Hepatitis delta virus (HDV) is a small RNA virus which needs Hepatitis B Surface Antigen for its envelope, for entry into hepatocytes and secretion. HDV chronic infection affects around 12 million ...people worldwide. HDV infection is believed to be the most severe form of viral hepatitis, with a high risk of developing cirrhosis and hepatocellular carcinoma. Pegylated interferons has been used and recommended by guidelines, although not approved, with low efficacy and poor tolerability. Bulevirtide (entry inhibitor) has been recently conditionally approved by the European Medicines Agency. These treatments have many advantages, but they have also limitations since there are non‐responders to these previous therapies. There is an urgent need to develop new drugs. In this article, we review antiviral treatments under development for HDV chronic infection (except bulevirtide reviewed in a specific article), including those in the HBV cure programme, outlining their respective mechanisms‐of‐action.
Mitochondria regulate hepatic lipid metabolism and oxidative stress. Ultrastructural mitochondrial lesions, altered mitochondrial dynamics, decreased activity of respiratory chain complexes, and ...impaired ability to synthesize adenosine triphosphate are observed in liver tissues from patients with alcohol-associated and non-associated liver diseases. Increased lipogenesis with decreased fatty acid β-oxidation leads to the accumulation of triglycerides in hepatocytes, which, combined with increased levels of reactive oxygen species, contributes to insulin resistance in patients with steatohepatitis. Moreover, mitochondrial reactive oxygen species mediate metabolic pathway signaling; alterations in these pathways affect development and progression of chronic liver diseases. Mitochondrial stress and lesions promote cell death, liver fibrogenesis, inflammation, and the innate immune responses to viral infections. We review the involvement of mitochondrial processes in development of chronic liver diseases, such as nonalcoholic fatty, alcohol-associated, and drug-associated liver diseases, as well as hepatitis B and C, and discuss how they might be targeted therapeutically.
People living with hepatitis B virus (HBV) chronic infection are exposed to high rates of liver complications including end-stage liver disease and hepatocellular carcinoma. Extrahepatic ...manifestations of HBV infection have long been underestimated. Several of these extrahepatic syndromes have been well described, including systemic vasculitides, glomerulonephritis, and cutaneous manifestations. Other manifestations have been more recently described such as hematological malignancies and neurological diseases. These extrahepatic manifestations are associated with significant morbidity and mortality. Although not completely understood, underlying mechanisms include HBV-induced local and systemic inflammation. Suppression of HBV replication usually improves extrahepatic manifestations. This review will discuss how HBV induces inflammation and the extrahepatic manifestations of HBV infection to guide clinical management.
Coronavirus disease 2019 (COVID-19) started as an epidemic in Wuhan in 2019, and has since become a pandemic. Groups from China identified and sequenced the virus responsible for COVID-19, named ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and determined that it was a novel coronavirus sharing high sequence identity with bat- and pangolin-derived SARS-like coronaviruses, suggesting a zoonotic origin. SARS-CoV-2 is a member of the Coronaviridae family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of vertebrates. The rapid release of the sequence of the virus has enabled the development of diagnostic tools. Additionally, serological tests can now identify individuals who have been infected. SARS-CoV-2 infection is associated with a fatality rate of around 1–3%, which is commonly linked to the development of acute respiratory distress syndrome (ARDS), likely resulting from uncontrolled immune activation, the so called “cytokine storm”. Risk factors for mortality include advanced age, obesity, diabetes, and hypertension. Drug repurposing has been used to rapidly identify potential treatments for COVID-19, which could move quickly to phase III. Better knowledge of the virus and its enzymes will aid the development of more potent and specific direct-acting antivirals. In the long term, a vaccine to prevent infection is crucial; however, even if successful, it might not be available before 2021-22. To date, except for intravenous remdesivir and dexamethasone, which have modest effects in moderate to severe COVID-19, no strong clinical evidence supports the efficacy of any other drugs against SARS-CoV-2. The aim of this review is to provide insights on the discovery of SARS-CoV-2, its virology, diagnostic tools, and the ongoing drug discovery effort.
For HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct‐acting antivirals (DAA) showing high potency, favourable ...tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan‐genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN‐based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross‐resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.
COMMENTARY ON: Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun ...JH, O’Boyle DR 2nd, Lemm JA, Wang C, Knipe JO, Chien C, Colonno RJ, Grasela DM, Meanwell NA, Hamann LG. Nature. 2010;465(7294):96–100. Copyright (2010). Abstract reprinted with permission from Macmillan Publishers Ltd. http://www.ncbi.nlm.nih.gov/pubmed/20410884 Abstract: The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
Chronic hepatitis C is one of the leading causes of chronic liver disease with approximately 170 million people infected worldwide. Sustained virological response (SVR) is equivalent to viral ...eradication and associated with a reduction in the risk of cirrhosis. Nowadays the treatment for hepatitis C virus (HCV) genotype 1 chronic infection is the addition of direct acting antivirals (DAA) with a protease inhibitor (telaprevir or boceprevir) to the pegylated interferon (PEG‐IFN) plus ribavirin (RBV) regimen. The future management of patients with these new molecules will require good clinical practice, knowledge of indications, management of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet and require studies in special populations (HIV‐HCV coinfected patients, transplanted patients, etc.…) and also in HCV non‐1 genotype patients and in non‐responders. Second generation DAA are in development. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. The aim of this review is to summarize mechanisms of action and results obtained with DAAs.
There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct‐acting antivirals (DAAs) from different families NS5B nucleotide inhibitors, NS5B ...non‐nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI) have been developed. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to 12 weeks or less. As of 2016 several regimens will be approved with additive potencies, without cross‐resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAA combinations that have been approved and/or have completed phase 3 clinical trials for HCV infection and discusses future perspectives.
Chronic hepatitis C is one of the leading causes of chronic liver disease, with approximately 170 million people infected worldwide. The severity of disease varies from asymptomatic chronic infection ...to cirrhosis and hepatocellular carcinoma (HCC). Sustained virological response (SVR) is long lasting, associated with a reduced risk of cirrhosis and HCC. In the near future, standard of care (SOC) treatment of hepatitis C virus (HCV) will include the addition of direct‐acting antivirals (DAAs) with a protease inhibitor to the pegylated interferon (PEG‐IFN) plus ribavirin (RBV). In HCV genotype 1 patients, promising results have been reported when the protease inhibitor telaprevir or boceprevir is added to the SOC, increasing SVR rates from less than 50% (PEG‐IFN plus RBV) to 70% (in patients treated with a triple combination of PEG‐IFN, RBV plus a protease inhibitor). The future management of patients with these new molecules will require good clinical practice, knowledge of indications, prediction of side effects and monitoring for antiviral resistance. Certain major medical needs are still unmet, requiring studies in special populations (human immunodeficiency virus–HCV‐coinfected patients, transplanted patients, etc.) in genotype non‐1 patients and in absolute non‐responders. Combinations of antivirals with additive potency that lack cross resistance and with a good safety profile may provide new regimens in the future to make HCV the first chronic viral infection eradicated worldwide with a finite duration of combination DAA therapy without IFN. There is ongoing development of new molecules such as HCV enzyme inhibitors. The aim of this review is to summarize the results obtained with DAAs: protease and polymerase inhibitors.
A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need.
We conducted a phase 3, ...double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group.
Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).
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