Efficacy and safety of the 12-week sofosbuvir-coblopasvir regimen in treatment of chronic hepatitis C / 临床肝胆病杂志

Objective To investigate the efficacy and safety of the 12-week regimen with sofosbuvir and coblopasvir hydrochloride in the treatment of chronic hepatitis C (CHC) in northwest China. Methods This study enrolled 101 patients with CHC of any genotype who received sofosbuvir (400 mg) combined with coblopasvir hydrochloride (60 mg) for 12 weeks in The First Affiliated Hospital of Air Force Medical University, The Second Affiliated Hospital of Air Force Medical University, The Second Affiliated Hospital of Xi'an Jiaotong University, and Baoji Central Hospital from July 1 to December 31, 2021, among whom 13 had liver cirrhosis and 88 did not have live cirrhosis. Other antiviral drugs such as ribavirin were not added regardless of the presence or absence of liver cirrhosis or the genotype of CHC. Related clinical data ere extracted, including HCV RNA quantification and liver biochemical parameters at baseline, at week 12 of treatment, and at 12 weeks after drug withdrawal. The primary endpoints were sustained virologic response at 12 weeks after the end of treatment (SVR12) and safety at week 12 of treatment, and the secondary endpoint was the effect of the 12-week treatment on liver biochemical parameters. The non-normally distributed continuous data were expressed as M ( P 25 - P 75 ), and the Mann-Whitney U test was used for comparison between groups. Results A total of 101 patients were included in the analysis, among whom there were 55 male patients (54.5%) and 46 female patients, and the median age was 53 years. Among these patients, 12.8% had liver cirrhosis, 1.0% had liver cancer, 3.0% were treatment-experienced patients, and 3.0% had type 2 diabetes. As for genotype distribution, 8% had CHC genotype 1, 60% had CHC genotype 2, 19% had CHC genotype 3, and 6% had CHC genotype 6, and genotype was not tested for 7% of the patients. After 12 weeks of treatment, all 101 patients had a HCV RNA level of below the lower limit of detection and an SVR12 rate of 100%, with a significant reduction in the serum level of alanine aminotransferase (ALT) from baseline to week 12 of treatment ( P < 0.05). Among these patients, 22.7% had concomitant medications such as atorvastatin calcium, aspirin, metformin, nifedipine, bicyclol, and compound glycyrrhizin. The incidence rate of adverse events was 16.8%, and fatigue (12.9%) was the most common adverse event. Conclusion The 12-week treatment with sofosbuvir and coblopasvir hydrochloride can obtain high SVR12 in CHC patients in northwest China and has good antiviral safety, with a significant improvement in abnormal serum ALT at week 12 of treatment.

Primer reporte en Perú sobre terapia con antivirales de acción directa para hepatitis C crónica en pacientes VIH-positivos / First report in Peru on direct-acting antiviral therapy for chronic hepatitis C in HIV-positive patients

RESUMEN Objetivo : Presentar la experiencia clínica con antivirales de acción directa (AAD) para hepatitis C crónica en pacientes VIHpositivos. Materiales y métodos : Serie de casos longitudinal y prospectiva de pacientes VIH-positivos tratados con AAD para hepatitis C crónica entre mayo de 2019 y abril de 2020 en el Servicio de Infectología del Hospital Nacional Guillermo Almenara Irigoyen, EsSalud. El desenlace primario fue la respuesta viral sostenida del virus de hepatitis C (VHC) a las 12 semanas de completada la terapia con AAD. Los desenlaces secundarios fueron tolerabilidad y seguridad. Resultados : Diez pacientes fueron incluidos en el estudio, dos fueron mujeres (20%). Dos pacientes presentaron cirrosis (20%). La totalidad de los pacientes tuvo la carga viral del VIH suprimida antes de la terapia con AAD. Los pacientes recibieron un esquema de 12 semanas con base en sofosbuvir: uno con daclatasvir por separado, y los nueve restantes con velpatasvir combinados en una sola tableta por día. La respuesta viral sostenida del VHC fue evaluable en nueve casos. En estos, la carga viral del VHC fue no detectable. No se registraron ocurrencias en cuanto a tolerabilidad y seguridad durante la terapia con los AAD indicados. Conclusiones : La presente investigación es la primera experiencia clínica en Perú con AAD para hepatitis C crónica en pacientes VIH-positivos. La respuesta virológica, la tolerabilidad y la seguridad frente a daclatasvir y velpatasvir, cada uno junto o combinado con sofosbuvir, fueron óptimas en la serie de casos presentada.

ABSTRACT Objective : To present the clinical experience with direct-acting antivirals (DAAs) for chronic hepatitis C in HIV-positive patients. Materials and methods : Longitudinal and prospective case series of HIV-positive patients treated with DAAs for chronic hepatitis C between May 2019 and April 2020 at the Infectious Diseases Service of Hospital G. Almenara, EsSalud. The primary outcome was sustained virologic response to hepatitis C virus (HCV) 12 weeks after completion of DAA therapy. Secondary outcomes were tolerability and safety. Results : Ten patients were included in the study, two were women (20%). Two patients had cirrhosis (20%). All patients had suppressed HIV viral load prior to DAA therapy. Patients received a 12-week regimen based on sofosbuvir: one with daclatasvir separately, and the remaining nine with velpatasvir combined in a single tablet per day. The sustained virological response of HCV was evaluable nine cases. In these, the HCV viral load was undetectable. No occurrences were recorded regarding tolerability and safety during therapy with the indicated DAAs. Conclusions : This present investigation is the first clinical experience in Peru with DAAs for chronic hepatitis C in HIV-positive patients. Virologic response, tolerability, and safety against daclatasvir and velpatasvir, each in conjunction or in combination with sofosbuvir, were optimal in the case series presented.

Selection dynamics of HCV genotype 3 resistance-associated substitutions under direct-acting antiviral therapy pressure

ABSTRACT The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.

Clinical characteristics and risk factors of chronic hepatitis C complicated by fatty liver / 中国基层医药

Objective:To analyze the clinical characteristics and risk factors of chronic hepatitis C (CHC) complicated by fatty liver.Methods:The clinical data of 258 patients with chronic hepatitis C who received treatment in The First People's Hospital of Huzhou from March 2017 to March 2021 were included in this study. They were divided into simple CHC group and CHC complicated by fatty liver group according to whether they had fatty liver. General data, liver function, coagulation function and blood lipid indexes were compared between the two groups.Results:Among 258 patients with CHC infection, 81 cases had fatty liver, accounting for 31.40%; 177 cases did not have fatty liver, accounting for 69.14%. There were no significant differences in age, sex, and history of smoking and alcohol use between the two groups (both P > 0.05). Body mass index (BMI) differed significantly between the two groups ( χ2 = 29.81, P < 0.001). BMI in the CHC complicated by fatty liver group was slightly higher than that in the simple CHC group. There were no significant differences in history of hypertension and coronary heart disease between the two groups (both P > 0.05). There were significant differences in the presence of hypertriglyceridemia and the increase of low-density lipoprotein between the two groups ( χ2 = 8.53, 6.99, P = 0.004, 0.008). There were no significant differences in the presence of hypercholesterolemia and the reduction of high-density lipoprotein (both P > 0.05). There were no significant differences in liver function indexes such as alanine aminotransferase and aspartate aminotransferase between the two groups (both P > 0.05). The level of γ-glutamyltransferase (γ-GGT) was significantly different between the two groups ( t =-8.71, P < 0.001). There was no significant difference in activated partial thromboplastin time between the two groups ( P > 0.05). There were significant differences in prothrombin time (PT) and international normalized ratio (INR) between the two groups [PT: (10.10 ± 0.67) seconds vs. (11.99 ± 1.33) seconds; INR: 0.91 ± 0.07 vs. 0.98 ± 0.11; t = 9.74, 4.46, both P < 0.001]. There were no significant differences in fasting blood glucose and blood uric acid levels between the two groups (both P > 0.05). Fasting insulin (FINS) differed significantly between CHC complicated by fatty liver and simple CHC groups [(16.82 ± 1.15) mlU/L vs. (12.52 ± 1.06) mlU/L, t = -24.33, P < 0.001]. The general data and clinical data were compared between the two groups. BMI, hypertriglyceridemia, high- and low-density lipoprotein, γ-GGT, PT, INR and FINS differed significantly between the two groups. Multivariate logistic regression results showed that BMI ≥ 24 kg/m 2, hypertriglyceridemia, γ-GGT, PT, INR and FINS were independent risk factors for CHC complicated by fatty liver ( P = 0.017, 0.003, 0.021, 0.034, 0.004, 0.001). After 6 months of treatment, CHC RNA negative conversion rate in the simple CHC group was significantly higher than that in the CHC complicated by fatty liver group ( χ2 = 7.32, P = 0.010). Conclusion:The related risk factors of CHC complicated by fatty liver include BMI, hypertriglyceridemia, elevated low-density lipoprotein, γ-GGT, PT, INR and FINS, among which, BMI, hypertriglyceridemia, γ-GGT, PT, INR and FINS are independent risk factors. In addition, CHC complicated by fatty liver may affect the efficacy of antiviral therapy.

Clinical effect of direct-acting antiviral agents in treatment of chronic hepatitis C patients with thrombocytopenia / 临床肝胆病杂志

Objective To investigate the clinical effect of direct-acting antiviral agent (DAA) in the treatment of chronic hepatitis C (CHC) patients with thrombocytopenia and its effect on platelet count (PLT). Methods A retrospective analysis was performed for 83 CHC patients with thrombocytopenia (PLT 100×10 9 /L at baseline had a greater increase in PLT( P < 0.05). Conclusion CHC patients with thrombocytopenia have significant improvements in liver function and LSM after receiving DAA treatment and obtaining SVR12, and baseline LSM is an independent predictive factor for PLT elevation. There is a significant increase in PLT from baseline to EOT and SVR12.

Hepatitis E virus infection increases the risk of diabetes and severity of liver disease in patients with chronic hepatitis C virus infection

OBJECTIVES: Co-infection with hepatitis A or B viruses may aggravate liver injury in patients infected with hepatitis C virus (HCV). However, few studies have assessed co-infection with hepatitis E virus (HEV) and HCV. Therefore, this study aimed to assess the prevalence and impact of HEV infection among Brazilian patients with chronic HCV infection. METHODS: This observational study included adult patients with chronic HCV infection who were naive to antiviral therapy from January 2013 to March 2016. A total of 181 patients were enrolled, and HEV serology and PCR were performed for all patients. RESULTS: Seropositivity for anti-HEV IgG was detected in 22 (12.0%) patients and anti-HEV immunoglobulin M in 3 (1.6%). HEV RNA showed inconclusive results in nine (4.9%) patients and was undetectable in the remaining patients. HEV serology positive patients had more severe liver disease, characterized by liver fibrosis ≥3 versus ≤2 (p<0.001), Aspartate Aminotransferase-to-Platelet Ratio Index of ≥1.45 (p=0.003), and Fibrosis-4 score of ≥3.25 (p=0.001). Additionally, the odds of HEV-positive patients developing diabetes mellitus were 3.65 (95% CI 1.40-9.52) times the corresponding odds of HEV-negative patients. A case-control-based histological analysis (n=11 HEV-HCV-positive patients and n=22 HCV-positive patients) showed no significant differences between the groups. CONCLUSIONS: This prevalence is higher than that reported in previous studies of the general population in Brazil. Thus, HEV infection may influence the severity of liver disease and may represent an additional risk of developing diabetes mellitus in patients with HCV infection.

The cut off value of liver stiffness measurement needs to be lowered to predict liver fibrosis after sustained virologic response in chronic hepatitis C patients / 临床肝胆病杂志

Objective To further verify the ability of noninvasive diagnostic method for liver fibrosis in predicting liver fibrosis in chronic hepatitis C patients followed up after sustained virologic response (SVR) based on liver biopsy. Methods A prospective cohort study was performed for the chronic hepatitis C patients who attended Beijing YouAn Hospital, Capital Medical University, from October 2015 to December 2017, and all patients were followed up regularly after SVR and underwent liver biopsy. The diagnostic efficiency of the noninvasive diagnostic method for liver fibrosis was verified based on pathological results. The receiver operating characteristic (ROC) curve was used to evaluate the ability of LSM, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) in the diagnosis of liver fibrosis, and STATA and R language were used to compare the area under the ROC curve (AUC). Results A total of 96 patients were successfully enrolled. The LSM after SVR was significantly lower than that at baseline, and LSM had a significantly larger AUC than APRI (0.89 vs 0.67, P < 0.05) and FIB (0.89 vs 0.69, P < 0.05) in the diagnosis of liver cirrhosis after SVR. LSM at a cut-off value of 7.95 kPa, and based on the best specificity, the diagnosis of liver cirrhosis could be considered when LSM was greater than 9.15 kPa, with a positive likelihood ratio of 5.91%; progressive liver fibrosis could be excluded based on LSM < 6.85 kPa, with a negative predictive value of 0.98. Follow-up time and antiviral regimen had no influence on the diagnostic ability of LSM. Conclusion The cut off value of LSM needs to be lowered to predict liver fibrosis after SVR in chronic hepatitis C patients.

Virological response to direct-acting antiviral therapy and changes in liver fibrosis indices in chronic hepatitis C patients with different alanine aminotransferase and aspartate aminotransferase levels in a real-world setting / 临床肝胆病杂志

ObjectiveTo investigate the virologic response to direct-acting antiviral (DAA) therapy and the changes in liver stiffness measurement (LSM), fibrosis-4 (FIB-4), and aspartate aminotransferase-to-platelet ratio index (APRI) after treatment in chronic hepatitis C (CHC) patients with different alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at baseline in a real-world setting. MethodsCHC patients who attended the outpatient service of Department of Infectious Diseases, Peking University First Hospital, from December 2017 to May 2020 were enrolled, and virologic response rate was calculated. The Wilcoxon rank-sum test was used to compare LSM, FIB-4, and APRI between groups at baseline and at 12 weeks after treatment, and the chi-square test was used for comparison of categorical data between groups. ResultsA total of 48 CHC patients were enrolled, among whom 33.3% had abnormal ALT or AST at baseline. Among these patients, the virologic response rate was 85.4% at week 4 of treatment and 100% at the end of treatment and at 12, 24, and 48 weeks after treatment, and there were significant changes from baseline to 12 weeks after treatment in LSM ［6.1 (51-12.4) kPa vs 8.6 (5.7-16.9) kPa, Z=-1.676, P=0.043］ and APRI ［0.24(0.19-0.48) vs 0.42(0.23-1.17), Z=-2.050, P=0027］. From baseline to 12 weeks after treatment, the patients with abnormal ALT or AST at baseline had significant changes in LSM ［89(5.6-13.1) kPa vs 14.4(8.0-28.2) kPa, Z=-1.679, P=0.047］ and APRI ［0.44(0.25-0.50) vs 1.29(0.99-2.09), Z=-3.427, P=0.001］. ConclusionCHC patients achieve a high sustained virologic response rate after DAA therapy, and the patients with abnormal ALT or AST at baseline tend to have more significant improvements in LSM and APRI than those without such abnormality.

Association of inosine triphosphate pyrophosphatase gene polymorphisms with ribavirin combined with direct-acting antiviral agent in treatment of hepatitis C patients with hemolytic anemia / 临床肝胆病杂志

Objective To investigate the influencing factors for ribavirin (RBV)-induced hemolytic anemia in the treatment of chronic hepatitis C, and to provide a reference for the early prediction of ribavirin-related hemolytic anemia in clinical practice. Methods A total of 49 patients with chronic hepatitis C who attended or were hospitalized in Hebei Petrochina Central Hospital from January 2018 to July 2019 and received antiviral therapy with direct-acting antiviral agent (DAA) and RBV were enrolled, with a major allele of C allele and a minor allele of A allele at the rs1127354 locus of the inosine triphosphate pyrophosphatase (ITPA) gene, and the patients with AA and AC genotypes were compared with those with CC genotype. During treatment, RBV was reduced to 600 mg when hemoglobin (Hb) level was < 100 g/L and was withdrawn when Hb level was < 85 g/L. Routine blood test, liver function, liver stiffness measurement, HCV RNA, HCV genotype, and ITPA genotype were measured before antiviral therapy, and the routine blood test was performed at weeks 2, 4, 8, and 12 of treatment. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. Results A total of 49 patients were enrolled in this study, among whom 22 had chronic hepatitis C and 27 had liver cirrhosis, with a sustained virologic response (SVR) rate of 95.9%. The dose of RBV was reduced in 3 patients (2 in the AA/AC group and 1 in the CC group) due to anemia, and RBV was withdrawn in 3 patients (1 in the AA/AC group and 2 in the CC group); all these 6 patients had liver cirrhosis and finally achieved SVR. During the anti-HCV therapy with DAA+RBV, there was relatively mild RBV-related hemolysis, and the maximum reduction in Hb from baseline was compared between the patients with AA/AC genotype at ITPA rs1127354 and those with CC genotype, which showed no significant difference between the two groups ( Z =-0.18, P =0.87). Conclusion During the treatment with RBV+DAA, RBV is withdrawn or reduced for liver cirrhosis patients due to anemia, and no obvious statistical relation is observed between ITPA genotype and the maximum reduction in Hb from baseline. Therefore, detection of ITPA genotype before the application of RBV does not improve safety during treatment, and it is not recommended to perform conventional detection of ITPA gene polymorphisms.

Association of inosine triphosphate pyrophosphatase gene polymorphisms with ribavirin combined with direct-acting antiviral agent in treatment of hepatitis C patients with hemolytic anemia / 临床肝胆病杂志

Objective To investigate the influencing factors for ribavirin (RBV)-induced hemolytic anemia in the treatment of chronic hepatitis C, and to provide a reference for the early prediction of ribavirin-related hemolytic anemia in clinical practice. Methods A total of 49 patients with chronic hepatitis C who attended or were hospitalized in Hebei Petrochina Central Hospital from January 2018 to July 2019 and received antiviral therapy with direct-acting antiviral agent (DAA) and RBV were enrolled, with a major allele of C allele and a minor allele of A allele at the rs1127354 locus of the inosine triphosphate pyrophosphatase (ITPA) gene, and the patients with AA and AC genotypes were compared with those with CC genotype. During treatment, RBV was reduced to 600 mg when hemoglobin (Hb) level was < 100 g/L and was withdrawn when Hb level was < 85 g/L. Routine blood test, liver function, liver stiffness measurement, HCV RNA, HCV genotype, and ITPA genotype were measured before antiviral therapy, and the routine blood test was performed at weeks 2, 4, 8, and 12 of treatment. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. Results A total of 49 patients were enrolled in this study, among whom 22 had chronic hepatitis C and 27 had liver cirrhosis, with a sustained virologic response (SVR) rate of 95.9%. The dose of RBV was reduced in 3 patients (2 in the AA/AC group and 1 in the CC group) due to anemia, and RBV was withdrawn in 3 patients (1 in the AA/AC group and 2 in the CC group); all these 6 patients had liver cirrhosis and finally achieved SVR. During the anti-HCV therapy with DAA+RBV, there was relatively mild RBV-related hemolysis, and the maximum reduction in Hb from baseline was compared between the patients with AA/AC genotype at ITPA rs1127354 and those with CC genotype, which showed no significant difference between the two groups ( Z =-0.18, P =0.87). Conclusion During the treatment with RBV+DAA, RBV is withdrawn or reduced for liver cirrhosis patients due to anemia, and no obvious statistical relation is observed between ITPA genotype and the maximum reduction in Hb from baseline. Therefore, detection of ITPA genotype before the application of RBV does not improve safety during treatment, and it is not recommended to perform conventional detection of ITPA gene polymorphisms.

Clinical effect of elbasvir/grazoprevir in treatment of chronic hepatitis C in the real world / 临床肝胆病杂志

ObjectiveTo investigate the clinical effect of elbasvir/grazoprevir in the treatment of patients with genotype 1b chronic hepatitis C (CHC). MethodsA total of 99 patients with genotype 1b CHC and compensated cirrhosis who received elbasvir/grazoprevir treatment for 12 weeks and completed treatment and follow-up for 12 weeks after drug withdrawal in Tianjin Third Central Hospital from December 2018 to October 2019 were enrolled. Related clinical data, serological markers, virological indices, and liver stiffness measurement were collected at baseline, at the end of treatment, and at week 12 after drug withdrawal, and virologic response was observed. The Friedman test and Wilcoxon signed rank sum test were used to observe virologic response rate and the changes in liver function and liver stiffness measurement at the end of treatment and at week 12 after drug withdrawal, and the safety of elbasvir/grazoprevir was evaluated. ResultsFor the 99 patients treated with elbasvir/grazoprevir for 12 weeks, the proportion of patients with HCV RNA below the lower limit of detection was 100% at the end of treatment and 99% at week 12 after drug withdrawal. There were significant reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from baseline to the end of treatment (Z=-5.857 and -5.941, both P＜0.05). Liver stiffness measurement decreased from 10.5 kPa at baseline to 8.0 kPa at week 12 after drug withdrawal (Z=-4.036, P＜0.05). Among the 99 patients, 24 patients with compensatory cirrhosis reached a virologic response rate of 100% at the end of treatment and at week 12 after drug withdrawal, as well as significant reductions in ALT and AST from baseline (both P＜0.05), and liver stiffness measurement decreased from 21.1 kPa at baseline to 17.5 kPa at the end of treatment (Z=-1.832, P=0.067) and 13.6 kPa at week 12 after drug withdrawal (Z=-3.182, P=0.001). Compared with the non-liver cirrhosis group, the liver cirrhosis group had significantly greater reductions in liver stiffness measurement (P＜0.05). The patients had good tolerance throughout the treatment, and 4 patients reported mild adverse events during the treatment. ConclusionPatients with genotype 1b CHC have a high virologic response rate to elbasvir/grazoprevir in the real world, with significant improvements in liver function and liver stiffness measurement and good tolerance.

Change and clinical significance of T helper 9 cells in previously untreated patients with chronic hepatitis C / 临床肝胆病杂志

ObjectiveTo investigate the changes of T helper 9 (Th9) cells, interleukin-9 (IL-9), and related transcription factors in previously untreated patients with chronic hepatitis C, as well as their association with clinical indices. MethodsA total of 29 previously untreated patients with chronic hepatitis C who attended Hainan Provincial People’s Hospital from December 2018 to July 2019 were enrolled, and 15 healthy individuals were enrolled as healthy controls. The patients with chronic hepatitis C received sofosbuvir/velpatasvir antiviral therapy for 12 weeks, and then plasma and peripheral mononuclear cells (PBMCs) were isolated. Flow cytometry was used to measure the percentage of CD3+CD4+IL-9+ Th9 cells in PBMCs; ELISA was used to measure the plasma level of IL-9; quantitative real-time PCR was used to measure the relative mRNA expression of IL-9 and the transcription factors PU.1 and Foxo1 in PBMCs. The t-test or the paired t-test was used for comparison between two groups, and a Pearson correlation analysis was used to investigate correlation. ResultsCompared with the healthy controls, the previously untreated chronic hepatitis C patients had significantly lower percentage of peripheral Th9 cells (0.92%±0.14% vs 1.14%±0.21%, t=4.31, P＜0.001) and plasma IL-9 level (248.2±66.97 pg/ml vs 309.02±88.48 pg/ml, t=2.63, P=0.012). The previously untreated chronic hepatitis C patients had significantly lower relative mRNA expression of IL-9 and PU.1 than the healthy controls (t=20.67 and 23.21, both P＜0.001), while there was no significant difference in the relative mRNA expression of Foxo1 between the previously untreated chronic hepatitis C patients and the healthy controls (P＞0.05). In the previously untreated chronic hepatitis C patients, the percentage of peripheral Th9 cells, IL-9 level, and mRNA expression of IL-9 and PU.1 were negatively correlated with HCV RNA (r=-0.46, -0.38, -0.52, and -0.41, all P＜0.05), but they were not correlated with the level of alanine aminotransferase (all P＞0.05). Sofosbuvir/velpatasvir antiviral therapy achieved virologic response in 29 chronic hepatitis C patients, and the percentage of peripheral Th9 cells and the mRNA expression of PU.1 after antiviral therapy were significantly higher than those at baseline (t=2.20 and 6.52, both P＜0.05), while there were no significant changes in the plasma level of IL-9 and the relative mRNA expression of IL-9 from baseline to after treatment (both P＞0.05). ConclusionChronic hepatitis C virus infection may suppress the activation of Th9 cells, suggesting that Th9 cells might be involved in the chronicity of hepatitis C virus infection.

Efficacy of elbasvir/grazoprevir in treatment of genotype 1 chronic hepatitis C: A real-world study / 临床肝胆病杂志

ObjectiveTo investigate the efficacy and safety of elbasvir/grazoprevir in patients with genotype 1 hepatitis C in the real world. MethodsA total of 35 patients with hepatitis C who received elbasvir/grazoprevir treatment in Guangzhou Eighth People’s Hospital, Guangdong Provincial Hospital of Traditional Chinese Medicine, and Guangdong General Hospital from August 2018 to March 2019 were enrolled, treated for 12 weeks, and then followed up for 12 weeks after drug withdrawal. The patients were observed in terms of sustained virologic response at week 12 after drug withdrawal (SVR12), biochemical response, and incidence rate of adverse events during treatment and follow-up. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between groups, and the Mann-Whitney U test was used for further comparison between two groups; the chi-square test was used for comparison of categorical data between groups. A logistic regression analysis was used to investigate the risk factors for virologic response in patients with hepatitis C. ResultsAmong the 35 patients with HCV infection, 97.1% (34/35) had genotype 1b HCV and 2.9% (1/35) had genotype 1a HCV; of all patients, 28 (80%) were non-cirrhotic patients with chronic hepatitis C and 7 (20%) had compensated liver cirrhosis. At the end of treatment, the virologic response rate of 100% (28/28) and SVR12 was 94.74% (18/19). In addition, age, sex, baseline HCV RNA load, previous treatment history, presence or absence of liver cirrhosis, renal function, and presence or absence of other diseases did not affect the treatment outcome (all P＞0.05). There were significant changes in the levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and albumin from baseline to the end of 12-week treatment (Z=-7.131, -6.797, -3.060, and -2.875, all P＜0.05). No patient experienced drug withdrawal during treatment. ConclusionThis study confirms that elbasvir/grazoprevir has good efficacy and safety in the treatment of hepatitis C in domestic real-world studies.

Cardiac Disorder in Chronic Hepatitis C

Chronic hepatitis C (CHC) has a high prevalence in the world. In addition to hepatic complications with cirrhosis in about 20% of patients and high risk for hepatocarcinoma, extrahepatic manifestations may also occur. Cardiac involvement in patients with CHC is associated with several factors, such as increased risk for coronary artery disease, primary cardiomyopathies, or hemodynamic and electrophysiological changes observed in liver cirrhosis. Furthermore, antiviral treatment may, in rare cases, causes cardiovascular adverse effects. Cardiac arrhythmias are the main form of clinical presentation, and, often, markers of poor prognosis in individuals with advanced liver disease. Although some mechanisms that justify these changes have already been reported, many questions remain unanswered, especially about the true involvement of the hepatitis C virus in the genesis of primary cardiac abnormalities, and the risk factors for cardiac-related complications of antiviral treatment

An integrated analysis of elbasvir/grazoprevir in Korean patients with hepatitis C virus genotype 1b infection

BACKGROUND/AIMS: In the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies.METHODS: This was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or Child-Pugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL).RESULTS: SVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs.CONCLUSIONS: In this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection.

Efficacy of precision therapy with direct-acting antiviral drugs for patients with chronic HCV genotype 1b infection / 中华临床感染病杂志

Objective To evaluate the efficacy of precision therapy with direct-acting antiviral drugs (DAAs) for patients with chronic HCV gene type 1b infection.Methods One hundred and thirteen patients with chronic HCV genotype 1b infection admitted in the Department of Infectious Diseases of First Hospital of Shanxi Medical University from January 2018 to July 2019 were enrolled,including 89 patients with chronic hepatitis and 24 patients with cirrhosis.Different DAAs therapeutic schedule were taken based on liver function, kidney function, complication and treatment costs.Seventy-two patients were treated with pan-genotype drugs, including 43 patients treated with Sofosbuvir and Velpatasvir (SOF+VEL), 13 treated with Sofosbuvir and Ribavirin ( SOF +RBV), and 16 treated with Sofosbuvir and Daclatasvir ( SOF +DCV).Forty one patients were treated with specific genotype DAAs , including 15 treated with Ombitasvir and Dasabuvir (OBV+DSV), and 26 treated with Elbasvir and Grazoprevir tablets (EBR+GZR).Pair t test and Chi-square test were used to compare virological response rate , the liver function and the adverse reactions were observed.Results The super-rapid virological response (SRVR) rate with DAAs treatment at 1 week was 88.5%(100／113),and the rapid virological response ( RVR) at 4 weeks of treatment was 98.2%(111／113).There was no significant differences in SRVR and RVR among the patients treated with five treatment regimens (χ2 ＝5.95 and 1.04,P＞0.05), all the patients obtained complete early virological response (CEVR) at 12 weeks and sustained virological response ( SVR12) at 12 weeks after treatment. Besides, there were no significant differences in SRVR and RVR between pan-genotype and gene-specific drugs (χ2 ＝0.03 and 0.17, P＞0.05),both CEVR and SVR12 reached 100% in all patients.The liver transaminase levels were improved in patients undergoing pan-genotype or gene-specific drugs treatment. Mild adverse reactions were observed in 5 cases, hemolysis occurred in 1 patient and it was cured after replacement of drugs.Conclusion Both pan-genotype and specific genotypes of DAAs can achieve high virological response rates.Genotypic testing should be performed before antiviral therapy , in order to accurately select treatment options and to save costs.

Characteristics of chronic hepatitis C in the elderly and the progress of antiviral therapy / 中华临床感染病杂志

Elderly patients have become a special concern in the management of hepatitis C .Their HCV exposure time is long and the risk of liver disease and extrahepatic complications is high .With the advent of direct antiviral drugs (DAA), the treatment of chronic hepatitis C has been significantly improved , and the cure rate of virology can be more than 90% in the elderly patients , with a high safety.However, elderly patients often have more underlying diseases and the drug use will be more complicated , resulting in drug interaction ( DDI) and increasing the challenge of treatment management.This article reviews the requirements for comprehensive evaluation of elderly patients before DAA treatment , including liver and kidney function, combined drug use and potential DDI.The monitoring of adverse events and DDI , and the countermeasures are also discussed in the article.

Efficacy and safety of yimitasvir phospha combined with sofosbuvir in patients with chronic hepatitis C virus infection / 中华传染病杂志

Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.

Real world study of daclatavir combined with sofosbuvir treatment in chronic hepatitis C / 中华传染病杂志

Objective@#To investigate the efficacy and safety of daclatavir combined with sofosbuvir treatment in chronic hepatitis C (CHC) in the real world.@*Methods@#A total of 56 CHC patients administrated with daclatavir (60 mg/d) combined with sofosbuvir (400 mg/d) in Huzhou Central Hospital from February to June in 2018 were enrolled. All patients were administrated with daclatavir combined with sofosbuvir for 12 weeks and followed up for 24 weeks. The virological response and the effect of antiviral therapy on hepatic fibrosis were analyzed. Non-structural protein 5A (NS5A) region mutation sequence was detected by Sanger method. Safety and the adverse events were observed. The t test, chi-square test and Mann-Whitney U test were used to analyze the data.@*Results@#Hepatitis C virus (HCV) RNA of all patients treated with daclatavir and sofosbuvir was undectable after eight-week treatment. Sustained virological response at 12 weeks post-treatment (SVR12) was 98.1% (52/53). Gender, globulin, insulin, triglyceride and hemoglobin were correlated with virus clearance (χ2= 4.47, t=2.51, U=1.98, U=2.32 and t=2.03, respectively, all P<0.05). At 12 weeks of the end of the treatment, serum procollagen type Ⅲ, collagen type Ⅳ, liver stiffness measurement (LSM) value, aspartate aminotransferase-to-platelet ratio Index (APRI) score and fibrosis index based on the four factors (FIB-4) score were all improved (U=2.03, 2.15, 2.19, 2.12 and 2.26, respectively, all P<0.05). At 24 weeks of the end of treatment, these indexes showed clear improvement (U=2.09, 2.28, 2.24, 2.33 and 2.46, respectively, all P<0.05). Eight patients had Y93H or L31M resistance-related substitution mutations. Two out of eight patients with variants had negative coversion of HCV RNA and 44.4% (20/45) showed no variants after two weeks of treatment. There was no significant difference (χ2 = 1.11, P > 0.05). During the treatment, patients developed dizziness, fatigue, nausea and vomiting, panic, insomnia, sleepiness and sexual function enhancement.@*Conclusion@#Daclatavir in combination with sophobuvir shows high virological response and good safety in the treatment of chronic hepatitis C, and liver fibrosis is improved after clearance of HCV.

Effects of direct-acting antiviral agents on the frequency of myeloid-derived suppressor cells in patients with chronic hepatitis C / 中华传染病杂志

Objective@#To investigate the effects of direct-acting antiviral agents (DAA) therapy on the frequency of myeloid-derived suppressor cells (MDSC) and their subset of monocytic myeloid-derived suppressor cells (M-MDSC) in chronic hepatitis C (CHC) patients.@*Methods@#A total of 32 treatment-naive CHC patients and 16 healthy controls were recruited at Third Affiliated Hospital of Sun Yat-Sen University from June 2016 to June 2017. The peripheral blood mononuclear cells (PBMC) were separated from the peripheral blood of patients with CHC before DAA therapy, at four weeks after DAA therapy, at 12 weeks after DAA therapy and 12 weeks after the end of DAA therapy. The frequencies of MDSC and M-MDSC were detected by the flow cytometer. The t test, U test and chi-square test was employed to analyze the data.@*Results@#All the 32 treatment-naive patients achieved the rapid virological response and no virological breakthrough was observed. Before DAA therapy, the frequency of MDSC in CHC patients was 2.18%, which was higher than healthy individuals (0.60%; Z=-4.593, P<0.01), and positively correlated with the plasma levels of hepatitis C virus (HCV) RNA (r=0.688, P<0.01) and aspartate aminotransferase (r=0.735, P<0.01). After four weeks of DAA therapy, the frequency of MDSC decreased significantly to 1.07%, with no statistical significance compared to the controls (Z=-1.221, P>0.05). However, at 12 weeks after DAA therapy, the MDSC frequency increased, with statically significance compared to the controls (1.64% vs 0.60%, Z=-3.117, P=0.002). At 12 weeks after the end of DAA therapy, the MDSC frequency had decreased to 1.29% again, with no statistical significance compared to the controls (Z=-1.387, P=0.664). The changes of M-MDSC frequency were slightly different. Before DAA therapy, the frequency of M-MDSC in CHC patients was higher compared to healthy controls (1.66% vs 0.81%, Z=-2.745, P<0.01). The frequencies of M-MDSC were 0.91%, 1.09% and 1.10% at four, 12 weeks after DAA and 12 weeks after the end of DAA therapy, respectively. The differences were not statistically significant compared to the controls (Z=-0.589, -1.028 and -0.486, respectively, all P>0.05).@*Conclusion@#Immune status of the peripheral MDSC and M-MDSC can return to normal after DAA therapy in CHC patients.