Aging impairs fibrosis-4 index after sustained virologic response by direct-acting antivirals in chronic hepatitis C infection.

INTRODUCTION AND OBJECTIVES: Sustained virologic response (SVR) is achieved in most cases of C-type liver disease after direct-acting antiviral (DAA) therapy. Although liver fibrosis improves, the degree of improvement is different. This study aimed to analyze the factors involved in improving liver fibrosis using the fibrosis 4 (FIB-4) index. MATERIAL AND METHODS: Patients were monitored for >3 years after SVR. At the start of therapy (SOT), liver fibrosis was categorized as either mild (<1.45 n = 28), moderate (1.45-3.25 n = 139), or advanced (>3.25 n = 236) based on the FIB-4 index. The FIB-4 index in the advanced group decreased significantly compared to that of the other two, so we selected the advanced group as the analysis target. SOT and end of therapy (EOT) factors that contributed to the FIB-4 index ≤3.25 at 3 years after therapy were examined using a multivariate analysis. RESULTS: Among the SOT factors, age (<72 years old), absence of liver cirrhosis (LC), alanine transferase (ALT) (≥50 U/L), platelet (PLT) (≥10.2 × 104/mm3), and total bilirubin (T.Bil) (<0.8 mg/dl) were the significant factors contributing to the improvement of the FIB-4 index. Among the EOT factors, age (<72 years), PLT (≥12.0 × 104/mm3), and hemoglobin (Hb) (≥12.1 g/dl) were the significant factors contributing to the improvement of FIB-4 index. CONCLUSIONS: Factors involved in the improvement of liver fibrosis after SVR were young age, absence of LC, low T.Bil., high ALT, high PLT, and high Hb levels. The levels of T.Bil, PLT, and Hb were considered to be related to portal hypertension. Aging strongly impaired the improvement in liver fibrosis.

Factors affecting the recovery of hepatic reserve after sustained virologic response by direct-acting antiviral agents in chronic hepatitis C virus-infected patients.

BACKGROUND AND AIM: Since the advent of direct-acting antiviral (DAA) therapy, the total eradication of hepatitis C virus has been achievable with the recovery of hepatic reserve after achievement of sustained virologic response (SVR). Hence, here, we examined the factors affecting the recovery of hepatic reserve. METHODS: We followed up 403 patients (male: 164, female: 239; genotype 1: 299, genotype 2: 104; median age: 69 years) for at least 3 years after they achieved SVR to DAA therapy. Of these patients, 75 (18.6%) had a history of hepatocellular carcinoma (HCC). Biochemical tests were periodically performed, and the hepatic reserve was evaluated based on the albumin-bilirubin grade. We examined background factors such as age, biochemical test results, HCC occurrence and portosystemic shunt by computed tomography. RESULTS: At the start of treatment, the albumin-bilirubin grades were grades 1, 2, and 3 in 241, 157, and 5 patients, respectively, and 3 years later, 117 of 162 (72%) patients with grade 2 or 3 improved to grade 1. Multivariate analysis identified the HCC occurrence after achievement of SVR (hazard ratio [HR]: 3.08, P < 0.0138), male sex (HR: 3.45, P = 0.0143), hemoglobin level of <11.5 g/dL (HR: 4.19, P = 0.0157), the presence of a portosystemic shunt (HR: 3.07, P = 0.0349), and alanine aminotransferase levels <45 U/L (HR: 2.67, P = 0.0425) as factors inhibiting improvement to grade 1. However, old age was not an inhibitory factor. CONCLUSION: Our results demonstrate that hepatic reserve could be improved even in elderly patients over a long course of time.

Zinc deficiency in patients with chronic liver disease in Japan.

AIM: This study aimed to determine the distributions of serum zinc levels and the prevalence of zinc deficiency in patients with chronic liver disease (CLD) in actual clinical practice, and to analyze the association between serum zinc levels and clinical characteristics. METHODS: This study analyzed 1973 patients with CLD, including 749 with liver cirrhosis, who were admitted to Sapporo Kosei General Hospital in 2017. RESULTS: Zinc deficiency, defined as a serum zinc level of <60 µg/dL, was observed in 555 patients overall (28.1%), including 182 (14.9%) patients without liver cirrhosis and 373 (49.8%) with liver cirrhosis. When marginal zinc deficiency was included, zinc deficiency (serum zinc level <80 µg/dL) was observed in 1594 (80.8%) patients overall, including 924 (75.5%) patients without liver cirrhosis and 670 (89.5%) with liver cirrhosis. Serum zinc levels were most strongly correlated with serum albumin levels. Of the 257 CLD patients with an albumin level of <3.5 g/dL, 234 (91.1%) had a serum zinc level of <60 µg/dL. CONCLUSIONS: Zinc deficiency is common in patients with CLD. Serum zinc levels should be regularly measured, particularly in patients with liver cirrhosis.

Evaluation of treatment with zinc acetate hydrate in patients with liver cirrhosis complicated by zinc deficiency.

AIM: In Japan, no zinc preparation had been approved for therapeutic purposes before March 2017. Zinc acetate hydrate was recently approved for the treatment of hypozincemia. We evaluated the efficacy and safety of treatment with zinc acetate hydrate. METHODS: A total of 97 patients with cirrhosis complicated by hypozincemia were treated with zinc acetate hydrate, and their serum zinc normalization rates; factors contributing to normalization; changes in blood ammonia levels; branched-chain amino acids-to-tyrosine ratios; levels of albumin, hemoglobin, alkaline phosphatase, serum copper, and iron; incidence of adverse events; improvement in subjective symptoms; and serum zinc levels taken at 3 months post-treatment were determined. RESULTS: The cumulative serum zinc normalization rates, when normalization was defined as achievement of a serum zinc level ≥80 µg/dL, after 2, 4, and 6 months of treatment were 64.9%, 80.3%, and 82.5%, respectively. Multivariate analysis identified an albumin level of ≥3.3 g/dL and branched-chain amino acids to tyrosine ratio of ≥3.46 as factors contributing to zinc normalization within 3 months of treatment. Treatment resulted in a significant decrease in blood ammonia and serum copper levels, and significant increases in branched-chain amino acids-to-tyrosine ratios and alkaline phosphatase levels. Seven (7.2%) patients prematurely discontinued treatment due to hypocupremia. By the end of treatment, subjective symptoms had resolved in 46.2% of patients. By 3 months post-treatment, serum zinc levels had reverted to levels close to those at baseline. CONCLUSIONS: Treatment with zinc acetate hydrate resulted in normalization of serum zinc levels at a high rate. The main reasons for discontinuation of treatment included hypocupremia.

Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens.

BACKGROUND & AIMS: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. METHODS: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. RESULTS: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. CONCLUSIONS: SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.

Analysis of hepatitis B surface antigen (HBsAg) using high-sensitivity HBsAg assays in hepatitis B virus carriers in whom HBsAg seroclearance was confirmed by conventional assays.

AIM: We investigated the utility of high-sensitivity hepatitis B surface antigen (HBsAg) assays compared with conventional HBsAg assays. METHODS: Using serum samples from 114 hepatitis B virus (HBV) carriers in whom HBsAg seroclearance was confirmed by conventional HBsAg assays (cut-off value, 0.05 IU/mL), the amount of HBsAg was re-examined by high-sensitivity HBsAg assays (cut-off value, 0.005 IU/mL). Cases negative for HBsAg in both assays were defined as consistent cases, and cases positive for HBsAg in the high-sensitivity HBsAg assay only were defined as discrepant cases. RESULTS: There were 55 (48.2%) discrepant cases, and the range of HBsAg titers determined by high-sensitivity HBsAg assays was 0.005-0.056 IU/mL. Multivariate analysis showed that the presence of nucleos(t)ide analog therapy, liver cirrhosis, and negative anti-HBs contributed to the discrepancies between the two assays. Cumulative anti-HBs positivity rates among discrepant cases were 12.7%, 17.2%, 38.8%, and 43.9% at baseline, 1 year, 3 years, and 5 years, respectively, whereas the corresponding rates among consistent cases were 50.8%, 56.0%, 61.7%, and 68.0%, respectively. Hepatitis B virus DNA negativity rates were 56.4% and 81.4% at baseline, 51.3% and 83.3% at 1 year, and 36.8% and 95.7% at 3 years, among discrepant and consistent cases, respectively. Hepatitis B surface antigen reversion was observed only in discrepant cases. CONCLUSIONS: Re-examination by high-sensitivity HBsAg assays revealed that HBsAg was positive in approximately 50% of cases. Cumulative anti-HBs seroconversion rates and HBV-DNA seroclearance rates were lower in these cases, suggesting a population at risk for HBsAg reversion.

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis.

BACKGROUND & AIMS: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV). METHODS: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes. RESULTS: In the Japanese phase 3 study, SVR12 was achieved by 91% of patients with cirrhosis (n = 22) and 84% of patients without cirrhosis (n = 200); in the global phase 3 study, SVR12 was achieved by 84% of patients with cirrhosis (n = 206) and by 85% of patients without cirrhosis (n = 437). The frequency of serious adverse events, adverse events leading to treatment discontinuation and treatment-emergent grade 3/4 laboratory abnormalities was low (<10%) and similar among patients with (n = 229) or without (n = 689) compensated cirrhosis receiving DCV+ASV. Grade 3/4 reductions in platelets and neutrophils were more common among patients with cirrhosis (1.3 and 2.2%, respectively) compared with those without cirrhosis (both 0.6%). Grade 3/4 liver function test abnormalities were less common among patients with cirrhosis (1.8%) compared with those without cirrhosis (3.5-4.7%). Alanine aminotransferase elevations were not associated with hepatic decompensation. CONCLUSIONS: The safety and efficacy of DCV+ASV were similar in patients with or without compensated cirrhosis. This all-oral, interferon- and ribavirin-free combination is an effective and well-tolerated treatment option for patients with HCV GT1b infection and cirrhosis. Trial registrations numbers: Clinicaltrials.gov identifiers: NCT01012895; NCT01051414; NCT01581203; NCT01497834.

Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy.

Patients 1 and 2 were treatment-naive women who had genotype 1b chronic hepatitis C. Both had IL-28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance-associated variants (RAV) in non-structural (NS)3 and NS5A regions confirmed wild-type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post-treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug-resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct-acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.

Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese hepatitis C virus patients.

BACKGROUND AND AIM: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. METHODS: Treatment-naive patients (20-70 years; baseline viral load, ≥ 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥ 100,000 IU/mL) received daclatasvir plus asunaprevir. RESULTS: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). CONCLUSION: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

UNLABELLED: 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).

Efficacy of telaprevir-based therapy for difficult-to-treat patients with genotype 2 chronic hepatitis C in Japan.

AIM: This study assessed the efficacy and safety of telaprevir in combination with peginterferon-α-2b (PEG IFN) and ribavirin (RBV), for Japanese difficult-to-treat patients with hepatitis C virus (HCV) genotype 2 who had not achieved sustained virological response (SVR) during prior treatment. METHODS: In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750 mg, every 8 h) for 12 weeks and PEG IFN/RBV for 24 weeks. RESULTS: The SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure. CONCLUSION: Telaprevir, in combination with PEG IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR.

Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir.

BACKGROUND & AIMS: Daclatasvir and asunaprevir are NS5A and NS3 protease-targeted antivirals currently under development for treatment of chronic hepatitis C virus infection. Clinical data on baseline and on-treatment correlates of drug resistance and response to these agents are currently limited. METHODS: Hepatitis C virus genotype 1b Japanese patients (prior null responders to PegIFN-α/RBV [n=21] or PegIFN-α/RBV ineligible or intolerant [n=22]) were administered daclatasvir/asunaprevir for 24 weeks during a phase 2a open-label study. Genotypic and phenotypic analyses of NS3 and NS5A substitutions were performed at baseline, after virologic failure, and post-treatment through follow-up week 36. RESULTS: There were three viral breakthroughs and four relapsers. Baseline NS3 polymorphisms (T54S, Q80L, V170M) at amino acid positions previously associated with low-level resistance (<9-fold) to select NS3 protease inhibitors were detected in four null responders and three ineligibles, but were not associated with virologic failure. Baseline NS5A polymorphisms (L28M, L31M, Y93H) associated with daclatasvir resistance (<25-fold) were detected in five null responders and six ineligibles. All three viral breakthroughs and 2/4 relapsers carried a baseline NS5A-Y93H polymorphism. NS3 and NS5A resistance-associated variants were detected together (NS3-D168A/V, NS5A-L31M/V-Y93H) after virologic failure. Generally, daclatasvir-resistant substitutions persisted through 48weeks post-treatment, whereas asunaprevir-resistant substitutions were no longer detectable. Overall, 5/10 patients with baseline NS5A-Y93H experienced virologic failure, while 5/10 achieved a sustained virologic response. CONCLUSIONS: The potential association of a pre-existing NS5A-Y93H polymorphism with virologic failure on daclatasvir/asunaprevir combination treatment will be examined in larger studies. The persistence of treatment-emergent daclatasvir- and asunaprevir-resistant substitutions will require assessment in longer-term follow-up studies.

Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options.

BACKGROUND & AIMS: Improved therapeutic options for chronic hepatitis C virus (HCV) infection are needed for patients who are poor candidates for treatment with current regimens due to anticipated intolerability or low likelihood of response. METHODS: In this open-label, phase 2a study of Japanese patients with chronic HCV genotype 1b infection, 21 null responders (<2 log10 HCV RNA reduction after 12 weeks of peginterferon/ribavirin) and 22 patients intolerant to or medically ineligible for peginterferon/ribavirin therapy received dual oral treatment for 24 weeks with the NS5A replication complex inhibitor daclatasvir (DCV) and the NS3 protease inhibitor asunaprevir (ASV). The primary efficacy end point was sustained virologic response at 12 weeks post-treatment (SVR12). RESULTS: Thirty-six of 43 enrolled patients completed 24 weeks of therapy. Serum HCV RNA levels declined rapidly, becoming undetectable in all patients on therapy by week 8. Overall, 76.7% of patients achieved SVR12 and SVR24, including 90.5% of null responders and 63.6% of ineligible/intolerant patients. There were no virologic failures among null responders. Three ineligible/intolerant patients experienced viral breakthrough and four relapsed post-treatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases, generally mild, were the most common adverse events; three discontinuations before week 24 were due to adverse events that included hyperbilirubinemia and transaminase elevations (two patients). CONCLUSIONS: Dual therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin, was well tolerated and achieved high SVR rates in two groups of difficult-to-treat patients with hepatitis C virus genotype 1b infection.

A genome-wide association study of HCV-induced liver cirrhosis in the Japanese population identifies novel susceptibility loci at the MHC region.

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). METHODS: A total of 682 HCV-induced LC cases and 1045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. RESULTS: Eight SNPs which showed possible associations (p<1.0 × 10(-5)) at the GWAS stage were further genotyped using 936 LC cases and 3809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (pcombined=9.15 × 10(-11) and 1.45 × 10(-10), odds ratio (OR)=1.46 and 1.37, respectively). We also found that HLA-DQA1(*)0601 and HLA-DRB1(*)0405 were associated with the progression from CHC to LC (p=4.53 × 10(-4) and 1.54 × 10(-4) with OR=2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1(*)0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. CONCLUSIONS: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients.

Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders.

UNLABELLED: Patients with chronic hepatitis C virus (HCV) infection and previous null response to pegylated interferon (Peg-IFN) and ribavirin (RBV) have limited therapeutic options. HCV genotype 1 is the most common worldwide and the most difficult to treat; genotype 1b is the most common subtype of genotype 1 outside North America. The enhanced antiviral activity achieved by combining two direct-acting antiviral (DAA) agents may improve clinical outcomes. This open-label, phase IIa study included 10 patients with chronic HCV genotype 1b infection and previous null response (<2 log(10) reduction in HCV RNA after 12 weeks) to Peg-IFN and RBV. Patients received dual DAA treatment for 24 weeks with the nonstructural protein 5A replication complex inhibitor, daclatasvir (60 mg once-daily), and the nonstructural protein 3 protease inhibitor, asunaprevir (initially 600 mg twice-daily, then subsequently reduced to 200 mg twice-daily). The primary efficacy endpoint was the proportion of patients with sustained virologic response (SVR) at 12 weeks post-treatment (SVR(12) ). Nine patients completed 24 weeks of treatment; 1 patient discontinued treatment after 2 weeks. In the 9 patients who completed the full course of treatment, HCV RNA was undetectable at week 8 and remained undetectable through the end of treatment; all 9 patients achieved SVR(12) and SVR(24) . HCV RNA also remained undetectable post-treatment in the patient who discontinued after 2 weeks. There was no viral breakthrough. Diarrhea and headache, generally mild, were the most common adverse events; transaminase elevations were reported in 3 patients, but did not result in discontinuation. CONCLUSIONS: Dual therapy with daclatasvir and asunaprevir, without Peg-IFN and RBV, can achieve high SVR rates in difficult-to-treat patients with HCV genotype 1b infection and previous null response to Peg-IFN and RBV.

Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan.

BACKGROUND & AIMS: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. METHODS: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B). RESULTS: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020). CONCLUSIONS: Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C.

BACKGROUND: Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent. METHODS: We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins. RESULTS: Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes. CONCLUSIONS: Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.

Efficacy of Switching from Kanamycin Sulfate to Rifaximin in Patients with Hepatic Cirrhosis.

Objective This study evaluated the efficacy associated with switching to rifaximin in patients with hepatic cirrhosis receiving kanamycin sulfate for the treatment of hepatic encephalopathy and hyperammonemia. Methods We included 37 patients who switched from kanamycin sulfate to rifaximin at our institution from January 2017 to December 2018. The onset of hepatic encephalopathy and changes in blood ammonia values during a six-month period were retrospectively evaluated. Results There were 4 (11%) patients with hepatic encephalopathy at the time of switching from kanamycin sulfate to rifaximin. The cumulative incidence of hepatic encephalopathy was 3% and 16% at 3 and 6 months later, respectively. The blood ammonia levels at the time of switching to rifaximin and at 3 and 6 months later were 94 (range, 20-243) µg/dL, 95 (range, 33-176) µg/dL, and 81 (range, 32-209) µg/dL, respectively, and no significant changes were observed. However, in the 11 patients receiving an oral dose of <1,500 mg/day of kanamycin sulfate, the blood ammonia levels at the time of switching and at 3 and 6 months later were 136 (range, 35-243) µg/dL, 95 (range, 33-150) µg/dL, and 63 (range, 43-124) µg/dL, respectively. Furthermore, the blood ammonia levels significantly decreased at the time of the switching to rifaximin and at three and six months later (p=0.043 and p=0.011, respectively). Conclusion Switching to rifaximin in hepatic cirrhosis patients receiving kanamycin sulfate to treat hepatic encephalopathy and hyperammonemia showed effects that were equivalent to or greater than the original therapy, thereby demonstrating the clinical efficacy.

Bile duct adenoma: imaging features and radiologic-pathologic correlation.

PURPOSE: This study aimed to reveal characteristic imaging features of bile duct adenoma (BDA) by radiologic-pathologic correlation. MATERIALS AND METHODS: We retrospectively analyzed pathological and imaging findings of seven patients with BDA. RESULTS: The median maximum diameter of BDA was 5.5 mm. Six lesions had hemispheric morphology. Seven lesions were located in the liver subcapsular region, and proliferation of bile ductules without atypia and fibrous stroma was observed. Two lesions had different microscopic findings. In both lesions, proliferation of bile ductules without atypia was observed in the margin. In one lesion, the percentage of fibrosis and hyalinization was higher at the center than at the margin. In the other lesion, inflammatory cell infiltration was observed in the center. On contrast-enhanced imaging, BDAs showed hypervascularity in the early phase and prolonged enhancement in the delayed phase. On contrast-enhanced multidetector computed tomography during hepatic arteriography, two lesions showed ring-like enhancement in the first phase and prolonged enhancement in the second phase. These were the different histopathologic features of BDAs between the margin and center. CONCLUSION: Bile duct adenoma can be characterized as a small semicircular lesion located in the liver subcapsular region, which show hypervascularity in the early phase with prolonged enhancement.