Predictive model of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension.

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C.

BACKGROUND: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. AIM: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. MATERIALS AND METHODS: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-ß, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-ß were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). CONCLUSION: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

Comparison of Daclatasvir and Asunaprevir for Chronic HCV 1b Infection with Telaprevir and Simeprevir plus Peginterferon and Ribavirin, with a Focus on the Prevention of Occurrence and Recurrence of Hepatocellular Carcinoma.

OBJECTIVES: The efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and α-fetoprotein (AFP) as suppressive markers of HCC were also measured. METHODS: Patients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups. RESULTS: No difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEG-IFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups. CONCLUSION: The preventive effect of the IFN-free, all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV.

Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population.

OBJECTIVE: The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. METHODS: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. RESULTS: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. CONCLUSION: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population.

Medication-related factors affecting discharge to home.

To assess the reasons for barriers to home discharge by determining whether they were predicted by medication, clinical variables, and patient characteristics, the retrospective cohort study of 282 patients discharged from Kanazawa Red Cross Hospital in Kanazawa, Japan from January 2011 to December 2012 was performed. The percentage of patients discharged was 67.4%. By multivariate logistic analysis, significant differences in home discharge destination were determined by six factors: the duration of hospitalization before discharge (odds ratio (OR) 0.993; 95% 95% confidence interval (CI) 0.988-0.999), the presence of excretion assistance (OR 0.115; 95% CI 0.043-0.308), individual payment of medical expense (OR 0.344; 95% CI 0.146-0.811), the degree of independent living for the demented elderly (OR4.570; 95% CI 1.969-10.604), presence of the primary caregiver (OR 8.638; 95% CI 3.121-23.906), and admission to a hospital from home (OR 5.483; 95% CI 2.589-11.613). This study suggests that necessity of excretion assistance, long duration of hospitalization, and high individual payment of medical expense were barriers to home discharge. In contrast, three factors i.e., admission to a hospital form home, low degree of independent living for the demented elderly, and presence of the primary caregiver, favored home discharge. The relation between a patient's status (cognitive status and incontinence) and a caregiver has an important effect on the home discharge. However, medication characteristics appeared to have little effect on recuperation destination.

Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotypes 2a and 2b and high viral load.

OBJECTIVE: We investigated the impact of host genetics represented by the single nucleotide polymorphism (SNP) of the IL28B gene and viral genetic variations within the nonstructural protein 5A (NS5A) [including the interferon (IFN)/ribavirin (RBV) resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR)] on the outcome of pegylated IFN and RBV (PEG-IFN/RBV) treatment. METHODS: Sixty-six patients infected with hepatitis C virus (HCV)-2a or HCV-2b who received PEG-IFN/RBV for 24 weeks were examined. RESULTS: In HCV-2a, the major genotype of IL28B SNP showed a tendency toward association with sustained virological response (SVR) and rapid virological response (RVR), and four or more mutations in IRRDR (IRRDR[2a] ≥4) and one or more mutations in ISDR plus its carboxyl-flanking region (ISDR/+C[2a] ≥1) were significantly associated with SVR and RVR. In HCV-2b, one or more mutations in the N-terminal part of IRRDR (IRRDR/N[2b] ≥1) were significantly associated with RVR. Multivariate analysis identified the major genotype of IL28B SNP and IRRDR[2a] ≥4 as independent predictive factors of SVR in HCV-2a, with IRRDR[2a] ≥4 being more powerful than the IL28B SNP. Also, IRRDR[2a] ≥4 in HCV-2a and IRRDR/N[2b] ≥1 in HCV-2b were significant determiners of RVR. CONCLUSION: The NS5A sequence heterogeneity and IL28B SNP are useful factors to predict the sensitivity to PEG-IFN/RBV therapy in HCV-2a and HCV-2b infections.

Outcome of double-filtration plasmapheresis plus interferon treatment in nonresponders to pegylated interferon plus ribavirin combination therapy.

OBJECTIVES: We assessed the outcome of double-filtration plasmapheresis (DFPP) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients infected with hepatitis C virus (HCV)-1b whose HCV had not disappeared during PEG-IFN/RBV combination therapy, or who had relapsed after the end of the therapy. Additionally, we investigated factors predictive of sustained virological response (SVR), including host and viral genetic factors, to DFPP plus IFN/RBV therapy. METHODS: A total of 40 patients infected with HCV-1b whose HCV virus had not been eradicated by previous PEG-IFN/RBV therapy were enrolled for treatment by DFPP plus IFN/RBV. Rapid virological response (RVR) and SVR were assessed, and pretreatment factors associated with SVR - the interleukin (IL)28B gene, the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR) - were analyzed. RESULTS: Of the 40 patients, 9 (23%) achieved RVR and 10 (25%) achieved SVR. The significant factors associated with SVR were IL28B major and RVR, as assessed by multivariate analysis (p = 0.0182, p = 0.0005). CONCLUSION: Patients whose HCV is not eradicated by previous PEG-IFN/RBV would be good candidates for combined DFPP and IFN/RBV retreatment provided they demonstrate IL28B major and have achieved RVR.