Publications by authors named "Satawat Thongsawat"

38 Publications

The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Jun 15. Epub 2021 Jun 15.

Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background And Aim: Sodium-glucose cotransporter 2 inhibitors have shown excellent results in glucose control in type 2 diabetes mellitus (T2DM) patients, while also promoting weight loss. These mechanisms may be beneficial in the treatment of non-alcoholic fatty liver disease (NAFLD). Our study aims to investigate the effect of dapagliflozin on hepatic and visceral fat contents and related biochemical markers in T2DM with NAFLD patients.

Methods: This is a double-blinded placebo-controlled randomized, single-center study. Non-insulin-dependent T2DM patients with NAFLD were prospectively enrolled and randomly assigned to receive either dapagliflozin (10 mg/day) or placebo for 12 weeks. The primary end-point was the changes in intrahepatic lipid contents, evaluated by the liver attenuation index.

Results: Of 40 patients enrolled, 38 patients completed the study (dapagliflozin group, n = 18; placebo group, n = 20). Baseline demographic and laboratory findings were similar in both groups. After 12 weeks of treatment, dapagliflozin significantly decreased intrahepatic lipid contents demonstrated by an increase in liver attenuation index in comparison with the placebo treatment (5.8 ± 5.1 vs 0.5 ± 6.1 Hounsfield units, P = 0.006). Significant reduction in bodyweight, bodyfat, visceral fat/subcutaneous fat ratio, hemoglobin A1c, and alanine aminotransferase were also observed in the dapagliflozin-treated group as compared with the placebo group (all P < 0.05). There was no significant difference in adipokines including adiponectin, leptin, and tumor necrosis factor-α changes between the dapagliflozin-treated group and the placebo group (all P = nonsignificant).

Conclusion: Dapagliflozin treatment for 12 weeks is associated with improvement in hepatic fat content, a decrease in visceral fat and bodyweight, enhanced glycemic control, and improved liver biochemistry among T2DM patients with NAFLD.
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http://dx.doi.org/10.1111/jgh.15580DOI Listing
June 2021

Human fascioliasis presenting as liver abscess: clinical characteristics and management.

Hepatol Int 2021 Jun 17;15(3):804-811. Epub 2021 Apr 17.

Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Background: Human fascioliasis, caused by the liver flukes F. hepatica, and F. gigantica, is a neglected tropical disease that causes health problems in many regions of the world. This disease can be classified as either acute or chronic based depending on the clinical manifestations and laboratory findings.

Methods: We retrospectively reviewed the demographic data, clinical features, radiologic manifestations, and the response to specific treatment of patients diagnosed with hepatic fascioliasis as well as fasciola liver abscess in Thailand.

Results: A total of 175 patients were included in the study, 126 patients were females (72%), while the mean age was 47.8 years (16-84 years). The most common symptoms were abdominal pain (74.9%), weight loss (29.1%) and fever (28%). Peripheral eosinophilia was observed in 92% of patients. The typical radiologic findings discovered conglomerated hypodensity which are rim-enhancing lesions located in the subcapsular and peripheral region of the liver. Most of patients were improved after a single dose of triclabendazole treatment. Adding antibiotic had no statistical impact on treatment outcome (p = 0.78).

Conclusions: Human fascioliasis presents with a wide clinical spectrum; therefore, a high index of suspicion is required to establish a correct diagnosis. Clinicians need to be aware of hepatic fascioliasis when patients in such endemic areas present as hypereosinophilia and typical liver imaging. Prompt specific treatments will contribute towards a satisfactory outcome in patients.
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http://dx.doi.org/10.1007/s12072-021-10180-zDOI Listing
June 2021

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.

Lancet Gastroenterol Hepatol 2021 06 16;6(6):448-458. Epub 2021 Apr 16.

Ministry of Health, Kuala Lumpur, Malaysia.

Background: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV.

Methods: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183.

Findings: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment.

Interpretation: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality.

Funding: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.
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http://dx.doi.org/10.1016/S2468-1253(21)00031-5DOI Listing
June 2021

Efficacy and Safety of Clidinium/Chlordiazepoxide as an Add-on Therapy in Functional Dyspepsia: A Randomized, Controlled, Trial.

J Neurogastroenterol Motil 2020 Apr;26(2):259-266

Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background/aims: The treatment of refractory functional dyspepsia (FD) is a challenge. Clidinium/chlordiazepoxide is a combination of antispasmodic and anxiolytic drugs that has been used as an adjunct treatment for FD in clinical practice with limited supporting evidence of efficacy. The aim of the study is to assess the efficacy and safety of clidinium/chlordiazepoxide as an adjunct treatment to a proton pump inhibitor (PPI) in refractory dyspepsia.

Methods: We performed a study of patients who met the Rome IV criteria for FD who failed to respond to PPIs. Patients were randomly assigned to groups that received clidinium/chlordiazepoxide or placebo as an add-on treatment to PPI for 4 weeks. The primary outcome was the rate of responders, which was defined as a > 50% reduction in dyspepsia symptom score after 4 weeks of treatment. The secondary outcomes were an improvement in the quality of life and the safety profile.

Results: Between March 2017 and February 2018, 78 patients were enrolled. The rates of responders in the clidinium/chlordiazepoxide group and placebo groups were 41.03 % and 5.13% at week 4 ( < 0.001). The clidinium/chlordiazepoxide group also showed significant improvement in overall quality of life over placebo. However, the clidinium/chlordiazepoxide group had more frequent drowsiness than the placebo group (30.27% vs 6.52%, = 0.034). There were no major adverse events in either group.

Conclusions: Clidinium/chlordiazepoxide significantly improved dyspeptic symptoms and quality of life. This combination may be used as an add-on therapy in FD patients without major adverse events.
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http://dx.doi.org/10.5056/jnm19186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176503PMC
April 2020

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

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

The Bioavailability and Pharmacokinetics of Silymarin SMEDDS Formulation Study in Healthy Thai Volunteers.

Evid Based Complement Alternat Med 2018 19;2018:1507834. Epub 2018 Jul 19.

Pharmacy Service Center, Pharmacy Faculty, Chiang Mai University, Chiang Mai 50200, Thailand.

The present study aimed to determine the pharmacokinetic parameters and bioavailability of silymarin 140 mg SMEDDS formulation. An open-label, single-dose pharmacokinetic study was conducted. Twelve healthy volunteers were included in the study. After the volunteers had fasted overnight for 10 h, a single-dose generic silymarin 140 mg SMEDDS soft capsule was administered. Then 10 ml blood samples were taken at 0.0, 0.25, 0.50, 0.75, 1.0, 1.33, 1.67, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, and 12.0 h. The plasma silybin concentrations were analyzed using validated LC-MS/MS. The pharmacokinetic parameters were analyzed and calculated. The pharmacokinetic parameters were calculated after silymarin had been administered as a single capsule. The mean (range) C was 812.43 (259.47-1505.47) ng/ml at 0.80 (0.25-1.67) h (t). The mean (range) AUC and AUC were 658.80 (268.29-1045.01) ng.h/ml and 676.98 (274.10-1050.96) ng.h/ml, respectively. The mean k and t were 0.5386 h and 1.91 h, respectively. The silymarin SMEDDS formulation soft capsule showed rapid absorption and high oral bioavailability.
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http://dx.doi.org/10.1155/2018/1507834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077530PMC
July 2018

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with -Mutated Hepatocellular Carcinoma.

Clin Cancer Res 2018 10 27;24(19):4650-4661. Epub 2018 Jun 27.

Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York.

Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with -mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with -mutant unresectable or metastatic HCC. Eligible patients with mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Of 1,318 patients screened, 59 (4.4%) had a mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in (63.0%), (48.1%), and β-catenin (; 37.0%). Prospective testing for family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of -mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3588DOI Listing
October 2018

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B.

N Engl J Med 2018 Mar;378(10):911-923

From the Institut de Recherche pour le Développement Unité Mixte Internationale 174-Program for Health, Prevention, and Treatment (PHPT) (G.J., N.N.-G.-H., L.D., N.S., T.R.C.), the Faculty of Associated Medical Sciences, Chiang Mai University (G.J., N.N.-G.-H., L.D., W.K., N.S., T.R.C., W.S.), Nakornping Hospital (A.L.), Health Promotion Center Region 1 (S.S.), the Medical Department, Sanpatong Hospital (V.K.), and the Department of Internal Medicine, Faculty of Medicine, Chiang Mai University (S. Thongsawat), Chiang Mai, the Obstetrics and Gynecology Department, Chiangrai Prachanukroh Hospital (J.A.), and Mae Chan Hospital (S.B.), Chiang Rai, Prapokklao Hospital, Chantaburi (P.Y.), Banglamung Hospital (P.K.) and Chonburi Hospital (C.B., N. Chotivanich), Chonburi, Nopparat Rajathanee Hospital (O.P.N.A.), Bhumibol Adulyadej Hospital (S. Prommas), and the Faculty of Medicine, Chulalongkorn University (T.P.), Bangkok, Khon Kaen Hospital, Khon Kaen (T.S.), Samutprakarn Hospital, Samutprakarn (P. Sabsanong), Samutsakhon Hospital, Samutsakorn (S.V.), Chiang Kham Hospital (C.P.) and Phayao Hospital (P. Suriyachai), Phayao, Lampang Hospital, Lampang (P.L.), Lamphun Hospital, Lamphun (W.M.), Maharaj Nakornratchasrima Hospital, Nakornratchasrima (P.P.), and the Department of Disease Control, Ministry of Public Health, Nonthaburi (S. Thanprasertsuk) - all in Thailand; the Department of Immunology and Infectious Diseases (G.J., N.N.-G.-H., T.R.C.) and the Center for Biostatistics in AIDS Research (L.H., C.T.), Harvard T.H. Chan School of Public Health, and the Gastrointestinal Unit, Massachusetts General Hospital (R.T.C.) - both in Boston; the Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom (T.R.C.); the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (G.K.S., N. Chakhtoura); the Office of the Global AIDS Coordinator, Department of State, Washington, DC (D.H.W.); the Centers for Disease Control and Prevention, Atlanta (T.V.M., N.P.N.); and Université Paris Descartes, INSERM Unité 1223, Institut Pasteur, the Department of Hepato-Gastroenterology, Cochin University Hospital, Paris (S. Pol).

Background: Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin.

Methods: In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group).

Results: From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29).

Conclusions: In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .).
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http://dx.doi.org/10.1056/NEJMoa1708131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895092PMC
March 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

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

Ritonavir-boosted danoprevir plus peginterferon alfa-2a and ribavirin in Asian chronic hepatitis C patients with or without cirrhosis.

J Gastroenterol Hepatol 2016 Oct;31(10):1757-1765

Genentech, South San Francisco, California, USA.

Background And Aim: Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G)1 infection.

Methods: Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level ≥ 10  IU/mL received ritonavir-boosted danoprevir 125/100 mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12 weeks after end of treatment (SVR12).

Results: Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14.

Conclusions: Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.
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http://dx.doi.org/10.1111/jgh.13374DOI Listing
October 2016

Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen.

BMC Infect Dis 2016 08 9;16:393. Epub 2016 Aug 9.

Chonburi Hospital, 69 M.2, Sukhumvit Rd., Ban-suan, Muang, Chonburi, 20000, Thailand.

Background: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV.

Methods: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1:1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age ≥18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre-entry), negative hepatitis C serology, creatinine clearance >50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a ≥9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT >300 IU/L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age.

Discussion: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines.

Trial Registration: ClinicalTrials.gov Identifier NCT01745822 .
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http://dx.doi.org/10.1186/s12879-016-1734-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977630PMC
August 2016

Treatment outcomes and validation of the stopping rule for response to peginterferon in chronic hepatitis B: A Thai nationwide cohort study.

J Gastroenterol Hepatol 2016 Nov;31(11):1874-1881

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

Background And Aims: Peginterferon has demonstrated effectiveness in clinical trials in patients with chronic hepatitis B (CHB). However, its efficacy in real-life settings remains unclear. We investigated the efficacy of peginterferon for CHB and validated the performance of previously identified response predictors in clinical practice.

Methods: We analyzed prospectively collected data from a Thai nationwide cohort of CHB patients treated with peginterferon alfa-2a (180 µg/week, 48 weeks).

Results: Among a total of 233 patients, mostly with genotype B or C, sustained response was observed in 23% of 135 hepatitis B e antigen (HBeAg)-positive patients (HBeAg seroconversion with hepatitis B virus [HBV] DNA < 2000 IU/mL) and 42% of 98 HBeAg-negative patients (HBV DNA < 2000 IU/mL with aminotransferase normalization) at 24 weeks after treatment. Age, sex, presence of cirrhosis, genotype, and pretreatment levels of aminotransferase, HBV DNA, and hepatitis B surface antigen (HBsAg) were not identified as significant predictors of sustained response. In HBeAg-positive patients, HBsAg > 20 000 IU/mL at week 12 provided a good stopping rule, with a negative predictive value of 96%. In HBeAg-negative patients, the performance of 12-week stopping rules of no decline in HBsAg with a < 2log decline in HBV DNA and a < 10% log decline in HBsAg showed modest negative predictive values of 80% and 66%, respectively, for achieving sustained response.

Conclusion: Outcomes in CHB patients treated with peginterferon in a clinical setting are similar to those demonstrated in clinical trials. Application of the early stopping rule based on HBsAg quantification may allow individualization of therapy, particularly in HBeAg-positive patients.
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http://dx.doi.org/10.1111/jgh.13378DOI Listing
November 2016

Analysis of mutations in the core and NS5A genes of hepatitis C virus in non-responder and relapser patients after treatment with Peg-IFN-α and ribavirin.

Virusdisease 2016 Mar 18;27(1):55-62. Epub 2016 Jan 18.

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand.

Mutations in several regions of HCV genome are shown to correlate with response to interferon (IFN) treatment. Persistence of HCV infection and poor susceptibility to treatment might be contributed by mutations arising within HCV genome which enable the virus to escape from host immune response/IFN treatment. This study investigated mutations in core and NS5A genes of HCV from non-responder and relapser patients after treatment with Peg-IFN-α and ribavirin. Viral RNA was extracted from patient sera and core and NS5A genes were amplified by RT-PCR. Nucleotide sequences of the core and NS5A genes were determined by direct sequencing, and converted to amino acid sequences. Nucleotide and amino acid sequences in the core region, ISDR, PKRBD, and V3 regions within NS5A after treatment were highly conserved when comparing to their corresponding sequences obtained before treatment. Interestingly, when comparing the virus from relapsers to those from non-responders, the number of mutations after treatment in N-terminal region of NS5A of virus from relapsers was significantly higher than those from non-responders (P < 0.05). Amino acid mutations at the N-terminus of NS5A of the virus in relapsers might help the virus to survive and somehow relapse after the cessation of the treatment.
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http://dx.doi.org/10.1007/s13337-015-0300-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758312PMC
March 2016

Three-day versus five-day somatostatin infusion combination with endoscopic variceal ligation in the prevention of early rebleeding following acute variceal hemorrhage: A randomized controlled trial.

Hepatol Res 2015 Dec 6;45(13):1276-82. Epub 2015 Apr 6.

Gastrohepatology Unit, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Aim: Combined pharmacological and endoscopic therapy is recommended for initial treatment of acute variceal bleeding (AVB). The optimal duration of therapy with a vasoactive agent is not well established. The aim of this study was to compare the efficacy and safety of 3-day and 5-day somatostatin treatment in the prevention of early rebleeding after endoscopic variceal ligation (EVL).

Methods: In a double-blind, prospective trial, cirrhotic patients with AVB who underwent EVL were randomly assigned to receive a continuous infusion of somatostatin for either 3 days or 5 days.

Results: A total of 95 patients were enrolled; 50 patients in the 3-day group and 45 patients in the 5-day group after initial hemostasis by combination therapy with somatostatin and EVL. Both groups were comparable in terms of baseline data. Very early and early rebleeding within 5 days and 42 days occurred in one and three patient (2%, 6%) in the 3-day group and three and two patients (6.67%, 4.45%) in the 5-day group (P = 0.342, 0.735), respectively. Overall, eight patients died (three from variceal rebleeding and five from causes other than variceal bleed); four (8%) in the 3-day group and four (8.89%) in the 5-day group (P = 0.876). Multivariate analysis revealed that none of the factors was a predictor of rebleeding. No serious side-effects and complications were observed.

Conclusion: A 3-day course of somatostatin is as effective as a 5-day course for the control of variceal bleeding and prevention of early rebleeding when used as combination therapy with EVL.
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http://dx.doi.org/10.1111/hepr.12503DOI Listing
December 2015

Influence of amino acid variations in the NS3, NS4A and NS4B of HCV genotypes 1a, 1b, 3a, 3b and 6f on the response to pegylated interferon and ribavirin combination therapy.

Virus Res 2015 Jan 11;196:37-43. Epub 2014 Nov 11.

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address:

Background: It has been suggested that HCV proteins, core, NS3/4A, NS4B, and NS5A, contribute to the resistance of HCV to IFN and ribavirin (RBV) treatments.

Aim: To assess the effects of HCV amino acid variations in NS3, NS4A and NS4B of HCV subtypes 1a, 1b, 3a, 3b and 6f on the response to pegylated interferon (Peg-IFN) and RBV therapy.

Methods: One hundred and thirty four HCV isolates of genotypes 1a, 1b, 3a, 3b and 6f obtained from HCV patients both before and at week 4 of treatments were evaluated. Amino acid sequences of NS3, NS4A and NS4B were analyzed and in compared to reference sequences of corresponding genotypes.

Results: The data revealed that amino acid variations within the full-length NS3, protease and helicase domains of NS3 of HCV 1a from responders were significantly higher than those from treatment failure groups as compared to reference sequences of each corresponding genotype. Similar results were observed in the full-length and helicase domain but not in the protease domain of HCV 1b. However, the number of amino acid variations in NS3 of HCV 3a, 3b and 6f as well as in NS4A and NS4B showed no difference between the viruses from responders and treatment failure group. Analysis of amino acid variations both before and at week 4 of treatment revealed that the mean number of amino acid variation in the full-length NS3 of HCV 3a and 3b from responders were also significantly higher than those from the treatment failure group.

Conclusion: Our study suggests that the increase of amino acid variations within the NS3 protein of HCV 1a, 1b, 3a and 3b were associated with the response to Peg-IFN and RBV treatment in Thai patients.
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http://dx.doi.org/10.1016/j.virusres.2014.11.003DOI Listing
January 2015

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

J Gastroenterol Hepatol 2015 Jan;30(1):184-91

Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.

Background And Aims: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections.

Methods: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events.

Results: The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 μg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups.

Conclusions: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665).
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http://dx.doi.org/10.1111/jgh.12671DOI Listing
January 2015

Normal Solid Gastric Emptying Values Measured by Scintigraphy Using Asian-style Meal:A Multicenter Study in Healthy Volunteers.

J Neurogastroenterol Motil 2014 Jul;20(3):371-8

GI Motility Research Unit, Division of Gastroenterology, Department of Medicine Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background/aims: To report gastric emptying scintigraphy, normal values should be established for a specific protocol. The aim of this study was to provide normal gastric emptying values and determine factors affecting gastric emptying using Asian rice-based meal in healthy volunteers.

Methods: One hundred and ninety-two healthy volunteers were included at 7 tertiary care centers across Thailand. Gastric emptying scintigraphy was acquired in 45 degree left anterior oblique view immediately after ingestion of a 267 kcal steamed-rice with technetium-99m labeled-microwaved egg meal with 100 mL water for up to 4 hours.

Results: One hundred and eighty-nine volunteers (99 females, age 43 ± 14 years) completed the study. The medians (5-95th percentiles) of lag time, gastric emptying half time (GE T1/2) and percent gastric retentions at 2 and 4 hours for all volunteers were 18.6 (0.5-39.1) minutes, 68.7 (45.1-107.8) minutes, 16.3% (2.7-49.8%) and 1.1% (0.2-8.8%), respectively. Female volunteers had significantly slower gastric emptying compared to male (GE T1/2, 74 [48-115] minutes vs. 63 (41-96) minutes; P < 0.05). Female volunteers who were in luteal phase of menstrual cycle had significantly slower gastric emptying compared to those in follicular phase or menopausal status (GE T1/2, 85 [66-102] mintes vs. 69 [50-120] minutes or 72 [47-109] minutes, P < 0.05). All of smoking volunteers were male. Smoker male volunteers had significantly faster gastric emptying compared to non-smoker males (GE T1/2, 56 [44-80] minutes vs. 67 [44-100] minutes, P < 0.05). Age, body mass index and alcohol consumption habits did not affect gastric emptying values.

Conclusions: A steamed-rice with microwaved egg meal was well tolerated by healthy volunteers. Gender, menstrual status and smoking status were found to affect solid gastric emptying.
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http://dx.doi.org/10.5056/jnm13114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102158PMC
July 2014

Resource Utilization and Direct Medical Costs of Chronic Hepatitis C in Thailand: A Heavy but Manageable Economic Burden.

Value Health Reg Issues 2014 May 30;3:12-18. Epub 2013 Oct 30.

Roche Thailand Ltd., Bangkok, Thailand.

Objective: To estimate the cost for the management of chronic hepatitis C (CHC) and related morbidities by using a payer perspective in Thailand.

Methods: Data elements were extracted from medical records of 542 patients newly diagnosed with CHC in five tertiary care hospitals across Thailand. All patients were divided into five health states: noncirrhotic CHC, hepatitis C virus (HCV)-related compensated cirrhosis, HCV-related decompensated cirrhosis, HCV-related hepatocellular carcinoma, and HCV-related liver transplantation. Resource utilization data for each patient during a 12-month follow-up study period were compiled, and reference prices published by the Thai government were used to estimate the cost for each health state. The average cost was calculated and categorized into various groups, for example, laboratory and diagnostic tests, procedures, medication, and hospitalization.

Results: The average number of outpatient visits per patient was approximately six visits in all cohorts. The HCV-related hepatocellular carcinoma and liver transplantation cohorts had a higher average number of inpatient admissions per patient. The average number of days per admission varied from fewer than 3 days to 1 week or more across all the health states. The average annual total cost per patient varied across all health states from approximately 170,000 to 600,000 baht, and medication cost was the largest portion in every cohort, except the HCV-related liver transplantation cohort in year 1. Among all medications, the average annual antiviral medication cost per patient was the largest portion in the noncirrhotic CHC and HCV-related compensated cirrhosis cohorts.

Conclusions: CHC was a costly disease in Thailand. The average annual medication cost was the largest portion in every health state, except HCV-related liver transplantation.
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http://dx.doi.org/10.1016/j.vhri.2013.09.002DOI Listing
May 2014

Hepatitis C virus genotypes circulating in patients with chronic hepatitis C in Thailand and their responses to combined PEG-IFN and RBV therapy.

J Med Virol 2014 Aug 29;86(8):1360-5. Epub 2014 Apr 29.

Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Different genotypes of hepatitis C virus (HCV) are circulating in different areas of the world. In Thailand, distribution of HCV genotypes has been investigated mostly in the central area while the information in other regions is limited. This study aimed to determine the HCV genotypes circulating in chronic hepatitis C patients in Chiang Mai, Thailand and to investigate the response of different HCV genotypes to pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment. Patients infected chronically with HCV were treated with PEG-IFN/RBV based on the standard regimens for each HCV genotype and followed up the patients until the end of treatment and 6 months afterward. Out of 158 patients, three major HCV genotypes and eight subtypes were identified. Genotype 3 was the most predominant at 54.5%, followed by genotypes 1 (31%) and 6 (14.5%). Among subtypes, 3a was the most prevalent subtype (45%), followed by 1b (18.4%), 1a and 6f (each at 12.6%), 3b (9.5%), and 6a, 6i, 6n (each at 0.63%). Patients with genotype 3 showed higher rate of responding to the treatment at 80.2% compared to genotypes 1 (73.5%) and 6f (65%). Additionally, patients with genotype 6f showed higher rate of relapsing (25%) compared to genotypes 1 and 3 (14.3% and 16.3%, respectively). In conclusion, this study reported multiple HCV genotypes circulated in Thai patients and the response of different HCV genotypes to PEG-IFN/RBV treatment.
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http://dx.doi.org/10.1002/jmv.23962DOI Listing
August 2014

Clinical features and prognostic factors for liver cancer from a referral center in northern Thailand.

J Med Assoc Thai 2013 May;96(5):531-7

Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background: Primary liver cancer included hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the leading cancer with high mortality in Thailand. We aim to evaluate the overall survival and predictor of mortality in patients with HCC and CCA.

Material And Method: We reviewed medical records of 786 patients with liver mass between July 2007 and June 2010, 287 patients were HCC and 449 patients were CCA. The overall survival and prognostic variables for survival were analyzed.

Results: The mean age of HCC patients and CCA patient were 53.8 years and 59.2 years. Male was predominant, 85% and 74% in HCC and CCA. By BCLC staging for HCC, patients at early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) were 40 (13.9%), 105 (36.6%), 95 (33.1%), and 43 (15.0%). Among 449 CCA patients, 143 (31.8%) were intrahepatic type and 306 (68.2%) were ductal type. The mean follow-up time for HCC and CCA patients were 20.1 and 16.7 months. The 1-year, 2-year, and 3-year survival of HCC and CCA were 55%, 34%, 31.3% and 54%, 21.2%, 19.1%, respectively. Predictor of death in HCC patients included portal vein thrombosis and did not receive any treatment (p < 0.05). Meanwhile, the predictor of death in CCA patient included intrahepatic type, total bilirubin > 2 mg/dl, CA 19-9 > 100, and unresectable tumor (p< 0.05).

Conclusion: The survival of patients who received any type of treatment was much better than in the past. Still, in patients with advanced disease whom only supportive treatments were provided, the prognosis is grave.
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May 2013

Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling.

J Virol 2012 Aug 6;86(16):8581-91. Epub 2012 Jun 6.

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5A's contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment.
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http://dx.doi.org/10.1128/JVI.00533-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421739PMC
August 2012

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study.

J Hepatol 2012 Jun 10;56(6):1247-53. Epub 2012 Feb 10.

Department of Gastroenterology and Hepatopancreatology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.

Background & Aims: TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6.

Methods: The study consisted of 7 days of monotherapy with TMC435 (200mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42.

Results: Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log(10)IU/ml) from baseline was the greatest for genotypes 6 (-4.35 ± 0.29) and 4 (-3.52 ± 0.43), followed by genotypes 2 (-2.73 ± 0.71) and 5 (-2.19 ± 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.

Conclusions: The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.
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http://dx.doi.org/10.1016/j.jhep.2011.12.033DOI Listing
June 2012

Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B.

Liver Int 2011 May 16;31(5):676-84. Epub 2011 Mar 16.

New Zealand Liver Unit, Auckland City Hospital, Auckland, New Zealand.

Background: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB).

Aims: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial.

Methods: Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years.

Results: Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial.

Conclusions: Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.
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http://dx.doi.org/10.1111/j.1478-3231.2011.02490.xDOI Listing
May 2011

Insulin resistance is independently associated with significant hepatic fibrosis in Asian chronic hepatitis C genotype 2 or 3 patients.

J Gastroenterol Hepatol 2011 Jul;26(7):1182-8

Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA.

Background And Aim: The role of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C infection (CHC) has yielded conflicting data and few studies have been performed in Asian-region populations. We retrospectively investigated the relationship between host metabolic variables, including IR and hepatic steatosis, to hepatic fibrosis in Asian-region CHC genotype 2/3 patients.

Methods: A total of 303 treatment-naïve Asian-region patients with CHC genotype 2/3 were enrolled in a multicenter phase 3 study of albinterferon alfa-2b plus ribavirin for 24 weeks. IR was defined as Homeostasis Model for Assessment of IR (HOMA-IR) > 2. Baseline liver biopsy was evaluated by a single expert histopathologist. Post hoc subgroup logistic regression modeling selected for independent variables associated with significant fibrosis (METAVIR stage F2-F4).

Results: Insulin resistance was available in 263 non-diabetic Asian-region patients (hepatitis C virus-2 [HCV-2] = 171, HCV-3 = 92), and 433 non-Asian region patients (407 "Caucasian"); METAVIR fibrosis prevalence F0-F1 (minimal fibrosis)= 201 (77%) and F2-F4 (significant fibrosis) = 59 (23%), and steatosis prevalence of grade 0 = 169 (65%), grade 1 = 64 (25%), grade 2/3 = 27 (10%). Median HOMA-IR was 1.8 (interquartile range: 1.2-2.7); 100 (38%) patients had HOMA-IR > 2. Factors independently associated with significant fibrosis included HOMA-IR (odds ratio [OR]= 8.42), necro-inflammatory grade (OR = 3.17), age (OR = 1.07) and serum total cholesterol levels (OR = 0.008). This was similar to non-Asian region patients, but steatosis was not associated with significant fibrosis in either cohort.

Conclusions: In this subgroup study of Asian-region HCV genotype 2 or 3 patients, insulin resistance, along with age, cholesterol levels and necro-inflammation, but not steatosis may be associated with significant hepatic fibrosis.
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http://dx.doi.org/10.1111/j.1440-1746.2011.06722.xDOI Listing
July 2011

Bioequivalence study of the two 1.5 g cefoperazone and sulbactam IM injections in Thai healthy male volunteers.

J Med Assoc Thai 2008 Nov;91(11):1760-4

Department of Pharmaceutical Science, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.

Objective: To perform a bioequivalence study of the two 1.5 g cefoperazone (1.0 g) and sulbactam (0.5 g) between Cefper and Sulperazon injections.

Material And Method: The present study was performed in 24 Thai healthy male volunteers who were intramuscularly injected a single dose of 1.5 g cefoperazone and sulbactam. A single dose, two periods, two sequences, double blind randomized crossover with a one-week washout period was used. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after intramuscular injection and determined for cefoperazone and sulbactam plasma concentration by validated HPLC-UV methods. The pharmacokinetic parameters were analyzed by noncompartmental analysis and the ANOVA was carried out.

Results: Tax of both cefoperazone and sulbactam for volunteers who were injected with either Cefper or Sulperazon injection were not significantly different (p > 0.05). The 90% confidence intervals of the log of ratio of either C(max) or AUC(last) or AUC(inf) of both cefoperazone and sulbactam between 1.5 g Cefper and Sulperazon injections were within the bioequivalence range of 0.80-1.25.

Conclusion: The 1.5 g cefoperazone and sulbactam injection of Cefper and Sulperazone used in the present study are bioequivalent.
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November 2008

Diverse contexts of zoonotic transmission of simian foamy viruses in Asia.

Emerg Infect Dis 2008 Aug;14(8):1200-8

Division of International Programs, National Primate Research Center, University of Washington, Seattle, Washington 98195, USA.

In Asia, contact between persons and nonhuman primates is widespread in multiple occupational and nonoccupational contexts. Simian foamy viruses (SFVs) are retroviruses that are prevalent in all species of nonhuman primates. To determine SFV prevalence in humans, we tested 305 persons who lived or worked around nonhuman primates in several South and Southeast Asian countries; 8 (2.6%) were confirmed SFV positive by Western blot and, for some, by PCR. The interspecies interactions that likely resulted in virus transmission were diverse; 5 macaque taxa were implicated as a potential source of infection. Phylogenetic analysis showed that SFV from 3 infected persons was similar to that from the nonhuman primate populations with which the infected persons reported contact. Thus, SFV infections are likely to be prevalent among persons who live or work near nonhuman primates in Asia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562341PMC
http://dx.doi.org/10.3201/eid1408.071430DOI Listing
August 2008

Occult hepatitis C virus infection during an outbreak in a hemodialysis unit in Thailand.

J Med Virol 2008 May;80(5):808-15

Faculty of Medicine, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand.

Control of hepatitis C virus (HCV) in hemodialysis populations is a major public health priority, but the preferred methods to prevent and rapidly detect HCV outbreaks in these populations remains subject to debate. We enrolled 231 hemodialysis patients at three dialysis centers in Chiang Mai, Thailand. Patients were followed every 6 months for 3 years and tested for the presence of serum HCV antibody and HCV RNA at each visit. We additionally isolated and tested peripheral blood mononuclear cells (PBMCs) for HCV RNA collected at the 30-month follow-up visit. Fifty-one study participants negative for anti-HCV at the baseline enrollment visit seroconverted over the course of the 3-year follow-up period. Of 11 individuals who transiently lost detectable serum HCV viremia, we were able to detect HCV RNA from the PBMCs of two individuals. Our results suggest that occult HCV infection may be common among hemodialysis patients, and serum HCV RNA testing may be supplemented with PBMC testing to maximize diagnostic sensitivity and aid in outbreak containment. Further work on the diagnostic implications of HCV compartmentalization in hemodialysis and other settings is urgently needed.
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http://dx.doi.org/10.1002/jmv.21126DOI Listing
May 2008

Telbivudine versus lamivudine in patients with chronic hepatitis B.

N Engl J Med 2007 Dec;357(25):2576-88

University Department of Medicine, Queen Mary Hospital, Hong Kong, China.

Background: Reducing hepatitis B virus (HBV) replication to minimal levels is emerging as a key therapeutic goal for chronic hepatitis B.

Methods: In this double-blind, phase 3 trial, 1370 patients with chronic hepatitis B were randomly assigned to receive 600 mg of telbivudine or 100 mg of lamivudine once daily. The primary efficacy end point was noninferiority of telbivudine to lamivudine for therapeutic response (i.e., a reduction in serum HBV DNA levels to fewer than 5 log10 copies per milliliter, along with loss of hepatitis B e antigen [HBeAg] or normalization of alanine aminotransferase levels). Secondary efficacy measures included histologic response, changes in serum HBV DNA levels, and HBeAg responses.

Results: At week 52, a significantly higher proportion of HBeAg-positive patients receiving telbivudine than of those receiving lamivudine had a therapeutic response (75.3% vs. 67.0%, P=0.005) or a histologic response (64.7% vs. 56.3%, P=0.01); telbivudine also was not inferior to lamivudine for these end points in HBeAg-negative patients. In HBeAg-positive and HBeAg-negative patients, telbivudine was superior to lamivudine with respect to the mean reduction in the number of copies of HBV DNA from baseline, the proportion of patients with a reduction in HBV DNA to levels undetectable by polymerase-chain-reaction assay, and development of resistance to the drug. Elevated creatine kinase levels were more common in patients who received telbivudine, whereas elevated alanine aminotransferase and aspartate aminotransferase levels were more common in those who received lamivudine.

Conclusions: Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine. (ClinicalTrials.gov number, NCT00057265 [ClinicalTrials.gov].).
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http://dx.doi.org/10.1056/NEJMoa066422DOI Listing
December 2007