Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.

Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."

Treatment of non-alcoholic steatohepatitis with Phyllanthus urinaria: a randomized trial.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a common liver disease that may progress to cirrhosis and hepatocellular carcinoma. There is currently no approved pharmacological treatment for NASH. Phyllanthus urinaria is a commonly used hepatoprotective herb that ameliorates NASH in animal studies. We aimed to test the hypothesis that Phyllanthus was superior to placebo in improving histological non-alcoholic fatty liver disease (NAFLD) activity score. METHODS: This was a placebo-controlled parallel-group double-blind randomized controlled trial. Patients with histology-proven NASH were randomized to receive Phyllanthus or placebo for 24 weeks. The primary endpoint was change in NAFLD activity score from baseline to week 24. Secondary endpoints included changes in individual histological parameters, liver biochemistry and metabolic profile. RESULTS: We enrolled 60 patients (40 received Phyllanthus and 20 received placebo). The change in NAFLD activity score was -0.8 ± 1.4 in the Phyllanthus group and -0.3 ± 1.3 in the placebo group (P = 0.24). The change in steatosis, lobular inflammation, ballooning and fibrosis was also similar between the two groups. Within the Phyllanthus group, although there was reduction in hepatic steatosis (-0.2 ± 0.7; P = 0.039) and ballooning grades (-0.4 ± 0.5; P < 0.001), the change was small and of limited clinical significance. Furthermore, there was no significant difference in the changes in alanine aminotransferase, aspartate aminotransferase, fasting glucose and lipid profile between the two groups. CONCLUSIONS: Phyllanthus is not superior to placebo in improving NAFLD activity score in NASH patients.

A hospital clinic-based survey on traditional Chinese medicine usage among chronic hepatitis B patients.

OBJECTIVES: To survey the pattern of traditional Chinese medicine usage among chronic hepatitis B patients. DESIGN: Self-administered questionnaire survey. SETTING: Hepatitis clinic at a university hospital in Hong Kong. MAIN OUTCOME MEASURES: Proportion of chronic hepatitis B patients who have ever used traditional Chinese medicine for the treatment of chronic hepatitis B and factors associated with the use. RESULTS: Three hundred and sixty-two patients completed the survey (response rate 93%). One hundred and sixteen (32%) patients reported history of traditional Chinese medicine usage. One hundred and five (91%) patients felt that Chinese medicine had few or no side effects. Most (81%) patients did not inform their physicians on Chinese medicine usage. On multivariate analysis, recent travel to Mainland China, perceived active hepatitis and family members with chronic hepatitis B were independent factors associated with the use of Chinese medicine. CONCLUSIONS: Chronic hepatitis B patients commonly use traditional Chinese medicine. As patients seldom inform the physicians about the use of Chinese medicine, doctors should explicitly enquire about this because of potential therapeutic implications.