Publications by authors named "Pisit Tangkijvanich"

137 Publications

Synthesis of sorafenib analogues incorporating a 1,2,3-triazole ring and cytotoxicity towards hepatocellular carcinoma cell lines.

Bioorg Chem 2021 Mar 17;112:104831. Epub 2021 Mar 17.

Department of Chemistry, Faculty of Science, Silpakorn University, Nakhon Pathom 73000, Thailand. Electronic address:

A series of 1,2,3-triazole-containing Sorafenib analogues, in which the aryl urea moiety of Sorafenib (1) was replaced with a 1,2,3-triazole ring linking a substituted phenoxy fragment, were prepared successfully via Huisgen 1,3-dipolar cycloaddition and nucleophilic aromatic substitution. The studies of cytotoxicity towards human hepatocellular carcinoma (HCC) cell lines, HepG2 and Huh7, indicated that p-tert-butylphenoxy analogue 2m showed significant inhibitory activity against Huh7 with IC = 5.67 ± 0.57 µM. More importantly, 2m showed low cytotoxicity against human embryonal lung fibroblast cell line, MRC-5, with IC > 100 µM, suggesting its highly selective cytotoxic activity (SI > 17.6) towards Huh7 which is much superior to that of Sorafenib (SI = 6.73). The molecular docking studies revealed that the analogue 2m bound B-RAF near the binding position of Sorafenib, while it interacted VEGFR2 efficiently at the same binding position of Sorafenib. However, 2m exhibited moderate inhibitory activity toward B-RAF, implying that its anti-Huh7 effect might not strictly relate to inhibition of B-RAF. Wound healing and BrdU cell proliferation assays confirmed anti-cell migration and anti-cell proliferative activities towards Huh7. With its inhibitory efficiency and high safety profile, 2m has been identified as a promising candidate for the treatment of HCC.
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http://dx.doi.org/10.1016/j.bioorg.2021.104831DOI Listing
March 2021

Novel viral markers and the prediction of off-treatment relapse in chronic hepatitis B patients: A systematic review.

J Gastroenterol Hepatol 2021 Apr 2. Epub 2021 Apr 2.

Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background And Aim: Hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are novel markers that reflect intrahepatic cccDNA and could be useful in the prediction of relapse after nucleos(t)ide analogues (NA) discontinuation. The aim of the study is to perform a systematic review on this issue.

Methods: Medline/Pubmed database was searched using text terms related to HBcrAg, RNA, NAs, discontinuation, and relapse. Included studies were those that enrolled adult patients who had been on NAs for more than 6 months with available information on end-of-treatment (EOT) HBcrAg and/or HBV RNA and relapse rates.

Results: Sixteen studies were included. Virological and clinical relapse rates ranged from 11% to 100% and 11% to 73%, respectively. Low or undetectable EOT HBcrAg levels were associated with low off-treatment relapse rates in most studies with area under the receiver operating characteristic curve (AUROC) of 0.69-0.70 for predicting virological relapse (VR) and 0.61-0.77 for predicting clinical relapse (CR). Undetectable EOT HBV RNA was associated with a lower risk of off-treatment relapse with AUROC of 0.65-0.76 for predicting VR and 0.66-0.73 for predicting CR. Combined EOT HBcrAg and HBV RNA performed better in predicting off-treatment relapse than either test alone with AUROC of 0.816-0.846 for predicting CR. None of the patients with double-negative HBV RNA and HBcrAg developed CR.

Conclusion: Combining HBcrAg with HBV RNA or HBsAg improved the discriminating abilities in the prediction of off-treatment relapse of each test. Patients with double-negative HBcrAg and HBV RNA at EOT had low risks of relapse and could be considered for NA discontinuation.
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http://dx.doi.org/10.1111/jgh.15516DOI Listing
April 2021

Liver fibrosis improvement assessed by magnetic resonance elastography and Mac-2-binding protein glycosylation isomer in patients with hepatitis C virus infection receiving direct-acting antivirals.

Hepatol Res 2021 Feb 21. Epub 2021 Feb 21.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Aim: Fibrosis regression has been observed in patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antivirals. This study was aimed at evaluating dynamic changes of serum Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with HCV genotype 1 receiving elbasvir/grazoprevir.

Methods: M2BPGi were serially measured at baseline, during and after therapy. Its diagnostic performance at baseline and sustained virological response at 24 weeks after treatment (SVR24) were compared with transient elastography (TE) and the aspartate aminotransferase/platelet ratio index (APRI) using magnetic resonance elastography (MRE) as a reference.

Results: Overall, 60 HCV mono-infected and 36 HCV/HIV co-infected patients were included with SVR24 rates of 93.3% and 97.2%, respectively. At baseline, TE, M2BPGi and APRI were correlated with MRE (r = 0.788, r = 0.703 and r = 0.564, respectively, p < 0.001). The area under the receiver operator characteristics curves for TE, M2BPGi and APRI in differentiating significant fibrosis were 0.88 (95% confidence interval; 0.81-0.95, p < 0.001), 0.86 (0.79-0.94, p < 0.001) and 0.74 (0.64-0.83, p < 0.001), respectively. The corresponding figures for cirrhosis were 0.95 (0.90-1.00, p < 0.001), 0.96 (0.92-1.00, p < 0.001) and 0.88 (0.79-0.97, p < 0.001), respectively. Compared with baseline, all fibrosis markers significantly declined after achieving SVR24. The correlations of TE, M2BPGi and APRI with MRE at time of SVR24 were r = 0.587 (p < 0.001), r = 0.457 (p < 0.001) and r = 0.293 (p = 0.004), respectively. In multivariate analysis, high baseline alanine aminotransferase level, HCV mono-infection and advanced fibrosis were factors associated with M2BPGi reduction.

Conclusions: HCV eradication is associated with liver fibrosis improvement. M2BPGi has a better performance than APRI in monitoring liver fibrosis in patients treated with direct-acting antivirals. This marker is applicable in resource-limited settings where imaging-based modalities are not widely accessible.
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http://dx.doi.org/10.1111/hepr.13630DOI Listing
February 2021

Improvement of Gut Diversity and Composition after Direct-Acting Antivirals in HCV-Infected Patients with or without HIV Coinfection.

J Infect Dis 2021 Feb 17. Epub 2021 Feb 17.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)-infected patients with or without human immunodeficiency virus (HIV) is unclear.

Methods: We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir/grazoprevir from a clinical trial. Fecal specimens collected at pre-treatment and 12 weeks post-treatment were analyzed using amplicon-based 16S rRNA sequencing.

Results: Sustained virological response (SVR12) rates in the mono- and co-infection groups were similar (98.4%vs.95.8%). Pre-treatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha-diversity but displayed declined Firmicutes/Bacteroidetes ratio. The improvement of microbial dysbiosis was observed in responders achieving SVR12 across fibrosis stages but was not found in non-responders. Responders with low degree of fibrosis exhibited a recovery in alpha-diversity to level comparable with healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders.

Conclusions: This study indicates short-term effect of DAAs in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might potentially contribute towards the reduction of HCV-related complications among infected individuals.
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http://dx.doi.org/10.1093/infdis/jiab094DOI Listing
February 2021

Successful direct-acting antiviral therapy improves circulating mucosal-associated invariant T cells in patients with chronic HCV infection.

PLoS One 2020 31;15(12):e0244112. Epub 2020 Dec 31.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Objectives: Mucosal-associated invariant T (MAIT) cells have been shown to contribute in the pathogenesis of various liver diseases, including chronic hepatitis C virus (HCV) infection. This study was aimed at investigating the frequency, phenotype, and function of circulating MAIT cells, as well as their alterations after successful direct-acting antivirals (DAAs) in HCV-infected patients with or without HIV infection.

Methods: A total 85 patients (51 HCV-monoinfection and 34 HCV/HIV-coinfection), who received elbasvir/grazoprevir from a clinical trial and 20 healthy controls were included. MAIT cells in blood were characterized using flow cytometry at baseline and 24 weeks post-treatment.

Results: HCV-monoinfected and HCV/HIV-coinfected patients achieved similar sustained virological response rates (SVR24, 94.1% vs. 97.1%). Circulating MAIT cells in the monoinfection and coinfection groups were presented at low frequencies in comparison with healthy controls (median, 1.1% vs. 1.1% vs. 2.4%, P<0.001) and exhibited features of chronic activation and impaired functional capacity. A negative correlation between circulating MAIT cell frequency and liver stiffness assessed by magnetic resonance elastography was observed. Compared with baseline, increased in circulating MAIT cells after successful DAA therapy was mainly detected in HCV-monoinfected patients compared with HCV/HIV-coinfected individuals. Moreover, MAIT cell restoration was predominantly observed among patients with significant fibrosis to cirrhosis (F2-F4).

Conclusions: These data indicated that dysregulation of MAIT cells might play a role in the progression of chronic HCV infection. Partial restoration of MAIT cell frequency and function was observed after successful DAA therapy, particularly in HCV-monoinfected patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244112PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775079PMC
March 2021

Amplification-free DNA Sensor for the One-Step Detection of the Hepatitis B Virus Using an Automated Paper-Based Lateral Flow Electrochemical Device.

Anal Chem 2021 02 16;93(5):2879-2887. Epub 2020 Dec 16.

Electrochemistry and Optical Spectroscopy Center of Excellence (EOSCE), Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand.

Until now, an electrochemical lateral flow assay (eLFA) capable of detecting nucleic acids has remained a challenge and has been scarcely explored because of its complicated multistep nature. Here, we report an automated paper-based eLFA device for the quantitative detection of the hepatitis B virus (HBV)-the major cause of liver cirrhosis and hepatocellular carcinoma (HCC). Using a time-delayed microfluidic strategy fabricated on paper, an automated and precisely sequenced solution transfer was enabled by single sample loading. A gold metallization strategy was employed for the signal-on electrochemical detection of the target DNA. Furthermore, a pyrrolidinyl peptide nucleic acid (so-called "acpcPNA") was used as a probe in this study because it offers higher specificity and yields lower background currents than those of traditional probes. Under optimal conditions, a broad dynamic range (10 pM to 2 μM) with an excellent detection limit (down to 7.23 pM) was achieved. The overall operation can be completed within 7 min of sample loading. The proposed sensor was successfully applied in HBV DNA detection in sera from patients without any amplification step (e.g., PCR) required, thus simplifying the operation further. Additionally, the results obtained from this present device are in accordance with the standard real-time PCR, thus supporting the accuracy of the method.
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http://dx.doi.org/10.1021/acs.analchem.0c04283DOI Listing
February 2021

Incident Liver Cirrhosis, Associated Factors, and Cardiovascular Disease Risks Among People Living With HIV: A Longitudinal Study.

J Acquir Immune Defic Syndr 2021 Apr;86(4):463-472

HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objectives: We investigated the incidence and associated factors of liver cirrhosis and cardiovascular disease risks among people living with HIV (PLHIV) in a Thai cohort.

Design: A prospective cohort analysis.

Methods: Participants with at least one reliable transient elastography measurement during follow-up, who had pretreatment alanine transaminase, AST, and platelet count at HIV treatment initiation were included. Liver cirrhosis was defined as AST to Platelet Ratio Index >1.5 or fibrosis-4 (FIB-4) >3.25 or liver stiffness by transient elastography >12.5 kPa and confirmed by imaging or liver biopsy. Competing-risk regression was used to identify factors associated with liver cirrhosis. Time-updated 10-year atherosclerotic CVD (ASCVD) risks were compared between PLHIV with or without liver cirrhosis.

Results: A total of 1069 participants (33% women, 9% hepatitis C virus, and 16% hepatitis B virus) with the median age and CD4 at cART initiation of 32 years and 240 cells/mm3 were included. During 8232 person-years, 124 (12%) developed liver cirrhosis after a median of 6.9 (2.4-13.7) follow-up years [incidence, 1.5 (95% confidence interval: 1.3 to 1.8) per 100 person-years]. In multivariable analysis, the factors independently associated with liver cirrhosis were time-updated HIV viremia, hepatitis B virus, and hepatitis C virus coinfection, diabetes mellitus, high-density lipoproteins <40 mg/mL, and d4T exposure. The median time-updated 10-year ASCVD risk score was statistically higher among cirrhotic PLHIV vs. noncirrhosis [4.9% (interquartile range, 2.3-9.7) vs. 2.4% (interquartile range, 1.3-4.9), P < 0.001].

Conclusion: PLHIV with metabolic diseases were more likely to develop liver cirrhosis, independent of hepatitis coinfections, and ASCVD risks were higher among cirrhotic individuals.
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http://dx.doi.org/10.1097/QAI.0000000000002585DOI Listing
April 2021

Circulating microtranscriptome profiles reveal distinct expression of microRNAs in severe leptospirosis.

PLoS Negl Trop Dis 2020 11 11;14(11):e0008809. Epub 2020 Nov 11.

Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.

Biomarkers to predict the severity of leptospirosis are still lacking. This study aimed to identify and validate microRNAs in patients with severe leptospirosis, that could potentially be used as biomarkers for predicting an unfavorable outcome. Serum samples were collected from participants with definite diagnosis of leptospirosis. The participants were divided into two groups, non-severe and severe leptospirosis, as defined by the Specific Organ Sequential Organ Failure (SOFA) Score of more than two in any organ. Microtranscriptome analysis was performed using the NanoString miRNA Expression Assay. The expression level of candidate miRNAs was then validated by quantitative RT-PCR. Based on the NanoString, the microtranscriptome profile of the severe group was significantly different from that of the non-severe group. Upregulation of miR155-5p, miR362-3p, miR502-5p, miR601, miR1323, and miR630 in the severe group were identified, and further investigated. A total of 119 participants were enrolled in the validation cohort. Serum miR155-5p and miR630 levels were significantly higher in the severe group compared to the non-severe group. The combined use of miR155-5p or miR-630 with serum bicarbonate levels had an AUC of 0.79 (95%CI; 0.69-0.89, p<0.001) in identifying the severity of the disease. This data provides the first evidence that the microtranscriptome profiles of patients with severe leptospirosis were different from the non-severe group. Serum miR155-5p and miR630 levels might be novel biomarkers for identifying severe leptospirosis.
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http://dx.doi.org/10.1371/journal.pntd.0008809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682886PMC
November 2020

Acute liver failure and death predictors in patients with dengue-induced severe hepatitis.

World J Gastroenterol 2020 Sep;26(33):4983-4995

Department of Medicine, Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University, and Thai Red Cross, Bangkok 10330, Thailand.

Background: Liver injury in patients with dengue infection is common. Most patients have mild and transient hepatitis. Acute liver failure (ALF) in dengue infection is rare but results in an extremely poor prognosis.

Aim: To identify prognostic predictors of ALF and death in patients with dengue-induced severe hepatitis (DISH).

Methods: We retrospectively reviewed 2311 serologically confirmed adolescent and adult dengue patients who were hospitalized during a 12-year study period (between 2007 and 2019) at the university hospital of King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Patients with DISH [ = 134 (5.80%)], defined as a baseline transaminase > 10 times the normal reference cut-off level, and DISH with subsequent ALF as defined by the American Association for the Study of the Liver Diseases 2011 criteria [ = 17 (0.74%)], were included. Predictors of ALF and in-hospital death were identified using logistic regression analysis.

Results: Of the 151 dengue-infected patients with severe liver injury or ALF, 51% were female, with a mean age of 27.9 ± 14.5 years. Capillary leakage syndrome (CLS) occurred in 68.2% ( = 103) of DISH and 100% of ALF patients. The mortality rate was low in DISH patients (0.8%) but was remarkably high if ALF developed (58.8%). In univariate analysis, age, sex, hematocrit, white blood count, atypical lymphocyte count, platelet count, international normalized ratio (INR), bilirubin, serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, alkaline phosphatase, albumin, creatinine, Model for End-Stage Liver Disease (MELD) score, presence of liver comorbidity and presence of CLS were identified as potential prognostic parameters for ALF or death. In multivariate analysis, the MELD score remained the only predictor of ALF with an adjusted odds ratio (aOR) of 1.3 [95% confidence interval (CI): 1.1-1.5; = < 0.001]. An initial MELD score ≥ 15 was associated with ALF from DISH with an area under the receiver operating characteristic (AUROC) of 0.91, 88.2% sensitivity and 87.3% specificity. Regarding mortality prediction, the deterioration of liver function to ALF was the most significant factor related to death in DISH patients (aOR 108.5, 95%CI: 5.5-2145.4, = 0.002). Other independent factors associated with death included baseline INR (aOR 10.4, 95%CI: 2.6-40.5, = 0.001). An INR ≥ 1.5 predicted death from DISH with an AUROC of 0.83 (81.8% sensitivity and 86.8% specificity).

Conclusion: The MELD score is the best predictor of ALF in DISH patients, a complication from dengue that is associated with high mortality. The presence of ALF and the baseline INR level are independent markers of death in DISH patients.
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http://dx.doi.org/10.3748/wjg.v26.i33.4983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476175PMC
September 2020

Efficacy of elbasvir/grazoprevir therapy in HCV genotype-1 with or without HIV infection: role of HCV core antigen monitoring and improvement of liver stiffness and steatosis.

Antivir Ther 2020 Sep 10. Epub 2020 Sep 10.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: The combination of elbasvir and grazoprevir (EBR/GZR) has been approved for treating HCV infection. This study aimed to evaluate the efficacy of EBR/GZR in terms of sustained virological response (SVR) and improvement of liver fibrosis in Thai patients with HCV genotype-1 (GT1). The utility of serum HCV core antigen (HCVcAg) as an alternative to HCV RNA in assessing SVR was also investigated.

Methods: A total of 101 HCV GT1-infected patients (65 monoinfection and 36 HIV coinfection) who received EBR/GZR for 12-16 weeks were included. Liver stiffness (LS) and controlled attenuation parameter (CAP) were measured by transient elastography. Serum HCVcAg was measured in parallel with HCV RNA.

Results: The overall SVR12 and SVR24 rates in the cohort were 98.0% and 95.0%, respectively. SVR24 rates were consistently high (90.0% to 100%) across all subgroups of patients. A significant LS decline ³30% was observed more frequently in cirrhotic than non-cirrhotic individuals who achieved SVR (63.3% versus 30.3%; P=0.003). The magnitude of LS decline following HCV eradication was comparable between HCV monoinfection and HCV-HIV coinfection. The reduction of CAP was also observed in responders who had significant steatosis at baseline. Compared with HCV RNA, HCVcAg testing displayed high sensitivity (100%) and specificity (99.0-100%) in determining SVR12 and SVR24.

Conclusions: This study confirms that EBR/GZR is effective for HCV GT1-infected Thai patients with or without HIV infection. HCV eradication is associated with LS and CAP improvement regardless of HIV status. HCVcAg testing could be a potential replacement for HCV RNA for assessing SVR in resource-limited settings.
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http://dx.doi.org/10.3851/IMP3370DOI Listing
September 2020

Hepatitis B surface antigen, core-related antigen and HBV RNA: Predicting clinical relapse after NA therapy discontinuation.

Liver Int 2020 12 3;40(12):2961-2971. Epub 2020 Aug 3.

Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Background & Aims: The safe discontinuation of nucleos(t)ide analogue therapy remains challenging in chronic hepatitis B. We investigated the potential role of quantitative hepatitis B surface antigen, hepatitis B core-related antigen and hepatitis B virus RNA at the end of treatment in predicting off-therapy relapse.

Methods: Patients who fulfilled the stopping criteria of the Asian Pacific Association for the Study of the Liver guideline were enrolled. Virological relapse was defined as hepatitis B virus DNA level greater than 2000 IU/mL, and clinical relapse was defined as virological relapse plus alanine aminotransferase level of more than twice the upper limit of normal.

Results: Ninety-two patients participated. The combination of end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA levels was most predictive of clinical relapse. Multivariate analysis revealed that end-of-treatment hepatitis B core-related antigen and hepatitis B virus RNA were independently associated with clinical relapse. During follow-up, no patients with undetectable hepatitis B core-related antigen (<3.0 log U/mL) and hepatitis B virusRNA (<2.0 log copies/mL) at end of treatment developed clinical relapse, in comparison with 22.9% and 62.5% patients with detectable levels of one or both biomarkers respectively. End-of-treatment quantitative hepatitis B surface antigen was linked to a likelihood of hepatitis B surface antigen clearance.

Conclusions: The combined hepatitis B core-related antigen and hepatitis B virus RNA assays at end of treatment were highly predictive of subsequent clinical relapse. These novel biomarkers could potentially be used to identify patients who could safely discontinue nucleos(t)ide analogue therapy.
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http://dx.doi.org/10.1111/liv.14606DOI Listing
December 2020

Large transmission cluster of acute hepatitis C identified among HIV-positive men who have sex with men in Bangkok, Thailand.

Liver Int 2020 09 20;40(9):2104-2109. Epub 2020 Jul 20.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

A rapidly emerging and highly concentrated hepatitis C virus (HCV) outbreak has recently been observed among both acute and chronic HIV-positive men who have sex with men (MSM) in Bangkok, Thailand. NS5B regions of the HCV genome were amplified using nested PCR and sequenced. Phylogenetic inference was constructed by Maximum Likelihood methods and clusters were identified with support and genetic distance thresholds of 85% and of 4.5%. Forty-eight (25 acute HIV and 23 chronic HIV) MSM with incident HCV infection were included in the analysis. HCV genotype (GT) was 85% GT 1a and 15% GT 3a or 3b. Median age at HCV diagnosis was 34 (interquartile range, 28-41) years. 83.3% (40/48) had history of syphilis infection and 36% (16/44) reported crystal methamphetamine use. Only 2 (4%) reported ever injecting drugs, both crystal methamphetamine. In the phylogenetic clustering analysis, 83% belonged to one of two clusters: one large (75%) and one small (8%) cluster. All clusters were GT 1a. MSM with acute HIV infection were more likely to be in a cluster (92%) than those with chronic infection (74%). HCV screening should be regularly performed for MSM in ART clinics, and offering direct-acting antiviral agents to all MSM with HCV infection might contain the HCV epidemic from expanding further.
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http://dx.doi.org/10.1111/liv.14578DOI Listing
September 2020

Decreased of BAFF-R expression and B cells maturation in patients with hepatitis B virus-related hepatocellular carcinoma.

World J Gastroenterol 2020 May;26(20):2645-2656

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

Background: Recent evidence has indicated the role of B cells and B cell-activating factor (BAFF) in the development of hepatocellular carcinoma (HCC).

Aim: To characterize circulating BAFF receptor expression and B cell subpopulations in patients with hepatitis B virus (HBV)-related HCC.

Methods: Peripheral blood samples collected from 41 patients with chronic HBV infection (25 patients without HCC and 16 patients with HCC) and 9 healthy controls were assessed for BAFF receptors [BAFF-R(B cell-activating factor receptor), transmembrane activator and cyclophilin ligand interactor, B-cell maturation antigen] and B cell subpopulations by multicolor flow cytometry.

Results: The frequency of BAFF-R expressing B cells to total B cells was significantly lower in patients with HCC (3.39% ± 2.12%) compared with the non-HCC group (5.37% ± 1.90%) and healthy controls (6.23% ± 2.32%), whereas there was no difference in transmembrane activator and cyclophilin ligand interactor and B-cell maturation antigen. The frequencies of CD27IgD memory B cells, CD27IgD class-switched memory B cells and plasmablasts were significantly lower in the patients with HCC compared to patients without HCC (1.23 ± 1.17 3.09 ± 1.55, = 0.001, 0.60 ± 0.44 1.69 ± 0.86, < 0.0001 and 0.16 ± 0.12 0.37 ± 0.30, = 0.014, respectively). However, the ratio of naïve and transitional B cell did not differ significantly between the three groups. In addition, decreased BAFF-R expression on B cells was significantly correlated with large tumor size and advanced tumor stage.

Conclusion: Our data demonstrated BAFF-R expression was reduced in B cells that involved with the frequencies of B cells maturation in patients with HCC. The depletion of BAFF-R might play an important role in the development of HCC in patients with chronic HBV infection.
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http://dx.doi.org/10.3748/wjg.v26.i20.2645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265148PMC
May 2020

Hepatitis B Core-Related Antigen to Indicate High Viral Load: Systematic Review and Meta-Analysis of 10,397 Individual Participants.

Clin Gastroenterol Hepatol 2021 Jan 29;19(1):46-60.e8. Epub 2020 Apr 29.

Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France. Electronic address:

Background & Aims: To eliminate hepatitis B virus (HBV) infection, scale-up of testing and treatment in resource-limited countries is crucial. However, access to nucleic acid testing to quantify HBV DNA, an essential test to examine treatment eligibility, remains severely limited. We assessed the performance of a novel immunoassay, HBV core-related antigen (HBcrAg), as a low-cost (less than US $15/assay) alternative to nucleic acid testing to indicate clinically important high viremia in chronic HBV patients infected with different genotypes.

Methods: We searched Medline, Embase, Scopus, and Web of Science databases through June 27, 2018. Three reviewers independently selected studies measuring HBV DNA and HBcrAg in the same blood samples. We contacted authors to provide individual participant data (IPD). We randomly allocated each IPD to a derivation or validation cohort. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity/specificity.

Results: Of 74 eligible studies, IPD were obtained successfully for 60 studies (81%). Meta-analysis included 5591 IPD without antiviral therapy and 4806 treated with antivirals. In untreated patients, the pooled area under the receiver operating characteristic curve and optimal cut-off values were as follows: 0.88 (95% CI, 0.83-0.94) and 3.6 log U/mL to diagnose HBV DNA level of 2000 IU/mL or greater; and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/mL for 200,000 IU/mL or greater, respectively. In the validation set, the sensitivity and specificity were 85.2% and 84.7% to diagnose HBV DNA level of 2000 IU/mL or greater, and 91.8% and 90.5% for 200,000 IU/mL or greater, respectively. The performance did not vary by HBV genotypes. In patients treated with anti-HBV therapy the correlation between HBcrAg and HBV DNA was poor.

Conclusions: HBcrAg might be a useful serologic marker to indicate clinically important high viremia in treatment-naïve, HBV-infected patients.
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http://dx.doi.org/10.1016/j.cgh.2020.04.045DOI Listing
January 2021

Diagnostic and prognostic roles of circulating miRNA-223-3p in hepatitis B virus-related hepatocellular carcinoma.

PLoS One 2020 24;15(4):e0232211. Epub 2020 Apr 24.

Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Circulating microRNAs (miRNAs) have been shown to dysregulate in many cancer types including hepatocellular carcinoma (HCC). The purpose of this study was to examine the potential diagnostic or prognostic roles of circulating miRNAs in patients with hepatitis B virus (HBV)-related HCC.

Methods: Paired cancerous and adjacent non-cancerous liver tissue specimens of patients with HBV-related HCC were used as a discovery set for screening 800 miRNAs by a Nanostring quantitative assay. Differentially expressed miRNAs were then examined by SYBR green quantitative RT-PCR in a validation cohort of serum samples obtained from 70 patients with HBV-related HCC, 70 HBV patients without HCC and 50 healthy controls.

Results: The discovery set identified miR-223-3p, miR-199a-5p and miR-451a significantly lower expressed in cancerous tissues compared with non-cancerous tissues. In the validated cohort, circulating miR-223-3p levels were significantly lower in the HCC group compared with the other groups. The combined use of serum alpha-fetoprotein and miR-223-3p displayed high sensitivity for detecting early HCC (85%) and intermediate/advanced stage HCC (100%). Additionally, serum miR-223-3p had a negative correlation with tumor size and BCLC stage. On multivariate analysis, serum miR-223-3p was identified as an independent prognostic factor of overall survival in patients with HCC. In contrast, circulating miRNA-199a-5p and miR-451a did not show any clinical benefit for the diagnosis and prognostic prediction of HCC.

Conclusions: Our results demonstrated that miR-223-3p was differentially expressed in cancerous compared with paired adjacent non-cancerous tissues. In addition, circulating miRNA-223-3p could represent a novel diagnostic and prognostic marker for patients with HBV-related HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182200PMC
July 2020

Screening for non-alcoholic fatty liver disease in community setting: A cohort study using controlled attenuation parameter-transient elastography.

JGH Open 2020 Apr 4;4(2):245-250. Epub 2019 Sep 4.

Department of Medicine, Division of Gastroenterology, Faculty of Medicine Chulalongkorn University Bangkok Thailand.

Background/aim: The global problems of chronic liver disease and non-alcoholic fatty liver disease (NAFLD) are increasing. We examined the prevalence of NAFLD and significant liver stiffness in an asymptomatic population and identified the predictors of significant fibrosis in NAFLD.

Method: We prospectively enrolled Thai subjects, aged 18-80 years, from four regions (Bangkok, Central, North, South) of Thailand from March 2013 to November 2016. All participants underwent controlled attenuation parameter (CAP) measurement for liver fat quantification and transient elastography (TE) for liver stiffness measurement (LSM). NAFLD was defined as liver fat ≥10% (CAP ≥ 306 dB/m). Of 1145 participants, 782 (68.3%) were eligible for analysis.

Result: The mean age ± standard deviation (SD) was 53.1 ± 4.6 years, and 71.6% were female. The mean ± SD values of CAP and LSM of the overall cohort were 241.9 ± 61.4 dB/m and 5.5 ± 3.8 kPa, respectively. The prevalence of NAFLD was 18.0%, whereas 5.4% of the cohort had nonobese NAFLD (BMI < 25 kg/m), and 2.8% had lean NAFLD (BMI < 23 kg/m). The prevalence of significant liver fibrosis (≥F2) in NAFLD subjects was 18.4%. On multivariate analysis, the degree of significant fibrosis in NAFLD was significantly associated with male gender and a history of dyslipidemia.

Conclusion: NAFLD with significant fibrosis (≥F2) is prevalent in asymptomatic populations. The predictors of significant fibrosis in NAFLD were male gender and dyslipidemia. Screening for NAFLD using CAP/TE in asymptomatic populations should be considered in hospitals with available facilities.
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http://dx.doi.org/10.1002/jgh3.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144791PMC
April 2020

Reverse transcriptase droplet digital PCR vs reverse transcriptase quantitative real-time PCR for serum HBV RNA quantification.

J Med Virol 2020 Mar 26. Epub 2020 Mar 26.

Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, Bangkok, Thailand.

Serum hepatitis B virus (HBV) RNA is a novel marker reflecting the activity of covalently closed circular DNA. However, the methodology for detecting HBV RNA has been a technical challenge. In this study, the performance of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for quantifying HBV RNA was compared with that of reverse transcription quantitative real-time PCR (RT-qPCR) in serum samples collected from treatment-naïve patients with different phases of chronic hepatitis B (CHB). A total of 417 serum samples, including 136 HBeAg-positive CHB and 281 HBeAg-negative CHB were examined. HBV RNA levels measured by RT-ddPCR and RT-qPCR showed a high degree of linearity and quantitative correlation. The limit of detections of RT-ddPCR and RT-qPCR assays were 10 and 10 copies/mL, respectively. Our results also demonstrated that RT-ddPCR was superior to RT-qPCR in terms of its consistency for quantifying HBV RNA across all concentrations. In the HBeAg-positive group, serum HBV RNA levels based on RT-ddPCR were moderately correlated with HBV DNA (r = 0.591, P < .001) and HBsAg (r = 0.502, P < .001). Among patients with HBeAg-negative CHB, serum HBV RNA levels were moderately correlated with HBV DNA (r = 0.603, P < .001) but had weak correlation with HBsAg (r = 0.203, P = .001). In summary, RT-ddPCR could enhance the sensitivity of serum HBV RNA detection, particularly among the HBeAg-negative group with low viral loads. Thus, RT-ddPCR could serve as an optimal method for HBV RNA quantification in clinical practice.
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http://dx.doi.org/10.1002/jmv.25792DOI Listing
March 2020

Real-world effectiveness and safety of sofosbuvir and nonstructural protein 5A inhibitors for chronic hepatitis C genotype 1, 2, 3, 4, or 6: a multicentre cohort study.

BMC Gastroenterol 2020 Mar 5;20(1):47. Epub 2020 Mar 5.

Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: We investigated real-world effectiveness and safety of sofosbuvir and the nonstructural protein 5A inhibitors in the treatment of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, 4, or 6.

Methods: We analyzed data from 1021 patients with HCV infection (506 with genotype 1; 16 with genotype 2; 314 with genotype 3; 13 with genotype 4; 166 with genotype 6) who received 12 to 24 weeks of daclatasvir plus sofosbuvir (n = 767), ledipasvir/sofosbuvir (n = 197), or sofosbuvir/velpatasvir (n = 57), with or without ribavirin in 12 centers across Thailand to estimate sustained virologic response at post-treatment week 12 (SVR12).

Results: Overall, SVR12 rate was 98.0% (95% confidence interval [CI], 96.7-98.8%) with daclatasvir plus sofosbuvir, 97.9% (95% CI, 94.8-99.2%) with ledipasvir/sofosbuvir, and 96.5% (95% CI, 88.1-99.0%) with sofosbuvir/velpatasvir. SVR12 was achieved by 99.2% (95% CI, 97.9-99.7%) of subjects with genotype 1 infection, 100% (95% CI, 78.5-100%) of those with genotype 2 infection, 96.7% (95% CI, 94.0-98.2%) of those with genotype 3 infection, 90.9% (95% CI, 62.3-98.4%) of those with genotype 4 infection, and 96.7% (95% CI 92.5-98.6%) of those with genotype 6 infection. Patients with advanced liver disease were at risk of treatment failure. Only four patients discontinued treatment before week 4 due to non-hepatic adverse events.

Conclusions: In this large cohort of patients with various HCV genotypes managed in the real-world practice setting, daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, and sofosbuvir/velpatasvir achieved high SVR rates with good safety profile, comparable to those observed in clinical trials.
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http://dx.doi.org/10.1186/s12876-020-01196-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057522PMC
March 2020

Awareness, knowledge, and practice for hepatitis B infection in Southeast Asia: a cross-sectional study.

J Infect Dev Ctries 2019 07 31;13(7):656-664. Epub 2019 Jul 31.

Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Introduction: The prevalence of hepatitis B virus (HBV) infection in Southeast Asia is high. Awareness and early detection are essential for timely prevention and treatment.

Methodology: We examined the awareness of, knowledge about, practices and views on treatment for HBV infection in Southeast Asia. A cross-sectional survey was conducted from December 2016 to February 2017 among individuals from six nations in Southeast Asia-Myanmar, Thailand, Vietnam, Cambodia, the Philippines, and Singapore. The study population comprised healthcare and non-healthcare personnel.

Results: In total, 799 healthcare personnel and 1079 non-healthcare personnel completed an online survey. The prevalence of the awareness of their own HBV infection status and risk of this regionally endemic infection was 85.6% (684/799) among healthcare personnel and 54.0% (583/1079) among non-healthcare personnel. Similarly, 85.9% of healthcare personnel and 45.5% of non-healthcare personnel had good knowledge about disease transmission, complications, and the need for treatment, and 76.6% of healthcare personnel and 39.8% of non-healthcare personnel followed good HBV infection-prevention practices. Overall, 90.6% found the idea of treatment acceptable. Awareness had a significant impact on both knowledge and practice scores among both healthcare personnel and non-healthcare personnel (p < 0.01) but without statistically significant differences in treatment acceptance between the two groups (p = 0.61).

Conclusions: Awareness of HBV infection was relatively low among non-healthcare personnel in Southeast Asian populations. The provision of additional hepatitis B awareness campaigns is crucial to eliminating viral hepatitis in the region.
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http://dx.doi.org/10.3855/jidc.10479DOI Listing
July 2019

Evaluation of aspartate aminotransferase to platelet ratio index and fibrosis 4 scores for hepatic fibrosis assessment compared with transient elastography in chronic hepatitis C patients.

JGH Open 2020 Feb 26;4(1):69-74. Epub 2019 Jun 26.

Department of Medicine Khon Kaen University Khon Kaen Thailand.

Background And Aim: Fibrotic stage (FS) assessment is essential in chronic hepatitis C treatment cascade. Liver stiffness measurement (LSM) using transient elastography (TE) is reliable and correlated with liver biopsy. However, TE may not be widely available. This study aimed to evaluate the diagnostic performances of aspartate aminotransferase to platelet ratio index (APRI) and fibrosis 4 (FIB-4) scores compared with TE.

Methods: We conducted a multicenter, cross-sectional study, including all chronic hepatitis C virus (HCV) monoinfection patients with successful and reliable LSM, at 10 centers in Thailand from 2012 to 2017. Characteristics and laboratory data within 3 months of TE were retrospectively reviewed. Using TE as a reference standard, the diagnostic performances of APRI and FIB-4 were evaluated. TE cut-off levels of 7.1 and 12.5 kPa represented significant fibrosis (SF) and cirrhosis, respectively.

Results: The distribution of FS by TE in 2000 eligible patients was as follows: no SF 28.3%, SF 31.4%, and cirrhosis 40.3%. APRI ≥ 1 provided 70.1% sensitivity and 80.6% specificity, with an area under the receiver operator characteristics curve (AUROC) of 0.834 for cirrhosis. The specificity increased to 96.3% when using a cut-off level of APRI ≥ 2. FIB-4 ≥ 1.45 provided a sensitivity, specificity, and AUROC of 52.4%, 91.0%, and 0.829 for cirrhosis, respectively. For SF, APRI performed better than FIB-4, with an AUROC of 0.84 0.80 ( < 0.001). APRI score < 0.5 and FIB-4 score > 1.45 yielded sensitivities of 82.3% and 74.4% and specificities of 65.4% and 69.8%, respectively.

Conclusions: APRI and FIB-4 scores had good diagnostic performances for FS assessment compared with TE, especially for cirrhosis. APRI may be used as the noninvasive assessment in resource-limited settings for HCV patients' management.
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http://dx.doi.org/10.1002/jgh3.12219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008156PMC
February 2020

Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Regulates Host Gene PPM1A Related to Hepatocellular Carcinoma.

Microrna 2020 ;9(3):232-239

Center of Excellence in Systems Biology, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

Background: Hepatitis B is a liver infection disease caused by the Hepatitis B Virus (HBV) that can become chronic and develop into hepatocellular carcinoma. HBV was classified as a double-stranded DNA virus. Currently, there is a report showing that HBV virus-encoded miRNA called HBV-miR-3 controls the replication of HBV. However, the regulation of HBV-miR-3 in host cells remains unclear.

Objective: This study aimed to investigate the regulation of HBV-miR-3 in host gene target which is related to chronic HBV infection and HCC process.

Methods: In this study, we analyzed the read count of HBV-miR-3 from next-generation sequencing of chronic hepatitis patients in Pegylated interferon alpha-2a (PEG-IFN-α-2a) treatment. To understand the regulation of HBV-miR-3 in host cells, the HBV-miR-3 recognition sites were predicted in host target genes using miRDB. The effect of HBV-miR-3 in host cells was examined using qPCR and 3' UTR dual luciferase assay.

Results: The read count of HBV-miR-3 was found in chronic hepatitis patients before treatment. Moreover, the decrease of HBV-miR-3 was correlated with response group of chronic hepatitis patients after treatment. On the other hand, the abundance of HBV-miR-3 showed no difference in nonresponse group of chronic patients after PEG-IFN-α-2a treatment. To study the role of HBV-miR-3 in patients, four HBV-miR-3 target regions from Protein phosphatase 1A (PPM1A) and DIX domain containing 1 (DIXDC1) were identified in the human genome using miRDB. Interestingly, we found that HBV-miR-3 hybridized with PPM1A mRNA. The mRNA expression from RT-qPCR showed no difference between HepG2 transfected with pSilencer_scramble or pSilencer_HBV-miR-3. However, the reporter assay showed that PPM1A mRNA was suppressed by HBV-miR-3. The protein expression of PPM1A showed a decrease in cells overexpressing HBV-miR-3. Finally, the HBV-miR-3 can promote cell proliferation in cells overexpressing HBV-miR-3.

Conclusion: This study is the first report showed the HBV encoded miRNA can regulate host gene expression. HBV-miR-3 silenced PPM1A by inhibiting the translation process of PPM1A. The downregulation of PPM1A promotes cell proliferation related to HCC development.
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http://dx.doi.org/10.2174/2211536608666191104105334DOI Listing
January 2020

Genetic associations of vitamin D receptor polymorphisms with advanced liver fibrosis and response to pegylated interferon-based therapy in chronic hepatitis C.

PeerJ 2019 11;7:e7666. Epub 2019 Sep 11.

Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.

Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the C > T (rs12979860) SNP and five VDR SNPs, comprising T > C (rs2228570), C > T (rs1544410), G > A (rs757343), C > A (rs7975232), and A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the rs1544410 C, rs7975232 C, and rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12-5.58], < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04-3.91], = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31-2.28], < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10-2.58], = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07-2.37], = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, = 0.03). The rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06-2.51], = 0.03) and age ≥55 years (OR = 2.25; 95% CI [1.54-3.32], < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.
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http://dx.doi.org/10.7717/peerj.7666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744935PMC
September 2019

Association between Hepatitis B Surface Antigen Levels and the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection: Systematic Review and Meta-Analysis.

Asian Pac J Cancer Prev 2019 08 1;20(8):2239-2246. Epub 2019 Aug 1.

Centre of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Thailand.

Background: The role of hepatitis B surface antigen (HBsAg) levels in predicting the risk of developing hepatocellular carcinoma (HCC) has remained unclear. The aim of this study was to obtain the most up-to-date estimated measure of the association between HBsAg levels and the development of HCC in patients. Methods: We performed a systematic review by searching for relevant studies on PubMed, Scopus, ProQuest and the Cochrane Central Register of Controlled Trials from January 2002 to November 2017. We presented the effects of HBsAg levels at each cut-off value as the odds ratios (ORs) at 95% confidence interval (CI). We also investigated HCC and its potential risk factors including HBeAg, and HBV DNA. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42018081138. Results: We selected 10 studies representing 12 541 cases. At the 100 IU/ml cut-off, the OR for HCC at the high HBsAg level versus the low level was 4.99 (95% CI, 3.01–8.29) with high inconsistency (I2=79%). At the 1,000 IU/ml threshold, the pooled OR for HCC at the high HBsAg versus the low level was 2.46 (95% CI, 2.15–2.83) with low variance. We also found correlations between the risk of HCC and male gender (OR=2.12), hepatitis B e-antigen positivity (OR=2.99), or hepatitis B (HBV) viral load ≥ 2,000 IU/ml (OR=4.37). Conclusion: Our study revealed that HBsAg levels ≥ 100 IU/ml, and notably >1,000 IU/ ml, are associated with an increased risk of HCC development.
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http://dx.doi.org/10.31557/APJCP.2019.20.8.2239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852811PMC
August 2019

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon-based therapy in patients with hepatitis B e antigen-negative chronic hepatitis B.

J Viral Hepat 2019 12 10;26(12):1481-1488. Epub 2019 Sep 10.

Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long-term outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG-IFN)-based therapy. Serial serum samples from 91 patients with HBeAg-negative CHB previously treated with PEG-IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post-treatment follow-up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre-treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut-off 2.0 log  copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut-off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG-IFN-based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising "stopping rule" in patients infected with HBV genotypes B or C.
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http://dx.doi.org/10.1111/jvh.13195DOI Listing
December 2019

Genetic variation in STAT4 is associated with treatment response to pegylated interferon in patients with chronic hepatitis B.

Asian Pac J Allergy Immunol 2019 Aug 18. Epub 2019 Aug 18.

Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Signaling pathways in the STAT4 gene play an essential role in interferon-mediated antiviral effects.

Objective: This study was aimed at investigating the role of rs7574865, a single nucleotide polymorphism (SNP) in STAT4, in patients with chronic hepatitis B (CHB) treated with pegylated interferon (PEG-IFN).

Methods: A total 261 Thai patients (115 HBeAg-positive and 146 HBeAg-negative CHB) treated with 48-week PEG-IFN were recruited. Virological response (VR) at 48 weeks post treatment was defined as HBeAg seroconversion plus HBV DNA < 2,000 IU/mL for HBeAg-positive CHB and HBV DNA < 2,000 IU/mL for HBeAg-negative CHB. The SNP was analyzed by TaqMan PCR assay.

Results: The distribution of GG, GT and TT genotypes of rs7574865 was 41.8%, 42.9% and 15.3%, respectively. There was no different in its distribution according to HBeAg status. Overall, patients with TT genotype, compared with non-TT genotype, achieved higher VR (64.3% vs. 30.5%; P < 0.001) and HBsAg clearance (23.8% vs. 5.0%; P < 0.001). There was the same trend in the HBeAg-positive group (VR, 52.4% vs. 30.9%; P = 0.077; HBsAg clearance, 23.8% vs. 6.4%; P = 0.028) and in the HBeAg-negative group (VR, 68.4% vs. 32.3%; P = 0.004; HBsAg clearance, 21.1% vs. 4.7%; P = 0.026). Multiple regression analysis demonstrated that low baseline HBsAg level and TT genotype were factors independently associated with VR and HBsAg clearance.

Conclusions: Our data support that SNP rs7574865 is associated with response to PEG-IFN therapy in Thai patients with CHB, regardless of baseline HBeAg status. Thus, the determination of this SNP could maximize cost-effectiveness of PEGIFN in patients with CHB.
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http://dx.doi.org/10.12932/AP-020419-0533DOI Listing
August 2019

Next generation sequencing identifies baseline viral mutants associated with treatment response to pegylated interferon in HBeAg-positive chronic hepatitis B.

Virus Genes 2019 Oct 29;55(5):610-618. Epub 2019 Jul 29.

Department of Biochemistry, Faculty of Medicine, Center of Excellence in Hepatitis and Liver Cancer, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand.

Current data of hepatitis B virus (HBV) variants associated with treatment outcome identified by next generation sequencing (NGS) are limited. This study was aimed at determining the role of baseline sequence variations in the enhancer II (EnhII), basal core promotor (BCP) and pre-core (PC) regions of HBV genotype C in patients treated with pegylated interferon (PEG-IFN). Patients with HBeAg-positive chronic hepatitis B (CHB) treated with 48-week PEG-IFN were enrolled. Combined response (CR) at week 96 was defined by HBeAg seroconversion plus HBV DNA < 2000 IU/mL and HBsAg < 1000 IU/mL. Pre-treatment viral mutations were characterized by Sanger sequencing and NGS (Miseq Illumina platform). Among 47 patients (32 male, mean age 32.4 years), CR was achieved in 12 (25.5%) individuals. Overall, NGS was superior to Sanger sequencing in detecting mutations (61.7% vs. 38.3%, P < 0.001). Based on NGS, the prevalence of T1753V (T1753C/A/G) and A1762T/G1764A variants were significantly lower in responders compared to non-responders (8.3% vs. 51.4%, P = 0.009 and 33.3% vs. 68.6%, P = 0.032, respectively). No significant difference between groups was found regarding C1653T and G1896A mutants. The absence of T1753V and A1762T/G1764A mutations were factors associated with CR (OR 11.65, 95%CI 1.36-100.16, P = 0.025, and OR 4.36, 95%CI 1.08-17.63, P = 0.039, respectively). The existence of pre-treatment T1753V, A1762T/G1764A mutations and their combination yielded negative predictive values of 94.7%, 85.7% and 93.8%, respectively. The presence of HBV mutants in the BCP region determined by NGS at baseline was associated with poor treatment outcome in patients with HBeAg-positive CHB receiving PEG-IFN.
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http://dx.doi.org/10.1007/s11262-019-01689-5DOI Listing
October 2019

Association of NTCP polymorphisms with clinical outcome of hepatitis B infection in Thai individuals.

BMC Med Genet 2019 05 22;20(1):87. Epub 2019 May 22.

Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.

Background: Single nucleotide polymorphisms (SNPs) in the sodium taurocholate co-transporting polypeptide (NTCP) have been showed to be associated with natural history of hepatitis B virus (HBV) infection. However, it is unclear whether the SNPs are related to the clinical outcome of HBV infection in Thai individuals.

Methods: The rs2296651 and rs4646287 polymorphisms of NTCP were determined by allelic discrimination using commercial TaqMan probes in blood samples of 1021 Thai individuals. These subjects included 610 patients with chronic HBV infection [CHB, 305 with hepatocellular carcinoma (HCC) and 305 without HCC], 206 subjects with spontaneous HBV clearance and 205 healthy controls who were age and gender-matched.

Results: The frequencies of rs2296651 A minor allele in the CHB group, the HBV clearance group and healthy controls were 7.8, 7.3 and 13.9%, respectively. For rs4646287, the frequencies of T minor allele of the corresponding groups were 10.4, 8.0 and 9.5%, respectively. Compared with healthy controls, the frequencies of rs2296651 GA + AA genotypes were significantly lower in the CHB group (P < 0.001) and in the HBV clearance group (P = 0.001). There was no difference in their distribution between the HBV clearance and CHB groups. Among the CHB group, the distribution of GA + AA genotypes in patients with HCC were significantly lower than in patients without HCC (P = 0.014). The frequencies of HBeAg positivity in patients harboring GG and GA + AA genotypes were 39.8 and 23.5%, respectively (P = 0.004). Among patients with HCC, the mean HBV DNA of the corresponding genotypes were 4.9 ± 1.3 vs. 2.7 ± 1.0 log IU/mL, respectively (P < 0.001). There was no difference in genotype and allele frequencies of rs4646287 polymorphism among all studied groups.

Conclusions: Our results showed that rs2296651 polymorphism was associated with a decreased risk of susceptibility to HBV infection and the development of HCC. These data suggest that the NTCP polymorphism might have an influence on natural history of HBV infection in Thai individuals. This abstract was partly presented at the American Association for the Study of Liver Diseases (AASLD) Meeting 2018, November 9-13, 2018, in San Francisco, CA, USA and was published in Hepatology 2018; 68:1237A-1238A.
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http://dx.doi.org/10.1186/s12881-019-0823-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532194PMC
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

Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands.

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

The expression profile of Jagged1 and Delta-like 4 in hepatocellular carcinoma.

Asian Pac J Allergy Immunol 2021 Mar;39(1):44-52

Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Notch signaling has been linked to many cancers. However, there is still limited information about the expression and role of the Notch ligand in hepatocellular carcinoma (HCC).

Objective: To investigate the expression of JAG1 and DLL4 in HCC tissues.

Methods: One hundred and forty-five HCC tissues in paraffin block since 2009 to 2016 at King Chulalongkorn Memorial hospital were assayed for JAG1 and DLL4 by immunohistochemistry. All the sections were separately analyzed in tumor and adjacent non-tumor tissue and scoring based on intensity and quantity of immunoreaction. Kruskal-Wallis H test examined the correlation between JAG1 and DLL4 protein expression and clinical pathology.

Results: The expression of JAG1 and DLL4 of tumor cells is 57.2% (83/145) and 88.9% (129/145), respectively. The expression of JAG1 is significantly higher in tumor tissues than adjacent non-tumor tissues (P = 0.002), and significantly increased in patients with age < 60 years old (P = 0.007). Interestingly, the DLL4 expression is also expressed in the normal liver tissue and DLL4 expression is not associated with any of the clinical parameters. When we performed a subgroup analysis, in HCC patients without a viral infection analysis, JAG1 is significantly increased in HCC patients with low albumin level (≤ 3.5) (P = 0.043).

Conclusions: JAG1 expression is increased in HCC and seems to correlate with HCC patients with earlier onset and lower albumin level, whereas DLL4 expression did not significantly correlate with any clinical features.
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http://dx.doi.org/10.12932/AP-040818-0388DOI Listing
March 2021

Circulating BAFF and CXCL10 levels predict response to pegylated interferon in patients with HBeAg-positive chronic hepatitis B.

Asian Pac J Allergy Immunol 2019 Jan 13. Epub 2019 Jan 13.

Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Thailand.

Background: B-cell activating factor (BAFF), an essential cytokine for B lymphocytes activation, has been implicated in the pathogenesis of chronic viral hepatitis. However, the role of BAFF in patients with chronic hepatitis B (CHB) undergoing antiviral therapy is unknown.

Methods: Patients with HBeAg-positive CHB treated with 48-week pegylated interferon (PEG-IFN; n = 42), who had stored plasma samples during treatment were recruited. Serial plasma levels of BAFF and C-X-C motif chemokine 10 (CXCL10) during therapy were measured.

Results: Combined response (CR), defined as HBeAg seroconversion with HBV DNA < 2,000 IU/mL plus HBsAg decline ≥ 1 log10 IU/mL at 24 weeks post-treatment, was achieved in 11 (26.2%) patients. BAFF levels were elevated during treatment but decreased to pre-treatment levels after PEG-IFN cessation in both responders and non-responders. Low baseline BAFF (< 770 pg/ml) and high CXCL10 (≥ 320 pg/ml) levels were independently associated with CR in multivariate analysis. Baseline CXCL10/BAFF ratio of ≥ 0.45 was predictive of CR with positive and negative predictive values of 61.5 and 89.7%, respectively.

Conclusions: In summary, low baseline BAFF and high CXCL10 levels were associated with treatment response to PEGIFN. The combined measurement of these immune markers may help individualized decision-making in patients with HBeAg-positive CHB.
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http://dx.doi.org/10.12932/AP-050718-0365DOI Listing
January 2019