Genotype 1b-infected Patients Research Articles

Genotype-specific versus pangenotypic regimens in patients infected with hepatitis C virus genotype 1b in real-world settings.

Introduction: The introduction of direct-acting antivirals (DAAs) has provided us with hope to eliminate hepatitis C virus (HCV) infection as a significant public health problem in the coming years. Objective: Our study aimed to compare the effectiveness and safety of genotype-specific and pangenotypic regimens in genotype 1b–infected patients treated in real-world settings. Patients and methods: Patients were selected from 990 HCV-infected individuals treated with DAAs in the Department of Infectious Diseases in Kielce, Poland, who had the therapy initiated between July 1, 2015 and December 31, 2020. Results: A total of 795 genotype 1b–infected patients with a median age of 51 years, female predominance (55%), and a 21.1% rate of cirrhosis were included in the analysis. A total of 69.9% of patients were treated with genotype-specific regimens. Those patients were significantly older, more often were treatment experienced, and had advanced liver fibrosis and cirrhosis compared with patients assigned to pangenotypic regimens. An overall sustained virologic response rate of 97.9% in the intention-to-treat (ITT) analysis and 99% after excluding nonvirologic nonresponders was achieved, with no significant difference between patients in the 2 treatment arms. Significantly higher proportions of men (P = 0.001) and DAA-experienced patients (P = 0.049) were documented among virologic nonresponders. Conclusions: We confirmed very high effectiveness and a good safety profile of both genotype-specific and pangenotypic regimens used in patients with genotype 1b HCV infection, and we found no differences between these 2 generations of medications. Male sex and previous treatment with DAAs were identified as negative predictors for therapy effectiveness.

Comparative effectiveness of 8 versus 12 weeks of Ombitasvir/Paritaprevir/ritonavir and Dasabuvir in treatment-naïve patients infected with HCV genotype 1b with non-advanced hepatic fibrosis

PurposeSince 2017 treatment-naïve patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting. Materials and methodsWe analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0–F2). ResultsA total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0–F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response. ConclusionsThis real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin.

NS5A Gene Analysis by Next Generation Sequencing in HCV Nosocomial Transmission Clusters of HCV Genotype 1b Infected Patients.

Background: The aim of the study was to investigate the intra-host variability through next-generation-sequencing (NGS) of the NS5A-gene in nosocomial transmission-clusters observed in two Italian hospitals among hepatitis C virus (HCV)-genotype-1b infected patients. Methods: HCV-sequencing was performed by Sanger-sequencing (NS3 + NS5A + NS5B) and by NGS (NS5A, MiSeq-Illumina) in 15 HCV-1b infected patients [five acute with onco-hematologic-disease and 10 (4/6 acute/chronic) with β-thalassemia]. Resistance-associated-substitutions (RAS) were analysed by Geno2pheno-algorithm. Nucleotide-sequence-variability (NSV, at 1%, 2%, 5%, 10% and 15% NGS-cutoffs) and Shannon entropy were estimated. Phylogenetic analysis was performed by Mega6-software and Bayesian-analysis. Results: Phylogenetic analysis showed five transmission-clusters: one involving four HCV-acute onco-hematologic-patients; one involving three HCV-chronic β-thalassemia-patients and three involving both HCV-acute and chronic β-thalassemia-patients. The NS5A-RAS Y93H was found in seven patients, distributed differently among chronic/acute patients involved in the same transmission-clusters, independently from the host-genetic IL-28-polymorphism. The intra-host NSV was higher in chronic-patients versus acute-patients, at all cutoffs analyzed (p < 0.05). Even though Shannon-entropy was higher in chronic-patients, significantly higher values were observed only in chronic β-thalassemia-patients versus acute β-thalassemia-patients (p = 0.01). Conclusions: In nosocomial HCV transmission-clusters, the intra-host HCV quasispecies divergence in patients with acute-infection was very low in comparison to that in chronic-infection. The NS5A-RAS Y93H was often transmitted and distributed differently within the same transmission-clusters, independently from the IL-28-polymorphism.

NS5A gene analysis by next generation sequencing in HCV nosocomial transmission clusters of HCV genotype 1b infected patients

NS5A gene analysis by next generation sequencing in HCV nosocomial transmission clusters of HCV genotype 1b infected patients

Efficacy and safety of 12 weeks of daclatasvir, asunaprevir plus ribavirin for HCV genotype-1b infection without NS5A resistance-associated substitutions

Treatment with daclatasvir plus asunaprevir (DCV+ASV) for 24 weeks provided a sustained virologic response (SVR) rate of over 90% in hepatitis C virus genotype 1b (HCV-1b) infected patients without non-structural 5A (NS5A) resistance-associated substitutions (RASs) at the L31 and Y93 sites. In this study, we investigated whether adding ribavirin to the DCV+ASV combination could shorten the original treatment regimen to 12 weeks without compromising the treatment efficacy for HCV-1b patients without NS5A RASs. In the prospective, open-label, single-arm, nationwide multi-center phase III study, a total of 70 interferon-naïve or interferon-experienced HCV-1b patients without baseline L31/Y93 RASs received daclatasvir (60mg/day) and asunaprevir (100mg twice daily) plus weight-based ribavirin (1000-1200mg/day) for 12 weeks, with a 12-week post-treatment follow-up. The primary end-point was the rate of undetectable HCV RNA 12 weeks post-treatment (SVR12). The SVR12 rate was 97.1% (68/70) and 100% (68/68) in the full-analysis-set and the per-protocol population, respectively. None of the 68 patients who completed the 12-week treatment experienced relapse during post-treatment follow-up. Two patients withdrew from the study at treatment days 21 and 34 due to anorexia and fatigue, which were considered ribavirin-related and resolved post medication cessation. A total of 4 serious adverse events were reported and considered treatment-unrelated. No deaths or grade 4 adverse events requiring hospitalization was observed throughout the study. Truncated regimen of DCV+ASV plus ribavirin for 12 weeks was highly effective and safe in HCV-1b patients without NS5A L31/Y93 RAS.

Efficacy of direct-acting antiviral treatment in patients with compensated liver cirrhosis: A multicenter study.

Although the development of new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. This large-scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b-infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety-two patients (4.3%) previously received DAA-based treatment. Seven hundred and forty-five patients (34.9%) had cirrhosis. Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10-7 ). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10-3 ), no previous DAA-based treatment (P = 2.54 × 10-14 ), low HCV-RNA levels (P = 1.64 × 10-6 ), wild-type non-structural protein 5A L31/Y93 (P = 7.33 × 10-13 ), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10-14 ) were independent factors contributing to SVR. Except for patients with DAA-based treatment history, absence of cirrhosis (P = 2.15 × 10-3 ; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA-naïve patients. This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment.

Eight weeks of Paritaprevir/r/Ombitasvir + Dasabuvir in HCV genotype 1b with mild‐moderate fibrosis: Results from a real‐world cohort

The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort. We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded. A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n=85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494)IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7weeks after EOT. Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.

Determination of Sustained Virological Response in Hepatitis C Virus Genotypes by the Number of Mutations in the E2 and NS5A-ISDR Regions: A Meta-Analysis

Since last few decades hepatitis C virus (HCV) has been a major cause of death due to the involvement of acute and chronic type of liver diseases throughout the world. Genotype variability and mutations occurring at different regions of HCV genome provides a critical parameter for the study of sustained virological response (SVR) against mono and combinational therapies. Most of these mutations occurring in E2 and NS5A-ISDR regions in HCV genotypes play a significant role in SVR against Interferon-monotherapy and combination therapy. Therefore, the aim of the present study is to evaluate the SVR in various genotypes and the role of mutations in specific regions. In line with this, the NS5A and E2 proteins of HCV genotype 1 were found to suppress the double-stranded (ds) RNA-dependent protein kinase (PKR), which in turn is entailed in the cellular antiviral response stimulated by interferon (IFN). The response to IFN therapy varies between genotypes, with response rates among patients infected with types 2 and 3 nearly two-three-fold greater than in patients infected with type 1. Surprisingly, a considerable percentage of HCV genotype 3a infected patients do not react to treatment at all. In Japan, a link was observed between the numbers of mutations in an “interferon sensitivity determining region” (ISDR) and the result of interferon treatment in genotype 1b infected patients. Therefore, we published data on E2 (PePHD) and NS5A-ISDR regions including our data on SVR of different HCV genotypes, the relationship between the number and patterns of mutations in the E2 (PePHD) and NS5A-ISDR regions and responsiveness to IFN therapy.

Hepatic decompensation during paritaprevir/ritonavir/ombitasvir/dasabuvir treatment for genotype 1b chronic hepatitis C patients with advanced fibrosis and compensated cirrhosis.

Background and aimHepatic decompensation is a severe on-treatment adverse event for chronic hepatitis C treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Till now, few papers regarding on-treatment hepatic decompensation have been reported. The study aims to analyze the general feature and predictive factors of on-treatment hepatic decompensation in hepatitis C virus (HCV) genotype 1b-infected patients with advanced fibrosis and compensated cirrhosis who receive treatment with PrOD.MethodsA real-word cohort enrolled 189 HCV genotype 1b patients with advanced fibrosis and compensated cirrhosis treated with 12-week PrOD. Clinical and laboratory data were analyzed between patients with and without on-treatment hepatic decompensation.ResultsThe sustained virologic response rate at 12 weeks after treatment was 97.3% in HCV subtype 1b patients with advanced fibrosis and cirrhosis. On-treatment hyperbilirubinemia (total bilirubin >2 mg/dL) occurred in 27 (14.3%) patients, and the incidence of the increase of total and direct form bilirubin was significantly different during treatment between patients with Child-Turcotte-Pugh score 5 and score 6. Five (18.5%) hyperbilirubinemia patients progressed to hepatic decompensation. Older age (adjusted OR: 1.2, 95% CI: 1.0–1.4) and albumin ≤3.6 g/dL (adjusted OR: 10.4, 95% CI: 1.3–81.2) may be two predictors for on-treatment hepatic decompensation by multivariate analysis.ConclusionsPrOD is an effective direct-acting antiviral agent for antiviral therapy in HCV genotype 1b patients with advanced fibrosis and cirrhosis. Hyperbilirubinemia is possibly the early warning feature of on-treatment hepatic decompensation. This serious adverse event of on-treatment hepatic decompensation is not common. Older age and low baseline albumin level may be predictive factors.

Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct-Acting Antiviral Therapy.

Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (±1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy.

Daclatasvir and asunaprevir combination therapy for patients with chronic hepatitis C virus genotype 1b infection in real world.

Background/AimsPrevious studies have reported a high rate of sustained virologic response (SVR) and a low rate of serious adverse events with the use of daclatasvir (DCV) and asunaprevir (ASV) combination therapy. We evaluated the efficacy and safety of DCV and ASV combination therapy for patients with chronic hepatitis C virus (HCV) genotype 1b infection in real world.MethodsWe enrolled 278 patients (184 treatment-naïve patients) from five hospitals in Daegu and Gyeongsangbuk-do. We evaluated the rates of rapid virologic response (RVR), end-of-treatment response (ETR), and SVR at 12 weeks after completion of treatment (SVR12). Furthermore, we investigated the rate of adverse events and predictive factors of SVR12 failure.ResultsThe mean age of patients was 59.5 ± 10.6 years, and 140 patients (50.2%) were men. Seventy-seven patients had cirrhosis. Baseline information regarding nonstructural protein 5A (NS5A) sequences was available in 268 patients. Six patients presented with pretreatment NS5A resistance-associated variants. The RVR and the ETR rates were 96.6% (258/267) and 95.2% (223/232), respectively. The overall SVR12 rate was 91.6% (197/215). Adverse events occurred in 17 patients (7.9%). Six patients discontinued treatment because of liver enzyme elevation (n = 4) and severe nausea (n = 2). Among these, four achieved SVR12. Other adverse events observed were fatigue, headache, diarrhea, dizziness, loss of appetite, skin rash, and dyspnea. Univariate analysis did not show significant predictive factors of SVR12 failure.ConclusionsDCV and ASV combination therapy showed high rates of RVR, ETR, and SVR12 in chronic HCV genotype 1b-infected patients in real world and was well tolerated without serious adverse events.

Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1

Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230–239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.

Celebrating industry’s innovations

Passion, perseverance, and a multidisciplinary team: That’s what the American Chemical Society’s 2017 Heroes of Chemistry awardees say are the key components of developing successful commercial products that benefit humanity. Six teams of industrial chemical scientists, from Bristol-Myers Squibb, Corning, the Dow Chemical Company, DuPont Crop Protection, Genentech, and Merck & Co., received ACS’s most prestigious industry award during the ACS national meeting in Washington, D.C., in August. Industrial chemical scientists represent more than half of ACS’s membership, and the Heroes of Chemistry Award is one way that the society celebrates their achievements. The following are snapshots of the winning teams and their life-changing products. Bristol-Myers Squibb: Daklinza (daclatasvir) and Sunvepra (asunaprevir) Daklinza (daclatasvir) and Sunvepra (asunaprevir) are direct-acting antiviral agents, which in combination have produced hepatitis C cure rates of greater than 90% in genotype 1b-infected patients. “...

Prevalence of hepatitis C virus-resistant association substitutions to direct-acting antiviral agents in treatment-naïve hepatitis C genotype 1b-infected patients in western China.

BackgroundDirect-acting antivirals (DAAs) against hepatitis C virus (HCV) are potent and highly efficacious. However, resistance-associated substitutions (RASs) relevant to DAAs can impair treatment effectiveness even at baseline. Moreover, the prevalence of baseline RASs in HCV genotype 1b-infected patients in western China is still unclear.Materials and methodsDirect sequencing of the HCV NS3, NS5A, and NS5B regions was performed in baseline serum samples of 70 DAAs treatment-naïve HCV 1b-infected patients in western China. The sequences were analyzed with MEGA version 5.05 software. Evolutionary patterns of RASs and amino-acid covariance patterns in the NS3, NS5A, and NS5B genes were analyzed by MEGA and Cytoscape (version 3.2.1), respectively.ResultsThe presence of at least one RAS in the NS3 region (C16S, T54S, Q80R/L, A87T, R117H, S122G, V132I, V170I) was observed in 85.48% (53 of 62) of patients, RASs in the NS5A region (L28M, R30Q, Q54H, P58S/T, Q62H/R, Y93H) were observed in 42.42% (28 of 66) of patients, and RASs in the NS5B region (N142S, A300T, C316N, A338V, S365A, L392I, M414L, I424V, A442T, V499A, S556G) were observed in 100% (44 of 44) of patients. Evolutionary patterns of RASs and amino-acid covariance patterns for the NS3, NS5A, and NS5B genes are reported.ConclusionThe prevalence of RASs relevant to DAAs detected in the NS3, NS5A, and NS5B regions of HCV 1b from DAA treatment-naïve patients is high. Therefore, more attention should be paid to RASs associated with DAAs in the upcoming DAA-treatment era in China.

A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital-c network study.

The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12weeks, and sofosbuvir-ledipasvir alone for 24weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24weeks, respectively (P=.002). The baseline characteristics of patients treated for 12weeks were significantly different from those treated for 24weeks as regards their younger age (P=.002), prevalence of Child-Pugh class A (P=.002), lower MELD scores (P=.001) and smaller number of nonresponders (P=.04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P=.007 and P=.008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12weeks was less effective than sofosbuvir-ledipasvir alone given for 24weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.

Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study.

The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12weeks of SMV/Peg-IFN/RBV followed by 12weeks of Peg-IFN/RBV with or without 24weeks of FLV. The SVR rate and adverse events were compared between the two groups. Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24weeks after treatment, and safety profiles were also similar between the two groups. This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.

Naturally occurring drug resistance associated variants to hepatitis C virus direct-acting antiviral agents in treatment-naive HCV genotype 1b-infected patients in China.

The direct-acting antiviral agents (DAAs) have drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the resistance-associated variants (RAVs) to DAAs may hamper treatment. There was a lack of data on the prevalence of pre-exist RAVs in Chinese HCV-infected patients. We performed nested PCR assays on 74 HCV genotype 1b-infected patients to amplify HCV viral regions of NS3, NS5A, and NS5B to investigate the prevalence of RAVs to DAAs in treatment-naive HCV genotype1b-infected patients in China. The mutations A156S, T54S, and D168Y of the NS3/4A region were found in 18.33% (11/60), 6.67% (4/60), and 1.67% (1/60) of the successfully amplified cases. Mutations Q30R, L31M, and H58P of the NS5A region were confirmed in 57.63% (34/59), 1.69%(1/59), and 86.44% (51/59) of the cases. Mutations C316N, S365A, M414L, M423I, Y448H, I482T, I482 V, V494L, P495S, and V499A of the NS5B region were detected in 100% (60/60), 3.33% (2/60), 5.88% (3/51), 1.96% (1/51), 1.96% (1/51), 5.88% (3/51), 1.96% (1/51), 3.92% (2/51), 5.88% (3/51), and 15.69% (8/51) of cases, respectively. Naturally occurring RAVs to DAAs pre-exist in treatment-naive Chinese HCV genotype 1b-infected patients and the characteristic is different from that in Europe and the United States. Clinicians should consider RAVs upon the introduction of DAA-based antiviral therapy.

日本人高齢ジェノタイプ1b型C型肝炎ウイルス感染患者におけるオムビタスビル/パリタプレビル/リトナビルの安全性および有効性―GIFT-I試験の事後解析―

日本人高齢ジェノタイプ1b型C型肝炎ウイルス感染患者におけるオムビタスビル/パリタプレビル/リトナビルの安全性および有効性―GIFT-I試験の事後解析―

Portal Hypertension Does Not Preclude the Efficacy of Direct-acting Anti-Hepatitis C Viral Therapy

Totally, 113 patients were included in this study; 26 with CSPH and 87 without CSPH. HCV genotype 1b-infected patients were treated with either daclatasvir plus asunaprevir or sofosbuvir plus ledipasvir. HCV genotype 2-infected patients were treated with sofosbuvir plus ribavirin. Sustained virological response (SVR) rates were equally good in patients with CSPH (96%) and in those without CSPH (93%). In patients who achieved SVR, prompt improvements in the hepatic function were observed. Recovery was more pronounced in patients with CSPH. There was no early treatment discontinuation and no hepatic decompensation.

Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection

DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies. In this phase 3 study, DCV-TRIO for 12weeks and daclatasvir plus asunaprevir (DUAL) for 24weeks were studied in Japanese patients infected with HCV genotype 1 (99% genotype 1b). SVR12 rates ≥95% were achieved in both treatment-naive (N=152) and interferon-experienced (N=65) cohorts treated with DCV-TRIO for 12weeks and were comparable across patient subgroups, including patients aged ≥65years and those with cirrhosis. DUAL recipients (N=75) had an SVR12 rate of 87%. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98% with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92%) DCV-TRIO recipients, and 7/16 (44%) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10% of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3% of DCV-TRIO and DUAL recipients, respectively. Seven patients (9%) discontinued DUAL due to adverse events. No deaths occurred. SVR12 was achieved by 96% of Japanese patients with HCV genotype 1 infection after 12weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.