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Lianjiang Huang,1 Li Fu,2 Xiaoyan Hu,3 Xiaoliang Liang,1 Guozhong Gong,4 Chunhong Xie,1 Feiyang Zhang,3 Ying Wang,3 Yingshun Zhou3 1Department of Clinical Laboratory, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, 361021, People’s Republic of China; 2The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Department of Pathogen Biology, School of Basic Medicine, Public Center of Experimental Technology of Pathogen Biology Technology Platform, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of Clinical Laboratory, Suining First People’s Hospital, Suining, 629000, People’s Republic of ChinaCorrespondence: Yingshun Zhou; Ying WangDepartment of Pathogen Biology, School of Basic Medicine, Public Center of Experimental Technology of Pathogen Biology Technology Platform, Southwest Medical University, No. 1, Xianglin Road, Luzhou, 646000, People’s Republic of ChinaTel +86-830-3160073Email yingshunzhou@swmu.edu.cn; wyingnbgg@163.comObjective: The aim of this study was to use whole-genome sequencing to characterize Klebsiella pneumoniae SKp2F and Klebsiella variicola SKv2E, both carrying blaKPC, co-isolated from the same sputum specimen.Methods: Antimicrobial susceptibility testing was performed using microbroth dilution. Biofilm formation was determined by crystal violet staining and virulence was measured by a serum killing assay. Whole-genome sequencing of SKp2F and SKv2E was performed using an Illumina sequencer and the genetic characteristics were analyzed by computer.Results: SKp2F and SKv2E were sensitive only to tigecycline and polymyxin among the tested antibiotics. The biofilm-forming ability of SKv2E is stronger than that of SKp2F. The grades of serum resistance of SKp2F and SKv2E are 4 and 3. MLST analysis of the 6,115,610 bp and 5,403,687 bp of SKv2E and SKp2F showed associations with ST1615 and ST631, respectively. SKv2E carried 13 resistance genes (blaKPC-2, blaTEM-1A, blaLEN17, aadA16, arr-3, qnrB4, oqxA/B, dfrA27, sul1, tetD, fosA, qacEΔ 1) and SKp2F carried 23 (blaKPC-2, blaCTX-M-3, blaTEM-1B, blaCTX-M-65, blaSHV-27, aac(6ʹ)-IIa, rmtB, arr-3, aph(3ʹ)-Ia, aadA16, qnrS1, aac(6ʹ)-Ib-cr, qnrB91, oqxA/B, mph(A), tet(A), fosA, dfrA27, and two copies of qacEΔ 1-sul1). Most of them were carried by various mobile genetic elements, such as IncFIB(K)/IncFII(K)/IncFII(Yp), IncFII(K) plasmid, Tn6338, and In469. Both SKv2E and SKp2F carried a large number of virulence factors, including type 1 and 3 fimbriae, capsule, aerobactin (iutA), ent siderophore (entABCDEFS, fepABCDGfes), and salmochelin (iroE/iroEN). SKv2E also carried type IV pili (pilW), fimbrial adherence (steB, stfD), and capsule biosynthesis gene (glf).Conclusion: blaKPC-2-carrying K. variicola and K. pneumoniae, which carried multiple resistance genes, virulence factors, and highly similar mobile genetic elements, were identified from the same specimen, indicating that clinical samples may carry multiple bacteria. We should avoid misidentification, and bear in mind that resistance genes carrying mobile genetic elements can be transmitted or integrated between bacteria in the same host.Keywords: Klebsiella variicola, Klebsiella pneumoniae, carbapenem-resistant Enterobacteriaceae, CRE, blaKPC

BACKGROUND Tenofovir amibufenamide (TMF) can provide more efficient delivery than tenofovir disoproxil fumarate (TDF). AIM To compare the efficacy and safety of TMF and TDF for 48 weeks in patients with chronic hepatitis B (CHB). METHODS We performed a randomised, double-blind, non-inferiority study at 49 sites in China. Patients with CHB were assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo. The primary efficacy endpoint was the proportion of patients with hepatitis B virus (HBV) DNA less than 20 IU/mL at week 48. We also assessed safety, particularly bone, renal and metabolic abnormalities. RESULTS We randomised 1002 eligible patients. The baseline characteristics were well balanced between groups. After a median 48 weeks of treatment, the non-inferiority criterion was met in all analysis sets. In the HBeAg-positive population, 50.2% of patients receiving TMF and 53.7% receiving TDF achieved HBV DNA less than 20 IU/mL. In the HBeAg-negative population, 88.9% and 87.8%, respectively, achieved HBV DNA less than 20 IU/mL in the TMF and TDF groups. Patients receiving TMF had significantly less decrease in bone mineral density at both hip (P

AIMS Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough ) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction. METHODS The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. RESULTS Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL-1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL-2 and TBIL-3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively. CONCLUSIONS Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL-based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.

Purpose Chronic hepatitis B virus (HBV) infection is a key determinant of hepatocellular carcinoma (HCC). However, the mechanism by which HBV contributes to the development of HCC remains to be further explored. HBV-encoded miR-3 (HBV-miR-3) is a newly discovered microRNA that can affect the replication of HBV, but its influence on host genes is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is expressed at low levels in most cancer cells. How HBV-miR-3 acts on PTEN to induce tumorigenesis has not been clarified. Materials and methods PTEN protein expression was evaluated in HBV-miR-3-transfected cells and HBV-related liver cancer and paracancerous tissues. A luciferase reporter assay was employed to identify the HBV-miR-3 binding site on the 3'-untranslated region (3'-UTR) of PTEN. Cell apoptosis was assessed by flow cytometry. Cell proliferation was evaluated by colony formation assays. Transwell assays were used to detect cancer cell invasion. Results HBV-miR-3 was identified only in HBV-replicating HCC cells and HBV-infected patients. HBV-miR-3 expression in liver cancer tissues was higher than that in paracancerous tissues, and the corresponding PTEN expression was significantly decreased. Wild-type HBV-miR-3 bound to the 3'-UTR of PTEN and downregulated its protein expression in a dose-dependent manner. Moreover, the inhibition of HBV-miR-3 rescued PTEN protein expression. Furthermore, HBV-miR-3 reduced liver cancer cell apoptosis, enhanced cell invasion, and promoted cell proliferation. Conclusion HBV-miR-3 binds to the 3'-UTR of PTEN mRNA and downregulates PTEN protein expression, thereby reducing cell apoptosis and enhancing cell invasion and proliferation. These results indicate that HBV-miR-3 contributes to the development of HBV-related HCC and may be a therapeutic target for this cancer.

Highlights • Novaferon considered as a potential antiviral drug for COVID-19. • Novaferon inhibited viral replication and protected cells from SARS-CoV-2 attack. • Antiviral effects of Novaferon for COVID-19 patients observed in randomized trial. • Inhalation of Novaferon for COVID-19 treatment was safe., Background The anti-viral effects of Novaferon, a potent antiviral protein drug on COVID-19 was evaluated in laboratory, and in a randomized, open-label, parallel group trial. Methods In laboratory, the inhibition of Novaferon on viral replication in cells infected with SARS-CoV-2, and on prevention of SARS-CoV-2 entry into healthy cells was determined. Antiviral effects of Novaferon in COVID-19 patients with treatment of Novaferon, Novaferon plus Lopinavir/Ritonavir, or Lopinavir/Ritonavir were evaluated. The primary endpoint was the SARS-CoV-2 clearance rates on day 6 of treatment, and the secondary endpoint was the time to SARS-CoV-2 clearance. Results Novaferon inhibited the viral replication (EC50 = 1.02 ng/ml), and prevented viral infection (EC50 = 0.10 ng/ml). Results from the 89 enrolled COVID-19 patients showed that both Novaferon and Novaferon plus Lopinavir/Ritonavir groups had significantly higher viral clearance rates on day 6than Lopinavir/Ritonavir group (50.0% vs.24.1%, p = 0.0400, and 60.0% vs.24.1%, p = 0.0053). Median time to viral clearance were 6 days, 6 days, and 9 days for three groups respectively, a 3-dayreductionin both Novaferon and Novaferon plus Lopinavir/Ritonavir groups compared with Lopinavir/Ritonavir group. Conclusions Novaferon exhibited anti-SARS-CoV-2 effects in vitro and in COVID-19 patients. These data justified the further evaluation of Novaferon. Trial registration number number ChiCTR2000029496at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/).

BACKGROUND: SARS-CoV-2 causes high mortality risk in older patients. This study aims to characterize the clinical features of older and younger SARS-CoV-2 infected patients. RESULTS: A total of 239 patients were divided into the younger group (

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child–Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child–Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor &lt, 5), implying that CYP2C19 testing makes sense for precision medicine of Child–Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child–Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.

Objective The aim of this study was to use whole-genome sequencing to characterize Klebsiella pneumoniae SKp2F and Klebsiella variicola SKv2E, both carrying blaKPC, co-isolated from the same sputum specimen. Methods Antimicrobial susceptibility testing was performed using microbroth dilution. Biofilm formation was determined by crystal violet staining and virulence was measured by a serum killing assay. Whole-genome sequencing of SKp2F and SKv2E was performed using an Illumina sequencer and the genetic characteristics were analyzed by computer. Results SKp2F and SKv2E were sensitive only to tigecycline and polymyxin among the tested antibiotics. The biofilm-forming ability of SKv2E is stronger than that of SKp2F. The grades of serum resistance of SKp2F and SKv2E are 4 and 3. MLST analysis of the 6,115,610 bp and 5,403,687 bp of SKv2E and SKp2F showed associations with ST1615 and ST631, respectively. SKv2E carried 13 resistance genes (blaKPC-2, blaTEM-1A, blaLEN17, aadA16, arr-3, qnrB4, oqxA/B, dfrA27, sul1, tetD, fosA, qacEΔ1) and SKp2F carried 23 (blaKPC-2, blaCTX-M-3, blaTEM-1B, blaCTX-M-65, blaSHV-27, aac(6ʹ)-IIa, rmtB, arr-3, aph(3ʹ)-Ia, aadA16, qnrS1, aac(6ʹ)-Ib-cr, qnrB91, oqxA/B, mph(A), tet(A), fosA, dfrA27, and two copies of qacEΔ1-sul1). Most of them were carried by various mobile genetic elements, such as IncFIB(K)/IncFII(K)/IncFII(Yp), IncFII(K) plasmid, Tn6338, and In469. Both SKv2E and SKp2F carried a large number of virulence factors, including type 1 and 3 fimbriae, capsule, aerobactin (iutA), ent siderophore (entABCDEFS, fepABCDGfes), and salmochelin (iroE/iroEN). SKv2E also carried type IV pili (pilW), fimbrial adherence (steB, stfD), and capsule biosynthesis gene (glf). Conclusion blaKPC-2-carrying K. variicola and K. pneumoniae, which carried multiple resistance genes, virulence factors, and highly similar mobile genetic elements, were identified from the same specimen, indicating that clinical samples may carry multiple bacteria. We should avoid misidentification, and bear in mind that resistance genes carrying mobile genetic elements can be transmitted or integrated between bacteria in the same host.

HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB.A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo.Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

Background The current definitions and etiologies of acute-on-chronic liver failure (ACLF) are clearly very different between East and West. Aims This study aimed to develop an effective prognostic nomogram for acute-on-chronic hepatitis B liver failure (ACHBLF) as defined by the Asia Pacific Association for the Study of the Liver (APASL). Methods The nomogram was based on a retrospective study of 573 patients with ACHBLF, defined according to the APASL, at the Beijing Ditan Hospital. The results were validated using a bootstrapped approach to correct for bias in two external cohorts, including an APASL ACHBLF cohort (10 hospitals, N = 329) and an EASL-CLIF ACHBLF cohort (Renji Hospital, N = 300). Results Multivariate analysis of the derivation cohort for survival analysis helped identify the independent factors as age, total bilirubin, albumin, international normalized ratio, and hepatic encephalopathy, which were included in the nomogram. The predictive value of nomogram was the strongest compared with CLIF-C ACLF, MELD and MELD-Na and similar to COSSH-ACLF in both the derivation and prospective validation cohorts with APASL ACHBLF, but the CLIF-C ACLF was better in the EASL-CLIF ACHBLF cohort. Conclusions The proposed nomogram could accurately estimate individualized risk for the short-term mortality of patients with ACHBLF as defined by APASL.

Summary Background Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1–6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes. Methods In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1–6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov , number NCT02671500 , and is completed. Findings Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94–98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72–98]) of 28 patients without cirrhosis and seven (50% [23–77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir–velpatasvir treatment. Interpretation Consistent with data from other phase 3 studies, single-tablet sofosbuvir–velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis. Funding Gilead Sciences.

The COVID-19 pandemic causes severe morbidity and mortality. This multi-country study aimed to explore risk factors that drive mortality in COVID-19 patients who received neither dexamethasone nor remdesivir. We analyzed a cohort of 568 survivors and 507 non-survivors from China, European regions, and North America. Elderly males ≥70 years accounted for only 25% of survivors, but this rate was significantly higher in non-survivors from China (55%), European regions (63%), and North America (47%). Compared with survivors, non-survivors had more incidences of comorbidities such as cerebrovascular disease and chronic obstructive pulmonary disease (COPD, p-values

Aims This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised dosing regimen for patients with liver dysfunction. Methods The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic (ROC) curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed-effects method. Dosing simulations stratified by TBIL (TBIL-1: TBIL < 51 μmol/L; TBIL-2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL-3: TBIL ≥ 171 μmol/L) were performed. Results ROC curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance (CL), the volume of distribution (V) and oral bioavailability (F) were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole CL was significantly associated with total bilirubin (TBIL) and platelet count. The V increased with weight. Patients with TBIL-1 could be treated with loading dose of 400 mg every 12 hours (q12h) for first day and maintenance dose of 100 mg q12h intravenously or orally. TBIL-2 and TBIL-3 patients could be treated with loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily (qd) and 50 mg qd orally or intravenously, respectively. Conclusions TBIL-based dosing regimens provide a practical strategy for voriconazole maximizing treatment outcomes.

Objective To investigate the influence of storage time and temperature on plasma insulin levels and to establish a correction formula. Methods Venous blood samples were taken from 20 volunteers and processed as follows: whole blood samples, centrifuged samples, and separated plasma samples were stored at 4°C or 25°C. Insulin levels were determined by direct chemiluminescence at 0, 0.5, 1, 2, 4, and 8 hours. According to the correlation between the insulin concentration ratio and storage time, correction formulas for the insulin concentration were established. To verify the test, the venous blood samples of another 33 volunteers were processed in the same way. The insulin levels of the samples were corrected after 3, 6, 12, and 24 hours and compared with the value at 0 hours to verify the feasibility of the corrected formula. Results With the prolongation of storage time, the insulin levels of the whole blood samples at 4°C or 25°C and of the centrifuged samples at 25°C decreased gradually (P .05). Conclusions The insulin levels of the whole blood samples at 4°C or 25°C and of the plasma samples at 25°C gradually decreased with storage time. The effect of storage time on the insulin level can be reduced with the correction formulas.

The outcomes of hepatitis B virus (HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be self-limited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Background Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. Methods Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. Results All 206 enrolled patients achieved SVR12 (100%; 95% CI 98–100%), including 106 treatment-naive patients (100%; 95% CI 97–100%), which was superior to a historical SVR rate of 57% (p

BACKGROUND AND AIM Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naive, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (

Background and Aims: Hepatitis B surface antigen (HBsAg) loss is seldom achieved with nucleos(t)ide analog (NA) therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon (Peg-IFN) alfa-2a. We assessed HBsAg loss with 48- and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA. Methods: Hepatitis B e antigen (HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA

Information on the stage of liver fibrosis is essential for decisions on antiviral treatment for chronic hepatitis B virus (HBV). This paper aims to establish a non-invasive assessment model with serum markers using cloud computing and the Internet of Things for the evaluation of liver disease severity and its prognosis. Based on the Internet of Things, the multiple and key information system of liver fibrosis or cirrhosis are constructed using the serum markers data. In the cloud platform, the probability density functions of indexes are used to select the optimized indicators. The logistic regression is used to establish the non-invasive assessment model. The patients were selected with CHB and underwent liver biopsy in the Second Xiangya Hospital, Central South University. There are two inclusion criteria: first, the patient received a liver biopsy according to “Proclaim Prevention and Cure Guide For Chronic Hepatitis B”of Chinese Medical Association in 2015; second, the patient has a history of hepatitis B or HBV surface antigen (HBsAg) positive more than six months, and HBsAg and (or) HBV DNA is still positive. Results of clinical data applications show that the accuracy of the non-invasive assessment model reaches greater than 70% for the recognition of significant liver fibrosis. In addition, the discriminant accuracy can be improved by increasing the number of indicators. The established non-invasive assessment model can be used for auxiliary clinical diagnosis after the further validation.

The HBx protein of hepatitis B virus (HBV) is widely recognized to be a critical oncoprotein contributing to the development of HBV-related hepatocellular carcinoma (HCC). In addition, cationic amino acid transporter 1 (CAT-1) gene is a target of miR-122. In this study, we found that CAT-1 protein levels were higher in HBV-related HCC carcinomatous tissues than in para-cancerous tumor tissues, and that CAT-1 promoted HCC cell growth, proliferation, and metastasis. Moreover, HBx-induced decreases in Gld2 and miR-122 levels that contributed to the upregulation of CAT-1 in HCC. These results indicate that a Gld2/miR-122/CAT-1 pathway regulated by HBx likely participates in HBV-related hepatocellular carcinogenesis.

Background and AimIn 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-naive, Han ethnic, patients with chronic HCV infection. MethodsPatients 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 6months for untreated patients and every 3months for treated patients. ResultsAmong 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 24weeks 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 >1year). 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. ConclusionsThere 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.

Background As an important anti-HBV drug, pegylated interferon α (PegIFNα) offers promising clinical efficacy, but biomarkers that accurately forecast treatment responses are yet to be elucidated. Here, we evaluated whether HBV RNA could act as an early monitor of pegylated interferon responses. Methods We analyzed a phase 3, multicenter, randomized cohort of 727 HBeAg-positive non-cirrhotic patients receiving a 48-week treatment of PegIFNα-2a or PegIFNα-2b and a 24-week treatment-free follow-up. Serum levels of HBV RNA, HBV DNA, HBeAg, and HBsAg were measured at weeks 0, 12, 24, 48, and 72. Results HBeAg seroconversion and HBsAg loss at week 72 were observed in 217 (29.8%) and 21 (2.9%) patients, respectively. During the 48-week treatment, HBV RNA decreased more rapidly than HBV DNA and HBsAg, but HBV RNA and HBeAg shared similar dynamics with positive correlations. Multivariate regression analyses consistently revealed the significance of HBV RNA at weeks 0, 12, 24, and 48 to monitor HBeAg seroconversion but not HBsAg loss. Although baseline HBV RNA only showed a modest AUC performance, HBV RNA with a significant increase of AUC at week 12 outperformed other HBV biomarkers to forecast HBeAg seroconversion (p value Conclusion HBV RNA at week 12 is an effective monitor of HBeAg seroconversion in HBeAg-positive patients treated with pegylated interferons.

Background and Aims: Ravidasvir (RDV) is a new generation pangenotypic hepatitis C virus (HCV) NS5A inhibitor, with high barrier to baseline resistance-associated species. This is the first phase 2/3 study conducted in Mainland China confirming the efficacy and safety of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks in treatment-naïve noncirrhotic patients with genotype 1 infection in a large population. Methods: In this multicenter, randomized, double-blinded, placebo-controlled phase 2/3 trial (NCT03362814), we enrolled 424 treatment-naïve, noncirrhotic adult HCV genotype 1 patients. All patients were randomized at 3:1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day (body weight

To explore the prognostic factors for patients with drug-induced liver failure (DILF) and construct a logistic regression model (LRM). Methods: A retrospective analysis of clinical data was performed in 183 hospitalized patients, who were diagnosed with DILF in Xiangya Hospital, the Second Xiangya Hospital and the Third Xiangya Hospital, Central South University from January 2009 to January 2018. The patients were divided into an improved group (n=67) and an ineffective group (n=116) according to their prognosis. Univariate analysis was performed to screen for possible prognostic factors such as age, Tbil, SCr, PT and complications. According to the results of univariate analysis, the multivariate analysis was performed to determine the independent prognostic factors and construct a LRM. The LRM was compared with the model for end-stage liver disease (MELD), the predictive value of LRM and MELD was evaluated by receiver operating characteristic curve (ROC), the parameters such as area under the ROC (AUC) and total accuracy were compared between the 2 models and verified by another independent sample. Results: According to univariate analysis, there was significant differences in age, clinical type, hepatic encephalopathy, hepatorenal syndrome, WBC count, the ratio of aspartic acid transaminase (AST) to glutamine transaminase (ALT) (AST/ALT), Tbil, SCr, PT and alpha-fetoprotein (AFP) between the 2 groups (all P0.05). Multivariate analysis revealed that: AFP, PT, AST/ALT, hepatic encephalopathy and hepatorenal syndrome were independent prognostic factors for DILF, which could be applied to constructing a LRM. The AUC of LRM and MELD was 0.917 (95% CI 0.876 to 0.959) and 0.709 (95% CI 0.633 to 0.786) respectively, the total accuracy rate of prediction for the LRM and the MELD was 86.7% and 68.3% respectively, there was significant difference in AUC and total accuracy rate between the LRM and the MELD (P0.05). LRM was superior to MELD. Conclusion: AFP, PT, AST/ALT, hepatic encephalopathy and hepatorenal syndrome were independent prognostic factors for DILF; the LRM can well predict the prognosis in the DILF patients, which is superior to the MELD.目的：研究药物性肝衰竭(drug-induced liver failure，DILF)患者的预后影响因素，并构建其logistic回归模型(logistic regression model，LRM)。方法：回顾性分析2009年1月至2018年1月在中南大学湘雅医院、湘雅二医院及湘雅三医院感染病科收治的183例DILF患者的临床资料，根据其预后分为好转组(n=67)及无效组(n=116)。使用单因素分析对年龄，Tbil，SCr，PT及并发症等可能的预后影响因素进行初筛，基于单因素分析结果，进一步使用多因素分析筛选出独立的预后因素并构建LRM模型。将LRM模型与终末期肝病(model for end-stage liver disease，MELD)模型进行比较，采用受试者工作曲线(receiver operating characteristic curve，ROC)评估LRM模型和MELD模型的预测价值，比较两模型间ROC曲线下面积(area under the ROC curve，AUC)及总正确率等参数的优劣，并使用独立样本进行验证。结果：单因素分析提示：年龄，临床分型，肝性脑病，肝肾综合征，WBC计数，天门冬氨酸转氨酶/谷丙氨酸转氨酶(aspartic acid transaminase/glutarine transaminase，AST/ALT)比值，Tbil，SCr，PT和甲胎蛋白(alpha-fetoprotein，AFP)等指标在两组间的差异均有统计学意义(均P0.05)。多因素分析提示：AFP，PT，AST/ALT比值，肝性脑病和肝肾综合征为DILF患者独立的预后影响因素，可用于构建LRM模型。LRM模型和MELD模型的AUC分别为0.917(95% CI：0.876~0.959)和0.709(95% CI：0.633~0.786)，总正确率分别为86.7%和68.3%，差异有统计学意义(P0.05)。结论：AFP，PT，AST/ALT比值，肝性脑病和肝肾综合征为DILF患者独立的预后影响因素；LRM模型能较准确地预测DILF患者的短期预后，其应用价值优于MELD模型。.

Background and Aims Tenofovir alafenamide (TAF) has similar efficacy to tenofovir disoproxil fumarate (TDF) but with improved renal and bone safety in chronic hepatitis B patients studied outside of China. We report 3-year results from two phase 3 studies with TAF in China (Clinicaltrials.gov: NCT02836249 and NCT02836236). Methods Chinese hepatitis B e antigen (HBeAg)-positive and -negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks (3 years). Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis. Results Of the 334 patients (180 HBeAg-positive and 154 HBeAg-negative) randomized and treated, baseline characteristics were similar between groups. The overall mean age was 38 years and 73% were male. The mean HBV DNA was 6.4 log10 IU/mL. The median alanine aminotransferase was 88 U/L, and 37% had a history of antiviral use. At week 144, the proportion with HBV DNA

Hepatic fibrosis is characterized by abnormal accumulation of extracellular matrix (ECM). Hepatic stellate cells (HSCs) are the primary cells that produce ECM in response to hepatic injury, and transforming growth factor-beta (TGF-β) has been regarded as the central stimulus responsible for HSC-mediated ECM production. In the present study, we attempted to identify a critical factor in HSC activation and the underlying mechanism. By analyzing online microarray expression profiles, we found that the expression of high-affinity cationic amino acid transporter 1 (CAT1) was upregulated in hepatic fibrosis models and activated HSCs. We isolated and identified mouse HSCs (MHSCs) and found that in these cells, CAT1 was most highly upregulated by TGF-β1 stimulation in both time- and dose-dependent manners. In vitro, CAT1 overexpression further enhanced, while CAT1 silencing inhibited, the effect of TGF-β1 in promoting MHSC activation. In vivo, CAT1 silencing significantly improved the hepatic fibrosis induced by both CCl4 and non-alcoholic fatty liver disease (NAFLD). In summary, CAT1 was significantly upregulated in TGF-β1-activated MHSCs and mice with hepatic fibrosis. CAT1 silencing inhibited TGF-β1-induced MHSC activation in vitro and fibrogenic changes in vivo. CAT1 is a promising target for hepatic fibrosis treatment that requites further investigation in human cells and clinical practice.

Daclatasvir plus asunaprevir has demonstrated efficacy and safety in patients with chronic hepatitis C virus genotype 1b infection. This study focused on evaluating daclatasvir plus asunaprevir in interferon (±ribavirin)-ineligible or -intolerant Asian patients with genotype 1b infection from mainland China, Korea, and Taiwan. Interferon (±ribavirin)-ineligible and -intolerant patients with genotype 1b infection received daclatasvir 60 mg tablets once-daily plus asunaprevir 100 mg soft capsules twice-daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment Week 24 (SVR24). Of the 159 patients treated, 89.3% were Chinese, 65.4% were female, and 73.6% were interferon-intolerant. Cirrhosis was present in 32.7% of patients and 40.3% had IL28B non-CC genotypes. SVR24 was achieved by 145/159 (91.2%) patients (100% concordance with SVR12) and was similarly high in cirrhotic patients (47/52, 90.4%). SVR24 was higher in patients without baseline NS5A (L31M or Y93H) resistance-associated variants (RAVs) (137/139, 98.6%), including those with cirrhosis (43/44, 97.7%). Prevalence of baseline NS5A RAVs was low (19/159, 11.9%), particularly in mainland China (10/127, 7.9%). One death (0.6%), five serious adverse events (3.1%), and three grade 4 laboratory abnormalities (1.9%) occurred on-treatment; none were considered related to study drugs. Two patients (1.3%) discontinued due to adverse events. Treatment was generally well-tolerated regardless of cirrhosis status. Daclatasvir plus asunaprevir achieved a SVR24 rate of 91.2%, rising to 98.6% in patients without baseline NS5A RAVs, and was generally well tolerated in interferon (±ribavirin)-ineligible or -intolerant patients with genotype 1b infection from mainland China, Korea, and Taiwan. This article is protected by copyright. All rights reserved.

Background: Treatment with sofosbuvir/velpatasvir has resulted in high sustained virologic response rates in HCV-infected patients with genotype 1 to 6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes. Methods: Patients in China, Thailand, Vietnam, Singapore, and Malaysia with genotype 1-6 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label sofosbuvir/velpatasvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). The primary safety endpoint was adverse events leading to premature discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. Findings: Of the 375 patients in the study, 362 patients (97%) achieved SVR12 (95% CI: 94.1% to 98.1%). The SVR12 rate was >99% for patients with genotype 1, 2, or 6 HCV infection and 86% for patients with genotype 3. Among patients with genotype 3b, nearly all of whom had baseline NS5A RASs, the SVR12 rate was 89% in noncirrhotics (25 of 28 patients) and 50% in cirrhotics (7 of 14 patients). Overall, 47% of patients had baseline NS5A RASs, 94% of whom achieved SVR12. The most common adverse events were upper respiratory tract infection (10%) and headache (5%). There were no discontinuations due to adverse events; serious adverse events were reported in 3 patients (0.8%), none of which were assessed by the investigator as related to sofosbuvir/velpatasvir treatment. Interpretation: Consistent with data from Phase 3 studies, treatment with the single-tablet regimen of sofosbuvir/velpatasvir for 12 weeks provided high overall SVR12 rates in Asian patients, but those with genotype 3b and cirrhosis had lower rates of SVR12. Trial Registration Number: NCT02671500 Funding: Funding for this study was provided by Gilead Sciences. Declaration of Interest: Lai WEI has received research funding from AbbVie, Bristol-Myers Squibb, and Roche. Teerha PIRATVISUTH has served on advisory boards for Bristol-Myers Squibb, Bayer, and Mylan, has served as a speaker for Bristol-Myers Squibb, MSD, Bayer, and Mylan, and has received research funding from Bristol-Myers Squibb, Gilead, MSD, Fibrogen, and Bayer. Chee-Kiat TAN has served on advisory boards and as a speaker for Gilead. Luisa M. STAMM, Sophia LU, Hadas DVORY-SOBOL, Hongmei MO, and Diana M. BRAINARD are employees of and hold stock in Gilead. The remaining authors declare no conflicts of interest. Ethical Approval: Prior to enrollment and before any study procedures were conducted, written informed consent was obtained from all patients. The study was approved by the independent ethics committees at all participating sites and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection is characterized by higher serum HCV RNA loads compared with HCV mono-infection. However, the relationship between HIV and HCV replication remains to be clarified. HIV Vpr has been shown to play an essential role in HIV replication. In this study, we aimed to explore the role of Vpr in HCV replication and pathogenesis. We therefore used the genotype 2a full-length HCV strain JFH1 infection system and the genotype 1b full-length HCV replicon OR6 cell line to analyse the effects of Vpr on HCV replication. We found that Vpr promoted HCV 5′ UTR activity, HCV RNA replication and HCV protein expression in two HCV infection cell models. Additionally, lymphocyte-produced Vpr significantly induced HCV 5′ UTR activity and HCV replication in hepatocytes. We also found that Vpr upregulated the expression of miR-122 by stimulating its promoter activity. Furthermore, an miR-122 inhibitor suppressed the Vpr-mediated enhancement of both HCV 5′ UTR activity and HCV replication. In summary, our results revealed that the Vpr-upregulated expression of miR-122 is closely related to the stimulation of HCV 5′ UTR activity and HCV replication by Vpr, providing new evidence for how HIV interacts with HCV during HIV/HCV co-infection.

Medical therapy is rarely effective in patients with fulminant Wilson’s disease (FWD). Liver transplantation is limited by the lack of donor liver in most patients with FWD at the time of diagnosis. New Wilson’s index, model for end-stage liver disease (MELD) and Child-Pugh score are useful tools for decision-making of liver transplantation; however, none of them is an independent decisive tool. It is worthwhile to explore a more effective and practical therapeutic strategy and reevaluate the prediction systems for patients with FWD. Nine patients with FWD associated with hemolytic crisis and fulminant hepatic failure (FHF) were investigated. The clinical presentation, prognostic score and medical therapies of the patients were analyzed. In 7 of the 9 patients with FWD who received the comprehensive therapy of corticosteroid, copper-chelating agent (dimercaptopropansulfonate sodium) and therapeutic plasma exchange (TPE), 6 patients recovered from FHF. The remaining one had been improved through the comprehensive therapy but died of septicemia 51 days later. Two patients with spontaneous bacterial peritonitis (SBP) died from liver failure in three or five hospital days without plasma exchange or chelating therapy. All of the 9 patients with FWD presented with acute hepatic failure, severe jaundice and mild to severe hemolytic anemia. No marked difference in the incidence of severe hemolytic anemia was detected between the survival and deceased groups. However, the incidence and the degree of hepatic encephalopathy (HE) in the non-survival group were higher than those in the survival group. Unlike the deceased group, the survival group had no complications induced by bacterial infection. Compared to new Wilson’s index, Child-Pugh score and MELD score, the variation of prothrombin activity (PTA) between the survival and deceased groups was more evident. For patients with FWD, the episode of severe hepatic encephalopathy or/and spontaneous bacterial peritonitis indicates worse prognosis, and PTA is a recommendable predictor. An emergent liver transplantation should be considered for patients whose PTA is below 20%, or for those with severe HE or/and SBP. The comprehensive therapy of corticosteroid, copper-chelating agent and TPE is effective for patients without SBP and whose PTA is higher than 20%.

Background and Aims A number of studies have confirmed that antiviral therapy with nucleotide analogs (NAs) can improve the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative therapy. However, what factors affected the prognosis of HBV-HCC after removal of the primary tumor and inhibition of HBV replication? A meta-regression analysis was conducted to explore the prognostic factor for this subgroup of patients. Methods MEDLINE, EMBASE, Web of Science, and Cochrane library were searched from January 1995 to February 2014 for clinical trials evaluating the effect of NAs on the prognosis of HBV-HCC after curative therapy. Data were extracted for host, viral, and intervention information. Single-arm meta-analysis was performed to assess overall survival (OS) rates and HCC recurrence. Meta-regression analysis was carried out to explore risk factors for 1-year OS rate and HCC recurrence for HBV-HCC patients after curative therapy and antiviral therapy. Results Fourteen observational studies with 1284 patients met the inclusion criteria. Influential factors for prognosis of HCC were mainly baseline HBeAg positivity, cirrhotic stage, advanced Tumor-Node-Metastasis (TNM) stage, macrovascular invasion, and antiviral agent type. The 1-year OS rate decreased by more than four times (coefficient −4.45, P

Background & Aims Decreased levels of phosphatase and tensin homologue (PTEN) are associated with hepatocellular carcinoma (HCC) pathogenesis and poor prognosis in hepatitis C virus (HCV)-infected HCC patients. The molecular processes governing the reduction in PTEN and outcome of PTEN dysfunction in hepatocytes are poorly understood. Methods The levels of proteins and mRNA were assessed by real time PCR and immunoblot. PTEN promoter activity was measured by reporter assay. Signalling pathways were perturbed using siRNAs or pharmacological inhibitors. Results Here, we report that HCV down-regulates PTEN expression at the transcriptional level by decreasing its promoter activity, mRNA transcription, and protein levels. We further identify NS5A protein as a key determinant of PTEN reduction among HCV proteins. NS5A-mediated down-regulation of PTEN occurs through a cooperation of reactive oxygen species (ROS)-dependent Nuclear Factor- kappa B (NF-κB) and ROS-independent phosphoinositol-3-kinase (PI3K) pathways. Moreover, NS5A protects cells against apoptosis. In addition, we found that down-regulation of PTEN relieves its inhibitory effect on PI3K-Akt pathway and triggers cumulative activation of Akt. This PTEN-PI3K/Akt feedback network mediates the suppression of cell apoptosis caused by NS5A. Conclusions These data demonstrate that HCV NS5A down-regulates PTEN expression through a cooperation of ROS-dependent and -independent pathways that subsequently drives a PTEN-PI3K/Akt feedback loop to support cell survival. Our findings provide new insights suggesting that NS5A contributes to HCV-related hepatocarcinogenesis.

Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6.Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12).Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naïve, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three ( 1%) discontinued treatment because of adverse events, of whom one died because of treatment-unrelated adverse events.Sofosbuvir-based regimens were highly effective and safe in Chinese patients with HCV genotype 1, 2, 3, or 6, suggesting sofosbuvir could serve as the backbone for HCV treatment in China irrespective of genotype.

Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the mechanism is still needed to be elucidated. In this study, we explored the relationship between HBx and microRNA and their roles in hepato-carcinogenesis. Firstly, by global microarray-based microRNA profiling and qRT-PCR, we found miR-181a was strongly up-regulated in HepG2.2.15 cells (HBV positive) and pHBV1.3-expressing HepG2 cells, and HBx played a major role in it. Secondly, reduced PTEN protein expression in the presence of HBx was aslo mediated by miR-181a, and in the Luciferase reporter system, miR-181a inhibited the PTEN translation by binding the PTEN 3′-untranslated-region (UTR), and PTEN protein was decreased when epigenetic expression of miR-181a and rescued by knocking down miR-181a. Finally, HBx interrupted the balance between apoptosis and proliferation, which contributed to the development of hepatocellular carcinoma, was also related to the interaction of miR-181a and PTEN. Taken together, we presented here a novel cross-talk between miR-181a and PTEN which was raised by HBx, and this shined a new line in HBV-related hepato-carcinogenesis.

The composition of glycan in immunoglobulin G (IgG) has shown to affect various diseases and can be regulated by drugs and preventive vaccination. A hepatitis B surface antigen (HBsAg)-hepatitis B immunoglobulin (HBIG) immune complex (YIC) therapeutic vaccine for chronic hepatitis B (CHB) patients has undergone clinical trials. To explore for markers of CHB, which could be associated with responsiveness to YIC therapeutic vaccine, serum IgG glycosylation in CHB patients was analyzed. Kinetic changes of serum galactosylated IgG in 53 hepatitis Be antigen (HBeAg)-positive CHB patients treated with YIC were monitored by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) analysis. Whole blood cytokines were assayed by cytokine binding assay kits. All samples were back assayed before treatment, during therapy and follow-up for 6 months from a previous completed clinical trial. During YIC treatment, 26 patients with lower IgG galactosylation level at baseline [galactosylation level (Gal-ratio) = −0.29, 0.18 (mean, SD)] showed sustained increase of serum galactosylated IgG, and responded to YIC treatment by HBeAg seroconversion. While those who did not respond to YIC treatment [Gal-ratio = −0.40, 0.15 (mean, SD)] failed to show similar changes. Furthermore, this kinetic increase of galactosylated IgG correlated with marked up-regulated IL-2 level, confirming that effective cellular immune responses have participated in responsiveness. For HBeAg-positive CHB patients lower serum IgG galactosylation level may serve as an indicator for selecting a suitable subpopulation of candidates for YIC therapeutic vaccination.

Treatment-related adverse events (AE) were more frequent in older patients treated by pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC), and most of them required dose reduction. A meta-regression analysis was conducted to explore the possible reasons for this occurrence. We searched MEDLINE, EMBASE, and Web of Science through May 2013, for clinical trials examining the safety of PEG-IFN plus RBV in elderly patients with CHC. Data were extracted for host, viral, and outcome information. Single-arm meta-analysis was performed to evaluate AE. Meta-regression analysis was conducted to explore predictors for dose reduction secondary to AE. Eighteen observational studies met the inclusion criteria. The overall incidences of AE were 61.3 %. Dose reductions due to AE were 54.2 %. In patients with genotype 1, the rate of sustained virological response (SVR) was 36.9 %. In patients with genotypes 2 or 3, the rate of SVR was 72.8 %. Patients with more dose reduction due to AE have a tendency toward a lower likelihood of obtaining SVR (coefficient:−0.529), especially for genotype 1 patients. Host factors (male gender, coefficient 4.403; higher body weight, coefficient 0.140; and advanced fibrosis stage, coefficient 1.582) and viral factors (HCV genotype 1, coefficient 2.279) have a significant impact on dose reduction due to AE. Some host and viral factors affected dose reduction due to AE. Increasing rates of fibrosis with age may play a role as a mechanism affecting dose reduction secondary to AE and SVR in different age groups.

The aim of this study was to evaluate the simplified and revised scoring systems for the diagnosis of autoimmune hepatitis (AIH). Seventy-seven patients diagnosed with AIH via the revised scoring system were enrolled in this study. Statistical analysis was performed by means of the χ2 test and logistic regression analysis. A total of 39 patients with definite AIH and 38 patients with probable AIH were diagnosed by the revised scoring system, whereas among these 77 patients, the simplified scoring system classified nine cases as definite AIH, 39 as probable AIH and 29 without AIH. In this study, the parameters contributing to the discrepant diagnosis of AIH were compared using the revised and simplified systems. A χ2 test showed that antinuclear antibody (ANA) or smooth muscle antibody (SMA) titers were significantly lower in the patients with discrepant diagnoses (χ2=15.0, P=0.001). Logistic regression with backward selection revealed that for the discrepant diagnosis of patients, the presence of other concurrent autoimmune diseases [odds ratio (OR)=7.25; P=0.018; 95% confidence interval (CI), 1.41-37.29] was the only independent risk factor. In addition, the presence of anti-soluble liver antigen/liver-pancreas antigen (SLA/LP) or perinuclear antineutrophil cytoplasmic antibody (pANCA) (OR=0.12; P=0.022; 95% CI, 0.02-0.74), the level of immunoglobulin G (IgG) with 1-1.1 × Normal (N) (OR=0.02; P=0.044; 95% CI, 0.00-0.89) and ANA or SMA titers ≥1:80 (OR=0.04; P=