Hepatic adverse drug reactions in Malaysia: An 18-year review of the national centralized reporting system.

PURPOSE: To determine the incidence, demographic profile, background of reporters, causative agents, severity and clinical outcomes of hepatic adverse drug reaction (ADR) reports in Malaysia using the national ADR reporting database. METHODS: The ADR reports recorded between 2000 and 2017 were retrospectively analysed to identify hepatic ADR reports. The trend and characteristics of hepatic ADR cases were described. Multivariate disproportionality analysis of the causative agents was performed to generate signals of hepatic ADRs. RESULTS: A total of 2090 hepatic ADRs (1.77% of all ADRs) were reported with mortality rate of 12.7% among cases with known clinical outcomes. The incidence of hepatic ADR reporting in Malaysia increased significantly over 18 years from 0.26 to 9.45 per million population (P < .001). Antituberculosis drugs (n = 268, 12.82%) was the most common suspected class of causative agents with a reporting odds ratio (ROR) and 95% CI of 8.39 (7.26-9.70), followed by traditional/complementary medicines or herbal/dietary supplements (TCM/HDS) (n = 235, 11.24%, ROR 3.26 [2.84-3.75]), systemic antibacterials (n = 159, 7.61%, ROR 2.65 [2.25-3.13]), lipid modifying agents (n = 142, 6.79%, ROR 2.21 [1.86-2.63]) and amiodarone (n = 137, 6.56%, ROR 35.25 [28.40-43.75]). Most (72.9%) of the TCM/HDS were not registered with the authorities. CONCLUSIONS: Hepatic ADR cases have increased significantly in Malaysia, with antituberculosis drugs, systemic antibacterials, and TCM/HDS being the most common causative agents reported. Most TCM/HDS reported to be associated with hepatic ADR were not registered with the authorities.

Quantitative Hepatitis B e Antigen: A Better Predictor of Hepatitis B Virus DNA than Quantitative Hepatitis B Surface Antigen.

BACKGROUND: Hepatitis B surface antigen is usually secreted by infected hepatocytes in the form of subviral particles rather than infectious virions, while the hepatitis B e antigen originates from the core gene and is modified and secreted by hepatocytes into the circulation and functions as a marker of active viral replication. This study aimed to study the relationship between HBV DNA and quantitative hepatitis B surface and e antigen in Malaysian patients. METHODS: A total of 82 chronic hepatitis B patients were recruited for this study from the Hepatology Department of Selayang Hospital. Quantitative hepatitis surface and e antigen was performed retrospectively on frozen plasma using enzyme linked immunosorbent assay according to the manufacturer's instructions. Hepatitis B viral DNA was extracted from all plasma samples and quantified using real-time PCR. RESULTS: Quantitative hepatitis B surface and e antigens were found be high in 54.9% and 52.4% of the patients, respectively, while hepatitis B virus DNA level was high in 70.7%. The median of the viral load of HBV was 8,934.89 IU/mL and both hepatitis B surface and e antigens were also found to be high on average for qHBsAg (M = 5.19 IU/mL, SD ± 4. 33) and qHBeAg (M = 4.74IU/mL, SD ± 4.20), with qHBeAg being more strongly correlated to HBV DNA than qHBsAg (r = 0.893; p < 0.01). CONCLUSIONS: This study revealed HBeAg to be the most appropriate marker that correlates well with HBV DNA, thus not completely novel but confirmative, and related to the Malaysian situation.

Blood gene signature for early hepatocellular carcinoma detection in patients with chronic hepatitis B.

PURPOSE: Up to 25% of chronic hepatitis B (CHB) patients eventually develop hepatocellular carcinoma (HCC), a disease with poor prognosis unless detected early. This study identifies a blood-based RNA biomarker panel for early HCC detection in CHB. MATERIALS AND METHODS: A genome-wide RNA expression study was performed using RNA extracted from blood samples from Malaysian patients (matched HCC, CHB, controls). Genes differentiating HCC from controls were selected for further testing using quantitative real-time polymerase chain reaction. Finally, a 6-gene biomarker panel was identified and characterized using a training set (cohort I = 126), and tested against 2 test sets (cohort II = 222; cohort III = 174). The total number of samples used for each group is: HCC + CHB = 143, CHB = 211, control = 168. RESULTS: Our gene panel displays a consistent trend distinguishing HCC from controls in our test sets, with an area under receiver-operating characteristic curve of 0.9 in cohort III. Our independent test set (cohort III) showed that the gene panel had a sensitivity of 70% with a specificity of 92%. The biomarker profile for HCC was consistently detected in a small subgroup of CHB patients, thus potentially predicting early, preclinical cases of cancer that should be screened more intensively. CONCLUSION: The biomarkers identified in this study can be used as the basis of a blood-based test for the detection of early HCC in CHB.

Effects of one-year supplementation with Phyllanthus niruri on fibrosis score and metabolic markers in patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial.

Background and purpose: and purpose: Non-alcoholic fatty liver disease (NAFLD) is a significant global health concern with limited pharmacotherapy options. This study aimed to evaluate the effectiveness of a standardized extract of Phyllanthus niruri in mild-to-moderate NAFLD. Materials and methods: This was a 12-month randomized controlled trial, in which adults with a controlled attenuation parameter (CAP) score >250 dB/m and a fibrosis score <10 kPa were randomly assigned to receive a standardized P. niruri extract at a dose of 3,000 mg daily (n = 112) or a placebo (n = 114). The primary outcomes were changes in CAP score and liver enzyme levels, while the secondary outcomes were changes in other metabolic parameters. The analysis was performed on an intention-to-treat basis. Results: After 12 months, there was no significant difference in the change of CAP score between the intervention and control groups (-15.05 ± 36.76 dB/m vs. -14.74 ± 41.08 dB/m; p = 0.869). There was also no significant difference in the changes of liver enzyme levels between the two groups. However, the intervention group showed a significant reduction in fibrosis score, which was not observed in the control group (-0.64 ± 1.66 kPa versus 0.10 ± 1.61 kPa; p = 0.001). No major adverse events were reported in either group. Conclusion: This study showed that P. niruri did not significantly reduce CAP score and liver enzyme levels in patients with mild-to-moderate NAFLD. However, a significant improvement in fibrosis score was observed. Further research is needed to determine its clinical benefits at different dosages for NAFLD treatment.

Intraoperative blood loss and blood transfusion requirement among liver transplant recipients: A national single-center experience 2020.

BACKGROUND: Liver transplantation (LT) is a complicated surgical procedure with high risk for massive intraoperative blood loss due to pre-existing coagulopathy, portosystemic shunts with collateral circulations, and splenomegaly. The transfusion service will direct most of their resources toward LT programs with great impact on cost. The purpose of this study was to evaluate single center transfusion strategies and to identify the risk factors associated with the intraoperative blood loss and blood transfusion. METHODS: The study includes 18 patients who underwent LT at Hospital Selayang between January 2020 and December 2020. Retrospective analysis of data included preoperative assessment of coagulopathy, intraoperative blood loss, and blood component transfusion. RESULTS: The mean age in the study group was 36.4 ± 12.68 years. The mean intraoperative blood loss was 4450 ± 1646 ml requiring 4.17 ± 3.3 packed red blood cell (PRBC) units, 7.56 ± 5.5 platelet units, and 9.50 ± 6.0 fresh-frozen plasma units. The independent risk factor for high blood loss (HBL) group was lower preoperative platelet count and it is statistically significant (P = 0.024). The HBL group is associated with higher usage of PRBC (P = 0.024) and platelet units (P = 0.031) and it is statistically significant. The length of stay (LOS) in intensive care unit (ICU) averaging 8.6 ± 4.95 days, and there is no significant differences comparing the HBL and LBL group (P = 0.552). The mortality <90 days for all recipients was 22.2%. CONCLUSION: The preoperative platelet count for is the most important factor associated with HBL in LT procedure. The usage of PRBC and platelet units was statistically higher in the HBL group. Comparing HBL and LBL patients, there is no difference in terms of the LOS in ICU postoperatively. A larger sample size would be needed in view of relatively small sample size.

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.

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.

Assessing the impact of simplified HCV care on linkage to care amongst high-risk patients at primary healthcare clinics in Malaysia: a prospective observational study.

INTRODUCTION: To achieve the elimination of hepatitis C virus (HCV), substantial scale-up in access to testing and treatment is needed. This will require innovation and simplification of the care pathway, through decentralisation of testing and treatment to primary care settings and task-shifting to non-specialists. The objective of this study was to evaluate the feasibility and effectiveness of decentralisation of HCV testing and treatment using rapid diagnostic tests (RDTs) in primary healthcare clinics (PHCs) among high-risk populations, with referral of seropositive patients for confirmatory viral load testing and treatment. METHODS: This observational study was conducted between December 2018 and October 2019 at 25 PHCs in three regions in Malaysia. Each PHC was linked to one or more hospitals, for referral of seropositive participants for confirmatory testing and pretreatment evaluation. Treatment was provided in PHCs for non-cirrhotic patients and at hospitals for cirrhotic patients. RESULTS: During the study period, a total of 15 366 adults were screened at the 25 PHCs, using RDTs for HCV antibodies. Of the 2020 (13.2%) HCV antibody-positive participants, 1481/2020 (73.3%) had a confirmatory viral load test, 1241/1481 (83.8%) were HCV RNA-positive, 991/1241 (79.9%) completed pretreatment assessment, 632/991 (63.8%) initiated treatment, 518/632 (82.0%) completed treatment, 352/518 (68.0%) were eligible for a sustained virological response (SVR) cure assessment, 209/352 (59.4%) had an SVR cure assessment, and SVR was achieved in 202/209 (96.7%) patients. A significantly higher proportion of patients referred to PHCs initiated treatment compared with those who had treatment initiated at hospitals (71.0% vs 48.8%, p<0.001). CONCLUSIONS: This study demonstrated the effectiveness and feasibility of a simplified decentralised HCV testing and treatment model in primary healthcare settings, targeting high-risk groups in Malaysia. There were good outcomes across most steps of the cascade of care when treatment was provided at PHCs compared with hospitals.

Endoscopic ultrasound-guided hepaticogastrostomy using a partially covered metal stent in patients with malignant biliary obstruction after failed Endoscopic retrograde cholangiopancreatography.

BACKGROUND AND AIM: The advent of endoscopic ultrasound-guided biliary drainage (EUS-BD) has provided an inimitable alternative for gaining biliary access in patients who fail conventional endoscopic drainage. The antimigratory features of the partially covered metal stent (PCMS), namely, the flange head and uncovered portion of the stent, makes it a valuable option in patients undergoing EUS-guided hepaticogastrostomy (EUS-HGS). The aim of the study is to evaluate the clinical outcome of EUS-BD via the hepaticogastrostomy approach using PCMS in patients with malignant biliary obstruction after failed ERCP. METHODS: This is a single-center retrospective observational study of patients with malignant biliary obstruction undergoing EUS-HGS after failed ERCP between January 2018 and May 2019. The end-point of the study was to assess the technical and clinical success rate, as well as the stent- and procedure-related complications. RESULTS: There were 20 subjects in this study. The average age was 71.8 ± 7.6 years. Most patients were male, 16 (80%). Inaccessible papillae was the most common indication for this procedure, 16 (80%). Technical success was achieved in all patients. The average procedural time was 39.9 ± 1.3 min. Mean preprocedural bilirubin levels were 348.6 ± 28.8 and subsequently decreased to 108.94 ± 37.1 µmol/L at 2 weeks postprocedure. The clinical success rate was 95% (19/20), with one patient requiring percutaneous transhepatic biliary drainage (PTBD). There were no stent- or procedure-related complications reported in this study. CONCLUSION: EUS-HGS with PCMS is a feasible, effective, and safe alternative for biliary decompression in patients with failed endoscopic retrograde cholangiopancreatography (ERCP).

Genetic diversity of hepatitis B co-infection with hepatitis C, D and E viruses among Malaysian chronic hepatitis B patients.

BACKGROUND: Hepatitis B virus co-infection with other strains of viral hepatitis is associated with increased risk of liver cirrhosis and hepatic decompensation. OBJECTIVES: This is a prevalence study that assessed the genetic diversity of chronic hepatitis B patients and coinfection. METHODS: Chronic hepatitis B patients enrolled in this study were tested for antibodies of other hepatitis viruses using ELISA kits. Patient clinical profiles were collected and partial genes of HBV, HCV, and HEV were amplified, sequenced, and analyzed using phylogenetic analysis. The associations between variables were determined using the chi-squared test. RESULTS: Of the 82 patients recruited for this study, 53.7% were non-cirrhotic, 22.0% cirrhotic, 20.7% acute flare and 3.7% hepatocellular carcinoma. Majority (58%) of patients had a high level of ALT (≥34 U/L). Sequence analysis showed HBV (63.9%) belonged to genotype B, HEV belonged to genotype 4 while HCV belonged to genotype 3a and the genotypes were found to be significantly associated with the clinical stage of the patients (χ2=56.632; p<0.01). Similarly, Hepatitis B e antigen was also found to be significantly associated with the clinical stage of infection (χ2=51.952; p<0.01). CONCLUSION: This study revealed that genetic diversity was found to have a significant impact on the severity of infection.

The use of transient elastography and FibroTest for monitoring hepatotoxicity in patients receiving methotrexate for psoriasis.

IMPORTANCE: There is a need for noninvasive tools to monitor hepatotoxicity in patients with psoriasis who are receiving methotrexate sodium. OBJECTIVE: To evaluate the use of transient elastography (TE) and FibroTest (FibroSURE in the United States), an indirect serum marker of fibrosis, in this population. DESIGN, SETTING, AND PARTICIPANTS: Patients receiving methotrexate therapy for psoriasis between January 2008 and September 2009 were recruited from a dermatology outpatient department. Transient elastography and FibroTest were performed, and patients with abnormal results were considered for liver biopsy. Serial procollagen III peptide (PIIINP) results were recorded. INTERVENTIONS: Transient elastography uses pulse-echo ultrasonography to measure liver stiffness, and this result is an indirect measure of hepatic fibrosis. FibroTest is an indirect serum marker of hepatic fibrosis. MAIN OUTCOMES AND MEASURES: Procollagen III peptide, TE, and FibroTest results, as well as the need for liver biopsy in this cohort. RESULTS: Seventy-seven patients (41 male [53%]) were included. Fifty (65%) patients had a valid TE assessment, and 9 (18%) had an abnormal result (range, 7.1-11.3 kPa). Being overweight or obese increased the possibility of obtaining an invalid TE result significantly (P = .01). On univariate analysis body mass index (r = 0.40, P = .005) and age (r = 0.52, P = .005) were correlated with abnormal TE results. Seventy-one patients received a FibroTest and 11 of 70 analyzed (16%) had an abnormal result (METAVIR score >F1). Age (r = 0.31, P = .009), cumulative methotrexate dose (r = 0.31, P = .01), and duration of methotrexate therapy (r = 0.36, P = .002) were correlated with abnormal FibroTest results. There was no correlation between PIIINP levels and TE results or between PIIINP levels and FibroTest results. Steatosis was demonstrated in all 5 patients who received liver biopsies during the study. Two patients had hepatic fibrosis, with 1 showing a sinusoidal pattern of fibrosis attributed to steatohepatitis. CONCLUSIONS AND RELEVANCE: Transient elastography and FibroTest are effective noninvasive tools for monitoring hepatotoxicity in patients receiving methotrexate for psoriasis. We propose that the need for liver biopsy could be reduced if abnormalities in at least 2 tests (serial PIIINP, TE, or FibroTest) are required before biopsy is considered. This strategy should be evaluated in prospective studies.

Cerebral embolism following N-butyl-2-cyanoacrylate injection for esophageal postbanding ulcer bleed: a case report.

Systemic embolization is a rare but serious complication of variceal injection with cyanoacrylate. We report a case of cerebral embolism a few hours after an injection of Histoacryl into a bleeding esophageal post-banding ulcer. Echocardiogram revealed patent foramen ovale.