weighted MRI.

Immunoglobulin (IgG) 4-related disease is a systemic inflammatory disease, and it affects vascular system as aortitis, periaortitis, or aneurysm. However, due to a lack of serum biomarker on aortic damage and the multiorgan involvement, it is difficult to assess aortic inflammatory activity of IgG4-related disease. We described a case of IgG4-related pancreatitis and aortitis, which was visualized with magnetic resonance merged image of diffusion weighted and T1 weighted images. The aortic signal intensity or apparent diffusion coefficient value reduced or increased after oral prednisone administration, respectively. Magnetic resonance diffusion weighted image and apparent diffusion coefficient may be a useful imaging tool for assessment of vascular inflammation in IgG4-related aortitis.

Acute Liver Failure Due to Severe Hepatic Metastasis of Small-cell Lung Cancer Producing Adrenocorticotropic Hormone Complicating Ectopic Cushing Syndrome.

A 72-year-old man was admitted to a general hospital with progressive liver dysfunction, hypokalemia, hyperglycemia, and nodules in the lung and liver and then transferred to our institution on the seventh hospital day. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and neuron-specific enolase concentrations were extremely high. He developed acute liver failure, his consciousness and general condition deteriorated rapidly, and he died on Day 11. At the postmortem examination, he was found to have extensive metastases from small-cell lung cancer, including advanced hepatic metastases. This is the first reported case of acute liver failure caused by metastases derived from an ACTH-producing pulmonary small-cell carcinoma.

Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan.

BACKGROUND: The clinical course of chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and obesity. The K121Q polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP)-1 gene and the rs7566605 genotype located near insulin-induced gene 2 have been shown to be associated with insulin resistance and obesity. This study examined whether the K121Q polymorphism in ENPP1 or the rs7566605 genotype is associated with the clinical course of HCV infection. METHODS: The relationships between the clinical characteristics of 469 anti-HCV antibody-seropositive subjects (353 were positive for HCV core antigen or RNA, whereas 116 were negative for HCV RNA) and the polymorphisms were analyzed. RESULTS: No significant differences in body mass index, plasma glucose level, serum insulin level, and other biochemical markers were observed between subgroups of subjects with different genotypes at the K121Q polymorphism or rs7566605. The frequency of the homozygous wild-type genotype at K121Q in HCV carriers, however, was significantly higher than that in subjects who were negative for HCV RNA (84.5% vs. 75.9%; P < 0.05). Moreover, in HCV carriers, HCV core antigen levels in subjects homozygous for the wild-type genotype at K121Q were significantly higher than in heterozygous carriers of K121Q (5358 fmol/l vs. 4002 fmol/l; P = 0.04). In contrast, the rs7566605 genotype was not associated with hepatitis C viremia or with the HCV core antigen level. CONCLUSIONS: The K121Q variant of ENPP1 may be associated with hepatitis C viremia and core antigen levels in HCV carriers.

[A case study: interferon-beta-induced remission of ulcerative colitis in a patient with type C chronic hepatitis].

A 66-year-old man patient with chronic hepatitis (CH) C and complications from ulcerative colitis (UC) was treated with interferon-beta (IFN-beta). Endoscopically, the UC disease activity was moderate before IFN-beta treatment but was in remission eight week after treatment. However, a few months after stopping IFN treatment, endoscopy revealed that the UC disease activity had returned to moderate levels. This result shows that UC improved with IFN treatment.

Alanine aminotransferase flare-up in hepatitis C virus carriers with persistently normal alanine aminotransferase levels in a hyperendemic area of Japan.

BACKGROUND: The clinical features of hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferase (PNALT) levels (ALT < or = 34 IU/l) have not been fully elucidated. We investigated clinical factors associated with ALT flare-up in PNALT individuals in a HCV hyperendemic area of Japan. METHODS: We analyzed 101 HCV carriers who had PNALT between 1993 and 2000. The first occurrence of ALT flare-up (ALT > or = 35 IU/l) between 2001 and 2005 was evaluated by the Kaplan-Meier method. Multivariate analysis of factors predicting ALT flare-up were conducted using Cox proportional hazards models. RESULTS: The mean follow-up period was 2.8 years, and the 5-year cumulative incidence of ALT flare-up was estimated to be 31.8%. In multivariate analysis, an ALT level of 20-34 IU/l and a high serum ferritin level (> or =90 ng/ml) in the most recently available data up to the year 2000, as well as H63D heterozygosity in the HFE gene, were independently and strongly associated with the incidence of ALT flare-up (Hazard ratios = 5.6, 3.1, and 4.8, respectively). In addition, HFE H63D heterozygosity was significantly associated with higher serum ferritin levels in subjects with PNALT (153.8 + or - 73.3 ng/ml in subjects with the 63HD genotype vs. 89.4 + or - 51.3 ng/ml in subjects with the 63HH genotype, P = 0.043). CONCLUSIONS: HCV carriers with PNALT in this population were at risk for ALT flare-up. Basal ALT levels, serum ferritin levels, and HFE polymorphism are potentially important predictors of ALT flare-up.

Efficacy and safety of sofosbuvir and ledipasvir in Japanese patients aged 75 years or over with hepatitis C genotype 1.

AIM: To evaluate the efficacy and safety of a regimen containing sofosbuvir (SOF) and ledipasvir (LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1. METHODS: This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects (AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger (aged < 75 years) and elderly (aged ≥ 75 years). Virological data and AEs were analyzed by age group. RESULTS: The sustained virological response (SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding. CONCLUSION: Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.

Effect of hepatocyte growth factor on endogenous hepatocarcinogenesis in rats fed a choline-deficient L-amino acid-defined diet.

Hepatocyte growth factor (HGF) is a promising agent for the treatment of intractable liver disease, due to its mitogenic, anti-apoptotic, and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on the development of both hepatocellular carcinoma (HCC) and preneoplastic nodules in rats fed a choline-deficient L-amino acid-defined (CDAA) diet, an animal model of hepatocarcinogenesis resembling human development of HCC with cirrhosis. From weeks 13 to 48 of the CDAA diet, rh-HGF (0.1 or 0.5 mg/kg/day) was administered intravenously to rats in four-week cycles, with treatment for five consecutive days of each week for two weeks, followed by a two-week washout period. Treatment with rh-HGF significantly inhibited the development of preneoplastic nodules in a dose-dependent manner at 24 weeks. Although the numbers and areas of the preneoplastic nodules in rats treated with rh-HGF were equivalent to those in mock-treated rats by 60 weeks, the incidence of HCC was reduced by HGF treatment. Although one rat treated with low-dose rh-HGF exhibited a massive HCC, which occupied almost the whole liver, and lung metastases, HGF treatment did not increase the overall frequency of HCC. Administration of high-dose rh-HGF, however, induced an increase in the urinary excretion of albumin, leading to decreased serum albumin at 60 weeks. These results indicate that long-term administration of rh-HGF does not accelerate hepatocarcinogenesis in rats fed a CDAA diet. However, these findings do not completely exclude the potential of HGF-induced hepatocarcinogenesis; this issue must be resolved before rh-HGF can be used for patients with intractable liver diseases, especially those with cirrhosis.

Repeated intravenous injection of recombinant human hepatocyte growth factor ameliorates liver cirrhosis but causes albuminuria in rats.

Hepatocyte growth factor (HGF) is a promising agent for the treatment of liver cirrhosis because of its mitogenic and anti-fibrotic effects. We investigated the effect of recombinant human HGF (rh-HGF) on cirrhosis development; its pharmacokinetics and nephrotoxicity in rats with liver cirrhosis induced by 4-week treatment with dimethylnitrosamine (DMN). rh-HGF (0.3 mg/kg) was intravenously administered to rats once a day for 4 weeks in parallel with DMN treatment or twice a day for the last 2 weeks of DMN treatment. Repeated doses of rh-HGF increased the liver weight and serum albumin, and reduced serum ALT. The development of hepatic fibrosis was inhibited more efficiently by extended low-dose treatment with rh-HGF. In cirrhotic rats, serum levels of rh-HGF increased and clearance was decreased, leading to an increase in the area under the plasma-concentration time curve and a decrease in the steady-state volume of distribution. Repeated doses of rh-HGF led to increased urinary albumin excretion, but no rh-HGF-treated animals developed increased serum creatinine levels. Urinary albumin excretion returned to baseline after the cessation of rh-HGF. These results suggest that extended treatment with rh-HGF is required for the attenuation of cirrhosis, and repeated doses of rh-HGF cause adverse effects in extra-hepatic organs. These issues must be resolved before the widespread application of rh-HGF in the treatment of liver cirrhosis.

Spontaneous elimination of hepatitis C virus RNA in individuals with persistent infection in a hyperendemic area of Japan.

The natural course of hepatitis C virus (HCV) carriers is not well understood. We examined the clinical characteristics of individuals exhibiting spontaneous elimination of HCV as part of a cohort study of residents of a HCV hyperendemic area in Japan. In individuals who were judged to have persistent HCV infection in 1995, 302 had at least 4 annual ALT measurements between 1993 and 2000, and had not been treated with IFN. They were tested for the presence of HCV RNA in 2001 and/or 2002 and HCV RNA could not be detected in 20 of the 302 individuals. In these 20 individuals, 7 were confirmed to have detectable HCV RNA and 13 were not until 2000. Thus, 2.4% (7/289) were judged to have spontaneously eliminated the HCV infection during that 6-year period. Although there were no differences in age, sex, ALT levels, or serologically defined HCV genotype between individuals with and without exhibiting spontaneous elimination, there was a significant relationship between the elimination of HCV RNA and a low level of HCVcAg (<20pg/mL) (P<0.001) upon testing in 1995. These results suggest that spontaneous elimination of HCV RNA following persistent infection is rare and appears to be related to viral load.

[A case of gastric endocrine cell carcinoma with liver metastasis showing rapid growth during pregnancy and marked reduction by systemic chemotherapy after delivery].

A 28-year-old woman was given a diagnosis of gastric endocrine cell carcinoma with multiple liver metastases in 1997. Chemotherapy was administered for treatment after a distal gastrectomy and hepatic tumor resection, and she had shown no sign of relapse after 2002. In February 2004, she was in the third month of pregnancy, and experienced recurrent liver metastasis. Although the tumor grew rapidly from 3cm to 10cm during her pregnancy, its size was significantly reduced with systemic chemotherapy after delivery. This is a rare case in which a liver metastasis of a gastric endocrine cell carcinoma grew during the course of pregnancy.

Development of a rapid semi-quantitative immunochromatographic assay for serum hepatocyte growth factor and its usefulness in acute liver failure.

Measurement of serum human hepatocyte growth factor (HGF) by enzyme-linked immunosorbent assay (ELISA) is useful for the early diagnosis and prediction of prognosis of patients with acute liver failure (ALF). This ELISA methodology, however, is neither rapid nor convenient for use at the bedside. In this study, we have developed a rapid semi-quantitative immunochromatographic (IC) assay and evaluated its usefulness in assessing patients with acute hepatic injury. Only 100mul of serum is required; the assay can be easily completed in 20min. The values obtained using this novel assay correlated well with the values obtained using the standard ELISA protocol. In addition, the values obtained in the IC assay correlated with clinical course; increased serum HGF levels were associated with an increased frequency of ALF and death. These results indicate that this rapid semi-quantitative IC assay for HGF is useful for the early diagnosis of ALF and prediction of clinical outcome in acute hepatic injury.

The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet.

Administration of a choline-deficient, l-amino acid-defined (CDAA) diet to rats causes steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma, a pathology similar to that observed in non-alcoholic steatohepatitis (NASH). The aim of this study was to evaluate if a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, pioglitazone (PGZ), could ameliorate CDAA diet-induced fatty liver and cirrhosis. Rats were fed a CDAA diet for 1 week and were given the CDAA diet for an additional week with or without PGZ (2-week model). Also, after administration of the CDAA diet for 12 weeks, rats were administered the CDAA diet for an additional 4 weeks with or without PGZ (16-week model). The CDAA diet, administered for either one or 12 weeks, induced fatty liver or cirrhosis with up-regulation of hepatic PPAR-gamma expression, respectively. In the 2-week model, rats treated with PGZ for 1 week demonstrated significantly lower hepatic triglyceride content and serum levels of tumor necrosis factor-alpha. In the 16-week model, treatment for 4 weeks with PGZ ameliorated hepatic fibrosis with a decrease in the expression of procollagen, alpha-smooth muscle actin, and transforming growth factor-beta1 in comparison to rats without PGZ. These results suggest that PPAR-gamma agonist is a potential therapeutic modality to treat NASH.