Publications by authors named "Xieer Liang"

15 Publications

  • Page 1 of 1

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

Aliment Pharmacol Ther 2021 Aug 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

Methodology-dependent performance of serum HBV RNA in predicting treatment outcomes in chronic hepatitis B patients.

Antiviral Res 2021 05 10;189:105037. Epub 2021 Mar 10.

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

Background: Whether different serum HBV RNA detection assays can consistently predict treatment outcomes in patients with chronic hepatitis B remains controversial.

Methods: We enrolled 188 patients who had stopped nucleos(t)ide analogues (NAs) (STOP cohort-1, -2) and 78 receiving entecavir (ETV) therapy (ETV cohort) and used double-target (targeting both 5' and 3' ends of the HBV pregenome RNA [DT-RNA]) and three single-target (targeting the S-region [S-RNA], X-region [X-RNA], and poly-A tail of HBV RNA [PolyA-RNA]) assays to predict treatment outcomes.

Results: In STOP cohorts, DT-RNA, S-RNA and X-RNA at NAs cessation showed higher predictive powers for clinical relapse (time-dependent areas under the curve [AUCs] for years 1, 2, 3, and 4 ranged between 0.724 and 0.772 in cohort-1, and between 0.741 and 0.824 in cohort-2) than the PolyA-RNA (AUCs between 0.604 and 0.611 in cohort-1; and between 0.530 and 0.584 in cohort-2). The predictive power for 2-year HBeAg loss of the four targeted RNAs in the ETV cohort at 6 months were similar (AUCs, 0.848, 0.838, 0.825, and 0.801), and superior to that of the HBV DNA level at 6 months (AUC, 0.721).

Conclusion: The outcome prediction performance of serum HBV RNAs is methodology-dependent. PolyA-RNA detection was not recommended to predict off-treatment relapses.
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http://dx.doi.org/10.1016/j.antiviral.2021.105037DOI Listing
May 2021

Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues.

Aliment Pharmacol Ther 2020 08 1;52(4):692-700. Epub 2020 Jul 1.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background: Serum hepatitis B virus (HBV) RNA is a novel biomarker for evaluating treatment response. Detailed information regarding serum HBV RNA kinetics during treatment with nucleos(t)ide analogues (NAs) is limited.

Aims: To ascertain serum HBV RNA kinetics during long-term NA treatment and identify associated factors.

Methods: We enrolled 76 HBeAg-positive chronic hepatitis B patients receiving NA from randomised controlled trials. Laboratory assays were undertaken every 3 months. Factors associated with serum HBV RNA kinetics were identified by generalised estimating equations.

Results: Baseline serum HBV RNA was 8.5 ± 1.0 log  copies/mL. Decline in serum HBV RNA during NA therapy was biphasic: the first phase (HBV DNA detectable) had a fast decrease (median slope, -0.207 log  copies/mL/month) and was followed by a second phase (HBV DNA undetectable) with slow decrease (median slope, -0.071 log  copies/mL/month). In the first phase, factors independently associated with lower initial serum HBV RNA were male sex (OR, 0.685, P = 0.044), low baseline HBsAg (OR, 0.525, P = 0.001) and rapid virological response (RVR) (OR, 0.624, P = 0.031). In the second phase, only RVR was independently associated with serum HBV RNA kinetics, including its lower initial level (OR, 0.694, P = 0.043) and greater decline (OR, 0.966, P = 0.002). Based on viral dynamics, time needed to achieve undetectable serum HBV RNA from baseline was 43.56 (IQR: 29.49-66.40) months.

Conclusion: RVR was a significant determinant for biphasic decline in serum HBV RNA during NA treatment, which significantly influenced the treatment duration required to achieve undetectable serum HBV RNA.
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http://dx.doi.org/10.1111/apt.15890DOI Listing
August 2020

A missense variant in complement factor B (CFB) is a potential predictor of 24-week off-treatment response to PegIFNα therapy in Chinese HBeAg-positive chronic hepatitis B patients.

Aliment Pharmacol Ther 2020 02 14;51(4):469-478. Epub 2020 Jan 14.

GuangZhou, China.

Background: To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB).

Aim: To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients.

Methods: We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed.

Results: We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients.

Conclusions: CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.
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http://dx.doi.org/10.1111/apt.15624DOI Listing
February 2020

Development and validation of a model for hepatitis B e antigen seroconversion in entecavir-treated patients with chronic hepatitis B.

J Med Virol 2020 08 21;92(8):1206-1213. Epub 2019 Nov 21.

Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg-positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5-years ETV therapy in patients with CHB.
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http://dx.doi.org/10.1002/jmv.25628DOI Listing
August 2020

Quantifying and monitoring fibrosis in non-alcoholic fatty liver disease using dual-photon microscopy.

Gut 2020 06 28;69(6):1116-1126. Epub 2019 Sep 28.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

Objective: Fibrosis stage is strongly associated with liver-related outcomes and is a key surrogate endpoint in drug trials for non-alcoholic steatohepatitis. Dual-photon microscopy allows automated quantification of fibrosis-related parameters (q-FPs) and may facilitate large-scale histological studies. We aim to validate the performance of q-FPs in a large histological cohort.

Design: 344 patients with non-alcoholic fatty liver disease (NAFLD) underwent 428 liver biopsies (240 had paired transient elastography examination). Fibrosis stage was scored using the NASH Clinical Research Network system, and q-FPs were measured by dual-photon microscopy using unstained slides. Patients were randomly assigned to the training and validation cohorts to test the performance of individual q-FPs and derive optimal cut-offs.

Results: Over 25 q-FPs had area under the receiver-operating characteristics curves >0.90 for different fibrosis stages. Among them, the perimeter of collagen fibres and number of long collagen fibres had the highest accuracy. At the best cut-offs, the two q-FPs had 88.3%-96.2% sensitivity and 78.1%-91.1% specificity for different fibrosis stages in the validation cohort. q-FPs and histological scoring had nearly identical correlations with liver stiffness measurement, suggesting that the accuracy of q-FPs approached that of histological assessment. Among patients with paired liver biopsies, changes in the same q-FPs were associated with changes in fibrosis stage. At a median follow-up of 5.6 years, baseline q-FPs predicted liver-related events.

Conclusion: q-FP is highly accurate in the assessment of fibrosis in NAFLD patients. This automated platform can be used in future studies as objective and reliable evaluation of histological fibrosis.
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http://dx.doi.org/10.1136/gutjnl-2019-318841DOI Listing
June 2020

Longitudinal Change of Body Mass Index Is Associated With Alanine Aminotransferase Elevation After Complete Viral Suppression in Chronic Hepatitis B Patients.

J Infect Dis 2019 09;220(9):1469-1476

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background: Little is known about cause and intervention for alanine aminotransferase (ALT) elevation after complete viral suppression in patients with chronic hepatitis B (CHB).

Methods: In this prospective cohort study, patients with CHB who were treated with nucleos(t)ide analogs and maintained undetectable levels of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) for at least 6 months were enrolled. Patients were followed up at 6-month intervals, and anthropometric, biochemical, and virological assessments were performed.

Results: Of 1965 patients with median follow-up of 18.36 months, one third of patients experienced ALT elevation. Baseline high body mass index ([BMI] defined as ≥25 kg/m2), younger age, and liver cirrhosis independently increased the risk of longitudinal ALT elevation. At the end of follow-up, 89 (4.8%) patients reverted to low BMI, and 92 (5.0%) developed to high BMI. Compared with persistent high BMI, reversion to low BMI reduced the risk of ALT elevation (adjusted odds ratio [aOR], 0.38; 95% confidence interval [CI], 0.19-0.77); compared with persistent low BMI, onset of high BMI increased the risk of ALT elevation (aOR, 1.78; 95% CI, 1.02-3.11).

Conclusions: High BMI is an independent predictor for ALT elevation after complete HBV DNA suppression. Improvement of BMI may have a beneficial effect on ALT normalization and even long-term outcomes.
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http://dx.doi.org/10.1093/infdis/jiz326DOI Listing
September 2019

Long-term efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis B: 5-year results.

Hepatol Int 2019 May 11;13(3):260-269. Epub 2019 Apr 11.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

Background And Aim: Long-term treatment with tenofovir disoproxil fumarate (TDF) has demonstrated suppression of viral replication outside of China. This study aims to assess efficacy, resistance and safety of TDF for up to 240 weeks in Chinese patients with chronic hepatitis B virus (HBV) infection.

Methods: Patients (HBeAg-positive or HBeAg-negative) who were randomised to receive TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily in the 48-week double-blind phase (N = 498) were eligible to enter the open-label TDF phase (TDF-TDF and ADV-TDF groups) for additional 192 weeks.

Results: Overall, 457/512 (89.3%) randomised patients completed 240 weeks of treatment. Virological suppression was achieved in 84.5% and 87.9% in HBeAg-positive patients and 89.6% and 89.5% in HBeAg-negative patients in TDF-TDF and ADV-TDF groups, respectively, at week 240. The majority of patients from both groups had normalized alanine transaminase levels. More patients had HBeAg loss (41.7% vs. 36.4%) and HBeAg seroconversion (32.0% vs. 28.3%) in TDF-TDF than in ADV-TDF group, respectively. Only one HBeAg-positive patient in TDF-TDF group had HBsAg loss at week 240. No evidence of resistance to TDF was observed. The incidence of adverse events was similar in both groups (TDF-TDF, 56.4% vs. ADV-TDF, 51.6%). One patient had serum creatinine elevation ≥ 0.5 mg/dL above baseline, and three patients had confirmed grade 3/4 phosphorus abnormalities (< 2 mg/dL).

Conclusion: In Chinese patients with chronic HBV, long-term treatment with TDF showed sustained viral suppression without development of resistance up to 240 weeks. No new safety concerns were found with TDF in this patient population. Clinical Trial Registration ClinicalTrial.gov Identifier NCT01300234; GSK Clinical Study Register 114648.
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http://dx.doi.org/10.1007/s12072-019-09943-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529393PMC
May 2019

Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

Clin Infect Dis 2019 11;69(11):1969-1979

Medical University of Vienna, Austria.

Background: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand.

Methods: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients.

Results: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele.

Conclusions: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies.

Clinical Trials Registation: NCT01401400.
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http://dx.doi.org/10.1093/cid/ciz084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853659PMC
November 2019

Effect of hepatitis B virus subgenotype on antiviral response in nucleoside-treated hepatitis B envelope antigen-positive patients.

Hepatol Res 2018 Feb 6;48(2):134-143. Epub 2017 Jun 6.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou.

Aim: Previous studies have reported that hepatitis B virus (HBV) genotype is not a predictor of treatment response with nucleos(t)ide analog therapy. However, the impact of subgenotype on treatment response is unknown. The aim of this study is to identify the effect of HBV subgenotype on treatment response.

Methods: In this retrospective study, the derivation dataset comprised patients from the EFFORT study (NCT00962533) telbivudine monotherapy group; patients infected with genotypes B or C from the GLOBE (NCT00057265) and 015 (NCT00131742) studies formed the validation dataset. The HBV subgenotypes were determined using phylogenetic analysis based on the surface or overlapping polymerase gene. Molecular modeling was used to investigate relationships between positions of the substitutions within reverse transcriptase and genotypic resistance.

Results: Of the patients in the derivation dataset, 110, 24, 162, and 1 patients were classified as having HBV subgenotypes B2, C1, C2, or other, respectively, compared to 222, 146, 282, and 51 in the validation dataset, respectively. Patients infected with subgenotype C1 showed a higher virologic response rate and hepatitis B envelope antigen seroconversion rate, and lower genotypic resistance rate than those infected with subgenotypes B2 and C2. Patients with genotypic resistance to telbivudine with subgenotype C1 showed fewer secondary mutations. The crystal structure model of reverse transcriptase showed that these secondary mutations were located around the YMDD motif, which possibly influenced the chance of mutations at rtM204.

Conclusion: Hepatitis B virus subgenotype C1 is associated with better antiviral response to nucleoside analogs in hepatitis B envelope antigen-positive patients than B2 and C2 subgenotypes. The exact mechanism needs to be explored further.
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http://dx.doi.org/10.1111/hepr.12907DOI Listing
February 2018

Dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FP) to model disease progression in steatohepatitis.

Hepatology 2017 06 28;65(6):1891-1903. Epub 2017 Apr 28.

Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA.

There is a need for further refinement of current histological systems for assessment of hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). This study evaluated hepatic fibrosis in NAFLD using dual-photon microscopy-based quantitation of fibrosis-related parameters (q-FPs). Fifty test cohort subjects and 42 validation cohort subjects with NAFLD and the full spectrum of fibrosis were studied. q-FPs were measured in specific predefined regions of interest (general, vessel, perisinusoid, and vascular septa). Seventy q-FPs had inter- and intraobserver concordance ≥0.8 and were related to the NASH Clinical Research Network fibrosis staging. Of these, 16 q-FPs with the strongest correlations (P < 0.001 for all) were entered in a principal component analysis model (odds ratio [OR] 7.8, P < 0.001), which separated any stage of fibrosis versus no fibrosis, and cirrhosis versus earlier stages with the areas under the receiver operating characteristic curves of 0.88 and 0.93 (P ≤ 0.01 for both), respectively. In an independent multivariable analysis, four q-FPs-the number of collagen strands (OR 8.5, P = 0.004), strand length (OR 12.0, P = 0.02), strand eccentricity (OR 8.3, P = 0.004), and strand solidity (OR 8.0, P = 0.003)-were independently associated with fibrosis stages and were used to model fibrosis along a continuous linear scale using desirability functions; this linear scale of fibrosis measurement was also related to fibrosis stage (P < 0.0001). The robustness of both the multivariable model and the linear scale of measurement was confirmed in the validation cohort.

Conclusion: The q-FP model provides an accurate reproducible method to evaluate fibrosis in NAFLD along a quantitative and continuous scale. (Hepatology 2017;65:1891-1903).
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http://dx.doi.org/10.1002/hep.29090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444965PMC
June 2017

Effect of Telbivudine Versus Other Nucleos(t)ide Analogs on HBeAg Seroconversion and Other Outcomes in Patients with Chronic Hepatitis B: A Network Meta-Analysis.

Adv Ther 2016 04 26;33(4):519-31. Epub 2016 Feb 26.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Introduction: A comprehensive and up-to-date network meta-analysis (NMA) helps to determine the comparative efficacies of nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB). The aim of this NMA was to assess the efficacy of telbivudine versus adefovir, entecavir, lamivudine, and tenofovir in nucleos(t)ide-naïve hepatitis B e antigen (HBeAg)-positive patients with CHB.

Methods: A systematic review was conducted to search Medline, Medline-In Process, EMBASE, and the Cochrane Central Register of Controlled Trials databases for publications of randomized controlled trials (RCTs). NMA was performed to compare the efficacy outcomes of telbivudine versus other approved NAs at 1- and 2-year time points.

Results: A total of 75 RCTs were included in the systematic review. At the 1-year time point, telbivudine was associated with significantly higher rates of: (1) HBeAg seroconversion than adefovir [odds ratio (OR) 1.99 (95% credible interval (CrI): 1.05, 3.45)], entecavir [OR 2.00 (95% CrI: 1.44, 2.82)] and lamivudine [OR 1.49 (95% CrI: 1.10, 2.03)]; (2) HBeAg loss than entecavir [OR 1.85 (95% CrI: 1.28, 2.76)] and lamivudine [OR 1.62 (95% CrI: 1.20, 2.24)]; (3) alanine aminotransferase (ALT) normalization than lamivudine [OR 1.50 (95% CrI: 1.05, 2.21)]; and (4) hepatitis B virus (HBV) DNA suppression than adefovir [OR 2.77 (95% CrI: 1.28, 5.45)] and lamivudine [OR 2.97 (95% CrI: 1.99, 4.53)]. At the 2-year time point, the relative efficacy outcomes were not statistically significant.

Conclusion: At 1 year, telbivudine was superior to adefovir, entecavir and lamivudine in HBeAg seroconversion, and to entecavir and lamivudine in HBeAg loss. Telbivudine was also superior to lamivudine in ALT normalization and to adefovir and lamivudine in suppressing HBV DNA levels.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1007/s12325-016-0305-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846711PMC
April 2016

Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients.

J Gastroenterol Hepatol 2015 Apr;30(4):748-55

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background And Aim: Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE).

Methods: Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 10(5) copies/mL, alanine aminotransferase 1.3-10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed.

Results: At week 104, more patients in COMBO and OPTIMIZE groups achieved HBV-DNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV-DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.5%). Patients under MONO with early virological response showed superior efficacy at week 104 (HBV-DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated.

Conclusion: Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg-positive CHB patients. In lamivudine-treated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development.
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http://dx.doi.org/10.1111/jgh.12835DOI Listing
April 2015

Association between vitamin D level and viral load or fibrosis stage in chronic hepatitis B patients from Southern China.

J Gastroenterol Hepatol 2015 Mar;30(3):566-74

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background And Aim: The role of vitamin D playing in patients with chronic hepatitis C has been intensively studied. However, studies on the potential interaction between vitamin D level and chronic hepatitis B are still limited. This study aimed to explore whether any association existed between serum vitamin D level and liver histology or virological parameters in patients with chronic hepatitis B infection in Southern China.

Methods: 25-Hydroxyvitamin D serum levels were determined in a cohort of 242 treatment-naïve chronic hepatitis B patients. Histologic assessment was based on Knodell histologic activity index and Ishak fibrosis staging. Predictors of vitamin D insufficiency were identified using multivariate analysis.

Results: Mean 25-hydroxyvitamin D value was 33.90 ng/mL. The percentage of patients with different concentration of 25-hydroxyvitamin D (≥ 30 ng/mL, 20-30 ng/mL, < 20 ng/mL) were 59.9%, 31.4%, and 8.7%, respectively. Gender, season, age, and viral genotype were independent predictors of vitamin D insufficiency (< 30 ng/mL). Patients with genotype B virus infection had a lower mean 25-hydroxyvitamin D level (P = 0.023) and higher prevalence of vitamin D insufficiency than those with genotype C (P = 0.021), while no association was found between vitamin D status and viral load. In addition, 25-hydroxyvitamin D level did not significantly vary according to activity grade or fibrosis stage.

Conclusions: The prevalence of vitamin D insufficiency is relatively low in our cohort. Patients infected with genotype B had a higher prevalence of vitamin D insufficiency than genotype C. 25-Hydroxyvitamin D serum level is not associated with viral load or fibrosis stage in chronic hepatitis B patients.
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http://dx.doi.org/10.1111/jgh.12783DOI Listing
March 2015

qFibrosis: a fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients.

J Hepatol 2014 Aug 26;61(2):260-269. Epub 2014 Feb 26.

Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, #04-01, Singapore 138669, Singapore.

Background & Aims: There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients.

Methods: qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison.

Results: qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p<0.001) and human biopsies (p<0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93-0.99 for animal samples: 1-16 mm(2); AUC: 0.84-0.97 for biopsies: 10-44 mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15 mm) and under- and over-scoring by different pathologists (p<0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p=0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts.

Conclusions: qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice.
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http://dx.doi.org/10.1016/j.jhep.2014.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278959PMC
August 2014