Publications by authors named "Teerha Piratvisuth"

78 Publications

Role of lactulose for prophylaxis against hepatic encephalopathy in cirrhotic patients with upper gastrointestinal bleeding: A randomized trial.

Indian J Gastroenterol 2021 Jun 15. Epub 2021 Jun 15.

NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Background: We aimed to assess the efficacy of lactulose as prophylaxis against hepatic encephalopathy (HE) in cirrhotic patients with acute upper gastrointestinal bleeding (AUGIB).

Methods: We conducted a randomized, double-blinded, placebo-controlled, multicenter study from October 2012 to February 2014. Cirrhotic patients presenting with AUGIB (aged 18-80 years, without HE at the time of admission) were enrolled and randomized to receive blinded medications (both physically indistinguishable), labeled "Lactulose A" and "Lactulose B" for 5 days along with standard treatment depending on the type of bleeding (variceal and nonvariceal). The primary endpoint was the development of overt HE according to the West-Haven criteria. Modified intention-to-treat analysis was performed.

Results: Forty-six patients completed the protocol: Lactulose A (placebo, n = 22) and Lactulose B (lactulose, n = 24). There was no significant difference in baseline characteristics and clinical outcomes between the two groups. Nine (19.6%) patients developed HE: five (22.7%) in the placebo group and four (16.7%) in the lactulose group (p = 0.718). One patient (2.2%) died in lactulose group. All patients tolerated the medication and no significant difference in adverse effects was detected (59.1% in placebo vs. 50.0% in lactulose group, p = 0.536). On multivariate analysis, increased baseline Child-Turcotte-Pugh (CTP) score (odds ratio [OR] 2.176; 95% confidence interval [CI] 1.012-4.681, p = 0.047) and presence of diarrhea (OR 16.261; 95% CI 1.395-189.608, p = 0.026) were independent risk factors for the development of HE.

Conclusion: Five-day lactulose is ineffective as prophylaxis against HE in cirrhotic patients with AUGIB. Unnecessary treatment with laxatives should be avoided in these patients.

Trial Registration: Clinical trial registry number TCTR20200526003 (retrospectively registered).
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http://dx.doi.org/10.1007/s12664-021-01150-2DOI Listing
June 2021

Clinical Features, Endoscopic Findings, and Predictive Factors for Mortality in Tissue-Invasive Gastrointestinal Cytomegalovirus Disease between Immunocompetent and Immunocompromised Patients.

Gastroenterol Res Pract 2021 6;2021:8886525. Epub 2021 Apr 6.

NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Songkla 90110, Thailand.

Background And Aims: Tissue-invasive gastrointestinal cytomegalovirus (TI-GI CMV) disease is common in immunocompromised patients, but the increasing prevalence in immunocompetent patients has been reported. This study compared the clinical manifestations, endoscopic features, treatment outcomes, and predictors for inhospital mortality of TI-GI CMV between immunocompromised and immunocompetent patients.

Methods: Patients with HIV infection, malignancy, or receiving immunosuppressive agents (chemotherapy, high dose, or long-term corticosteroids) were defined as the immunocompromised group. Demographic and inhospital mortality data were obtained and retrospectively analyzed.

Results: A total of 213 patients (89 immunocompetent) with histologically confirmed TI-GI CMV were enrolled. Immunocompetent patients were older (70 vs. 52 years; < 0.001), had more GI bleeding as a presenting symptom (47.2% vs. 29.0%; = 0.010), and shorter symptom onset (2 vs. 14 days, = 0.018). Concomitant extra-GI involvement was only seen in the immunocompromised group (6.5% vs. 0%; = 0.02). Diffuse GI tract (14.5% vs. 4.5%; = 0.032) and esophageal involvement (14.5% vs. 5.6%; = 0.046) were more frequent in the immunocompromised, while small bowel involvement was more frequent in the immunocompetent group (19.1% vs. 8.1%; = 0.029). An overall inhospital mortality was 27.7%. There was no significant difference in inhospital survival probability between the two groups (Peto-Peto test, = 0.65). ICU admission (hazard ratio [HR] 7.21; 95% CI 2.55-20.36), sepsis or shock (HR 1.98; 95% CI 1.08-3.66), malnutrition (HR 2.62; 95% CI 1.05-7.01), and receiving chemotherapy (HR 5.2; 95% CI 1.89-14.29) were independent factors for inhospital mortality. Antiviral treatment for more than 14 days was the only protective factor to improve survival (Peto-Peto test, < 0.001).

Conclusions: Immunocompetent and immunocompromised patients with TI-GI CMV disease had distinct clinical and endoscopic characteristics. There was no significant difference in the inhospital mortality between the two groups. The factors for mortality were ICU admission, sepsis/shock, malnutrition, and receiving chemotherapy. Early diagnosis and initiation of antiviral treatment might improve the survival probability.
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http://dx.doi.org/10.1155/2021/8886525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052155PMC
April 2021

Validation of the "Six-and-Twelve" Prognostic Score in Transarterial Chemoembolization-Treated Hepatocellular Carcinoma Patients.

Clin Transl Gastroenterol 2021 02 18;12(2):e00310. Epub 2021 Feb 18.

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

Introduction: The "six-and-twelve" prognostic score was proposed recently to predict survival rate in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). However, it has not been validated externally. We validated this score and previous prognostic scores in Thai HCC patients treated with TACE.

Methods: We identified all HCC patients who underwent TACE between January 2007 and December 2018 at our hospital. The inclusion criteria were treatment-naive, unresectable HCC BCLC-A and BCLC-B; if cirrhosis was present, Child-Pugh score ≤7; and baseline performance status 0-1.

Results: Of 716 HCC patients undergoing TACE, 281 (mean age, 61.1 years; 73.0% men, 92.2% with cirrhosis) were eligible. Approximately half of the patients had hepatitis B virus. Median overall survival was 20.3 (95% confidence interval, 16.4-26.3) months. By stratifying with the "six-and-twelve" score (≤6, >6-12, >12), median (95% confidence interval) overall survival was 35.1 (26.4-53.0), 16.0 (11.6-22.6), and 7.6 (5.4-14.9) months, respectively. Area under the receiver operating characteristic curves (AUROCs) predicting death at 1, 2, and 3 years for the "six-and-twelve" score were 0.714, 0.700, and 0.688, respectively. Compared with the other currently available scores, the AUROC predicting death at 1 year for the "six-and-twelve" score was the most predictive and better than other models except the up-to-seven model.

Discussion: Our study confirms the value of the "six-and-twelve" score to predict survival rate of unresectable HCC treated with TACE. However, in our validation cohort, AUROC of the "six-and-twelve" score was slightly lower than that of the original Chinese cohort (0.73).
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http://dx.doi.org/10.14309/ctg.0000000000000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899857PMC
February 2021

Alcohol-Associated Liver Disease: East Versus West.

Clin Liver Dis (Hoboken) 2020 Dec 13;16(6):231-235. Epub 2021 Jan 13.

Division of Gastroenterology and Hepatology Department of Medicine Faculty of Medicine Prince of Songkla University Songkhla Thailand.

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http://dx.doi.org/10.1002/cld.920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805304PMC
December 2020

Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE).

Clin Gastroenterol Hepatol 2020 Dec 10. Epub 2020 Dec 10.

Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

Background & Aims: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation.

Methods: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders.

Results: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001).

Conclusions: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.
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http://dx.doi.org/10.1016/j.cgh.2020.12.005DOI Listing
December 2020

Very low probability of significant liver inflammation in chronic hepatitis B patients with low ALT levels in the absence of liver fibrosis.

Aliment Pharmacol Ther 2020 10 4;52(8):1399-1406. Epub 2020 Sep 4.

Rotterdam, The Netherlands.

Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment.

Aim: To study rates and determinants of clinically significant liver inflammation.

Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC-B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2).

Results: The cohort included 2991 patients; 1672 were HBeAg-positive. ALT was < ULN in 270 (9%), 1-2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1-2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis.

Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non-invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged.
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http://dx.doi.org/10.1111/apt.16067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540526PMC
October 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

An expert review on the use of tenofovir alafenamide for the treatment of chronic hepatitis B virus infection in Asia.

J Gastroenterol 2020 Sep 14;55(9):811-823. Epub 2020 Jul 14.

PMC, Allied and DHQ Hospital, Faisalabad, Pakistan.

Asia has intermediate-to-high prevalence and high morbidity of hepatitis B virus (HBV) infection. The use of guideline-recommended nucleos(t)ide analogs with high barrier to resistance, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), is one of the key interventions for curbing HBV infection and associated morbidity in Asia. However, there are some challenges to the use of ETV and TDF; while ETV is associated with high resistance in lamivudine (LAM)-exposed (especially LAM-refractory) patients; bone and renal safety issues are a major concern with TDF. Hence, a panel of twenty-eight expert hepatologists from Asia convened, reviewed the literature, and developed the current expert opinion-based review article for the use of TAF in the resource-constrained settings in Asia. This article provides a comprehensive review of two large, phase 3, double-blind, randomized controlled trials of TAF versus TDF in HBeAg-negative (study 0108) and HBeAg-positive (study 0110) chronic HBV patients (> 70% Asians). These studies revealed as follows: (1) non-inferiority for the proportion of patients who had HBV DNA < 29 IU/mL; (2) significantly high rate of normalization of alanine aminotransferase levels; (3) no incidence of resistance; and (4) significantly better bone and renal safety, with TAF vs. TDF up to 144 weeks. Considering the benefits of TAF, the expert panel proposed recommendations for optimizing the use of TAF in Asia, along with guidance on specific patient groups at risk of renal or bone disease suitable for TAF therapy. The guidance provided in this article may help clinicians optimize the use of TAF in Asia.
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http://dx.doi.org/10.1007/s00535-020-01698-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452871PMC
September 2020

Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study).

Hepatol Int 2020 Sep 4;14(5):690-700. Epub 2020 Jul 4.

Division of Hepatobiliary, Cipto Mangunkusuamo Hospital, University of Indonesia, Jakarta, Indonesia.

Background And Aims: COVID-19 is a dominant pulmonary disease, with multisystem involvement, depending upon comorbidities. Its profile in patients with pre-existing chronic liver disease (CLD) is largely unknown. We studied the liver injury patterns of SARS-Cov-2 in CLD patients, with or without cirrhosis.

Methods: Data was collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19.

Results: Altogether, 228 patients [185 CLD without cirrhosis and 43 with cirrhosis] were enrolled, with comorbidities in nearly 80%. Metabolism associated fatty liver disease (113, 61%) and viral etiology (26, 60%) were common. In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR = 2.1 (1.1-3.7), p = 0.01] and in cirrhotics, obesity, [64.3% vs. 17.2%, OR = 8.1 (1.9-38.8), p = 0.002] predisposed more to liver injury than those without these. Forty three percent of CLD without cirrhosis presented as acute liver injury and 20% cirrhotics presented with either acute-on-chronic liver failure [5 (11.6%)] or acute decompensation [4 (9%)]. Liver related complications increased (p < 0.05) with stage of liver disease; a Child-Turcotte Pugh score of 9 or more at presentation predicted high mortality [AUROC 0.94, HR = 19.2 (95 CI 2.3-163.3), p < 0.001, sensitivity 85.7% and specificity 94.4%). In decompensated cirrhotics, the liver injury was progressive in 57% patients, with 43% mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis patients.

Conclusions: SARS-Cov-2 infection causes significant liver injury in CLD patients, decompensating one fifth of cirrhosis, and worsening the clinical status of the already decompensated. The CLD patients with diabetes and obesity are more vulnerable and should be closely monitored.
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http://dx.doi.org/10.1007/s12072-020-10072-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334898PMC
September 2020

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

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

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

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

hbsag levels can be used to rule out cirrhosis in hbeag positive chronic hepatitis b: results from the sonic-b study.

J Infect Dis 2020 Apr 21. Epub 2020 Apr 21.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background & Aims: Serum HBsAg levels correlate with the duration of chronic HBV infection and may predict the extent of hepatic fibrosis.

Methods: We analysed data from the SONIC-B database, which contains data from 8 global randomized trials and two large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored and clinically relevant cut-offs were identified to rule out cirrhosis.

Results: The dataset included 2779 patients; 1866 HBeAg-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (Odds Ratio [OR] 0.419, P<0.001) and cirrhosis (OR 0.435, p<0.001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype specific HBsAg cut-offs had excellent NPVs (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cut-offs was comparable among patients in whom cirrhosis could not be ruled out with FIB-4.

Conclusions: HBV genotype specific HBsAg cut-offs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C and D and can be an adjunct to FIB-4 to reduce the need for further testing.
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http://dx.doi.org/10.1093/infdis/jiaa192DOI Listing
April 2020

Final analysis of the international observational S-Collate study of peginterferon alfa-2a in patients with chronic hepatitis B.

PLoS One 2020 10;15(4):e0230893. Epub 2020 Apr 10.

Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background And Aims: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma.

Methods: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up.

Results: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions.

Conclusions: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230893PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147799PMC
July 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

Re-bleeding and its predictors after capsule endoscopy in patients with obscure gastrointestinal bleeding in long-term follow-up.

BMC Gastroenterol 2019 Dec 16;19(1):216. Epub 2019 Dec 16.

Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand.

Background: Capsule endoscopy (CE) is the preferred diagnostic test of choice in the investigation of obscure gastrointestinal bleeding (OGIB). Although, a conservative strategy is recommended in the short-term, for cases with a negative result from CE, the impact of CE on long-term re-bleeding still remains unclear. Hence, the aim of this study was to determine the long-term re-bleeding rate along with predictors after CE in patients with OGIB.

Methods: We retrospectively reviewed 216 patients with OGIB, whom had received a CE examination, so as to investigate the cause of obscure GI bleeding; between July 2008 and March 2018. The patient's characteristics, medication use, CE finding, treatments strategy, re-bleeding episodes and follow-up information were collected from the institutional electronic medical chart and CE database. Re-bleeding free survival was evaluated using Kaplan-Meier curves with log rank test, whilst predictors associated with the re-bleeding episodes were analyzed via the use of Cox proportional hazard model.

Results: One hundred and thirty-three patients with OGIB, having received CE were enrolled in the analysis. The pool rate of re-bleeding was 26.3% (35/133) during a follow-up duration of 26 months after CE. Patients with positive CE study, without specific treatment, had higher rates of re-bleeding (47.6%) than those with positive study whom received specific treatment (25.7%), and negative study (20.8%) (p = 0.042). Although, the re-bleeding free survival was not significantly different among the groups (log rank test; P = 0.10). Re-bleeding events occurring within 6, 12, and 24 months after CE were 36, 64 and 92%, respectively. The high-frequency re-bleeding etiologies were the small bowel angiodysplasias and abnormal vascular lesions. Furthermore, independent predictors for re-bleeding after CE were patients with cirrhosis (hazard ratio, HR 4.06), incomplete CE visualization (HR 2.97), and a history of previous GI bleeding (HR 2.80).

Conclusions: The likelihood of re-bleeding after CE was higher in patients with positive CE study than those with negative study. Specific treatments, or therapeutic interventions for patients with detectable lesions reduced the probability of re-bleeding episodes in long-term follow-up. Close follow-up for recurrent bleeding is recommeded for at least 2 years after CE.
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http://dx.doi.org/10.1186/s12876-019-1137-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916023PMC
December 2019

Validation of original, expanded Baveno VI, and stepwise & platelet-MELD criteria to rule out varices needing treatment in compensated cirrhosis from various etiologies.

Ann Hepatol 2020 Mar - Apr;19(2):209-213. Epub 2019 Sep 25.

Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Introduction And Objectives: The Baveno VI criteria to rule out varices needing treatment (VNT) was introduced in 2015. Soon after, the expanded Baveno VI and stepwise platelet-MELD criteria were proposed to be equal/more accurate in ruling out VNT; however, neither has been widely validated. We aimed to validate all 3 criteria in compensated cirrhosis from assorted causes.

Materials And Methods: We conducted a cross-sectional study including all adult compensated cirrhotic patients who underwent endoscopic surveillance at our center from 2014 to 2018 and had transient elastography (TE), and laboratory data for criteria calculation within 6 months of endoscopies. Exclusion criteria were previous decompensation, unreliable/invalid TE results, and liver cancer. The diagnostic performances of all criteria were evaluated.

Results: A total of 128 patients were included. The major cirrhosis etiologies were hepatitis C and B (37.5% and 32.8%, respectively). VNT was observed in 7.8%. All criteria yielded high negative predictive values (NPVs)>95%, missed VNT was observed in 2%, 2.7%, and 2.8% in the original, expanded Baveno VI, and platelet-MELD criteria, respectively. The expanded Baveno VI and the platelet-MELD criteria yielded significantly better specificities and could spare more endoscopies than the original Baveno VI criteria.

Conclusions: All 3 criteria showed satisfactorily high NPVs in ruling out VNT in compensated cirrhosis from various causes. The expanded Baveno VI and the platelet-MELD criteria could spare more endoscopies than the original Baveno VI criteria. From a public health standpoint, the platelet-MELD criteria might be useful in a resource-limited setting where TE is not widely available.
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http://dx.doi.org/10.1016/j.aohep.2019.08.005DOI Listing
February 2021

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

Hepatitis B screening rates and reactivation in solid organ malignancy patients undergoing chemotherapy in Southern Thailand.

Clin Mol Hepatol 2019 12 17;25(4):366-373. Epub 2019 Jul 17.

Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.

Background/aims: Hepatitis B virus reactivation (HBVr) following chemotherapy (CMT) is well-known among hematologic malignancies, and screening recommendations are established. However, HBVr data in solid organ malignancy (SOM) patients are limited. This study aims to determine hepatitis B surface antigen (HBsAg) screening rates, HBV prevalence, and the rate of significant hepatitis caused by HBVr in SOM patients undergoing CMT.

Methods: Based on the Oncology unit's registration database from 2009-2013, we retrospectively reviewed records of all SOM patients ≥18 years undergoing CMT at Songklanagarind Hospital who were followed until death or ≥6 months after CMT sessions. Exclusion criteria included patients without baseline liver function tests (LFTs) and who underwent CMT before the study period. We obtained and analyzed baseline clinical characteristics, HBsAg screening, and LFT data during follow-up.

Results: Of 3,231 cases in the database, 810 were eligible. The overall HBsAg screening rate in the 5-year period was 27.7%. Screening rates were low from 2009-2012 (7.8-21%) and increased in 2013 to 82.9%. The prevalence of HBV among screened patients was 7.1%. Of those, 75% underwent prophylactic antiviral therapy. During the 6-month follow-up period, there were three cases of significant hepatitis caused by HBVr (4.2% of all significant hepatitis cases); all were in the unscreened group.

Conclusion: The prevalence of HBV in SOM patients undergoing CMT in our study was similar to the estimated prevalence in general Thai population, but the screening rate was quite low. Cases of HBVr causing significant hepatitis occurred in the unscreened group; therefore, HBV screening and treatment in SOM patients should be considered in HBV-endemic areas.
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http://dx.doi.org/10.3350/cmh.2018.0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933120PMC
December 2019

Vitamin D-Binding protein Gene Polymorphism Predicts Pegylated Interferon-Related HBsAg Seroclearance in HBeAg-Negative Thai Chronic Hepatitis B Patients: A Multicentre Study

Asian Pac J Cancer Prev 2019 Apr 29;20(4):1257-1264. Epub 2019 Apr 29.

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

Background: Vitamin D deficiency is related to poor clinical outcomes in patients with chronic hepatitis B virus (HBV) infection. Methods: We aimed to investigate the association between the genetic variants in the vitamin D metabolic pathway and the response to pegylated interferon (Peg-IFN) therapy in patients with HBeAg-negative chronic HBV infection. One hundred seven patients treated with Peg-IFN for 48 weeks were selected from 13 specialty hospitals. Eight genotypes of vitamin D cascade genes, including CYP27B1 (rs10877012), DHCR7 (rs12785878), CYP2R1 (rs2060793, rs12794714) and GC (rs4588, rs7041, rs222020, rs2282679), were found. Results: Eighty-two patients (83.7%) were infected with HBV genotype C. Eight patients had compensated liver cirrhosis (8.7%). At 24 weeks after treatment discontinuation, 41 patients (42.3%) achieved sustained treatment response, 53 (55.2%) obtained HBV DNA<2,000 IU/ml, 6 (5.6%) gained HBsAg seroclearance, 2 (1.9%) had HBsAg seroconversion and 69 (64.5%) exhibited alanine aminotransferase (ALT) normalization. Multivariate analysis revealed that baseline HBsAg level (OR =0.06, 95% CI: 0.08-0.49, p=0.008) and the GC rs222020 TT genotype (OR=17.72, 95% CI: 1.07-294.38, p=0.04) independently predicted sustained HBsAg seroclearance. In addition, this genotype was a predictor for normalization of ALT (OR=4.61, 95%CI: 1.59-13.40, p=0.005) after therapy. The HBsAg levels at baseline and during and post-treatment tended to be reduced with the GC rs222020 TT compared with the non-TT genotypes. The other studied polymorphisms were not associated with treatment response. Conclusions: The GC rs222020 TT genotype, which is a variant in the vitamin D-binding protein gene, could identify HBeAg-negative patients who have a high probability to achieve HBsAg clearance and ALT normalization after treatment with Peg-IFN.
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http://dx.doi.org/10.31557/APJCP.2019.20.4.1257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948901PMC
April 2019

Optimisation of the use of APRI and FIB-4 to rule out cirrhosis in patients with chronic hepatitis B: results from the SONIC-B study.

Lancet Gastroenterol Hepatol 2019 07 9;4(7):538-544. Epub 2019 Apr 9.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Toronto Centre for Liver Disease, University Health Network, Toronto, Canada. Electronic address:

Background: Ruling out the presence of cirrhosis is important for the management of chronic hepatitis B. We aimed to study and optimise the performance of two non-invasive indices for ruling out cirrhosis: the aspartate aminotransferase-platelet ratio index (APRI) and fibrosis score based on four factors (FIB-4).

Methods: We applied established cutoffs to rule in (APRI >2·00; FIB-4 >3·25) or rule out (APRI <1·00; FIB-4 <1·45) cirrhosis to data from eight global randomised trials that required baseline biopsy, and identified new cutoffs aiming for a sensitivity for detection of cirrhosis greater than 90% and a negative predictive value (NPV) of greater than 95% in the same dataset. We externally validated the new cutoffs using data from all consecutive biopsied patients from two tertiary referral hospitals in the Netherlands and Canada.

Findings: In the derivation dataset (n=2926; of whom 1750 were Asian); 340 (12%) individuals had cirrhosis. The validation cohort consisted of 1034 individuals (of whom 575 were Asian), with 155 (15%) individuals with cirrhosis. Application of conventional cutoffs for FIB-4 in the derivation dataset yielded unclassifiable results in 686 (23%) individuals, and 139 (41%) of the 340 patients with cirrhosis were misclassified as having no cirrhosis. Similarly, conventional cutoffs for APRI in the derivation dataset yielded unclassifiable results in 706 (24%) individuals, and 153 (45%) were misclassified as having no cirrhosis. An APRI of 0·45 or less had sensitivity of 91·5%, an NPV of 95·4%, and misclassified 29 (9%) of 340 individuals with cirrhosis in the derivation dataset, but performance was reduced in the validation set (22 [14%] of 155 individuals with cirrhosis misclassified). A FIB-4 score of 0·70 had a sensitivity of 90·9%, an NPV of 96·6%, and misclassified 31 (9%) of individuals with cirrhosis in the derivation dataset. In the validation cohort, the same score gave a sensitivity of 94·2%, an NPV of 97·3%, and misclassified nine (6%) of the individuals with cirrhosis. Subgroup analysis indicated that the new FIB-4 cutoff performed acceptably in all subgroups except for individuals aged 30 years or younger.

Interpretation: Conventional cutoffs for APRI and FIB-4 should not be used to guide management of patients with chronic hepatitis B due to high rates of misclassification. A newly identified and externally validated cutoff for FIB-4 (≤0·70) can be used to exclude cirrhosis in patients over 30 years of age.

Funding: Foundation for Liver and Gastrointestinal Research, Rotterdam, Netherlands.
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http://dx.doi.org/10.1016/S2468-1253(19)30087-1DOI Listing
July 2019

Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B.

J Viral Hepat 2019 09 23;26(9):1040-1049. Epub 2019 Jul 23.

Roche Products Ltd, Welwyn Garden City, UK.

In a multicentre, genome-wide association study to identify host genetic factors associated with treatment response in adult chronic hepatitis B patients, genotype data were obtained by microarray analysis from 1669 patients who received peginterferon alfa-2a for ≥ 24 weeks with/without a nucleos(t)ide analog. Treatment response was assessed at least 24 weeks post-treatment, using serological and/or virological endpoints. Thirty-six single-marker analyses and a gene-by-gene analysis were conducted. No single nucleotide polymorphisms (SNPs) achieved genome-wide significance (P < 5 × 10 ) in single-marker analyses, but suggestive associations (P < 1 × 10 ) were identified for 116 SNPs. In gene-by-gene analyses, one gene, FCER1A (rs7549785), reached genome-wide significance (P = 2.65 × 10 ) in East Asian patients for hepatitis B surface antigen (HBsAg) clearance, with a moderate effect size (odds ratio = 4.74). Eleven of 44 carriers (25%) of the A allele at rs7549785 achieved HBsAg clearance compared with 69/1051 (7%) noncarriers. FCER1A encodes the alpha subunit of the immunoglobulin E receptor. In a post hoc analysis of a homogenous patient subset, the strongest intragenic association was for rs7712322 (POLR3G, P = 7.21 × 10 ). POLR3G encodes the G subunit of the polymerase (RNA) III enzyme, involved in sensing and limiting infection by intracellular bacteria and DNA viruses, and as a DNA sensor in innate immune responses. FCER1A (rs7549785) and possibly POLR3G (rs7712322) are shown to be associated with peginterferon alfa-2a response in adult patients with chronic hepatitis B. Independent confirmation of these findings is warranted (clinicaltrials.gov number NCT01855997).
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http://dx.doi.org/10.1111/jvh.13107DOI Listing
September 2019

Peginterferon alfa-2a (40 kD) stopping rules in chronic hepatitis B: a systematic review and meta-analysis of individual participant data.

Antivir Ther 2019 ;24(2):133-140

Roche Products Ltd, Welwyn Garden City, United Kingdom.

Background: Peginterferon alfa-2a (PEG-IFN) treatment stopping rules in chronic hepatitis B (CHB) are clinically desirable. Previous studies exploring this topic contained important limitations resulting in inconsistent recommendations within the current treatment guidelines. We undertook a systematic review and individual patient data meta-analysis to identify the most appropriate PEG-IFN treatment stopping rules.

Methods: Roche's internal database, PubMed and conference abstracts were searched for studies that enrolled >50 treatment-naive patients with CHB who received PEG-IFN treatment for 48 weeks. Stopping rules were identified using receiver-operating characteristic curve analyses and pre-specified biomarker cutoff target performance characteristics (sensitivity >95%, specificity >10%, negative predictive value >90%). Robustness of proposed stopping rules was assessed using internal/external validation analyses.

Results: Eight study datasets were included in the meta-analysis (n=1,423; 765 hepatitis B e antigen [HBeAg]-positive, 658 HBeAg-negative patients). In general, performance of hepatitis B surface antigen (HBsAg) and HBV DNA cutoffs at weeks 12 and 24 was similar, and common biomarker cutoffs that met target performance criteria were identified across multiple patient subgroups. For HBeAg-positive genotype B/C and HBeAg-negative genotype D patients the proposed stopping rule is HBsAg >20,000 IU/ml at week 12. Alternatively, HBV DNA level cutoffs of >8 log and >6.5 log IU/ml, respectively, can be used instead. The proposed stopping rules accurately identify up to 26% of non-responders.

Conclusions: The meta-analysis demonstrates that early PEG-IFN discontinuation should be considered in HBeAg-positive genotype B/C and HBeAg-negative genotype D patients at week 12 of treatment based on HBsAg or HBV DNA levels.
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http://dx.doi.org/10.3851/IMP3304DOI Listing
May 2020

Safety margin of embolized area can reduce local recurrence of hepatocellular carcinoma after superselective transarterial chemoembolization.

Clin Mol Hepatol 2019 03 28;25(1):74-85. Epub 2019 Feb 28.

NKC Institute of Gastroenterology and Hepatology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Background/aims: We aimed to determine the relationship between the safety margin of an embolized area and local tumor recurrence (LTR) of patients with hepatocellular carcinoma (HCC) who underwent superselective transarterial chemoembolization (TACE).

Methods: The medical records of 77 HCC patients with 109 HCC nodules who underwent superselective TACE were retrospectively analyzed for LTR. Univariate and multivariate analyses were performed for 16 potential factors using Cox proportional hazard regression. Iodized oil deposition on cone-beam computed tomography (CBCT) imaging was divided into three grades: A=complete tumor staining and complete circumferential safety margin, B=complete tumor staining but incomplete safety margin, C=incomplete tumor staining. The effect of a safety margin on LTR was evaluated by comparison between grade A and B group.

Results: Univariate and multivariate analyses revealed that grade A iodized oil deposition and portal vein visualization were the only two independent significant factors of LTR (P<0.001 and P=0.029, respectively). The 12- and 24-month LTR rates of tumors for grade A (n=62), grade B (n=30), and grade C (n=17) were 16% vs. 41% vs. 100% and 16% vs. 61% vs. 100%, respectively (P<0.001). The tumors in the grade A group had a 75% risk reduction in LTR (odds ratio, 0.25; 95% confidence interval, 0.10 to 0.64; P=0.004) compared to the grade B group.

Conclusion: LTR was significantly lower when a greater degree of iodized oil deposition occurred with a complete circumferential safety margin. In superselective TACE, the safety margin of the embolized areas using intraprocedural CBCT affected LTR in HCC patients.
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http://dx.doi.org/10.3350/cmh.2018.0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435972PMC
March 2019

Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial.

Lancet Gastroenterol Hepatol 2019 02 14;4(2):127-134. Epub 2018 Dec 14.

Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes.

Methods: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed.

Findings: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment.

Interpretation: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(18)30343-1DOI Listing
February 2019

Findings from a large Asian chronic hepatitis C real-life study.

J Viral Hepat 2018 12 27;25(12):1533-1542. Epub 2018 Sep 27.

Hospital Ampang, Selangor, Malaysia.

There is a paucity of information on chronic hepatitis C (CHC) patients treated with direct antiviral agents (DAAs) in Asia. We invited Asia-Pacific physicians to collate databases of patients enrolled for CHC treatment, recording baseline clinical, virologic and biochemical characteristics, sustained virologic response at week 12 (SVR12) and virologic failure. SVR12 outcome was based on intention to treat (ITT). Multivariate analysis was used to assess independent risk factors for SVR12 using SPSS version 20. A total of 2171 patients from India (n = 977), Myanmar (n = 552), Pakistan (n = 406), Thailand (n = 139), Singapore (n = 72) and Malaysia (n = 25) were collected. At baseline, mean age was 49 years, 50.2% were males, and 41.8% had cirrhosis. Overall, SVR12 was 89.5% and by genotype (GT) based on ITT and treatment completion, respectively, was 91% and 92% for GT1, 100% and 100% for GT2, 91% and 97% for GT3, 64% and 95% for GT4, 87% and 87% for GT6 and 79% and 91% for GT untested. Patients with cirrhosis had SVR12 of 85% vs 93% for noncirrhosis (P < 0.001) (RR 2.1, 95% CI 1.4-3.1, P = 0.0002). Patients with GT1 and GT3 treated with sofosbuvir/ribavirin (SR) had 88% and 89% SVR12, respectively, but those GT6 treated with sofosbuvir/ledipasvir (SL) had only 77.6% SVR12. Multivariate analysis showed absence of cirrhosis was associated with higher SVR12 (OR 2.0, 95% CI 1.3-3.1, P = 0.002). In conclusion, patients with GT1 and GT3 with/without cirrhosis had surprisingly high efficacy using SR, suggesting that Asians may respond better to some DAAs. However, poor GT6 response to SL suggests this regimen is suboptimal for this genotype.
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http://dx.doi.org/10.1111/jvh.12989DOI Listing
December 2018

No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B.

PLoS One 2018 17;13(7):e0199198. Epub 2018 Jul 17.

St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.

Background & Aims: It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies.

Methods: Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients.

Results: The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients.

Conclusions: This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199198PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049926PMC
December 2018

Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study.

Antivir Ther 2018 ;23(1):67-75

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

Background: Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection.

Methods: A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL).

Results: Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients.

Conclusions: The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.
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http://dx.doi.org/10.3851/IMP3179DOI Listing
September 2019

Hepatitis B During Pregnancy in Endemic Areas: Screening, Treatment, and Prevention of Mother-to-Child Transmission.

Paediatr Drugs 2017 Jun;19(3):173-181

Department of Medicine, NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Hat Yai, 90110, Songkhla, Thailand.

The proper management of pregnant women infected with hepatitis B virus (HBV) is necessary to prevent maternal and fetal morbidity and mortality and to protect the baby from HBV infection. In the majority of cases, vertical transmission can be prevented with a universal screening program, HBV vaccine immunoprophylaxis, and administration of hepatitis B immunoglobulin (HBIg) for babies born to mothers with HBV. However, in mothers with a high viral load (>200,000 or >1,000,000 IU/ml, depending on the guideline), the chance of immunoprophylaxis failure remains high. The standard recommendation is to give an antiviral agent during the third trimester in these patients. US FDA pregnancy category B agents such as tenofovir and telbivudine are allowed through all trimesters of pregnancy. Breastfeeding for patients who receive antiviral agents can be allowed after a risk-benefit discussion with the patient.
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http://dx.doi.org/10.1007/s40272-017-0229-1DOI Listing
June 2017

Management of hepatitis C virus infection in the Asia-Pacific region: an update.

Lancet Gastroenterol Hepatol 2017 01 10;2(1):52-62. Epub 2016 Dec 10.

Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey.

The Asia-Pacific region has disparate hepatitis C virus (HCV) epidemiology, with prevalence ranging from 0·1% to 4·7%, and a unique genotype distribution. Genotype 1b dominates in east Asia, whereas in south Asia and southeast Asia genotype 3 dominates, and in Indochina (Vietnam, Cambodia, and Laos), genotype 6 is most common. Often, availability of all-oral direct-acting antivirals (DAAs) is delayed because of differing regulatory requirements. Ideally, for genotype 1 infections, sofosbuvir plus ledipasvir, sofosbuvir plus daclatasvir, or ombitasvir, paritaprevir, and ritonavir plus dasabuvir are suitable. Asunaprevir plus daclatasvir is appropriate for compensated genotype 1b HCV if baseline NS5A mutations are absent. For genotype 3 infections, sofosbuvir plus daclatasvir for 24 weeks or sofosbuvir, daclatasvir, and ribavirin for 12 weeks are the optimal oral therapies, particularly for patients with cirrhosis and those who are treatment experienced, whereas sofosbuvir, pegylated interferon, and ribavirin for 12 weeks is an alternative regimen. For genotype 6, sofosbuvir plus pegylated interferon and ribavirin, sofosbuvir plus ledipasvir, or sofosbuvir plus ribavirin for 12 weeks are all suitable. Pegylated interferon plus ribavirin has been replaced by sofosbuvir plus pegylated interferon and ribavirin, and all-oral therapies where available, but cost and affordability remain a major issue because of the absence of universal health coverage. Few patients have been treated because of multiple barriers to accessing care. HCV in the Asia-Pacific region is challenging because of the disparate epidemiology, poor access to all-oral therapy because of availability, cost, or regulatory licensing. Until these problems are addressed, the burden of disease is likely to remain high.
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http://dx.doi.org/10.1016/S2468-1253(16)30080-2DOI Listing
January 2017

Genetic variation in the vitamin D pathway CYP2R1 gene predicts sustained HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon: A multicenter study.

PLoS One 2017 15;12(3):e0173263. Epub 2017 Mar 15.

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

Evidence of a role of vitamin D in the immune system is increasing. Low serum vitamin D is associated with increased hepatitis B virus replication. Genome-wide association study (GWAS) data has revealed a number of the single nucleotide polymorphisms (SNPs) within the vitamin D synthetic pathway that affect vitamin D functions. We aimed to determine the association between SNPs in the vitamin D gene cascade and response to pegylated interferon (PegIFN) therapy in hepatitis B e-antigen (HBeAg)-positive patients. One hundred and eleven patients treated for 48 weeks with PegIFN-alfa 2a at 13 hospitals were retrospectively evaluated. Thirteen SNPs derived from vitamin D cascade-related genes, including DHCR7 (rs12785878), CYP27B1 (rs10877012), CYP2R1 (rs2060793, rs12794714), GC (rs4588, rs7041, rs222020, rs2282679), and VDR (FokI, BsmI, Tru9I, ApaI, TaqI), were genotyped. Thirty-one patients (27.9%) seroconverted to HBeAg after 24 weeks of treatment. Multivariate analysis found pretreatment qHBsAg <10,000 IU/mL (OR = 7.73, 95% CI: 2.36-25.31, P = 0.001), CYP2R1 rs12794714 TT genotype (OR = 4.16, 95% CI: 1.07-16.25, P = 0.04), and baseline ALT >2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31-11.22, P = 0.014) predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 CYP2R1 TT than the non-TT genotype. The rs12794714 CYP2R1 polymorphism may be a useful pretreatment factor predictive of sustained HBeAg seroconversion after PegIFN therapy. This study provides evidence that not only vitamin D level but also genetic variation of CYP2R1 in the vitamin D cascade influences host immune response in chronic HBV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351865PMC
September 2017

Simple Clinical Score to Predict 24-Week Survival Times in Patients with Inoperable Malignant Distal Biliary Obstruction as a Tool for Selecting Palliative Metallic or Plastic Stents.

J Gastrointest Cancer 2018 Jun;49(2):138-143

NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hatyai, Songkhla, Thailand.

Background And Aim: Endoscopic biliary drainage (EBD) is the mainstay treatment for inoperable malignant distal biliary obstruction (MDBO). Some authorities suggest that metallic stents are more cost-effective than plastic stents in patients with expected survival of at least 6 months. However, studies attempting to define the predictive factors for such survival times are limited. This study aims to develop a scoring system for predicting a survival time of <24 weeks in these patients.

Method: Patients with MDBO from inoperable periampullary cancers who underwent EBD at Songklanagarind Hospital during 2004-2009 were retrospectively analyzed. Baseline clinical, laboratory, and imaging data were retrieved. The survival time data were retrieved from the medical records and Thailand's civil registration database. Multivariate Cox regression model coefficients were used in the development of a survival time prediction scoring system.

Results: Ninety-eight patients were included. The overall median survival was 17.6 weeks. Fifty-seven (58.1%) survived <24 weeks. By multivariate analysis, cancer type and liver metastasis were significant predictive factors. The Simple Clinical Score (SCS) was calculated from (2× liver metastasis) + (1× pancreatic cancer) - (2× ampullary cancer) - (1× cholangiocarcinoma), when 1 and 0 were used for the presence and absence of each factor, respectively. The cutoff value of the score ≥0 had a sensitivity and specificity of 0.77 and 0.63, respectively, for predicting a survival time of <24 weeks, with AUC of 0.76. The median survival of patients with SCS <0 and ≥0 was 36.6 and 13.1 weeks, respectively.

Conclusion: The scoring system from this study may be beneficial for clinicians to select the appropriate stents in endoscopic biliary drainage in inoperable MDBO patients.
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http://dx.doi.org/10.1007/s12029-017-9918-9DOI Listing
June 2018
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