The Efficacy of Oligonol in Nonalcoholic Fatty Liver Disease: A Randomized Double-Blinded Placebo-Controlled Trial.

Introduction: Oligonol, an oligomerized-polyphenol from Litchi chinensis extract, has been shown to alleviate metabolic syndrome. The aim of this study was to evaluate the effects of oligonol in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Adult patients with NAFLD defined by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) ≥11% were enrolled and then randomly assigned to receive either oligonol or placebo capsules. Primary endpoint was ≥30% reduction in MRI-PDFF at 24 weeks. Secondary outcomes were reductions in bodyweight, waist circumference, alanine transaminase, fasting blood sugar, and lipid profiles at week 24. Results: Forty patients were enrolled (n = 20/group). Primary endpoint was achieved in 20% in the oligonol group and 15% in the placebo group (p = 0.50). The authors found a reduction in MRI-PDFF between weeks 0 and 24 in the oligonol group; however, the change was not different from the placebo group. Secondary outcomes were similar between two groups. Discussion: Oligonol has not shown a significant therapeutic effect in NAFLD. Future studies with a longer duration of therapy might be needed to achieve the primary endpoint. Clinical Trial Registration Number: Thai Clinical Trial Registry identification number: TCTR20200814001.

Litchi-Derived Polyphenol Alleviates Liver Steatosis and Gut Dysbiosis in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Double-Blinded, Placebo-Controlled Study.

Preclinical data suggest the role of litchi extract in alleviating non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. We aimed at investigating whether oligonol, a litchi-derived polyphenol, could improve liver steatosis and gut dysbiosis in patients with NAFLD. Adults with grade ≥2 steatosis, defined by an MRI proton density fat fraction (MRI-PDFF) of ≥11%, were randomly assigned to receive either oligonol or placebo for 24 weeks. The alteration in the MRI-PDFF and gut microbiota composition assessed by 16S ribosomal RNA sequencing were examined. There were 38 patients enrolled (n = 19 in each group). A significant reduction in the MRI-PDFF between week 0 and week 24 was observed in the oligonol group, while there was a non-significant decrease in the placebo group. A significant improvement in alpha-diversity was demonstrated in both of the groups. The oligonol-induced microbiota changes were characterized by reduced abundance of pathogenic bacteria, including Dorea, Romboutsia, Erysipelotrichaceae UCG-003 and Agathobacter, as well as increased abundance of short-chain fatty acids (SCFAs)-producing bacteria, such as Akkermansia, Lachnospira, Dialister and Faecalibacterium. In summary, this study is the first to provide evidence that supports that oligonol improves steatosis through the modulation of gut bacterial composition. Our results also support the beneficial and complementary role of oligonol in treating NAFLD.

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

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.

Telbivudine in combination with adefovir versus adefovir monotherapy in HBeAg-positive, lamivudine-resistant chronic hepatitis B.

PURPOSE: Lamivudine (LAM) resistance is common on lamivudine monotherapy for chronic hepatitis B. This study examined the safety and efficacy of telbivudine (LDT) given with adefovir (ADV) versus ADV monotherapy in patients with chronic, lamivudine-resistant HBV infection. METHODS: An open-label, 96 week study with planned recruitment of 150 HBeAg-positive, lamivudine-experienced Asian patients with a confirmed YMDD resistance mutation, randomized 1:1 to receive ADV alone or with LDT. The study was terminated early due to difficulty in enrolling monotherapy patients. At termination, 42 patients had received study medication for 8-61 weeks. Due to incomplete enrolment, summary statistics only were prepared, without significance testing. RESULTS: A total of 42 patients underwent rescue therapy (switch to ADV or LDT + ADV; n = 21 per group). Median treatment duration was 48 weeks in both groups. HBV DNA changes from baseline were greater in the LDT + ADV arm at all time points (Week 48: -7.4 log10 vs. -4.9 log10 copies/ml), and serum DNA was undetectable (<300 copies/mL) at week 48 in 38.5% (5/13) on LDT + ADV versus 0% (0/9) on ADV monotherapy Two patients (9.6%) on ADV monotherapy experienced virologic breakthrough without evidence of ADV resistance, but none on LDT + ADV; and no confirmed ADV resistance was observed in any on-treatment sample. HBeAg loss occurred in three patients on LDT + ADV and one patient on ADV monotherapy through week 48. Safety profiles were similar between the arms. CONCLUSION: LDT + ADV combination treatment showed better outcomes against lamivudine resistant HBV than ADV alone, with a similar safety profile.

APASL consensus statements and management algorithms for hepatitis C virus infection.

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL Consensus Statements and Management Algorithms for Hepatitis C Virus Infection" in December, 2010, in order to revise "Asian Pacific Association for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection (J Gastroenterol Hepatol 22:615-633, 2007)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Makuhari, Chiba, Japan on 19 December 2010. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations are presented in this review.

Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B.

BACKGROUND/AIMS: In the GLOBE trial, telbivudine treatment was identified as a significant, independent predictor of better outcomes at 2 years. We analyzed all telbivudine recipients in this trial to determine the predictors of optimal outcomes. METHODS: The intent-to-treat population comprised 458 HBeAg-positive and 222 HBeAg-negative telbivudine-treated patients. Multivariate logistic regression analyses were employed to evaluate baseline and/or early on-treatment variables. RESULTS: Baseline HBV DNA<9 log(10)copies/mL, or ALT levels > or = 2x above normal were strong pretreatment predictors for HBeAg-positive, but not for HBeAg-negative patients. However, non-detectable serum HBV DNA at treatment week 24 (TW24) was the strongest predictor for better outcomes for both groups. A combination of pretreatment characteristics plus TW24 response identified subgroups with the best outcomes: (1) HBeAg-positive patients with baseline HBV DNA<9 log(10)copies/mL, ALT > or = 2x above normal and non-detectable HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 89%, HBeAg seroconversion in 52%, telbivudine resistance in 1.8%; and (2) HBeAg-negative patients with baseline HBV DNA<7 log(10)copies/mL and non-detectable serum HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 91%, telbivudine resistance in 2.3%. CONCLUSION: During telbivudine treatment, non-detectable serum HBV DNA at treatment week 24 is the strongest predictor for optimal outcomes at 2 years.

Hepatocellular carcinoma in the Asia pacific region.

Primary liver cancer, particularly hepatocellular carcinoma (HCC) remains a significant disease worldwide. It is among the top three causes of cancer death in the Asia Pacific region because of the high prevalence of its main etiological agents, chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In this region, the incidence of HCC has been static over recent decades. Older age is a major risk factor; the incidence increasing sharply after age 40 years. There is a male predilection, with male to female ratio of 3:1, except in elderly Japanese with equal sex incidence or female predominance. In most Asia-Pacific countries, chronic HBV infection accounts for 75-80% of cases; Japan, Singapore and Australia/New Zealand are exceptions because of higher prevalence of HCV infection. In spite of advances in surgery, liver transplantation and newer pharmaco/biological therapies, the survival rate has improved only slightly over recent decades, and this could be attributable to earlier diagnosis ('lead-time bias'). The majority of patients present with advanced diseases, hence reducing the chance of curative treatment. The importance of HCC may decrease in two to three decades when the prevalence of chronic HBV infection decreases as a result of the universal HBV vaccination programs implemented in late 1980s in most Asia-Pacific countries, and because of reduced incidence of medical transmission of HCV. However, transmission of HCV by injection drug use, and rising prevalence of obesity and diabetes, both independent risk factors for HCC, may partly offset this decline.

Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B.

PURPOSE: The 2 reported trials investigated the effectiveness of treatment with peginterferon alfa-2a in Asian patients with chronic hepatitis B (CHB). METHODS: Patients with HBeAg-positive (n = 708) or HBeAg-negative (n = 332) CHB were enrolled in 2 randomized, double blind, placebo-controlled studies. Patients received peginterferon alfa-2a 180 mug once weekly, peginterferon plus lamivudine 100 mg per day, or lamivudine alone for 48 weeks. Patients were followed up at 6 and 12 months posttreatment. RESULTS: Peginterferon alfa-2a provided significantly higher rates of HBeAg seroconversion (31%) in HBeAg-positive patients than did lamivudine (19%, P = 0.005) 6 months posttreatment, irrespective of genotype. Of these, 83% achieving seroconversion during treatment or early posttreatment sustained their response at 12 months posttreatment. In patients who seroconverted, 69% maintained HBV DNA suppression at <10,000 copies/ml and alanine aminotrasferase (ALT) normalization. In HBeAg-negative patients, peginterferon produced a significantly higher combined response of HBV DNA at <20,000 copies/ml and ALT normalization (45%) than lamivudine (31%, P = 0.032), irrespective of genotype. Almost 80% of these patients sustained their response at 12 months posttreatment. CONCLUSIONS: In conclusion, a finite course of peginterferon alfa-2a provides significant and sustained treatment benefit in Asian CHB patients, who have traditionally been regarded as difficult to treat.

Interspousal transmission of hepatitis C in Thailand.

BACKGROUND: Previous studies evaluating the possibility of interspousal sexual transmission of hepatitis C virus (HCV) have yielded many conflicting results. Our study was carried out to determine the exact potential and risk factors of interspousal HCV transmission. METHODS: The spouses (54 men and 106 women; mean age +/-SD, 48 +/- 8 years) of 160 patients with HCV infection (106 men and 54 women) were serologically tested for HCV using a third-generation enzyme-linked immuno- sorbent assay (ELISA). Positive results were confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). For positive couples, the cluster nucleotides of the HCV gene and genotypes were compared on the basis of restriction fragment length polymorphism (RFLP), Innogenetic Line Probe Assay (INNO-LiPA), and direct sequencing. Similarly, phylogenetic tree and sequence homology analysis was performed in order to precisely verify interspousal transmission. Risk factors promoting interspousal HCV transmission were also identified. RESULTS: Throughout a mean duration of exposure of 23 + 5 years, most of the 160 partners had their usual and unprotected sexual relationships with the index patients. HCV-associated antibodies and HCV-RNA were detected in only 3 (1.88%) of the 160 spouses. Furthermore, homology and phylogenetic tree analysis could not clearly demonstrate that any one of these 3 positive spouses was infected with the same strain of HCV as that identified in the index cases. Because a positive group remained elusive, risk factors of interspousal HCV transmission could not be determined in this study. CONCLUSIONS: According to this study, interspousal transmission of HCV seems to be very rare. HCV-positive spouses should be firmly reassured that they can maintain their normal marital life.

Acute hepatitis associated with Barakol.

Barakol is a natural anxiolytic extracted from Cassia siamea, known as "Khi-lek" in Thailand. The authors studied the adverse effects of Barakol in 12 healthy Thai patients, aged 29-81 years (mean 52.5) who took Barakol 3-180 days (mean 76.9). Eight of them were admitted with the first episode of anorexia and jaundice for 4-60 days (mean 14.3) after taking 20-40 mg/day (2-4 tablets) of Barakol. There was no relationship between degree of symptom and dosage/duration of Barakol intake. Three asymptomatic cases were detected with increased aminotransferase from a routine check-up, including an 81 year old female who took half of the dosage for 120 days. The last one was a male patient who presented with low-grade fever and nausea and vomiting. All patients had neither a history of chronic liver disease nor known hepatotoxic substance ingestion. On admission, the mean total bilirubin was 5.7 mg/dl and liver function test (LFT) revealed moderate to severe hepatitis (Aspartate amino transferase (AST) range 111-1,473 U/L: mean = 692). None of them had detected viral markers. Liver biopsy was done in 3 cases and the histopathological findings were compatible with interface hepatitis. Two non-biopsy cases developed recurrent transaminitis after one-week re-challenging without informing the physician. Their symptoms and LFT completely improved within 2-20 weeks (mean 5.9) after Barakol abstinence.

Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C.

BACKGROUND & AIMS: Hepatitis B virus (HBV) isolates of genotype B (HBV/B) with or without the recombination with genotype C over the precore region plus core gene have been reported. METHODS: All the 41 HBV/B isolates having the recombination with genotype C (HBV/Ba) possessed the nucleotide 1838 of A in contrast to that of G in all 29 of those without the recombination (HBV/Bj). Taking advantage of this single nucleotide polymorphism, a restriction fragment length polymorphism method was developed that distinguished HBV/Ba from HBV/Bj. RESULTS: HBV/Bj was detected in 90 of the 97 (93%) carriers of HBV/B from Japan, whereas HBV/Ba occurred in all 177 carriers of HBV/B from other countries (China, 20; Hong Kong, 45; Taiwan, 32; Thailand, 30; Vietnam, 30; and the United States, 20 [all of an Asian ethnicity]). In a case-control study, hepatitis B e antigen (HBeAg) and the double mutation in the core promoter (T1762/A1764) were significantly more frequent in 80 carriers each of HBV/Ba than HBV/Bj (35% vs. 18%, P < 0.05 and 33% vs. 15%, P < 0.05, respectively). Differences in the prevalence of HBeAg were more conspicuous between the carriers of HBV/Bj and HBV/Ba older than 30 years (5 of 66 or 8% vs. 16 of 62 or 26%, P < 0.01). CONCLUSIONS: HBV/B having the recombination with genotype C is frequent in Asia, except in Japan, and HBeAg is more prevalent in carriers of HBV/Ba than HBV/Bj.

Hepatitis B virus genotypes and clinical manifestation among hepatitis B carriers in Thailand.

BACKGROUND: Hepatitis B virus (HBV) genotypes have distinct geographic distributions. The aim of the present study was to evaluate the distribution of HBV genotypes and their clinical relevance in Thailand. METHODS: Hepatitis B virus genotypes among 107 hepatitis B carriers residing in Thailand were evaluated using serologic and genetic methods. They were clinically classified into asymptomatic carriers with normal serum alanine transaminase (ALT) levels and patients with chronic liver disease, such as those with chronic hepatitis (CH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). RESULTS: Hepatitis B virus genotype distribution among the 107 patients was 25.2% for genotype B, 72.0% for genotype C and 2.8% for genotype D. The serum ALT levels, HBV-DNA and hepatitis B e antigen positivity were significantly higher in carriers infected with genotype C HBV than in those infected with genotype B (P < 0.05). The proportion of genotype B HBV was higher in asymptomatic carriers than in patients with CH and those who developed liver disease, such as LC and HCC (45.5, 16.9 and 25.0%, respectively; P < 0.05). In contrast, the proportion of genotype C HBV was higher in patients who developed liver disease and CH than in asymptomatic carriers (68.7, 83.0 and 50.0%, respectively; P < 0.05). Phylogenetic analysis based on entire genome sequences revealed three HBV isolates, which were classified into a subgroup of genotype C in isolates from South-East Asian countries. CONCLUSIONS: Genotypes B and C are the predominant types among hepatitis B carriers residing in Thailand and those genotypes influence the clinical manifestation in carriers with chronic hepatitis B infection.

Management of refractory ascites and hepatorenal syndrome.

Refractory ascites and hepatorenal syndrome (HRS) are the late complications of the terminal stages of cirrhosis. The definitions of refractory ascites and HRS proposed by the International Ascites Club in 1996 are now widely accepted, and are useful in diagnosis, treatment and research in this field. In both conditions, the only treatment of proven value for improved survival is liver transplantation. However, because of better understanding about the pathophysiology of HRS, including the roles of portal hypertension, ascites formation and hemodynamic derangements, treatments such as transjugular intrahepatic portasystemic shunt (TIPS) and new pharmacological agents may be considered to alleviate the problem prior to transplantation. Symptomatic treatment of refractory ascites includes TIPS and repeated large volume paracentesis. Transjugular intrahepatic portasystemic shunt can improve survival while waiting for liver transplantation. Practical management guidelines for TIPS and large volume paracentesis, including the prevention and management of further complications, are considered in this review.

Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene.

The entire nucleotide sequences of 70 hepatitis B virus (HBV) isolates of genotype B (HBV/B), including 38 newly determined and 32 retrieved from the international DNA database (DDBJ/EMBL/GenBank), were compared phylogenetically. Two subgroups of HBV/B were identified based on sequence divergence in the precore region plus the core gene, one with the recombination with genotype C and the other without it. The analysis over the entire genome of HBV/B by the SimPlot program located the recombination with genotype C in the precore region plus the core gene spanning nucleotide positions from 1740 to 1838 to 2443 to 2485. Within this genomic area, HBV/B strains with the recombination had higher nucleotide and amino acid homology to genotype C than those without the recombination (96.9 versus 91.1% in nucleotides and 97.0 versus 92.9% in amino acids). There were 29 HBV/B strains without the recombination, and they were all recovered from carriers in Japan. The remaining 41 HBV/B isolates having the recombination with genotype C were from carriers in China (12 strains), Hong Kong (3 strains), Indonesia (4 strains), Japan (3 strains), Taiwan (4 strains), Thailand (3 strains), and Vietnam (12 strains). Due to the frequency of the distribution of HBV/B without the recombination (29 of 32 isolates, or 91%) and the fact that it was exclusive to Japan, it was provisionally classified into the Bj (j standing for Japan) subgroup, and HBV/B with the recombination was classified into the Ba (a for Asia) subgroup. Virological differences between HBV/Bj and HBV/Ba may be reflected in the severity of clinical disease in the patients infected with HBV of genotype B, which seems to be under strong geographic influences in Asia.