Topomer CoMFA, HQSAR Study of Benzimidazole Derivative as NS5B Polymerase Inhibitor

Background: In recent years, the number of people infected with hepatitis C virus (HCV) has continued to grow, this becoming a major threat to global health, and new anti-HCV drugs are urgently needed. HCV NS5B polymerase is an RNA-dependent RNA polymerase (RdRp), which plays an important role in virus replication, and can effectively prevent the replication of HCV sub-genomic RNA in daughter cells. It is considered a very promising HCV therapeutic target for the design of anti-HCV drugs. Methods: In order to explore the relationship between the structure of benzimidazole derivatives and its inhibitory activity on NS5B polymerase, holographic quantitative structure-activity relationship (HQSAR) and Topomer comparative molecular field analysis (CoMFA) were used to establish benzimidazole QSAR model of derivative inhibitors. Results: The results show that for the Topomer CoMFA model, the cross-validation coefficient q2 value is 0.883, and the non-cross-validation coefficient r2 value is 0.975. The model is reasonable, reliable, and has good predictive ability. For the HQSAR model, the cross-validated q2 value is 0.922, and the uncross-validated r2 value is 0.971, indicating that the model data fits well and has high predictive ability. Through the analysis of contour map and color code diagram, 40 new benzimidazole inhibitor molecules were designed, and all of them have higher activity than template molecules, and the new molecules have significant interaction sites with protein 3SKE. Conclusion: The 3D-QSAR model established by Topomer CoMFA and HQSAR has good prediction results and the statistical verification is valid. The newly designed molecules and docking results provide theoretical guidance for the synthesis of new NS5B polymerase inhibitors, and for the identification of key residues that the inhibitor binds to NS5B, which helps to better understand its inhibitory mechanism. These findings are helpful for the development of new anti-HCV drugs.

Sofosbuvir-Based Therapies for Patients with Hepatitis C Virus Infection: Real-World Experience in China

Background and Aims. There is scarcity of data in literature regarding the treatment response to sofosbuvir- (SOF-) based therapies in Chinese patients with chronic Hepatitis C Virus (HCV) infection. The aim of this study was to evaluate the efficacy and safety of SOF-based regimens for chronic hepatitis C (CHC) patients without cirrhosis in a real-world setting in mainland China.Methods. A total of 226 patients receiving SOF plus daclatasvir (DCV), ledipasvir (LDV), or velpatasvir (VEL) were enrolled from December 2014 to June 2017. The primary observation point was the percentage of patients with a sustained virologic response (SVR) at posttreatment week 12 (SVR12), and all adverse events were monitored during treatment and follow-up period.Results. The overall SVR12 rate was 96% (216/226), and individual SVR12 ranged from 93% to 100% in different treatment groups. No significant differences of efficacy were detected between genotypes 1b and 6a (98% for GT 1b versus 100% for GT 6a, P=0.322). Comparing the high success rates in GT 1b and 6a patients, SVR12 was relatively low in GT 3a and 3b patients. A significant difference in efficacy was observed between GT 3 and not GT 3 patients (77% versus 98%, respectively, P<0.001). No significant differences in efficacy were detected among different regimens (93% versus 97% versus 100%, respectively, P=0.153), gender (95% for male versus 96% for female, P=0.655), or baseline HCV RNA lever (96% versus 95%, respectively, P=0.614). Similar SVR rates were also obtained in naïve and previously treated patients (98% versus 93%, respectively, P=0.100).Conclusions. NS5B polymerase inhibitor SOF plus one of the NS5A inhibitors, such as DCV, LDV, or VEL for 12 weeks was associated with high SVR12 rates and well tolerated in HCV-infected patients without cirrhosis. Moreover, patients with DAAs failure should be retreated with more effective regimens like SOF/VEL.

Efficacy and Safety of Sofosbuvir-containing Regimens in Chronic Hepatitis C Patients with Genotype 2 and 3: a Comprehensive Analysis of 18 Randomized Controlled Trials

Background and Aim: Sofosbuvir is a hepatitis C virus (HCV) NS5B polymerase inhibitor. The objective of this study was to explore the efficacy and safety of sofosbuvir for HCV genotype (GT) 2 and 3 infected patients.Method: We searched randomized controlled trials (RCTs) which analyzed the efficacy and safety of sofosbuvircontaining regimens for HCV GT 2/3 infected patients and collected data. The endpoints were sustained virological response 12- and 24-weeks after the cessation of therapy (SVR12 and SVR24), the adverse events (AEs) and the severe adverse events (SAEs).Results: Eighteen trials comprising 2,975 HCV GT 2/3 infected patients were included. The pooled estimate SVR12, SVR24, AEs and SAEs rates were 84.6% (95% CI: 83.2-86.0), 83.7% (95% CI: 82.0-85.2), 83.8 (95% CI: 82.3-85.3) and 3.9 (95% CI: 3.2-4.8). The SVR12 rate of sofosbuvir-containing regimens for HCV GT 2 infection was higher than that for HCV GT 3 infection (95.7% vs. 80.8%). The sofosbuvir combined with velpatasvir (with or without ribavirin) regimen presented a higher SVR12 rate and lower AEs rate than the sofosbuvir combined with ribavirin (with or without peg-IFN) regimen (94.9% vs. 80.7% for SVR12 rate; 69.3% vs. 87.7% for AEs rate).Conclusions: The sofosbuvir-containing regimens in patients with HCV GT 2 infection have better efficacy than in patients with HCV GT 3 infection.

Hepatitis C virus treatment advances for thalassaemia patients

Chronic infection with hepatitis C virus (HCV) is a major problem for thalassaemia patients, as blood transfusions before 1990 were associated with a high risk of HCV infection. Given the high prevalence of co-morbidities, thalassaemia patients are at an increased risk for dying from end-stage liver disease or hepatocellular carcinoma. HCV treatment in thalassaemia patients was challenging in the interferon-alfa (IFN) era not only due to its unfavourable safety and tolerability profile but due to necessary combined use of ribavirin (RBV) and the subsequent haemolysis and increased need for blood transfusions. The introduction of the current direct acting antivirals (DAAs), which can be used in IFNfree and RBV-free regimens, has dramatically improved the management of all HCV patients including those with thalassaemia. Currently, depending on HCV genotype and availability in each country, the main available DAAs combinations are the co-formulation of sofosbuvir with ledipasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/90 mg once daily),, the co-formulation of paritaprevir boosted by ritonavir with ombitasvir (NS3/4 protease inhibitor/ritonavir/NS5A inhibitor, two tablets of 75/50/12.5 mg once daily) perhaps with addition of dasabuvir (non-nucleos(t)ide analogue NS5B polymerase inhibitor, one tablet of 250 mg twice daily), the co-formulation of grazoprevir with elbasvir (NS3/4 protease inhibitor/NS5A inhibitor, one tablet of 100/50 mg once daily) and the co-formulation of sofosbuvir with velpatasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/100 mg once daily). In 2017, the co-formulation of glecaprevir with pibrentasvir (NS3/4 protease inhibitor/NS5A inhibitor, three tablets of 100/40 mg once daily) and the co-formulation of sofosbuvir with velpatasvir and voxilaprevir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor/ NS3/4 protease inhibitor, one tablet of 400/100/100 mg once daily) were also approved and started to be used in some countries. According to all international current guidelines, thalassaemia patients do not represent a special group for the current HCV treatment and can be treated with the same indications and regimens used for patients without haemoglobinopathies. However, in countries which still prioritize the use of DAAs according to the severity of liver disease, thalassaemia patients are often excluded from such prioritization and have access to DAAs therapy regardless of their fibrosis severity. Moreover, all guidelines recommend that thalassaemia patients should be preferentially treated not only with IFN-free but RBV-free DAAs regimens too. In a proper clinical trial, only a 12-week regimen of grazoprevir/ elbasvir has been evaluated and proven to be highly efficacious and well tolerated among patients with inherited blood disorders and HCV genotype 1 or 4 infection. In addition, different DAAs regimens have been reported to be safe and effective for the treatment of HCV thalassaemia patiens in clinical practice. Given the availability of the current effective and safe DAAs and the frequent follow-up of thalassaemia patients in a few specific units, such patients could be a targeted population for “HCV micro-elimination” on the road towards the global HCV elimination in each country.