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Although direct-acting antivirals (DAAs) have notably increased the sustained virological response (SVR) rates in hepatitis C virus (HCV)-infected adolescent patients, the efficacy and safety for young children under 3 years old remain unclear. Currently, no guidelines recommend DAA therapy for this situation worldwide. Furthermore, the China National Medical Products Administration has not approved any DAA for treating children below 12 years old. Here, we described the characteristics of two children approximately 2 years old, who were infected by HCV genotype 1b and had significant clinical symptoms. Both received 12 weeks of ledipasvir/sofosbuvir (Case 1: 45.00 mg/200 mg per day, weight 17 kg; Case 2: 33.75 mg/150 mg per day, weight 12 kg). They achieved SVR at 12 weeks after treatment completion without obvious treatment-related adverse effects. Therefore, the safety and benefits of ledipasvir/sofosbuvir treatment in children under 3 years old seem to be confirmed. Our findings require further evaluation.

Background/Aims Previous 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. Methods We 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. Results The 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. Conclusions DCV 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.

Background/AimsThe treatment with daclatasvir plus asunaprevir (DCV+ASV) is associated with potent antiviral effects in patients with genotype 1b hepatitis C virus (HCV) infection. We investigated the real-world efficacy, changes in liver stiffness and noninvasive fibrosis markers, and the safety of DCV+ASV treatment in Korean patients.Methods : In total, 363 patients with chronic hepatitis C were treated with DCV+ASV between August 2015 and January 2017. Finally, we analyzed the data of 270 patients who were monitored for at least 12 weeks after the end of treatment.Results : The mean age was 60.7 years, and females predominated (60.4%). Most patients (64.8%) were treatment-naïve, and 56 patients (20.7%) had cirrhosis. Two hundred fifty-seven (95.2%) and 251 (93.0%) patients achieved end-of-treatment responses and sustained virological responses at 12 weeks posttreatment (SVR12), respectively. The SVR12 rates were higher in patients who were

Background/AimsAlthough daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded.Methods : Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study.Results : Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged

Evaluation of the incidence and predictors of failure of direct-acting antiviral treatment for hepatitis C virus genotype 1b patients is important. Our retrospective cohort study assessed 172 Turkish patients who had received a full course of such treatment and could be checked for sustained virologic response. The overall treatment failure rate was 2.9% (5/172), all of whom relapsed. In three of these cases with sequencing data available, all had NS5A resistance-associated substitution. Multivariate analysis revealed that a 1 mg/dL increase in pre-treatment total bilirubin level was associated with a sevenfold increased likelihood of treatment failure. The baseline level of total bilirubin was the only significant independent predictor of direct-acting antiviral treatment failure. [ABSTRACT FROM AUTHOR]

Since 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. We 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). A 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. This 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. [ABSTRACT FROM AUTHOR]

In hepatitis C virus (HCV) infection viral and host factors can influence therapy outcome to pegylated interferon/ribavirin (PEG-IFN/RBV) and progression of liver fibrosis. Although novel direct-acting antivirals (DAAs) show newly successful treatment of hepatitis C infection, the majority of patients are unable to access this therapy because of cost and so remain untreated. Also, the efficacy of treatment with new therapy may be affected by the presence of resistance-associated substitutions (RASs). This study was designed to describe associations between baseline host and viral factors, progression of liver fibrosis and response to therapy with pegylated interferon/ribavirin (PEG-IFN/RBV) in patients with chronic hepatitis C (HCV) genotype 1b. We analyzed pre-treatment of 100 patients with chronic hepatitis C genotype 1b and related it to outcome of therapy. TaqMan assay was used to determine SNP rs12979860 in all patients. In our study there was significant correlation between age and response to therapy. Also, we found associations between a known route of transmission and age, gender, stage of liver fibrosis and therapy outcome. With respect to SNP rs12979860, the frequency of the CC genotype in the group with a sustained virologic response (SVR) was significantly higher than in the group of non-responders (NR). In contrast, there was no correlation between IL28B polymorphism and progression of liver fibrosis.

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p < 0.001), M133I (20.6% vs. 3.9%, p < 0.001), and Q181E (11.8% vs. 0.6%, p < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

Viral and host factors in hepatitis C virus (HCV) infection can influence on therapy outcome to pegylated interferon/ribavirin (PEG-IFN/RBV) and progression of liver fibrosis. Although novel direct-acting antivirals (DAAs) represent promising successful treatment of hepatitis C infection, the majority of patients are deprived of this therapy because of its expensiveness and therefore they remain untreated. Also, the efficacy of this novel treatment may be affected by the presence of resistance-associated substitutions (RASs). This study was designed to describe associations between baseline host and viral factors, progression of liver fibrosis and response to therapy with pegylated interferon/ribavirin (PEG-IFN/RBV) in patients with chronic hepatitis C (HCV) genotype 1b. Pre-treatment of 100 patients with chronic hepatitis C genotype 1b was analyzed, and related to outcome of therapy. TaqMan assay was used to determine SNP rs12979860 in all patients. In our study there was significant correlation between age and response to therapy. Also, we found associations between a known route of transmission and age, gender, stage of liver fibrosis and therapy outcome. With respect to SNP rs12979860, the frequency of the CC genotype in the group with a sustained virologic response (SVR) was significantly higher than in the group of non-responders (NR). In contrast, there was no correlation between IL28B polymorphism and progression of liver fibrosis. [ABSTRACT FROM AUTHOR]

Aim: Treatment with all‐oral direct‐acting antiviral agents (DAAs) elbasvir/grazoprevir (EBR/GZR) is associated with high sustained virologic response (SVR). The aim of this study was to evaluate the safety and treatment efficacy of EBR/GZR in hepatitis C virus (HCV)‐infected patients. Methods: This retrospective cohort study included 147 consecutive patients with chronic HCV genotype 1b infection who were treated with EBR (50 mg) plus GZR (100 mg) once daily for 12 weeks. The rates of SVR at 12 weeks after the end of treatment (SVR12) were evaluated based on patient baseline characteristics. Treatment efficacy was analyzed according to background chronic kidney disease (CKD), and retreatment efficacy in patients who failed to respond to previous DAAs. Results: The SVR12 was 94% (138 of 147 patients), based on intention‐to‐treat analysis. Rates of SVR12 were 97% (131 of 135) and 58% (7 of 12) in cases naïve to DAA treatment and failure to respond to prior DAAs, respectively. The SVR12 rates in patients with CKD stage 4–5 was 100% (8 of 8). All patients (4 of 4 patients) with stage 4–5 and advanced fibrosis (Fibrosis‐4 index ≥3.25) also achieved SVR12. Multivariate analysis that included the above variables identified pretreatment with other DAAs as an independent factor that was significantly and independently associated with non‐SVR12 (odds ratio, 97.5; P < 0.001). Relapsers of first DAAs, excluding the combination of ledipasvir and sofosbuvir, achieved SVR12. Characteristic novel non‐structural protein 5A substitutions were not detected after failure of retreatment with EBR/GZR. Conclusion: Treatment with EBR/GZR was highly efficacious with acceptable safety, even in patients with CKD stage 4–5. Retreatment of relapsers to prior DAAs, excluding ledipasvir and sofosbuvir, achieved SVR12. [ABSTRACT FROM AUTHOR]

Abstract Hepatic steatosis is common in patients infected with hepatitis C virus (HCV). Particularly in patients infected with non-genotype 3 HCV, hepatic steatosis is closely related to factors of the metabolic syndrome such as hyperlipidemia. However, the molecular mechanisms involved in this “metabolic” steatosis in non-3 genotype HCV infections are not well understood. Here, we aimed to develop an in vitro model to study the effect of genotype 1 HCV infection on hepatic lipotoxicity and lipid metabolism. Cellular lipid accumulation was induced in Huh-7 hepatoma cells transfected with HCV genotype 1b replicon (HCV+) by incubation with increasing doses of palmitic acid (C16:0) or oleic acid (C18:1 n-9) complexed to albumin mimicking hyperlipidemic conditions. Mock transfected hepatoma cells (HCV−) were used as controls. Incubation with oleic acid concentrations as high as 0.5 mM did not induce toxic effects in HCV+ or HCV− cells. In contrast, incubation with palmitic acid caused dose-dependently cytotoxic effects which were more pronounced in HCV+ compared to HCV− cells. Further analysis with subtoxic palmitic and oleic acid concentrations revealed a higher uptake of fatty acids and intracellular triglyceride accumulation in HCV+ compared to HCV− cells. Carnitine palmitoyltransferase I (CPT1) expression, indicative of mitochondrial beta-oxidation, was markedly stimulated by lipid exposure in HCV+ but not in HCV− cells. Furthermore, heme oxygenase 1 (HMOX1) expression levels increased in FA stimulated cells, and this increase was significantly higher in HCV+ compared to HCV− cells. In contrast, expression of the key enzymes of hepatic de novo lipogenesis fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD-1) was significantly reduced upon oleate exposure in HCV− but not in HCV+ cells. In summary, our newly developed cell culture model revealed effects of HCV genotype 1b infection on metabolic susceptibility to lipid accumulation and toxicity particularly to saturated lipids. These results may indicate that HCV (genotype 1b) infected individuals with hyperlipidemia may benefit from dietary or pharmacological intervention. [ABSTRACT FROM AUTHOR]

Objective: The first interferon-free regimen became available in Russia in 2015. It brought hope to HCV Gt1 patients with cirrhosis for whom interferonbased schemes found to be non-effective or contraindicated. 3D therapy was the only available etiotropic option for them. New safety data published after the start of our study significantly limited usage of this regimen among patients with non-compensated cirrhosis. The aim of this study was to evaluate efficacy and safety of the 3D interferon-free regimen among HCV Gt1b patients with non-compensated cirrhosis. Method: 66 patients (26 males and 40 females) with HCV Gt1b and non-compensated cirrhosis were enrolled. All of them were treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin for 12 weeks. Ribavirin was discontinued after 4 weeks of therapy due to onset of new data on the efficacy of 3D regimen without ribavirin in Turquoise III study published in September 2015 before the change of package insert. Child-Pugh score was assessed before the start of antiviral therapy as follows: 21 patients (31,8%) - 9 points, 11 patients (16,7%) - 8 points, 34 patients (51,5%) - 7 points. The key method used to evaluate study results was modified intent-to-treat (mITT) analysis because number of analyzed patients within treatment period changed after withdrawal caused by safety reasons but followed by assessment of efficacy among patients who discontinued treatment. Per protocol (PP) method was also used in addition to mITT. Results: Aviremia after 14 days of treatment was reached among 35 out of 65 patients (53,8%), rapid virologic response - among 79,7% patients (51/64). Each patient who received full 12-week course of treatment (n=60) including those who discontinued due to safety reasons (n=3) between 14th and 30th days of therapy reached SVR12 and SVR24. Assessment of Child-Pugh score in 6 months after EOT demonstrated decrease by 3-4 points among 21 patients (33,9%) and by 1-2 points among 35 patients. 66,1% patients reached clinical improvement in MELD score. Treatment discontinuation was caused by progression of hepatic encephalopathy and/or jaundice (4 cases). Those adverse events regressed among majority of patients after discontinuation of therapy. 3 deaths were reported (bacterial endocarditis, progression of hepatic encephalopathy and bleeding from gastric ulcers) during treatment period and 1 death in follow-up period due to progression of hepatocellular carcinoma. Conclusion: 3D therapy was effective in 100% patients (mITT) with HCV GT1b and non-compensated cirrhosis both among those who completed full therapy course and those who discontinued the therapy due to safety reasons. Safety analysis demonstrated that the rate of severe adverse events was comparable with natural course of HCV-infection in patients on non-compensated cirrhotic stage without antiviral treatment. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) NS5B polymerase is an attractive target for the development of novel and selective inhibitors of HCV replication. In this paper, the design, synthesis, and preliminary SAR studies of novel inhibitors of HCV NS5B polymerase based on the structure of tegobuvir have been described. The efforts to optimize the antiviral potency and reduce the treatment side effects with respect to genotype 1b resulted in the discovery of compound 3, which exhibited an EC 50 of 1.163 nM and a CC 50 >200 nM in a cell-based HCV replicon system assay. Additionally, testing for inhibition of the hERG channel showed a marked improvement over tegobuvir and the pharmacokinetic properties of compound 3 indicated that it was worthy of further investigation as a non-nucleoside inhibitor of HCV NS5B polymerase. [ABSTRACT FROM AUTHOR]

Hepatitis C virus infection is the most common chronic blood-borne infection and one of the most important causes of chronic liver disease. Knowing the predictors associated with pegylated interferon/ribavirin (PEG-IFN/RBV) combination therapy response is important for evidence-based treatment recommendations. The goal of this study was to identify host and viral factors of response to PEG-IFN/RBV treatment in chronic hepatitis C genotype 1b patients. We have examined the relationship between gender, age, level of alanine aminotransferase (ALT), viral load and liver fibrosis progression on therapy response. ALT level and viral load were evaluated before starting treatment with combination therapy. The elevated levels of ALT and route of HCV transmission were found to be significantly associated with the response to therapy in HCV-infected patients. Our findings may be useful for estimating a patient’s likelihood of achieving sustained viral response. [Projekat Ministarstva nauke Republike Srbije, br. OI 173049 i br. TR 37021]

Aim From a pharmacokinetic viewpoint, the use of ombitasvir/paritaprevir/ritonavir, one of the standards of care for genotype 1b chronic hepatitis C in Japan, could be possible in patients with impaired renal function. The aim of this study was to assess the efficacy and safety of this combination that have not yet been addressed in patients undergoing dialysis. Methods A retrospective, multicenter study evaluated the outcome of 12-week ombitasvir (non-structural protein [NS]5A inhibitor)/paritaprevir (NS3/4A protease inhibitor)/ritonavir combination therapy for dialysis patients. The primary end-point was sustained virologic response 12 weeks after therapy (SVR12). Results The subjects were 31 patients with a median age of 64 years (range, 49-85 years), including 10 cirrhotic patients. All of the 31 patients had an estimated glomerular filtration rate level <15 mL/min/1.73 m2, defined as end-stage renal disease (ESRD). Pre-existing resistance-associated substitutions at position L31 and Y93 of the NS5A region were detected in 0% and 3.6% (1/28), respectively. The rates of rapid virologic response, end-of-treatment response, and SVR12 were 93.5% (29/31), 100% (31/31), and 96.8% (30/31), respectively. The incidence of adverse events was 35.5% (11/31). Of the 11 patients, one discontinued the treatment due to erythema multiforme and thereafter relapsed. The most frequent adverse event was pruritus (6.5%; 2/31). Conclusions The present study suggests that ombitasvir/paritaprevir/ritonavir combination therapy is effective and safe for genotype 1b chronic hepatitis C patients undergoing dialysis due to ESRD. [ABSTRACT FROM AUTHOR]

Background & Aim In the mid-1990s, a group of Rh negative women was diagnosed with hepatitis C virus (HCV) genotype 1b infection, following administration of contaminated anti-D immunoglobulin in 1977–79. We aimed to describe their disease history and estimate the effect of selected host and treatment factors on disease progression. Methods We conducted a cohort study on the women infected with HCV. Information was collected from records at seven HCV treatment centres on demographics, treatment and health outcomes up to the 31st December 2013. We calculated cumulative incidence, case fatality, and sub hazard ratios (SHR) for disease progression using competing risks regression. Results Six hundred and eighty-two patients were included in the study. Among the chronically infected patients (n = 374), 35% completed interferon-based antiviral treatment; 42% of whom had a sustained virological response. At the end of 2013, 19%, 1.9%, and 4.9% of chronically infected patients had developed cirrhosis, hepatocellular carcinoma, and liver-related death, respectively, compared with 10%, 0.8%, and 2.4% at the end of 2008. At the end of 2013, 321 (86%) of the chronically infected patients remained alive, 247 (77%) of whom were still chronically infected. Factors associated with increased cirrhosis rates included high alcohol intake (aSHR = 4.9 [2.5–9.5]) and diabetes mellitus (aSHR = 5.0 [2.9–8.8]). Conclusions Development of liver-related outcomes accelerated with time, with the risk of cirrhosis, hepatocellular carcinoma, and liver-related death doubling in the last five years of follow-up, particularly in women with high alcohol consumption and diabetes mellitus. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of alcohol, and that data be collected on this cohort after a further five years to analyse the effect of subsequent antiviral treatment during this rapidly evolving period in HCV treatment history. Lay summary In the mid-1990s, a group of women were diagnosed with chronic hepatitis C virus (HCV) infection following receipt of contaminated anti-D immunoglobulin between 1977 and 1979 in Ireland. Seventy-two (19%) developed cirrhosis and 18 had died from liver-related causes (5%) after 36 years of infection. Disease progression accelerated in the last five years of follow-up, particularly in women with diabetes mellitus and high alcohol consumption. We recommend that patients with chronic HCV infection be advised of the additive harmful effect of high alcohol consumption. [ABSTRACT FROM AUTHOR]

Background and Aim In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. Methods Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index ≧ 3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P < 0.05 was considered as significant levels. Results Antiviral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P = 0.002 and P = 0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P = 0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4 weeks after the start of treatment. Conclusion Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations. [ABSTRACT FROM AUTHOR]

Background & Aims We investigated the efficacy and safety of simeprevir plus daclatasvir in treatment-naïve patients with chronic, genotype 1b hepatitis C virus infection and advanced liver disease, excluding patients with pre-defined NS5A resistance-associated substitutions. Methods This phase II, open-label, single-arm, multicentre study included patients aged ≥18 years with advanced fibrosis or compensated cirrhosis ( METAVIR F3/4). Patients with NS5A-Y93H or L31M/V resistance-associated substitutions at screening were excluded. Simeprevir (150 mg)+daclatasvir (60 mg) once daily was administered for 12 or 24 weeks; treatment could be extended to 24 weeks prior to or at the Week 12 visit. Primary efficacy endpoint was sustained virological response 12 weeks after the end of treatment. Results A total of 106 patients were treated; 27% patients were aged >65 years, 39% had cirrhosis, 53% had estimated glomerular filtration rate 30-89 mL/min, 14% had diabetes, and 38% had arterial hypertension. Overall, 42/106 received 12 weeks of treatment and 64/106 received 24 weeks of treatment. Ninety-seven (92%) patients achieved a sustained virological response 12 weeks after the end of treatment. The reasons for failure were viral breakthrough (n=7) at weeks 4-16, early treatment discontinuation (n=1) and viral relapse (n=1). Seventy-four (70%) patients had ≥1 adverse event during treatment, including six (6%) patients with ≥1 serious adverse event. Three (3%) patients discontinued treatment owing to adverse events. Conclusions Simeprevir+daclatasvir demonstrated strong antiviral activity and was well-tolerated in patients with hepatitis C virus genotype 1b infection, advanced liver disease and a high prevalence of comorbidities. However, viral breakthrough occurred in seven patients, making this regimen unsatisfactory. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) genotypes 1b and 2a are the major cause of liver disease in northern China; however, conventional detection tools are labor-consuming, technically demanding, and costly. Here, we assessed the specificity, sensitivity, and clinical utility of reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for detection of HCV genotypes 1b and 2a. Firstly, clinical samples were collected from HCV genotype 1b and 2a infected patients and the RNA were extracted. Secondly, specificity of RT-LAMP assay for detection HCV genotypes 1b and 2a were tested against viral genomes of other hepatitis viruses. Sensitivity of RT-LAMP assay was determined using serial dilutions of standard HCV genotypes 1b and 2a. The amplified products were detected by both electrophoresis and calcein/Mn2+-dependent visual methods. Finally, we compared the clinical detection rate of RT-LAMP to that of real-time PCR. RT-LAMP assay showed high specificity to detect HCV genotypes 1b and 2b since there was no cross-reactivity with other hepatitis viruses. Sensitivity of RT-LAMP was 100 IU/mL for both genotypes detected by either electrophoresis or calcein/Mn2+ -dependent visual methods. The detection rate of RT-LAMP assay in clinical samples was also comparable to that of real-time PCR without significant difference between the both assays. This study proposes a newly developed RT-LAMP assay for detection of HCV genotypes 1b and 2a. RT-LAMP is highly specific, sensitive, and simple diagnostic tool which would be useful for screening and early diagnosis of HCV especially in resource-limited environments. [ABSTRACT FROM AUTHOR]

Background and Aim In China, chronic hepatitis C virus (HCV) infection represents a considerable healthcare burden. Although interferon-based therapy has been the standard-of-care for many years, few long-term, real-life studies have assessed interferon-based treatment in China. The objective of CCgenos follow-up study was to analyze long-term treatment patterns and outcomes in a cohort of treatment-naïve, Han ethnic, patients with chronic HCV infection. Methods Patients who had participated in the CCgenos cross-sectional study were invited to enter this 5-year follow up. Clinical information and centralized HCV-RNA measures were collected at scheduled study visits every 6 months for untreated patients and every 3 months for treated patients. Results Among 512 patients enrolled, 334 (65.2%) received interferon-based treatment and 178 (34.8%) remained untreated over a median of 4.1 (1.2-4.3) years. A total of 82.8% (424/512) of patients had an IL28B CC genotype (GT); 60.7% (311/512) had HCV GT1b infection, including 121 (38.9%) untreated. Most patients with baseline cirrhosis were untreated (26/46, 56.5%). Among patients who completed treatment and 24 weeks of post-treatment follow up, the duration of interferon-based therapy was frequently longer than recommended (52.9% [92/174] of GT1b-infected were treated for > 1 year). Rates of sustained virologic response (SVR24) were 71.1% (226/318) overall; 62.4% (111/178) among patients with HCV GT1b infection; and 42.9% (15/35) among patients with cirrhosis. Conclusions There remains a high unmet need for effective HCV treatment in China, evidenced by a high proportion of patients remaining untreated by the current standard-of-care and relatively low SVR24 rates for patients with both GT1b infection and cirrhosis. [ABSTRACT FROM AUTHOR]

Acute pancreatitis, an uncommon side effect of pegylated interferon α (PEG-IFN α) and ribavirin (RBV) combination therapy, has rarely been reported in the English language literature. Here, acute pancreatitis associated with PEG-IFN plus RBV treatment is described in three patients with chronic hepatitis C, genotype 1b with high serum hepatitis C virus RNA levels. The patients had been started on weekly subcutaneous injections of PEG-IFN α (60, 80, and 90 μg) plus a daily oral dose of RBV (600 mg). The therapy was discontinued, however, because of the onset of acute pancreatitis (after 15 weeks, 48 weeks, and 3 weeks respectively). The drug-induced pancreatitis was diagnosed on the basis of elevated levels of amylase and lipase and the absence of other identifiable causes. High tumor necrosis factor-α was found in one patient and high interleukin-6 in the other two. The immune system stimulated by PEG-IFN and RBV combination therapy might have caused the acute pancreatitis. Further study is needed to clarify the mechanism of the onset of drug-induced pancreatitis by PEG-IFN and RBV combination therapy.

Background & Aims Daclatasvir plus asunaprevir ( DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus ( HCV) genotype 1b ( GT-1b) infection in the HALLMARK DUAL trial. This post hoc analysis was conducted to determine the efficacy and safety of this treatment in Asian patients. Methods Treatment-naive patients were randomly assigned (2:1; double-blinded) to receive DCV (60 mg once daily) plus ASV (100 mg twice daily) or placebo for 12 weeks. Subsequently, placebo patients entered another study, and the remaining patients continued treatment for an additional 12 weeks. Non-responders to peginterferon/ribavirin and ineligible/intolerant patients received dual therapy for 24 weeks. Sustained virological response at post-treatment Week 12 [sustained virological response ( SVR)12] and safety outcomes were evaluated. Results This post hoc analysis included 186 Asian patients (Korean, 78; Taiwanese, 85; others, 23), of whom 32.3% were cirrhotic. SVR12 was observed in 92.3, 78.6 and 80.0% of treatment-naive, ineligible/intolerant and non-responder patients, respectively, and was comparable with non-Asian patients. SVR12 by baseline factors including age, viral load, interleukin-28B genotype and cirrhosis status was similar between the Asian sub-cohorts. Among 18 Asian patients with NS5A-Y93H or NS5A-L31M/V resistance-associated variants ( RAVs), seven patients achieved SVR12. Multivariate regression analysis showed a significant influence of NS5A RAVs in both Asian and non-Asian cohorts. The incidence of serious adverse events in Asian patients was low (7.2%). Two Taiwanese patients had elevated alanine aminotransferase (≥5.1 × ULN); both achieved SVR12. Conclusions All-oral dual therapy with DCV + ASV resulted in high SVR rates and was well tolerated in Asian patients with HCV GT-1b infection. [ABSTRACT FROM AUTHOR]

Background: Despite the high prevalence of genotype 1b hepatitis C virus (HCV) among patients, a cell culture system that permits entire viral life cycle of genotype 1b isolates is limited. To develop a cell-cultured hepatitis C virus (HCVcc) of genotype 1b, the proper combination of HCV genomic variants and host cells is essential. HCV genomes isolated from patients with distinctive symptoms may provide the variants required to establish an HCVcc of genotype 1b. Results: We first established subgenomic replicons in Huh7 cells using HCV cDNAs isolated from two patients: one with fulminant hepatitis after liver transplantation (TPF1) and another with acute hepatitis and moderate symptoms (sAH). Replicons established from TPF1 and sAH showed mutations in NS4B and in NS3 and NS5A, respectively. Using these replication machineries, we constructed HCV genomic RNAs for each isolate. Virus infectivity was evaluated by a focus-forming assay, which is dependent on the intracellular expression of core antigen, and production of virus particles was assessed by density-gradient centrifugation. Infectious virus was only observed in the culture medium of cells transfected with TFP1 HCV RNA. A chimeric genome with the structural segment (5'-untranslated region [UTR] through NS2) from sAH and the replication machinery (NS3 through 3'-UTR) from TPF1 exhibited greater infectivity than did TFP1, despite formation of deficient virus particles in sAH, suggesting that this genomic segment potentiates virus particle formation. To identify the responsible variants, infectious virus formation was assessed in a chimeric genome carrying parts of the sAH structural segment of the TPF1 genome. A variant in NS2 (M170T) was identified that enhanced infectious virus formation. HCVcc carrying an NS2 gene encoding the M170T substitution and adaptive mutations in NS4B (referred to as TPF1-M170T) infected naïve cured Huh7 cells in a CD81-dependent manner. Conclusions: We established a novel HCVcc of genotype 1b in Huh7 cells by introducing an amino acid variant in NS2 and adaptive mutations in NS4B from HCV genomic RNA isolated from a patient with fulminant HCV after liver transplantation. [ABSTRACT FROM AUTHOR]

Background: Treatment-experienced chronic hepatitis C (CHC) genotype (GT) 1b represents a major medical burden in China. We evaluate the efficacy, safety and cost-effectiveness of ribavirin (RBV)-free pan-oral direct-acting antivirals (DAAs) in treatment-experienced Chinese with GT1b CHC, including patients with cirrhosis. Methods: One hundred forty treatment-experienced GT1b CHC Chinese with and without cirrhosis were included in this study. Ninety-four patients were treated with either daclatasvir (DCV, 60 mg)-sofosbuvir (SOF, 400 mg) (group 1, n = 46) or ledipasvir (LDV, 90 mg)-SOF (400 mg) (group 2, n = 48) for 12 weeks. Forty-six patients treated with pegylated interferon and RBV therapy for 72 weeks were enrolled as the control group (group 3). Patients were followed at 4-weekly intervals till 24 weeks after the end of treatment. Results: All patients in group 1 (46/46, 100 %) and 2 (48/48, 100 %) had achieved sustained virologic response at 24 weeks after the end of treatment (SVR 24), which was significantly higher than that of group 3 (13/46, 28.3 %) ( p < 0.001). The SVR 24 rates of cirrhotic patients in group 1 (27/27, 100 %) and 2 (27/27, 100 %) were also significantly higher than that of group 3 (3/25, 12 %) ( p < 0.001). Twelve weeks of RBV-free LDV-SOF and DCV-SOF was either cost-saving or cost-effective. Adverse events were significantly lower in group 1 and 2 compared with group 3 ( p < 0.001). Conclusion: Compared with standard therapies, 12 weeks of RBV-free DAA therapies is highly effective, well tolerated and cost-effective in treatment-experienced Chinese with GT1b CHC including patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Amino acid (aa) 70 substitution (R70Q/H) in the core protein of hepatitis C virus (HCV) genotype 1b has been shown to be one of the key factors in determining resistance for pegylated interferon-α plus ribavirin combination therapy (PEG-IFNα/RBV). But the exact mechanisms remain unclear. The aim of this study was to investigate the dynamic response of wild and mutant core codon 70 strains to PEG-IFNα/RBV treatment. Methods: One hundred twelve Chinese patients with chronic HCV 1b infection were enrolled and received a standard protocol of 48 weeks of PEG-IFNα/RBV therapy and 24 consecutive weeks of follow-up. Serial blood samples were obtained at pretreatment baseline, and again at weeks 2, 4, 8, 12, and 24 during therapy for the quantification of 70R and 70Q/H strains. Dynamic characteristics and association with early virological response (EVR), sustained virological response (SVR) and IL28B genotypes were analyzed. Results: Of the 112 patients enrolled in this study, 93.8 % (105/112) were infected with mixture of 70R and 70Q/H strains before treatment. The 70Q/H strain was dominant in 20.5 % of patients. 42.9 % of patients with dominant 70Q/H exhibited EVR versus 88.6 % of patients with dominant 70R (P < 0.001). Furthermore, 35.0 % of patients with dominant 70Q/H exhibited SVR versus 77.4 % with dominant 70R (P < 0.001). However, regardless of the dominant strain, virological response types or the IL28B SNP genotypes, 70Q/H strains always exhibited the same response to treatment as the 70R strains and the percentage of HCV harboring the 70Q/H substitution did not change significantly during treatment. Conclusions: Although the ratio of 70Q/H to 70R is related to the virological response, 70Q/H strains always exhibited the same response as the 70R strains during PEG-IFNα/RBV treatment. Substitution of R70Q/H alone is not enough to lead to resistance to therapy. Positive selection for 70Q/H induced by IFNα was not observed. [ABSTRACT FROM AUTHOR]

Background: Substitutions of amino acid (aa) 70 in the core region of hepatitis C virus genotype 1b (HCV 1b) are a predictor of the non-virological response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. The aim of our study was to develop quantitative real-time reverse transcription polymerase chain reaction (qPCR) assays to quantify wild-type (70 W) and mutant (70 M) strains of HCV 1b. Methods: We used the TaqMan system to quantify strains 70 W and 70 M. Codon 70 in the HCV 1b core region can be either CGN or CAN, therefore degenerate TaqMan minor groove binder (MGB) probes with inosine were used. We determined detection limits, sensitivity and specificity of the methods developed. Direct sequencing and cloning of the HCV core region were used to confirm the reliability of our new system. Serum samples from 138 Chinese patients infected with HCV 1b were examined with the system we developed and compared with results obtained from the Roche TaqMan RT-PCR HCV RNA quantitation system. Results: Degenerate MGB probes were able to clearly distinguish 70 W from 70 M. The detection limit was 103 copies/mL. Cross-reactivity tests confirmed the specificity of our method. Our system can effectively quantify 70 W and 70 M for 99.6% of patients with HCV 1b. Further tests involving cloning and sequencing confirmed the reliability of our system. Conclusions: We developed an assay system using degenerate TaqMan MGB probes with inosine to quantify wild-type and mutant viral RNAs of the HCV 1b core region at aa 70. Our developed assay system had high levels of sensitivity and accuracy, and could prove useful in investigating dynamic changes during PEG-IFN/RBV therapy to assess virological responses. [ABSTRACT FROM AUTHOR]

Aim: Initial hepatitis C virus (HCV) RNA reduction was investigated as a potential index for sustained virological response (SVR) in the treatment of interferon (IFN)-β followed by peginterferon plus ribavirin (PEG IFN/RBV). Methods: The treatment course was retrospectively analyzed in 64 genotype 1b patients with a HCV RNA level of 5.0 logIU/mL or higher. IFN-b was administrated twice a day for 2 weeks followed by 24 or 48 weeks of PEG IFN/RBV. The serum HCV RNA level was measured by real-time polymerase chain reaction before administration and at 1, 2 and 4 weeks of therapy. Results: By the duration of PEG IFN administration, the SVR rates were 11% (2/18, <19 weeks), 64% (23/36, 20-24 weeks) and 40% (4/10, 25-72 weeks) (P = 0.0011, X²-test). The SVR rate was high in patients in whom the HCV RNA level had decreased by 2.5 logIU/mL or greater at 1 week of IFN-β (29/55 [53%] vs 0/9 [0%], P = 0.0029, X²-test). Among these patients, the SVR rate was even higher in those with continuous reduction in the first 2 weeks after the switch to PEG IFN/RBV (27/45 [60%] vs 2/10 [20%], P = 0.0048). Age below 65 years, no previous IFN course and good initial HCV RNA reduction were significantly associated with SVR on multivariate analysis, and the SVR rate was 95% (18/19) among these patients. Conclusion: The 2.5 logIU/mL reduction in HCV RNA at 1 week of IFN-b and the continuous reduction just after the switch to PEG IFN/RBV are important SVR-predictive indices. [ABSTRACT FROM AUTHOR]