The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness. Modeling viral kinetics during therapy has provided important insights into the MOA and effectiveness of a variety of anti-HCV agents. Here, we show that understanding the effects of daclatasvir in vivo requires a multiscale model that incorporates drug effects on the HCV intracellular lifecycle, and we validated this approach with in vitro HCV infection experiments. The model predicts that daclatasvir efficiently blocks two distinct stages of the viral lifecycle, namely viral RNA synthesis and virion assembly/ secretion with mean effectiveness of 99% and 99.8%, respectively, and yields a more precise estimate of the serum HCV half-life, 45 min, i.e., around four times shorter than previous estimates. Intracellular HCV RNA in HCV-infected cells treated with daclatasvir and the HCV polymerase inhibitor NM107 showed a similar pattern of decline. However, daclatasvir treatment led to an immediate and rapid decline of extracellular HCV titers compared to a delayed (6-9 h) and slower decline with NM107, confirming an effect of daclatasvir on both viral replication and assembly/secretion. The multiscale modeling approach, validated with in vitro kinetic experiments, brings a unique conceptual framework for understanding the mechanism of action of a variety of agents in development for the treatment of HCV.direct-acting antiviral agents | mathematical modeling | viral dynamics H epatitis C virus (HCV) infection is a major health burden affecting about 150 million people worldwide (1) and ∼4.1 million in the United States (2), where it is the primary cause of liver cirrhosis and liver cancer (1). Until 2011, the most advanced antiviral therapy was pegylated interferon-α (IFN-α) plus ribavirin (Peg-IFN/RBV), with a cure rate of 50% or less in patients infected with HCV genotype 1, the most prevalent in the Western world.To obtain higher cure rates, drug development has focused mainly on inhibiting the function of nonstructural (NS) viral proteins with known enzymatic functions, such as the NS3-4A protease and the NS5B polymerase. Through the use of an innovative screening approach to search for nonenzymatic targets, daclatasvir (BMS-790052) was identified as a potent NS5A inhibitor (3). The functions of the NS5A protein are not fully elucidated, although in vitro studies suggest an essential role of NS5A in both viral replication (4-7) and assembly/release of infectious particles (8-11). The efficacy of daclatasvir as an antiviral agent was confirmed in a single ascending-dose study in which a mean 3.3-log 10 reduction in viral load 24 h after drug administration was observed in patients receiving a 1...

Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months’ follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0.73 log IU/mL in group 1 (95% CI 0.17–1.31; p=0.03) and −1.54 log IU/mL in group 2 (1.21–1.93; p<0.0001). Lonafarnib serum concentrations correlated with HDV RNA change (r2=0.78, p<0.0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0.75 days [SE 0.24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0.952 [SE 0.06] vs 0.739 [0.05], p<0.001), and the HDV half-life was 1.62 days (0.07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Health-related stigma is a cause of stress, alienation and discrimination that can serve as a barrier to prevention and care for infectious diseases such as HIV. Hepatitis B virus (HBV)-related stigma is common in Asian immigrants, but has not been formally evaluated. The aim of this study was to develop and validate the first HBV stigma instrument and to begin to evaluate HBV stigma in Chinese immigrants. The HBV stigma instrument was developed based on constructs from validated HIV stigma scales and organized into five domains. A written survey was compiled to include demographic data, HBV knowledge questions and stigma items. The survey was pilot tested in English and Chinese and then finalized. Data were obtained from 201 patients seen in an urban Chinatown Internal Medicine practice. The stigma items showed a high degree of reliability when assessed in aggregate (α = 0.85) as well as within individual domains. Stigma was greatest in the Fear of Contagion domain. Knowledge questions showed a corresponding deficit in understanding of modes of HBV transmission. An inverse relationship between stigma scores and familiarity with HBV provided evidence of construct validity. In multivariable analysis, having a family member with HBV and higher HBV knowledge subset scores were associated with lower degrees of stigma. In conclusion, the hepatitis B stigma instrument showed reliability and construct validity. The relationship identified between familiarity and knowledge regarding HBV with lower stigma scores provides the basis for the development of interventions to reduce HBV stigma.

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