Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients

Background/Aims@#Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. @*Methods@#This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. @*Results@#68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. @*Conclusions@#48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Drug induced liver injury: East versus West– a systematic review and meta-analysis

Drug induced liver injury (DILI) may be different in the East compared to the West due to differing disease prevalence, prescribing patterns and pharmacogenetic profiles. To review existing literature on causative agents of DILI in the East compared to the West, a comprehensive literature search was performed on electronic databases: MEDLINE/PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure without language restrictions. Studies which involve patients having DILI and reported the frequency of causative agents were included. A random effects model was applied to synthesize the current evidence using prevalence of class-specific and agent-specific causative drugs with 95% confidence intervals. Of 6,914 articles found, 12 showed the distribution of drugs implicated in DILI in the East with a total of 33,294 patients and 16 in the West with a total of 26,069 DILI cases. In the East, the most common agents by class were anti-tuberculosis drugs (26.6%), herbal and alternative medications (25.3%), and antibiotics (15.7%), while in the West, antibiotics (34.9%), cardiovascular agents (17.3%), and non-steroidal anti-inflammatory drugs (12.5%) were the commonest. For individual agents, the most common agents in the East were isoniazid-rifampicin-pyrazinamide (25.4%), phenytoin (3.5%), and cephalosporin (2.9%) while in the West, amoxicillin-potassium clavulanate combination acid (11.3%), nimesulide (6.3%), and ibuprofen (6.1%) were the commonest. There was significant heterogeneity due to variability in single-centre compared to multi-centre studies. Differences in DILI in the East versus the West both in drug classes and individual agents are important for clinicians to recognize.

Magnetic Resonance Elastography and Diffusion Weighted Imaging in the Evaluation of Hepatic Fibrosis in Chronic Hepatitis B

BACKGROUND/AIMS: Comparison of the accuracy of magnetic resonance elastography (MRE) and diffusion weighted imaging (DWI) for the diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: In this retrospective analysis, we investigated 63 patients with CHB and liver fibrosis. DWI was performed with both breath-hold (DWI-BH) and free-breathing (DWI-FB) sequences (b=0, 500). The mean liver stiffness and apparent diffusion coefficient (ADC) were calculated by drawing regions of interest maps. Fibrosis staging according to the METAVIR system was independently performed by an experienced pathologist. A receiver operating curve (ROC) analysis was conducted to determine the accuracy of MRE, DWI-BH and DWI-FB in the detection and stratification of liver fibrosis. The performance of the detection of significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) was also evaluated by comparing areas under the ROC. RESULTS: There was a moderate and significantly negative correlation between the ADC values and liver stiffness. The accuracies for the detection of ≥F2/≥F3/F4 stage fibrosis with DWI-FB, DWI-BH and MRE were 0.84/0.76/0.72, 0.72/0.83/0.79 and 0.99/0.99/0.98, respectively. The performance of MRE was significantly better than DWI-FB and DWI-BH. There were no significant differences between the performance of DWI-FB and DWI-BH. CONCLUSIONS: MRE is more accurate than DWI for the detection and stratification of liver fibrosis in CHB.

Time for Action on Viral Hepatitis

The recent outbreak of hepatitis C virus (HCV) at Singapore General Hospital (SGH) has highlighted the dangers of viral hepatitis. In this case, infection control and environmental contamination were the culprits, particularly, a drop of blood containing 5 million IU HCV. From a broader perspective, there has been a revolution in HCV therapy with the recent rapid evolution of short-term (12 weeks) safe, all oral directly- acting antiviral (DAA) therapy leading to cure rates of 90% to 100%, even in previously difficult to treat patients with liver cirrhosis, previous treatment failure and those on immunosuppression. Consequently, treating HCV in risk groups such as renal dialysis and haemophiliacs can eliminate a pool of infected patients to prevent future outbreaks. A seroprevalence study is needed to identify a possible "birth cohort" effect that could aid screening. For HBV, vaccination has reduced prevalence to 3.8%, but these patients are prone to complications such as HBV flares. Since 2014, 13 patients developed liver failure and were listed for liver transplantation at National University Hospital (NUH) but 6 died beforehand. This avoidable catastrophe is due to undiagnosed HBV infection or patients who did not return for follow-up. Good antiviral therapy is available, but the issues are similar to HCV, identification of patients and linkage to care. A cure seems likely in the future as pharmaceutical companies are developing new agents. Singapore has joined in this initiative with a recent award of a national research translational grant to better understand the pathophysiology and the processes needed for a cure of HBV.

A 2015 roadmap for the management of hepatitis C virus infections in Asia

The prevalence of hepatitis C virus (HCV) in Asia is 0.5% to 4.7%, with three different genotypes predominating, depending on the geographic region: genotype 1b in East Asia, genotype 3 in South and Southeast Asia, and genotype 6 in Indochina. Official approval for direct-acting antiviral agents (DAAs) in Asia lags significantly behind that in the West, such that in most countries the mainstay of therapy is still pegylated interferon and ribavirin (PR). Because the interleukin-28B genetic variant, associated with a high sustained virologic response (SVR), is common in Asians, this treatment is still acceptable in Asian patients with HCV infections. A roadmap for HCV therapy that starts with PR and takes into account those DAAs already approved in some Asian countries can provide guidance as to the best strategies for management, particularly of genotype 1 and 3 infections, based on SVR rates. Sofosbuvir and PR are likely to be the initial therapies for genotype 1 and 3 disease, although in the former these drugs may be suboptimal in patients with cirrhosis (62% SVR) and the extension of treatment to 24 weeks may be required. For difficult to treat genotype 3 infections in treatment-experienced patients with cirrhosis, a combination of sofosbuvir and PR result in an 83% SVR and is, therefore, currently the optimal treatment regimen. Treatment failure is best avoided since data on rescue therapies for DAA failure are still incomplete.

Attitudes, Practice and Educational Preferences Towards Evidence-Based Medicine among Physicians in a Large Teaching Hospital.

Evidence-based medicine (EBM) is an emerging must-know topic for today's physicians. The present literature is inadequate in identifying the attitudes, practice, and educational needs and preferred interventions of EBM. The objectives of this survey were to identify a) the attitude toward and practice of EBM among physicians, b) perceived benefits of EBM in daily practice, c) barriers to EBM practice, and d) preferred educational interventions. METHODS: This was a questionnaire-based cross-sectional survey of physicians in a single large teaching hospital. RESULTS: Overall, 56% of the physician respondents described the attitude towards EBM in their institution as positive. A similar number of physicians also reported the attitude of their colleagues towards EBM as favourable. 67% of the physicians believed EBM was useful in daily management of patients. In contrast, only 45% of the physicians actually practiced EBM in their daily patient management. The factors that discouraged them from actual practice include a lack of time, lack of exposure to EBM during their undergraduate curriculum, lack of endorsement, and fear of criticism by seniors. Physicians preferred less time consuming and less rigorous educational interventions such as clinical practice guidelines, journal club, and case review and discussion for teaching and learning EBM. INTERPRETATION: There are disconnects between belief and actual practice and between preferred and ideal educational interventions of EBM among physicians surveyed.

Public misperceptions about transmission of hepatitis B virus in Singapore

<p><b>INTRODUCTION</b>Hepatitis B virus (HBV) infection is endemic in Asia. Good public knowledge on disease transmission is one way of controlling spread of HBV. We aimed to study the general knowledge on HBV among the general public in Singapore, which is moderately prevalent with HBV.</p><p><b>MATERIALS AND METHODS</b>Before conducting a public education seminar on liver diseases, a 16-point questionnaire survey was conducted among the participants. Misperceptions (if any) were identified, and factors associated with knowledge score were analysed by multivariate analysis.</p><p><b>RESULTS</b>One hundred and ninety-two subjects completed the questionnaire. The mean age was 52 years, 78 (41%) were male, 183 (95%) were Chinese, 17 (9%) were known hepatitis B carriers and 73 (38%) had completed college education. The mean knowledge score was 10.7 (out of a maximum of 16). Most misperceptions were in the category of HBV transmission. At multivariate analysis, having college education was the only independent factor associated with a high knowledge score.</p><p><b>CONCLUSION</b>Although HBV infection is moderately prevalent in Singapore, many misperceptions existed among the general public, especially on the mode of transmission. Better education was related to better knowledge of HBV. Further public education should be targeted to clear the misperceptions identified, and be specifically targeted to the less educated.</p>