Efficacy and safety of ombitasvir/paritaprevir/ritonavir and ribavirin for chronic hepatitis patients infected with genotype 2a in Japan.

AIM: The aim of this study was to evaluate the efficacy and safety of community-based ombitasvir/paritaprevir/ritonavir plus ribavirin therapy for non-cirrhotic patients with hepatitis C virus (HCV) genotype 2a infection in a real-world setting. METHODS: Patients with HCV genotype 2a infection were enrolled in this study and received the therapy for 16 weeks at 11 specialized centers in Japan between October 2016 and July 2017. Among the 98 patients participating in the study, four patients were excluded because of the presence of cirrhosis and/or genotype 2b infection. The remaining 94 patients were subjected to the analysis. RESULTS: The patients consisted of 38 women and 56 men, with a median age of 63 years. The rate of sustained virologic response (SVR) was 97.9%. The SVR rates were similar between patients with and without ribavirin dose reduction (96.0% vs. 98.6%, respectively). Of the two patients in whom treatment failed, one patient completed the treatment but relapsed at 4 weeks post-treatment, whereas the other did not show virologic response and therefore discontinued treatment at week 9. At baseline, both patients had non-structural protein (NS)5A resistance-associated substitution (RAS) L31M but no NS3 RAS. At the time of relapse, the patient had NS5A RAS F28S. At the premature treatment discontinuation, the non-responder had NS3 RAS D168V and NS5A RAS T24S. Ribavirin-induced anemia was the most frequent adverse event. CONCLUSION: Community-based, 16-week, ombitasvir/paritaprevir/ritonavir plus ribavirin therapy was highly efficacious and safe in non-cirrhotic patients with HCV genotype 2a infection in a real-world setting.

TMED10 Protein Interferes with Transforming Growth Factor (TGF)-ß Signaling by Disrupting TGF-ß Receptor Complex Formation.

The intensity and duration of TGF-ß signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-ß signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-ß type I (also termed ALK5) and type II receptors (TßRII). Misexpression studies revealed that TMED10 attenuated TGF-ß-mediated signaling. A 20-amino acid-long region from Thr91 to Glu110 within the extracellular region of TMED10 was found to be crucial for TMED10 interaction with both ALK5 and TßRII. Synthetic peptides corresponding to this region inhibit both TGF-ß-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-ß was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed a decrease and increase in the tumor size, respectively. Thus, we determined herein that TMED10 expression levels are the key determinant for efficiency of TGF-ß receptor complex formation and signaling.

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein more reliably distinguishes liver fibrosis stages in non-alcoholic fatty liver disease than serum Mac-2 binding protein.

AIM: Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS: Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 × 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ -M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION: This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286).

Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants.

AIM: Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance-associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. METHODS: Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. RESULTS: The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 ≤ 20 ng/mL) (P = 5.91 × 10⁻5 , odds ratio = 5.015) and elderly age (>70 years) (P = 1.85 × 10-3 , odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL (P = 4.90 × 10-3 ). CONCLUSION: We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection.

Effects of sorafenib combined with low-dose interferon therapy for advanced hepatocellular carcinoma: a pilot study.

BACKGROUND: Sorafenib is a standard of care for advanced hepatocellular carcinoma (HCC). An in vitro study showed the synergistic effects of sorafenib and interferon for HCC. To clarify the efficacy, combination therapy with sorafenib and interferon was performed for patients with advanced HCC. METHODS: Pegylated interferon α-2a was administered every 2 weeks for the initial 4 weeks. Subsequently, it was combined with sorafenib. We evaluated the anti-tumor effect and biomarkers during treatment period. RESULTS: The subjects were 13 patients with advanced HCC complicated by hepatitis C virus (HCV)-related liver cirrhosis. A partial response, stable disease and progressive disease were noted in 4, 6, and 3 patients, respectively. The response rate, the disease control rate, the mean time to progression and the median survival time (MST) were 30.8 % (4/13), 76.9 % (10/13), 12.2 months, and 17.5 months, respectively. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001). In plasma vascular endothelial growth factor (VEGF), serum alpha-fetoprotein (AFP), AFP-L3, a protein induced by vitamin K absence or antagonist-II (PIVKA II), and hepatocyte growth factor (HGF), there was no pretreatment factor and no biomarker during the combination therapy to predict therapeutic effect in the present study. CONCLUSIONS: The results of this study suggest that combination therapy with sorafenib and interferon could be effective and safe in advanced HCC patients with HCV-related liver cirrhosis.

Vitamin D-related gene polymorphisms do not influence the outcome and serum vitamin D level in pegylated interferon/ribavirin therapy combined with protease inhibitor for patients with genotype 1b chronic hepatitis C.

Although several vitamin D-related gene polymorphisms were reported to affect the outcome of pegylated interferon/ribavirin (PR) therapy in chronic hepatitis C patients, there are no reports on the impact of the vitamin D-related gene polymorphisms in PR therapy combined with protease inhibitor (PI). Vitamin D-related gene polymorphisms were determined in 177 genotype 1b-infected chronic hepatitis C patients who received 12 weeks of PR therapy with telaprevir, a first-generation PI, followed by 12 weeks of PR therapy. The sustained virologic response (SVR) rate was 83.1% (147 of 177 patients). The frequencies of vitamin D-related gene polymorphisms were: 83 non-TT and 94 TT genotypes for GC, 97 non-AA and 80 AA genotypes for DHCR7, 151 non-AA and 26 AA genotypes for CYP2R1, 162 non-GG and 15 GG genotypes for CYP27B1, and 105 non-GG and 72 GG genotypes for VDR gene. Multivariate analysis extracted IL28B TT genotype (P = 2.05 × 10(-6)) and serum 25(OH) D3 level (P = 0.024) as independent factors contributing to the achieving of SVR. The SVR rate in IL28B TT genotype patients with serum 25(OH) D3 level of < 25 ng/ml was significantly low compared to other patients. None of the vitamin D-related gene polymorphisms affected the treatment outcome and serum 25(OH) D3 level. In conclusions, the IL28B polymorphism and serum 25(OH) D3 level contributed significantly and independently to SVR in PR combined with PI for genotype 1b-infected chronic hepatitis C patients. However, none of vitamin D-related gene polymorphisms had an impact on the treatment outcome and serum 25(OH) D3 level.

Influencing factors on serum 25-hydroxyvitamin D3 levels in Japanese chronic hepatitis C patients.

BACKGROUND: Serum 25-hydroxyvitamin D3 levels are generally lower in chronic hepatitis C patients than in healthy individuals. The purpose of this study is to clarify the factors which affect serum 25-hydroxyvitamin D3 levels using data obtained from Japanese chronic hepatitis C patients. METHODS: The subjects were 619 chronic hepatitis C patients. Serum 25-hydroxyvitamin D3 levels were measured by using double-antibody radioimmunoassay between April 2009 and August 2014. Serum 25-hydroxyvitamin D3 levels of 20 ng/mL or less were classified as vitamin D deficiency, and those with serum 25-hydroxyvitamin D3 levels of 30 ng/mL or more as vitamin D sufficiency. The relationship between patient-related factors and serum 25-hydroxyvitamin D3 levels was analyzed. RESULTS: The cohort consisted of 305 females and 314 males, aged between 18 and 89 years (median, 63 years). The median serum 25-hydroxyvitamin D3 level was 21 ng/mL (range, 6-61 ng/mL). On the other hand, the median serum 25-hydroxyvitamin D3 level in the healthy subjects was 25 ng/mL (range, 7-52), being significantly higher than that those in 80 chronic hepatitis C patients matched for age, gender, and season (p = 1.16 × 10(-8)). In multivariate analysis, independent contributors to serum 25-hydroxyvitamin D3 deficiency were as follows: female gender (p = 2.03 × 10(-4), odds ratio = 2.290, 95 % confidence interval = 1.479-3.545), older age (p = 4.30 × 10(-4), odds ratio = 1.038, 95 % confidence interval = 1.017-1.060), cold season (p = 0.015, odds ratio = 1.586, 95 % confidence interval = 1.095-2.297), and low hemoglobin level (p = 0.037, odds ratio = 1.165, 95 % confidence interval = 1.009-1.345). By contrast, independent contributors to serum 25-hydroxyvitamin D3 sufficiency were male gender (p = 0.001, odds ratio = 3.400, 95 % confidence interval = 1.635-7.069), warm season (p = 0.014, odds ratio = 1.765, 95 % confidence interval = 1.117-2.789) and serum albumin (p = 0.016, OR = 2.247, 95 % CI = 1.163-4.342). CONCLUSIONS: Serum 25-hydroxyvitamin D3 levels in chronic hepatitis C Japanese patients were influenced by gender, age, hemoglobin level, albumin and the season of measurement.

Serum 25-hydroxyvitamin D3 levels affect treatment outcome in pegylated interferon/ribavirin combination therapy for compensated cirrhotic patients with hepatitis C virus genotype 1b and high viral load.

AIM: Much is unknown about the effect of 25-hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus-related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25-hydroxyvitamin D3 , that contribute to a sustained virological response (SVR) in patients with cirrhosis. METHODS: We analyzed whether 25-hydroxyvitamin D3 contributes to the response to PEG IFN/RBV therapy among 134 cirrhotic patients. RESULTS: SVR was achieved in 43 patients. The median 25-hydroxyvitamin D3 level was 20 ng/mL. Univariate analysis showed that the following factors contributed to SVR: low-density lipoprotein cholesterol, albumin, 25-hydroxyvitamin D3 , core a.a.70 (a.a.70) substitutions, the number of mutations at the interferon sensitivity-determining region and IL28B genotype. Multivariate analysis identified IL28B genotype and 25-hydroxyvitamin D3 as independent factors contributing to SVR. Subsequently, SVR rate was examined by using 25-hydroxyvitamin D3 and other important factors. The SVR rate was 51.8% in patients with core a.a.70 wild and ≥15 ng/mL of 25-hydroxyvitamin D3 , whereas the SVR rate was 7.1% in patients with core a.a.70 wild and <15 ng/mL of 25-hydroxyvitamin D3 . The SVR rate was 56.9% in patients with IL28B major genotype and ≥15 ng/mL of 25-hydroxyvitamin D3 . Surprisingly, the SVR rate was 0% in patients with IL28B minor genotype and <15 ng/mL of 25-hydroxyvitamin D3 . CONCLUSION: IL28B genotype and 25-hydroxyvitamin D3 were identified as independent factors contributing to SVR. Stratified analyses according to core a.a.70 substitution and IL28B genotype suggested that 25-hydroxyvitamin D3 influences the outcome of PEG IFN/RBV therapy for cirrhosis.

Experience with enteral sulfonylurea monotherapy for extremely low birth weight infants with hyperglycemia.

Limited data are available on the effects of enteral sulfonylurea (SU) monotherapy in extremely low birth weight infants (ELBWIs) with hyperglycemia. Therefore, we report our experience with enteral SU monotherapy for hyperglycemic ELBWIs. We retrospectively evaluated 11 hyperglycemic ELBWIs (seven male infants, median gestational age = 24.9 wk) who received SU between January 2016 and December 2019. Blood glucose (BG) levels were monitored before and after SU initiation and evaluated for the occurrence of adverse effects. We administered SU at a median of 15 d (interquartile range [IQR]: 12-20 d) after birth, with the median maximum dose of 0.2 mg/kg/d (IQR: 0.125-0.3 mg/kg/d). Hyperglycemia improved in all patients, and the target BG levels were achieved without severe side effects at a median of 6 d (IQR: 4-8.5 d) after initiation of treatment. The incidence of hypoglycemia during SU treatment was observed in 18 events per 1000 patient hours; however, the patients were asymptomatic. Based on these results, enteral SU monotherapy may be considered as an option for hyperglycemic ELBWIs.

Risk factors for hyperglycemia in extremely low birth weight infants during the first 14 days.

BACKGROUND: There are limited data regarding the risk factors for hyperglycemia in extremely low birth weight infants (ELBWIs). The aim of this observational study was to investigate the incidence of hyperglycemia among ELBWIs during the first 14 days of life and identify independent risk factors for hyperglycemia development. METHODS: We retrospectively evaluated 55 ELBWIs (32 male infants) between January 2015 and March 2020. Hyperglycemia was diagnosed when the glucose level was ≥180 mg/dL. Demographic and clinical data were extracted from the patients' medical records. The risk factors associated with the onset of hyperglycemia were identified by Cox proportional hazards regression analysis with variables that had previously been identified as risk factors for hyperglycemia. RESULTS: Hyperglycemia developed in 23 patients (41.8%) within the first 14 days of life. Gestational age, chorioamnionitis, postnatal intravenous glucocorticoids, and probiotic type were included in the analysis. The results indicated that hyperglycemia was significantly associated with gestational age (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.48-0.87; P = 0.004). Further, Bifidobacterium breve (B. breve M-16V) use was related to hyperglycemia in ELBWIs (HR, 2.95; 95% CI, 1.10-7.87; P = 0.031). CONCLUSION: Hyperglycemia was strongly associated with lower gestational age and B. breve M-16V use in our study population. Although probiotic supplementation may be beneficial for preterm infants to reduce the incidence of necrotizing enterocolitis, the dextrin used as an excipient in B. breve M-16V may lead to an undesirable carbohydrate load in ELBWIs.

Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease.

BACKGROUND: Vitamin D has promising anti-proliferative and anti-fibrotic properties, but its clinical utility in nonalcoholic fatty liver disease (NAFLD) is unclear. AIMS: This study aimed to clarify the association between vitamin D levels, single nucleotide polymorphisms (SNPs) in vitamin D-related genes, and the histopathological severity of disease in patients with biopsy-proven NAFLD. METHODS: SNPs in CYP2R1, DHCR7, vitamin D binding protein (GC), CYP27B1, and vitamin D receptor (VDR) were determined for 229 consecutive patients with biopsy-proven NAFLD. RESULTS: In this study, vitamin D deficiency defined as 25-hydroxyvitamin-D3 levels of ≤20 ng/mL was found in 151 patients (65.9%). Multivariate analysis revealed that cold season, advanced fibrosis, and CYP2R1 rs1993116 genotype non-AA were independent factors significantly associated with vitamin D deficiency. Old age (p = 5.05 × 10-8), high body mass index (p = 2.13 × 10-2), low total-cholesterol (p = 1.46 × 10-4), low serum vitamin D level (p = 7.34 × 10-3), and VDR rs1544410 genotype CC (p = 9.15 × 10-3) were independent factors associated with advanced liver fibrosis. CONCLUSION: Serum 25-hydroxyvitamin-D3 levels and the VDR gene SNP were significantly and independently associated with the severity of liver fibrosis in patients with biopsy-proven NAFLD.

Usefulness of portal vein pressure for predicting the effects of tolvaptan in cirrhotic patients.

AIM: To elucidate influencing factors of treatment response, then tolvaptan has been approved in Japan for liquid retention. METHODS: We herein conducted this study to clarify the influencing factors in 40 patients with decompensated liver cirrhosis complicated by liquid retention. Tolvaptan was administered at a dosage of 7.5 mg once a day for patients with conventional diuretic-resistant hepatic edema for 7 d. At the initiation of tolvaptan, the estimated hepatic venous pressure gradient (HVPG) value which was estimated portal vein pressure was measured using hepatic venous catheterization. We analyzed the effects of tolvaptan and influencing factors associated with treatment response. RESULTS: Subjects comprised patients with a median age of 65 (range, 40-82) years. According to the Child-Pugh classification, class A was 3 patients, class B was 19, and class C was 18. Changes from the baseline in body weight were -1.0 kg (P = 2.04 × 10(-6)) and -1.3 kg (P = 1.83 × 10(-5)), respectively. The median HVPG value was 240 (range, 105-580) mmH2O. HVPG was only significant influencing factor of the weight loss effect. When patients with body weight loss of 2 kg or greater from the baseline was defined as responders, receiver operating characteristic curve analysis showed that the optimal HVPG cutoff value was 190 mmH2O in predicting treatment response. The response rate was 87.5% (7/8) in patients with HVPG of 190 mmH2O or less, whereas it was only 12.5% (2/16) in those with HVPG of greater than 190 mmH2O (P = 7.46 × 10(-4)). We compared each characteristics factors between responders and non-responders. As a result, HVPG (P = 0.045) and serum hyaluronic acid (P = 0.017) were detected as useful factors. CONCLUSION: The present study suggests that tolvaptan in the treatment of liquid retention could be more effective for patients with lower portal vein pressure.

Safety and efficacy of partial splenic embolization in telaprevir-based triple therapy for chronic hepatitis C.

OBJECTIVE: Pegylated-interferon/ribavirin (peg-IFN/RBV) therapy with a protease inhibitor is the standard therapy for genotype 1b chronic hepatitis C. Despite improving treatment outcomes, patients with thrombocytopenia are often difficult to treat because interferon commonly exacerbates thrombocytopenia. In this study, partial splenic embolization (PSE) was performed in patients with hypersplenism-induced thrombocytopenia to determine the effectiveness of this method as a potential treatment. METHODS: Patients were pretreated with PSE and then received triple combination therapy. The safety and efficacy of PSE was evaluated. RESULTS: Eighteen patients were analyzed, including 12 patients with the interleukin 28B (IL28B) major genotype and 12 patients with the inosine triphosphatase (ITPA) major genotype. The median embolization rate with PSE was 70% (range: 40-85%). PSE increased the patients' platelet counts from 71.5×10(3) /µL (53-99×10(3) /µL) to 121.5×10(3) /µL (70-194×10(3) /µL; p=0.0002). The patients' platelet counts fluctuated above 50×10(3) /µL during the treatment. Specifically, the increase in the platelet count was significantly associated with the ITPA major genotype compared with the minor genotype (p=0.0057 at 2 weeks, p=0.0031 at 3 weeks, and p=0.0148 at 4 weeks). Adherence to peg-IFN-α2b was sufficient (1.38 µg/kg/week). The rapid viral response rate was 72.2% (13/18), the end of treatment response rate was 88.9% (16/18), and the sustained virological response (SVR) rate was 66.7% (12/18). The SVR rate for patients with the IL28B major genotype was 83.3% (10/12). No adverse effect due to PSE pretreatment was found in any patients. Furthermore, no patient discontinued treatment due to thrombocytopenia. CONCLUSION: PSE, in conjunction with triple combination therapy, is a useful and safe method to treat genotype 1b chronic hepatitis C patients with hypersplenism-induced thrombocytopenia.

Serum 25(OH)D3 levels affect treatment outcomes for telaprevir/peg-interferon/ribavirin combination therapy in genotype 1b chronic hepatitis C.

BACKGROUND: Close relationships between chronic hepatitis C and vitamin D levels have been reported. For genotype 1b infection, the current standard of care is pegylated interferon/ribavirin therapy combined with a protease inhibitor. The present study analyzed the relationship between outcomes of triple therapy and serum 25(OH)D3 levels. METHODS: Factors contributing to sustained virological response were investigated in 177 patients with chronic hepatitis C who received telaprevir-based triple therapy in this prospective study. RESULTS: The sustained virological response rate was 86.9% in patients with 25(OH)D3 levels of >18 ng/ml; this was higher than the 66.7% in patients with 25(OH)D3 levels of ≤ 18 ng/ml (P=0.003). 25(OH)D3 levels and IL28B genotype were identified as significantly independent factors contributing to sustained virological response. The sustained virological response rate did not differ according to 25(OH)D3 levels in patients with the IL28B major genotype. The sustained virological response rate was 64.9% in patients with the IL28B minor genotype and 25(OH)D3 levels of >18 ng/ml, and was 38.5% in those with decreased 25(OH)D3 levels (P=0.045). CONCLUSIONS: In triple therapy, 25(OH)D3 levels were an independent factor contributing to sustained virological response. Of particular note, the sustained virological response rate was significantly lower in patients with the IL28B minor genotype.

Effect of fluvastatin on 24-week telaprevir-based combination therapy for hepatitis C virus genotype 1b-infected chronic hepatitis C.

OBJECTIVES: The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial. PATIENTS AND METHODS: Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups. RESULTS: There were 56 men and 60 women, median age 60 years (range, 28-71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P=0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin. CONCLUSION: In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients.

Relationship between HCV dynamics and sustained virological responses in chronic hepatitis C genotype 1b patients treated with telaprevir-based triple therapy.

OBJECTIVES: This study investigated the relationship between hepatitis C virus (HCV) dynamics and sustained virological response (SVR), as well as the efficacy of an extended treatment with telaprevir-based triple therapy among patients with chronic hepatitis C genotype 1b. METHODS: Among 220 patients receiving triple therapy for 24 weeks, the SVR rate was analyzed at each time point at which HCV RNA became undetectable. The SVR rates in the patients who did not achieve a rapid virological response (RVR) were compared with those in 27 patients who received triple therapy for 48 weeks. RESULTS: The SVR rates of interleukin 28B (IL28B) TT and non-TT patients were 100 versus 66.7% after 1 week, 97.6 versus 72.2% after 2 weeks, 95.2 versus 84.2% after 3 weeks, 93.1 versus 72.2% after 4 weeks, 76.9% versus 11.1% after 6 weeks, and 88.9 versus 14.3% after 8 weeks, respectively. All of the IL28B TT patients who showed undetectable HCV RNA levels until week 8 achieved an SVR. In contrast, the SVR rates in the IL28B non-TT patients who did not achieve RVR with 24 and 48 weeks of treatment were 11.8 and 62.5%, respectively (P=0.017). CONCLUSION: These results suggest that an SVR can frequently be achieved by IL28B TT patients, even with 24 weeks of treatment, when HCV RNA remains undetectable until week 8, and also that IL28B non-TT patients should have RVR values to achieve an SVR with 24 weeks of treatment. The SVR rate was low in IL28B non-TT patients treated for 24 weeks who did not achieve an RVR; however, it could increase when the treatment duration was extended to 48 weeks.

Efficacy of Alfacalcidol on PEG-IFN/ Ribavirin Combination Therapy for Elderly Patients With Chronic Hepatitis C: A Pilot Study.

BACKGROUND: Serum vitamin D concentration is reported to show a decrease in older age. Patients with chronic hepatitis C (CHC) in Japan are older on average than those in Western countries. Moreover, the outcome of pegylated-interferon (PEG-IFN)/ ribavirin therapy combined with vitamin D in elderly patients is unclear. OBJECTIVES: This pilot study explored the efficacy and safety of alfacalcidol as vitamin D source in PEG-IFN/ ribavirin combination therapy for elderly CHC patients infected with hepatitis C virus genotype 1b. PATIENTS AND METHODS: Consecutive twenty CHC patients aged ≥ 65 years were enrolled in this pilot study. Fifteen patients met the inclusion criteria and received PEG-IFN/ ribavirin therapy combined with alfacalcidol. Four-week lead-in of oral alfacalcidol was conducted, and it was subsequently and concurrently administered in PEG-IFN/ ribavirin combination therapy (vitamin D group). Age, gender, and IL28B genotype-matched patients, who received PEG-IFN/ ribavirin alone, were saved as control group (n = 15) to compare the treatment outcome with the vitamin D group. RESULTS: Subjects consisted of 14 males and 16 females, with a median age of 70 years (65-78). The serum 25 (OH) D3 concentration in females (20 ng/ml, 11-37) was significantly lower than males (27 ng/mL, 13-49) (P = 0.004). Sustained virological response (SVR) rates were 33.3% (5/15) in the control group and 80.0% (12/15) in the vitamin D group, respectively (P = 0.025). While no significant difference was shown in the (SVR) rate between the two groups among males (P = 0.592), in females the SVR rate was significantly higher in the vitamin D group (87.5%, 7/8) than the control group (25.0%, 2/8) (P = 0.041). The relapse rates in the groups with and without alfacalcidol were 7.7% (1/13) and 61.5% (8/13), respectively (P = 0.011). Interestingly, in females, the relapse in the control group was shown in 5 of 7 (71.4%), whereas in the vitamin D group the relapse rate was decreased (1/8, 12.5%) (P = 0.041). No specific adverse events were observed in the vitamin D group. CONCLUSIONS: PEG-IFN/ ribavirin combined with alfacalcidol may be effective and safe in elderly CHC patients. In particular, concomitant administration of alfacalcidol may lead to a reduced relapse rate, and consequently improving the SVR rate in elderly females.