Polymorphism in interferon λ3/interleukin-28B gene and risk to noncirrhotic chronic hepatitis C genotype 3 virus infection and its effect on the response to combined daclatasvir and sofosbuvir therapy.

Hepatitis C virus (HCV) infection is a considerable public-health problem and an important cause of liver disease with about 71 million people infected worldwide and more than 399 000 people die every year from hepatitis C-related liver diseases. The present study was, therefore, initiated to investigate the association of polymorphism in interferon λ3 (IFNL3) also known as interleukin-28B (IL-28B) gene with chronic HCV infection and association of these polymorphic variants with the combination daclatasvir and sofosbuvir HCV therapy response. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a total of 250 chronic HCV genotype three patients and 500 number of healthy controls. Our data revealed that the TT (minor) genotype of IFNL3 (rs12979860) and GG (minor) genotype of IFNL3 (rs8099917) exhibited a significant association with chronic HCV genotype 3 infection when compared with controls. The results of treatment response showed that CC (major) genotype of IFNL3 (rs12979860) and TT (major) genotype of IFNL3 (rs8099917) are associated with the likelihood of achieving a higher sustained virological response (SVR), to combined daclatasvir and sofosbuvir therapy, in genotype 3-infected HCV patients, whereas the individuals with TT (minor) genotype of IFNL3 (rs12979860) and GG (minor) genotype of IFNL3 (rs8099917) are more susceptible to chronic HCV infection and treatment relapse, suggesting a role of IFNL3 (rs12979860) and (rs8099917) in the treatment outcome of combined daclatasvir and sofosbuvir therapy in chronic HCV genotype 3 infection.

Real-life effectiveness and safety of the daclatasvir/asunaprevir combination therapy for genotype 1b chronic hepatitis C patients: An emphasis on the pretreatment NS5A resistance-associated substitution test.

This study aimed to investigate the real-life effectiveness and safety of daclatasvir (DCV) and asunaprevir (ASV) combination therapy in Korean patients. We consecutively enrolled patients with genotype 1b hepatitis C virus (HCV) infection treated with at least one dose of DCV/ASV combination therapy in seven tertiary hospitals of South Korea. The sustained virologic response (SVR) rates and safety according to intention-to-treat (ITT) and per-protocol (PP) analyses were evaluated. Among the 526 enrolled patients, 91% showed negative (87%) or "undetermined" (4%) resistance-associated substitution (RAS); 9% did not undergo RAS testing. The SVR rates for ITT and PP were 89.3% and 95.0% in treatment-naive patients and 93.2% and 95.6% in treatment-experienced patients, respectively. In PP analysis, negative RAS was associated with higher SVR (96.3%) than with "undetermined RAS" (85.7%) or "not tested for RAS" (84.4%). Adverse events were reported in 185 (35.4%) patients, and events leading to discontinuation were observed in 4.3% of the study population. Forty-two (8.0%) patients developed transaminase elevation (≥2 × upper normal limit), resulting in treatment discontinuation in six (1.1%) patients. DCV/ASV combination therapy showed acceptable efficacy in genotype 1b compensated HCV-infected patients with negative pretreatment RAS. Although most adverse events were tolerable to continue antiviral treatment, adequate monitoring for transaminase elevation is warranted.

Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents.

Many studies showed insulin resistance amelioration in HCV-patients achieving Sustained Virologic Response (SVR) but results on glycemic control in diabetic patients are unclear. This study aimed to assess fasting glucose (FG) and glycated hemoglobin (HbA1c) values before and after therapy with direct-acting antivirals (DAAs) in HCV-patients with type 2 diabetes mellitus (T2DM). Of the 122 consecutively recruited patients with chronic hepatitis C and T2DM, 110 patients were treated with DAAs and 12 remained untreated. Clinical, biochemical, virological, and metabolic features were collected both at baseline and at 12 weeks after the end of therapy (EOT) or after a comparable period of time in untreated patients. A total of 101 patients obtained a SVR (Group 1), while nine were relapsers. Group 2 (21 patients) was composed by the nine relapsers and the 12 untreated patients. A significant reduction of mean FG (134.3 ± 41.32 mg/dL vs 152.4 ± 56.40 mg/dL, P = 0.002) and HbA1c values (46.51 ± 16.15 mmoL/moL vs 52.15 ± 15.43 mmoL/moL, P < 0.001) was found in Group 1 but not in Group 2 (140.6 ± 47.87 mg/dL vs. 145.31 ± 30.18 mg/dL, P = 0.707, and 55.31 ± 20.58 mmoL/moL vs. 53.38 ± 9.49 mmoL/moL, P = 0.780). In Group 1, 20.7% of patients could reduce or suspend their antidiabetic therapy compared to none in Group 2 (P = 0.03), despite the significant weight increase observed in Group 1. SVR induced a significant amelioration of glycemic control in diabetic HCV-patients, despite a significant weight increase; larger prospective studies are needed to verify whether these results are maintained over the long-term.

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study.

We report the first real-world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir-based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi® , Gilead Sciences, n = 135) or generic sofosbuvir (Probirase® , Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86-93%); 91% (95% CI 84-95%) in patients who received Sovaldi® , and 89% (95% CI 84-93%) in patients who received Probirase® . Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis-related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi® or Probirase® . Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease-inhibitor-free regimes.

Characterization of clinical predictors of naturally occurring NS3/NS4A protease polymorphism in genotype 1 hepatitis C virus mono and HIV co-infected patients.

Spontaneously occurring resistance may impair the success of protease inhibitors based regimens in HCV treatment. This study aimed to evaluate associations between amino acid substitutions in NS3/NS4A domain and clinical features of 247 HCV mono or HCV/HIV co-infected patients. Fourteen samples (5.7%) harbored at least one resistance-associated substitution (RAS). The following RASs were detected in NS3 region: T54S (6-2.4%), V55A (7-2.8%), and Q80R (2-0.8%). S122G occurred in 86.9% of HCV genotype 1b samples with either natural polymorphisms or RASs. Advanced liver fibrosis and HIV co-infection were not related to NS3/NS4A amino acid substitutions.

Implementation of the ECHO® telementoring model for the treatment of patients with hepatitis C.

We aimed to implement the Extension for Community Healthcare Outcomes (ECHO) telementoring model for hepatitis C and to evaluate its outcomes in the health providers. Following the ECHO model, an hepatitis C teleECHO clinic was established at the Hospital Italiano in Argentina. The teleECHO clinic provides support and training to physicians from Patagonia who treat patients with hepatitis C. In order to evaluate the teleECHO clinic outcomes, physicians completed a survey focused on skills and competence in hepatitis C before and after 6 months of participating in the project. The survey consisted of 10 questions, which participants rated from 1 to 7 (1 no ability; 7 highest ability). To analyze the difference before and after participation in the project, Wilcoxon signed-rank test was used. During the first 6 months of implementation of the model, a total of 14 physicians from 12 sites in Patagonia agreed to participate in the survey. The median age of the participants was 42 years. Participants' primary specialties were Hepatology (55%), Infectious Diseases (25%), General Practice (10%), and other (10%). A significant improvement was observed in all the evaluated fields after 6 month of the participation in the teleECHO clinic, namely fibrosis staging, determining appropriate candidates for treatment, and selecting appropriate HCV treatment. In addition, their general interest in hepatitis C increased. We successfully replicated and implemented the first teleECHO clinic in Argentina. Physicians improved their ability to provide best practice care for patients with Hepatitis C. J. Med. Virol. 89:660-664, 2017. © 2016 Wiley Periodicals, Inc.

SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants.

SB 9200 is a novel, first-in-class oral modulator of innate immunity that is believed to act via the activation of the RIG-I and NOD2 pathways. SB 9200 has broad-spectrum antiviral activity against RNA viruses including hepatitis C virus (HCV), norovirus, respiratory syncytial virus, and influenza and has demonstrated activity against hepatitis B virus (HBV) in vitro and in vivo. In phase I clinical trials in chronically infected HCV patients, SB 9200 has been shown to reduce HCV RNA by up to 1.9 log10 . Here, we demonstrate the antiviral activity of SB 9200 against a HCV replicon system and patient derived virus. Using the HCV capture-fusion assay, we show that SB 9200 is active against diverse HCV genotypes and is also effective against HCV derived from patients who relapse following direct-acting antiviral treatment, including viruses containing known NS5A resistance-associated sequences. These data confirm the broad antiviral activity of SB 9200 and indicate that it may have clinical utility in HCV patients who have failed to respond to current antiviral regimens.

Decreased expression of interferon-stimulated genes in B cells of patients with chronic hepatitis C during interferon-free therapy potentially suggests the eradication of hepatitis C virus in the B cells: A cohort study.

AIMS: Hepatitis C virus (HCV) infection is monitored by the host innate immunity that includes the endogenous interferon (IFN), which up-regulates IFN-stimulated genes (ISGs). HCV is both hepatotropic and lymphotropic, but HCV replication in lymphoid cells is a controversial issue. Here, we analyzed the mRNA levels of the ISGs in B cells of HCV-infected patients during antiviral therapy and investigated the effects of viral eradication. METHODS: One hundred and eighty-one patients with chronic hepatitis C and 26 healthy volunteers were enrolled in this study. Levels of HCV RNA and mRNA of ISGs in B cells isolated from the patients were monitored before, during, and after antiviral therapy. RESULTS: HCV RNA was detected in B cells of 133/175 (76.0%) patients who achieved sustained virologic response (SVR) before therapy was started. The positive ratio of HCV RNA in B cells was higher in patients with genotype 1 and the non-major genotype of interleukin 28B. HCV RNA in B cells of most patients disappeared 1 week after antiviral therapy was started. The baseline expression of ISG mRNA was significantly higher in the patients than in the healthy volunteers. Levels of ISG mRNA were increased and remained high throughout the IFN-based therapy. In contrast, levels of ISG mRNA in patients who achieved SVR were significantly decreased 1 week after the IFN-free therapy was started and remained low during the therapy. CONCLUSIONS: These results suggested that IFN-free therapy potentially eradicated HCV in the B cells, leading to the down-regulation of endogenous ISGs. The level of ISG mRNA could be used as a marker for viral eradication in B cells.