Publications by authors named "Jidong Jia"

198 Publications

Pradefovir Treatment in Patients with Chronic Hepatitis B: Week 24 Results from a Multicenter, Double-blind, Randomized, Noninferiority, Phase 2 Trial.

Clin Infect Dis 2021 Sep 6. Epub 2021 Sep 6.

Department of Quality management, The 5th medical center of Chinese PLA General Hospital, Beijing, China.

Objectives: Pradefovir is a liver-targeted prodrug of adefovir, a nucleotide analog with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30mg, 45mg, 60mg, and 75mg) versus tenofovir disoproxil fumarate (TDF; 300mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study.

Methods: Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible.

Results: A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were HBeAg positive and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/ml with pradefovir doses of 30mg, 45mg, 60mg, and 75mg, respectively, compared to 5.12 log10 IU/ml with TDF. However, HBeAg loss was attained by more participants who received 45mg, 60mg or 75mg pradefovir than those receiving TDF (12%, 6%, 9% vs. 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30mg or 45mg groups, and serum phosphate levels were comparable among all groups. Most adverse events were mild (grade 1). No treatment-related severe adverse events were reported. Overall, adverse events and laboratory abnormalities were comparable to the TDF group.

Conclusions: Pradefovir exhibited comparable reductions in HBV DNA levels to TDF. All treatments were safe and well tolerated.
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http://dx.doi.org/10.1093/cid/ciab763DOI Listing
September 2021

Prevention of Mother-to-Child Transmission of Hepatitis B Virus in the Western Pacific Region.

Clin Liver Dis (Hoboken) 2021 Jul 30;18(1):18-21. Epub 2021 Aug 30.

Liver Research Center Beijing Friendship Hospital Capital Medical University Beijing China.

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http://dx.doi.org/10.1002/cld.1096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405051PMC
July 2021

Impact of Kasai procedure and the length of native liver survival time on outcomes of liver transplantation for biliary atresia.

Liver Transpl 2021 Sep 5. Epub 2021 Sep 5.

Liver Transplant Center, Clinical Center for Pediatric liver transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.

Objective: To explore the impact of the Kasai procedure (KP) and the length of native liver survival time (NLST) on outcomes of liver transplantation (LT).

Methods: Patients with biliary atresia (BA), who underwent LT in Beijing Friendship Hospital from January 2017 to December 2019, were enrolled and divided into non-KP (N-KP) and post-KP (P-KP) groups. The patients in the P-KP group were further divided into early failure (KP-EF) defined by NLST <1 year, medium failure (KP-MF; NLST 1-5 years), and late failure (KP-LF, NLST >5 years) subgroups. Clinical data at the baseline and during follow-up were collected. The inverse probability of treatment weighting method was used to evaluate the independent effect of KP and the length of NLST on clinical outcomes.

Results: Among 197 BA cases, N-KP group accounted for 43 (21.8%), KP-EF 71 (46.1%), KP-MF 59 (38.3%) and KP-LF 24 (15.6%) cases, respectively. Patients in the N-KP and KP-EF groups had the least growth and development, the worst liver function reserve, and the highest pediatric end-stage liver disease (PELD) score prior to LT (all p<0.001). The N-KP and KP-EF groups had significantly longer hospitalization and intensive care unit (ICU) stay post LT. Graft and overall-survival rates were both 93.0% in N-KP and 97.4% in P-KP groups, respectively. The mortality in P-KP groups was significantly lower compared to that of N-KP group with a hazard ratio (HR) of 0.2 (p=0.002). The risks of biliary and vascular complications and cytomegalovirus (CMV) infection post LT were significantly higher in KP-EF group than those in KP-MF and KP-LF groups (HR= 0.09, 0.16 and 0.27; all p<0.05).

Conclusion: The KP significantly improves post LT overall survival. Patients with early native liver failure after KP have significantly higher risks for biliary and vascular complications and CMV infection.
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http://dx.doi.org/10.1002/lt.26287DOI Listing
September 2021

Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma.

Cell Adh Migr 2021 Dec;15(1):249-260

Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

MarvelD3, a recently identified tight junction membrane protein, could be associated with hepatocellular carcinoma (HCC). We aimed to investigate the role of marvelD3 in Epithelial-Mesenchymal Transition (EMT) and migration of HCC and explore the underlying molecular mechanisms. First, we assessed marvlD3 expression in HCC and normal liver tissues and found loss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. Second, we detected that marvelD3 was downregulated in HCC cells with transforming growth factor β1 and snail/slug-induced EMT. Finally, we analyzed expression of marvelD3 protein was significantly associated with EMT and the NF-κB signaling pathway. Our study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells along with inhibiting NF-κB signaling pathway. , Hepatocellular carcinoma; , Tight junction; , MAL and related proteins for vesicle trafficking and membrane link; , Epithelialmesenchymal transition; , Nuclear factor kappa B; , Tight junction-associated marvel proteins; , Transforming growth factor-β1; , matrix metallopeptidase 9; , Real-time PCR; , Immunohistochemistry; , Immunofluorescence.
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http://dx.doi.org/10.1080/19336918.2021.1958441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331009PMC
December 2021

3-year Treatment of Tenofovir Alafenamide . Tenofovir Disoproxil Fumarate for Chronic HBV Infection in China.

J Clin Transl Hepatol 2021 Jun 28;9(3):324-334. Epub 2021 Apr 28.

The Sixth People's Hospital of Shenyang, Shenyang, Liaoning, China.

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 log 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 <29 IU/mL was similar among the two groups, with TAF at 83% vs. TDF at 79%, and TAF at 93% vs. TDF at 92% for the HBeAg-positive and -negative patients, respectively. In each study, higher proportions of TAF than TDF patients showed normalized alanine aminotransferase (via the American Association for the Study of Liver Diseases and the China criteria) and showed loss of HBsAg; meanwhile, the HBeAg seroconversion rates were similar. Treatment was well-tolerated among the TAF patients, who showed a smaller median decline in creatinine clearance (-0.4 vs. -3.2 mL/min; =0.014) and less percentage change in bone mineral density vs. TDF at hip (-0.95% vs. -1.93%) and spine (+0.35% vs. -1.40%).

Conclusions: In chronic hepatitis B patients from China, TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.
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http://dx.doi.org/10.14218/JCTH.2020.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237145PMC
June 2021

Association of central obesity with hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

Aliment Pharmacol Ther 2021 08 22;54(3):329-338. Epub 2021 Jun 22.

Guangzhou, China.

Background: Obesity is typically associated with metabolic dysfunction, but its impact on hepatocellular carcinoma (HCC) remains unclear in patients with chronic hepatitis B (CHB).

Aim: To study the effect of obesity on HCC development in patients with CHB receiving antiviral therapy.

Methods: We included patients from a Chinese multicentre, prospective, observational, treated CHB cohort in this study. General obesity was evaluated by body-mass index (BMI). Central obesity was evaluated by waist circumference, waist-to-hip ratio and waist-to-height ratio.

Results: A total of 5754 nucleos(t)ide analogue treated patients were enrolled in the analysis. The 5-year cumulative incidence of HCC was 2.9%. Waist-to-height ratio performed better in predicting HCC development than BMI, waist circumference or waist-to-hip ratio. Patients with central obesity (defined as waist-to-height ratio >0.5) had significantly higher 5-year incidence of HCC than those without central obesity in the overall population (3.9% vs 2.1%, hazard ratio [HR]: 2.06, P = 0.0001) and 745 propensity score matched pairs (4.7% vs 2.3%, HR: 2.04, P = 0.026), respectively. Besides cirrhosis status and aMAP HCC risk score, central obesity was also independently associated with HCC risk (HR: 1.63, P = 0.013). Waist-to-height ratio gain within 1 year was associated with a significantly higher HCC risk with an adjusted HR value of 1.88 (95% confidence interval: 1.12-3.13, P = 0.017).

Conclusions: Central obesity, evaluated by the waist-to-height ratio, was associated with a twofold increase in HCC risk among CHB patients receiving antiviral treatment, highlighting the important role of abnormal metabolic function in the progression of liver disease.
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http://dx.doi.org/10.1111/apt.16469DOI Listing
August 2021

Nondegradable Collagen Increases Liver Fibrosis but Not Hepatocellular Carcinoma in Mice.

Am J Pathol 2021 09 11;191(9):1564-1579. Epub 2021 Jun 11.

Department of Medicine, University of California San Diego, San Diego, California. Electronic address:

Although hepatocellular cancer (HCC) usually occurs in the setting of liver fibrosis, the causal relationship between liver fibrosis and HCC is unclear. in vivo and in vitro models of HCC involving Col mice (that produce a collagenase-resistant type I collagen) or wild-type (WT) mice were used to assess the relationship between type I collagen, liver fibrosis, and experimental HCC. HCC was either chemically induced in WT and Col mice or Hepa 1-6 cells were engrafted into WT and Col livers. The effect of hepatic stellate cells (HSCs) from WT and Col mice on the growth of Hepa 1-6 cells was studied by using multicellular tumor spheroids and xenografts. Collagen type I deposition and fibrosis were increased in Col mice, but they developed fewer and smaller tumors. Hepa 1-6 cells had reduced tumor growth in the livers of Col mice. Although Col HSCs exhibited a more activated phenotype, Hepa 1-6 growth and malignancy were suppressed in multicellular tumor spheroids and in xenografts containing Col HSCs. Treatment with vitronectin, which mimics the presence of degraded collagen fragments, converted the Col phenotype into a WT phenotype. Although Col mice have increased liver fibrosis, they exhibited decreased HCC in several models. Thus, increased liver type I collagen does not produce increased experimental HCC.
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http://dx.doi.org/10.1016/j.ajpath.2021.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406794PMC
September 2021

The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease.

J Hepatol 2021 Aug 19;75(2):454-461. Epub 2021 May 19.

Department of Infectious Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.

Fatty liver disease associated with metabolic dysfunction is of increasing concern in mainland China, the world's most populous country. The incidence of fatty liver disease is highest in China, surpassing the incidence in European countries and the USA. An international consensus panel recently published an influential report recommending a novel definition of fatty liver disease associated with metabolic dysfunction. This recommendation includes a switch in name from non-alcoholic fatty liver disease (NAFLD) to metabolic (dysfunction)-associated fatty liver disease (MAFLD) and adoption of a set of positive criteria for disease diagnosis that are independent of alcohol intake or other liver diseases. Given the unique importance of this proposal, the Chinese Society of Hepatology (CSH) invited leading hepatologists and gastroenterologists representing their respective provinces and cities to reach consensus on alternative definitions for fatty liver disease from a national perspective. The CSH endorses the proposed change from NAFLD to MAFLD (supported by 95.45% of participants). We expect that the new definition will result in substantial improvements in health care for patients and advance disease awareness, public health policy, and political, scientific and funding outcomes for MAFLD in China.
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http://dx.doi.org/10.1016/j.jhep.2021.05.003DOI Listing
August 2021

Hepatic stellate cells-specific LOXL1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice.

Hepatol Int 2021 May 20. Epub 2021 May 20.

Liver Research Center, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong'an Road, Xicheng District, Beijing, 100050, People's Republic of China.

Background And Aims: Lysyl oxidase-like-1 (LOXL1), a vital cross-linking enzyme in extracellular matrix (ECM) maintenance, promotes fibrosis via enhancement of ECM stability. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied.

Methods: We generated Loxl1 mice to selectively delete LOXL1 in hepatic stellate cells (HSCs) (Loxl1Gfap; Loxl1 as littermate controls) and then examined liver pathology and metabolic profiles in Loxl1Gfap fed with either a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. Thereafter, the findings from the animal model were confirmed in 23 patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD).

Results: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with the control diet, and LOXL1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes in the HSCs-specific LOXL1 knockout mice model. Interestingly, LOXL1 deficient in HSCs could attenuate hepatic steatosis and reverse the metabolic disorder by restoring adipose tissue function without altering the effect of hepatic lipogenesis gene expression in non-obese NASH model. More importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas it was inversely correlated with leptin levels, especially in non-obese NAFLD patients.

Conclusion: LOXL1 may contribute to fibrosis progression in non-obese NAFLD, and HSCs-specific knockout of LOXL1 attenuated liver steatosis, inflammation, fibrosis, , and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.
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http://dx.doi.org/10.1007/s12072-021-10210-wDOI Listing
May 2021

Comparison of fibrosis regression of entecavir alone or combined with pegylated interferon alpha2a in patients with chronic hepatitis B.

Hepatol Int 2021 Jun 7;15(3):611-620. Epub 2021 Mar 7.

Liver Research Center, Beijing Key Laboratory of Translational Medicine On Liver Cirrhosis, Beijing Friendship Hospital, National Clinical Research Center of Digestive Diseases, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.

Background And Aims: Antiviral treatment with necleos(t)ide analogues contributes to histological improvement and virologic response in chronic hepatitis B (CHB) patients. However, whether adding pegylated interferon alpha2a (Peg-IFN-α-2a) can help additional clinical benefit, particularly on fibrosis regression was still unknown.

Methods: Chronic hepatitis B patients with pre-treatment biopsy-proven Ishak fibrosis score 2, 3 or 4 were randomly assigned to entecavir (ETV) alone or ETV plus Peg-IFN-α-2a (Peg-IFN-α-2a add-on) group (1:2 ratio). Post-treatment liver biopsy was performed at week 78. Fibrosis regression was defined as decrease in Ishak fibrosis score by ≥ 1 stage or predominantly regressive categorized by P-I-R score. Serum HBV DNA levels were assessed at baseline and every 26 weeks, while HBsAg and HBeAg were evaluated at baseline and every 52 weeks.

Results: A total of 218 treatment-naive CHB patients were randomly assigned to ETV alone or Peg-IFN-α-2a add-on group. Totals of 155 patients (ETV alone: Peg-IFN-α-2a add-on, 47:108) were included in statistical analysis. Fibrosis regression rates were 68% (32/47) in the ETV alone and 56% (60/108) in Peg-IFN-α-2a add-on group (p = 0.144). Both groups showed a similar trend of virological suppression during the process of 104-week antiviral therapy (p = 0.132). HBeAg or HBsAg loss or seroconversion rates in the ETV alone group were lower than Peg-IFN-α-2a add-on group though without statistical significance.

Conclusions: Peg-IFN-α-2a add-on therapy did not yield additional fibrosis regression and virologic response than ETV alone therapy.
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http://dx.doi.org/10.1007/s12072-021-10162-1DOI Listing
June 2021

Hepatocellular Carcinoma Prediction Models in Chronic Hepatitis B: A Systematic Review of 14 Models and External Validation.

Clin Gastroenterol Hepatol 2021 Mar 3. Epub 2021 Mar 3.

National Clinical Research Center of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, Mainland China; Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background & Aims: The aim of our study was to characterize the performance of hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients through meta-analysis followed by external validation.

Methods: We performed a systematic review and meta-analysis of current literature, followed by external validation in independent multi-center cohort with 986 patients with CHB undergoing entecavir treatment (median follow-up: 4.7 years). Model performance to predict HCC within 3, 5, 7, and 10 years was assessed using area under receiver operating characteristic curve (AUROC) and calibration index. Subgroup analysis were conducted by treatment status, cirrhotic, race and baseline alanine aminotransferase.

Results: We identified 14 models with 123,885 patients (5,452 HCC cases), with REACH-B, CU-HCC, GAG-HCC, PAGE-B and mPAGE-B models being broadly externally validated. Discrimination was generally acceptable for all models, with pooled AUC ranging from 0.70 (95% CI, 0.63-0.76 for REACH-B) to 0.83 (95% CI, 0.78-0.87 for REAL-B) for 3-year, 0.68 (95% CI, 0.64-0.73 for REACH-B) to 0.81 (95% CI, 0.77-0.85 for REAL-B) for 5-year and 0.70 (95% CI, 0.58-0.80 for PAGE-B) to 0.81 (95% CI, 0.78-0.84 for REAL-B and 0.77-0.86 for AASL-HCC) for 10-year prediction. However, calibration performance was poorly reported in most studies. In external validation cohort, REAL-B showed highest discrimination with 0.76 (95% CI, 0.69-0.83) and 0.75 (95% CI, 0.70-0.81) for 3 and 5-year prediction. The REAL-B model was also well calibrated in the external validation cohort (3-year Brier score 0.066). Results were consistent in subgroup analyses.

Conclusions: In a systematic review of available HCC models, the REAL-B model exhibited best discrimination and calibration.
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http://dx.doi.org/10.1016/j.cgh.2021.02.040DOI Listing
March 2021

Seraprevir and sofosbuvir for treatment of chronic hepatitis C virus infection: A single-arm, open-label, phase 3 trial.

J Gastroenterol Hepatol 2021 Sep 2;36(9):2375-2382. Epub 2021 Feb 2.

Cirrhosis Department, Zhengzhou Sixth Municipal People's Hospital, Zhengzhou, China.

Background And Aim: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis.

Methods: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12).

Results: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention.

Conclusions: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.
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http://dx.doi.org/10.1111/jgh.15412DOI Listing
September 2021

Prediction of liver-related events in patients with compensated HBV-induced cirrhosis receiving antiviral therapy.

Hepatol Int 2021 Feb 18;15(1):82-92. Epub 2021 Jan 18.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China.

Background And Aims: Many models have been developed to predict liver-related events (LRE) in chronic hepatitis B, few focused on compensated HBV-induced cirrhosis. We aimed to describe the incidence of LRE and to determine independent risk predictors of LRE in compensated HBV-induced cirrhosis patients receiving antiviral therapy using routinely available parameters.

Methods: Prospective cohorts of treatment-naïve adults with compensated HBV-induced cirrhosis were enrolled. Patients were treated with entecavir (ETV) or ETV + thymosin-alpha1 (Thy-α1) or lamivudine (LAM) + adefovir (ADV). Data were collected at baseline and every 6 months. LRE was defined as development of decompensation, HCC or death.

Results: Totally 937 patients were included, 608 patients treated with ETV, 252 with ETV + Thy-α1, and 77 with LAM + ADV. After a median follow-up of 4.5 years, 88 patients developed LRE including 48 with HCC. The cumulative incidence of LRE at year 1, 3, and 5 was 2.1%, 7.0%, and 12.7%, respectively, and was similar for three treatment groups. All models using variables at month 6 or 12 had better fit than models using baseline values. The best model for prediction of LRE used PLT, GGT, and AFP at month 6 [AUC: 0.762 (0.678-0.814)], for hepatic decompensation-PLT, LSM and GGT at month 12 (AUC: 0.834 (0.675-0.919)), and for HCC-AFP and GGT at month 6 [AUC 0.763 (0.691-0.828)]. All models had negative predictive values of 94.0-98.8%.

Conclusion: Models using on-treatment variables are more accurate than models using baseline variables in predicting LRE in patient with compensated HBV-induced cirrhosis receiving antiviral therapy. ClincialTrials.gov number NCT01943617, NCT01720238, NCT03366571, NCT02849132.
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http://dx.doi.org/10.1007/s12072-020-10114-1DOI Listing
February 2021

Enhanced Two-Photon Absorption of Cross-Conjugated Chalcone Derivatives: Modulation of the Effective π-Conjugated Structure.

J Phys Chem A 2020 Dec 15;124(51):10808-10816. Epub 2020 Dec 15.

Department of Physics, Harbin Institute of Technology, Harbin 150001, China.

Three cross-conjugated chalcone derivatives , , and were designed and synthesized to develop excellent organic nonlinear optical (NLO) materials. In a Z-scan experiment, all compounds show good NLO absorption characteristics in the visible to near-infrared region. The photophysical mechanism is confirmed to be two-photon absorption (TPA)-induced excited-state absorption (ESA). Intramolecular charge transfer (ICT) observed in transient absorption spectra (TAS) significantly affects molecular NLO properties. We define the π-conjugated system that dominates the electron transition process in the cross-conjugated structure as the effective π-conjugated structure. Electron transition analysis shows a sufficiently strong ICT can effectively expand the effective π-conjugated structure in these cross-conjugated structures. The TPA cross sections of these compounds at 650 and 750 nm are only in the range of 17-97 GM. However, we achieve a significant enhancement of the TPA cross section at 580 nm (1737-2027 GM) by extending the effective π-conjugated structure. Excited by 580 nm femtosecond laser pulses, all compounds exhibit excellent OL performance and the minimum OL threshold is 4.71 × 10 J/cm. The results show that these cross-conjugated chalcone derivatives have promising applications in OL, and their NLO performance can be effectively improved by modulating the effective π-conjugated structure.
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http://dx.doi.org/10.1021/acs.jpca.0c08656DOI Listing
December 2020

Screening varices in patients with HBV-related cirrhosis on antiviral therapy: Platelet alone or together with LSM.

Liver Int 2021 02 18;41(2):369-377. Epub 2020 Dec 18.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis, National Clinical Research Center for Digestive Diseases, Beijing, China.

Background & Aims: Non-invasive assessment criteria to rule out high-risk varices (HRV) in compensated hepatitis B virus (HBV) cirrhosis on antiviral therapy remains unclear.

Methods: HBV-related compensated cirrhotic patients who underwent screening endoscopy during antiviral therapy were enrolled and randomly divided into the derivation and validation sets. HRV were defined as medium to large varices or small varices with red signs. Univariate and multivariate logistic analysis were used to determine the parameters associated with HRV.

Results: A total of 436 HBV-related compensated cirrhotic patients screened for varices were enrolled, the median duration of antiviral therapy was 4 years (IQR: 2.5-5.5 years). In the derivation set (N = 290, 17.2% with HRV), only platelet (PLT) count (OR = 0.972, 95% CI 0.961-0.984, P < .05) was independently associated with HRV, whereas liver stiffness measurement was not associated with the presence of HRV. With a PLT count cut-off value of 105 × 10 /L, unnecessary endoscopies could be spared in 56.9% patients, with a 3.6%. risk of missing HRV. In the validation cohort (N = 146, 16.4% with HRV), the proportion of patients that could safely spare endoscopies (61.0%) identified by this PLT count cut-off value was higher than that obtained by using Baveno VI criteria (34.9%), with an acceptable risk of missing HRV (3.4%).

Conclusion: Compared with the 'Baveno VI criteria or beyond' criteria, PLT count higher than 105 × 10 /L could safely spare more screening endoscopies without increasing the risk of missing HRV in patients with HBV-related compensated cirrhosis on antiviral therapy.
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http://dx.doi.org/10.1111/liv.14752DOI Listing
February 2021

Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: a phase III clinical trial.

BMC Gastroenterol 2020 Nov 19;20(1):391. Epub 2020 Nov 19.

School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China.

Background: To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics.

Methods: In the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint.

Results: The administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P = 0.05, P = 0.002 and P = 0.037, P = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543).

Conclusions: Tolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic.

Trial Registration: NCT01349348. Retrospectively registered May 2011.
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http://dx.doi.org/10.1186/s12876-020-01536-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678173PMC
November 2020

Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis.

J Gastroenterol Hepatol 2021 Jun 6;36(6):1423-1434. Epub 2020 Dec 6.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Disease, Beijing, China.

Background And Aim: We aimed to estimate the worldwide incidence and prevalence, with focus on the geographical differences and temporal trends.

Methods: Studies on epidemiology of primary biliary cholangitis (PBC) in PubMed, Embase, and Cochrane Library were systematically retrieved from inception to October 2, 2020. Random-effect model was applied to estimate the pooled PBC incidence and prevalence rates. Subgroup analysis, meta-regression, and sensitivity analysis were conducted to find out the cause for heterogeneity.

Results: Out of 3974 records identified through database searching, 47 population-based studies were finally included. The pooled global incidence and prevalence of PBC were 1.76 and 14.60 per 100 000 persons, respectively. Both the PBC incidence and prevalence were lower in the Asia-Pacific region (0.84, 9.82 per 100 000 persons) than that in North America (2.75, 21.81 per 100 000 persons) and Europe (1.86, 14.59 per 100 000 persons) (P < 0.05). The incidence and prevalence showed an increasing tendency in all three regions, with the fastest growth of prevalence in North America (P < 0.05). We found a similar incidence and a lower prevalence of PBC in Northern Europe than that in Southern Europe. A higher incidence and prevalence were observed in female individuals and in the elderly (60-79).

Conclusion: The PBC incidence and prevalence varied widely across regions, with North America being the highest, followed by Europe, and the lowest in the Asia-Pacific region. Both the incidence and prevalence showed an increasing tendency worldwide, especially in North America.
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http://dx.doi.org/10.1111/jgh.15329DOI Listing
June 2021

Purinergic signalling in liver diseases: Pathological functions and therapeutic opportunities.

JHEP Rep 2020 Dec 30;2(6):100165. Epub 2020 Jul 30.

Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation & National Clinical Research Center for Digestive Diseases, Beijing 100050, China.

Extracellular nucleotides, including ATP, are essential regulators of liver function and serve as danger signals that trigger inflammation upon injury. Ectonucleotidases, which are expressed by liver-resident cells and recruited immune cells sequentially hydrolyse nucleotides to adenosine. The nucleotide/nucleoside balance orchestrates liver homeostasis, tissue repair, and functional restoration by regulating the crosstalk between liver-resident cells and recruited immune cells. In this review, we discuss our current knowledge on the role of purinergic signals in liver homeostasis, restriction of inflammation, stimulation of liver regeneration, modulation of fibrogenesis, and regulation of carcinogenesis. Moreover, we discuss potential targeted therapeutic strategies for liver diseases based on purinergic signals involving blockade of nucleotide receptors, enhancement of ectonucleoside triphosphate diphosphohydrolase activity, and activation of adenosine receptors.
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http://dx.doi.org/10.1016/j.jhepr.2020.100165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575885PMC
December 2020

Long-term outcomes in Chinese patients with chronic hepatitis B receiving nucleoside/nucleotide analogue therapy in real-world clinical practice: 5-year results from the EVOLVE study.

Antivir Ther 2020 ;25(6):293-304

Bristol-Myers Squibb, Shanghai, China.

Background: In China, the optimal management of individuals living with chronic HBV infection (CHB) remains an unmet need. The EVOLVE Study was a 5-year prospective, longitudinal, observational study that compared the clinical outcomes in treatment-naive CHB patients receiving entecavir (ETV) or lamivudine (LAM)-based therapies.

Methods: Males or females aged ≥18 years, diagnosed with CHB regardless of cirrhosis or hepatitis B e antigen (HBeAg) status were enrolled from tier 2 city hospitals (between 2012-2014). The choice of initial therapy and subsequent treatment modifications was at the discretion of treating physicians. Key outcomes included treatment modifications, virological response (HBV DNA <300 copies/ml) and HBV disease progression.

Results: Of the 3,408 patients enrolled, 1,807 and 628 received ETV and LAM-based therapy, respectively. The mean age was 39.5 years, 74% were male and 22.9% had cirrhosis. The rate of treatment modification was higher in the LAM-based versus ETV group (25.9% versus 13.7%); viral breakthrough was the most common reason in the LAM-based group versus financial reasons in the ETV group. At week 240, the virological response rate was 73% in both treatment groups. Compared with LAM-based therapy, ETV was associated with a significantly lower incidence of viral breakthrough (12.6% versus 2.1%) and genotypic resistance (10.1% versus 1.2%; P<0.0001 for both); significantly lower risk of HBV disease progression (14.0% versus 10.7%; P=0.0113); and lower rates of progression to decompensated cirrhosis (9.6% versus 6.4%) and hepatocellular carcinoma (1.9% versus 0.8%).

Conclusions: This real-world, longitudinal study demonstrated a significantly lower risk of HBV-related disease progression, viral breakthrough and resistance with ETV versus LAM-based therapy. ClinicalTrials.gov NCT01726439.
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http://dx.doi.org/10.3851/IMP3372DOI Listing
January 2020

Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis.

J Clin Transl Hepatol 2020 Sep 11;8(3):255-261. Epub 2020 Sep 11.

Department of Infectious Diseases, Wuhan central hospital, Wuhan, Hubei, China.

Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety. We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment. Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy. The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.
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http://dx.doi.org/10.14218/JCTH.2020.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562795PMC
September 2020

Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single-arm, open-label, phase 3 trial.

Liver Int 2020 11 13;40(11):2685-2693. Epub 2020 Oct 13.

Department of Hepatology, the First Hospital of Jilin University, Changchun, China.

Background & Aim: An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection.

Methods: Treatment-naïve and interferon-experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12).

Results: Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty-one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow-up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention.

Conclusions: The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis.

Lay Summary: The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.
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http://dx.doi.org/10.1111/liv.14633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702130PMC
November 2020

East Asia expert opinion on treatment initiation for chronic hepatitis B.

Aliment Pharmacol Ther 2020 11 20;52(10):1540-1550. Epub 2020 Sep 20.

Hong Kong, SAR, China.

Background: Globally, chronic hepatitis B (CHB) is a major public health concern. Timely and effective management can prevent disease progression to cirrhosis and reduce the risk of hepatocellular carcinoma (HCC). Currently, there is no consensus on the clinical management of CHB in East Asia.

Aim: To establish an East Asia expert opinion on treatment initiation for CHB based on alanine aminotransferase (ALT) level, hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level, cirrhosis and HCC risk scores.

Methods: A meeting was held online with a panel of 10 experts from East Asia to discuss ALT, HBV DNA, cirrhosis and HCC risk scores. Indications for CHB treatment in the latest international guidelines were reviewed. Consensus was summarised to provide recommendations on the initiation of treatment for CHB.

Results: Anti-viral therapy is recommended for CHB patients with (a) HBV DNA ≥ 2000 IU/mL and ALT ≥ 1× upper limit of normal (ULN); (b) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and ≥ F2 fibrosis and/or ≥ A2 necroinflammation occurs; (c) cirrhosis and detectable HBV DNA; or (d) HBV DNA ≥ 2000 IU/mL, ALT < 1× ULN and a family history of cirrhosis or HCC, extrahepatic manifestations or age > 40 years. Patients with cirrhosis and/or HCC should be treated regardless of ALT levels if HBV DNA level is detectable. Initiating anti-viral therapy or close monitoring at 3-month intervals is recommended for CHB patients with at least two HCC risk factors.

Conclusions: These expert recommendations will contribute to a new standard of daily clinical practice in East Asia.
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http://dx.doi.org/10.1111/apt.16097DOI Listing
November 2020

2018 Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C in Chronic Kidney Disease Guideline Implementation: Asia Summit Conference Report.

Kidney Int Rep 2020 Aug 21;5(8):1129-1138. Epub 2020 May 21.

Kidney Disease: Improving Global Outcomes (KDIGO), Brussels, Belgium.

In 2018, Kidney Disease: Improving Global Outcomes (KDIGO) published a clinical practice guideline on the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection in chronic kidney disease (CKD). The guideline synthesized recent advances, especially in HCV therapeutics and diagnostics, and provided clinical recommendations and suggestions to aid healthcare providers and improve care for CKD patients with HCV. To gain insight into the extent that the 2018 guideline has been adopted in Asia, KDIGO convened an HCV Implementation Summit in Hong Kong. Participants included nephrologists, hepatologists, and nurse consultants from 8 Southeast Asian countries or regions with comparable high-to-middle economic ranking by the World Bank: mainland China, Hong Kong, Japan, Malaysia, Singapore, South Korea, Taiwan, and Thailand. Through presentations and discussions, meeting participants described regional practice patterns related to the KDIGO HCV in CKD guideline, identified barriers to implementing the guideline, and developed strategies for overcoming the barriers in Asia and around the world.
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http://dx.doi.org/10.1016/j.ekir.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403514PMC
August 2020

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

J Hepatol 2020 12 21;73(6):1368-1378. Epub 2020 Jul 21.

Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, China.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.

Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).

Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%.

Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.

Lay Summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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http://dx.doi.org/10.1016/j.jhep.2020.07.025DOI Listing
December 2020

Glecaprevir-pibrentasvir to treat chronic hepatitis C virus infection in Asia: two multicentre, phase 3 studies- a randomised, double-blind study (VOYAGE-1) and an open-label, single-arm study (VOYAGE-2).

Lancet Gastroenterol Hepatol 2020 09 16;5(9):839-849. Epub 2020 Jul 16.

Department of Infectious Diseases and Hepatology Unit, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address:

Background: Glecaprevir-pibrentasvir results in high rates of sustained virological response in patients with chronic hepatitis C virus (HCV) genotype 1-6 infection. Data for glecaprevir-pibrentasvir in non-Japanese Asian patients have been minimal. The aim of these studies was to assess the efficacy and safety of glecaprevir-pibrentasvir in treatment-naive and treatment-experienced Asian patients with chronic HCV genotype 1-6 infection without cirrhosis (VOYAGE-1) and with compensated cirrhosis (VOYAGE-2).

Methods: We did two phase 3 studies in treatment-naive and treatment-experienced patients with chronic HCV genotype 1-6 infection. VOYAGE-1 was a randomised, double-blind, placebo-controlled study that recruited patients without cirrhosis at 47 sites across China, South Korea, and Singapore. Randomisation was 2:1 with a fixed block size of three and stratified by geographical region and HCV genotype. Investigators, study site personnel, the study sponsor, and patients were masked to treatment allocation. VOYAGE-2 was a single-arm, open-label study that recruited patients with compensated cirrhosis at 34 sites across China and South Korea. Glecaprevir (300 mg) and pibrentasvir (120 mg) or placebo (VOYAGE-1, 2:1 ratio), administered as three tablets daily, was given for 8 weeks in patients without cirrhosis and for 12 weeks in those with cirrhosis (and for 16 weeks in treatment-experienced patients with genotype 3). The primary efficacy endpoint was the proportion of patients with a sustained virological response, defined as HCV RNA below the lower limit of quantification 12 weeks after the last dose of glecaprevir-pibrentasvir. We analysed efficacy and safety in all patients who received at least one dose of the study drug. These trials are registered with ClinicalTrials.gov, NCT03222583 (VOYAGE-1) and NCT03235349 (VOYAGE-2); both trials have been completed. This Article reports the results of the primary analysis for each study, undertaken when all patients who received glecaprevir-pibrentasvir (during the double-blind period in VOYAGE-1) had been followed up for 12 weeks following their last dose of study drug. Data from the double-blind period for placebo patients in VOYAGE-1 are also summarised.

Findings: Between Oct 4, 2017, and April 20, 2018, 546 patients with chronic HCV without cirrhosis were randomly assigned to treatment (363 to glecaprevir-pibrentasvir, 183 to placebo) in VOYAGE-1. One patient withdrew consent and did not receive treatment with glecaprevir-pibrentasvir. 352 of 362 patients who received glecaprevir-pibrentasvir achieved SVR12 (97·2% [95% CI 95·5-98·9]). Of 160 patients with compensated cirrhosis who were enrolled in VOYAGE-2 between Sept 29, 2017, and June 14, 2018, 159 of 160 achieved SVR12 (99·4%, 95% CI 98·2-100·0). 20 patients with HCV genotype 3b across both trials received glecaprevir-pibrentasvir; six of these patients were among the 11 patients who did not achieve SVR12. Upper respiratory tract infection was the most common adverse event (35 [10%] of 362 receiving glecaprevir-pibrentasvir and 18 [10%] of 183 receiving placebo in VOYAGE-1; 19 [12%] of 160 in VOYAGE-2). For patients receiving glecaprevir-pibrentasvir, serious adverse events occurred in three (<1%) of 362 patients in VOYAGE-1 and five (3%) of 160 patients in VOYAGE-2. Grade 3-4 adverse events in patients receiving glecaprevir-pibrentasvir occurred in five (1%) of 362 patients in VOYAGE-1 and six (4%) of 160 patients in VOYAGE-2; each type of event was experienced by at most one patient within a study. One patient with cirrhosis discontinued study drug because of an adverse event.

Interpretation: Glecaprevir-pibrentasvir showed high efficacy and an acceptable safety profile in these studies although responses were less common in the few patients with HCV genotype 3b. The results support the use of glecaprevir-pibrentasvir in these Asian populations.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S2468-1253(20)30086-8DOI Listing
September 2020

A High Serum Level of Taurocholic Acid Is Correlated With the Severity and Resolution of Drug-induced Liver Injury.

Clin Gastroenterol Hepatol 2021 05 4;19(5):1009-1019.e11. Epub 2020 Jul 4.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China. Electronic address:

Background & Aims: Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 (ABCB11) gene and expression of its product, ABCB11 (also called BSEP).

Methods: We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n = 100; healthy controls) and patients with chronic hepatitis B (n = 105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP was analyzed by immunohistochemistry in liver biopsy specimens.

Results: Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71-0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids.

Conclusions: In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids.
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http://dx.doi.org/10.1016/j.cgh.2020.06.067DOI Listing
May 2021

Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement.

Lancet Gastroenterol Hepatol 2020 08 23;5(8):776-787. Epub 2020 Jun 23.

Department of Medicine and Therapeutics, and Medical Data Analytic Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address:

The COVID-19 pandemic has spread rapidly worldwide. It is common to encounter patients with COVID-19 with abnormal liver function, either in the form of hepatitis, cholestasis, or both. The clinical implications of liver derangement might be variable in different clinical scenarios. With growing evidence of its clinical significance, it would be clinically helpful to provide practice recommendations for various common clinical scenarios of liver derangement during the COVID-19 pandemic. The Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic was formed to systematically review the literature with special focus on the clinical management of patients who have been or who are at risk of developing liver derangement during this pandemic. Clinical scenarios covering the use of pharmacological treatment for COVID-19 in the case of liver derangement, and assessment and management of patients with chronic hepatitis B or hepatitis C, non-alcoholic fatty liver disease, liver cirrhosis, and liver transplantation during the pandemic are discussed.
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http://dx.doi.org/10.1016/S2468-1253(20)30190-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308747PMC
August 2020

Irradiated and CCl -treated bone marrow-derived liver macrophages exhibit different gene expression patterns and phenotypes.

Scand J Immunol 2020 Nov 2;92(5):e12916. Epub 2020 Sep 2.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.

Myeloid cells infiltrate into the liver and differentiate into macrophages in different liver injury mouse models. However, the heterogeneity of bone marrow (BM)-derived LMs populations remains to be understood. To investigate this and understand the impact of the macrophage niche on the properties of recruited BM-derived macrophages, we used a non-myeloablation BM transplantation model to label and trace BM-derived LMs. Subsequently, we quantified the number of embryonic-derived liver-resident macrophages, BM-derived LMs and total LMs in CCl and irradiated acute liver injury mouse models, respectively. Finally, we compared the cell fate, gene expression patterns, chemokine signals, and surface markers of irradiated and CCl -treated BM-derived LMs. We observed that, as compared to CCl radiation generated a macrophage niche by depleting embryonic-derived liver-resident macrophages and induced the recruitment of BM-derived LMs that further settled in the liver. Irradiated and CCl -treated BM-derived LMs are different with respect to their cell fates, gene expression patterns, and chemokine expression and recruitment. They also have different surface markers shortly after differentiating from their progenitors. Our findings suggest that irradiated and CCl -treated LM populations derived from the bone marrow display different patterns of gene expression and phenotypes; these differences may be due to the availability of macrophage niche.
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http://dx.doi.org/10.1111/sji.12916DOI Listing
November 2020

A Predictive Model Using N-Glycan Biosignatures for Clinical Diagnosis of Early Hepatocellular Carcinoma Related to Hepatitis B Virus.

OMICS 2020 07 9;24(7):415-423. Epub 2020 Jun 9.

Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Early diagnosis of hepatic cancer is a major public health challenge. While changes in serum N-glycans have been observed as patients progress from liver fibrosis/cirrhosis to hepatocellular carcinoma (HCC), the predictive performance of N-glycans is yet to be determined for HCC early diagnosis as well as differential diagnosis from liver fibrosis/cirrhosis. In a total sample of 247 patients with hepatitis B virus-related liver disease, we characterized and compared the serum N-glycans in very early/early and intermediate/advanced stages of HCC and those with liver fibrosis/cirrhosis. Additionally, we performed a retrospective timeline analysis of the serum N-glycans 6 and 12 months before a diagnosis of the very early/early stage of HCC (EHCC). A predictive model was built, named hereafter as Glycomics-EHCC, incorporating the glycan peaks (GPs) 1, 2, and 4. The model showed a larger area under the receiver operating characteristic curve compared with a traditional model with the α-fetoprotein (0.936 vs. 0.731, respectively). The Glycomics-EHCC model had a sensitivity of 84.6% and specificity of 85.0% at a cutoff value of -0.39 to distinguish EHCC from liver fibrosis/cirrhosis. Moreover, the Glycomics-EHCC model was able to forecast a future EHCC diagnosis with a sensitivity and specificity over 90% and 85%, respectively, using the serum N-glycan biosignatures 6 or 12 months earlier when the patients were suffering from liver fibrosis/cirrhosis before being diagnosed with EHCC. This serum glycomic biosignature model warrants further clinical studies in independent population samples and offers promise to forecast EHCC and its differential diagnosis from liver fibrosis/cirrhosis.
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http://dx.doi.org/10.1089/omi.2020.0055DOI Listing
July 2020
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