Current and emerging antiviral treatments for hepatitis <scp>C</scp> infection

Doyle, Joseph S; Aspinall, Esther; Liew, Danny; Thompson, Alexander; Hellard, Margaret

doi:10.1111/j.1365-2125.2012.04419.x

Cited by 47 publications

(44 citation statements)

References 81 publications

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“…HCV infection is recognized as a major threat to global public health, with 130 to 150 million people worldwide being infected with the virus (1). Over the last decade, the standard therapy for chronic HCV infection has been a combination of pegylated interferon alpha and ribavirin (2), but that has greatly changed after the emergence of first direct-acting antivirals that selectively target HCV, i.e., telaprevir and boceprevir (3,4). These drugs, both used in combination with pegylated interferon and ribavirin, have brought significant benefits to patients who did not respond to the conventional therapy.…”

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confidence: 99%

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Saito

Shirasago

Suzuki

et al. 2015

J Virol

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Hepatitis C virus (HCV) exploits host membrane cholesterol and its metabolism for progeny virus production. Here, we examined the impact of targeting cellular squalene synthase (SQS), the first committed enzyme for cholesterol biosynthesis, on HCV production. By using the HCV JFH-1 strain and human hepatoma Huh-7.5.1-derived cells, we found that the SQS inhibitors YM-53601 and zaragozic acid A decreased viral RNA, protein, and progeny production in HCV-infected cells without affecting cell viability. Similarly, small interfering RNA (siRNA)-mediated knockdown of SQS led to significantly reduced HCV production, confirming the enzyme as an antiviral target. A metabolic labeling study demonstrated that YM-53601 suppressed the biosynthesis of cholesterol and cholesteryl esters at antiviral concentrations. Unlike YM-53601, the cholesterol esterification inhibitor Sandoz 58-035 did not exhibit an antiviral effect, suggesting that biosynthesis of cholesterol is more important than that of cholesteryl esters for HCV production. YM-53601 inhibited transient replication of a JFH-1 subgenomic replicon and entry of JFH-1 pseudoparticles, suggesting that at least suppression of viral RNA replication and entry contributes to the antiviral effect of the drug. Collectively, our findings highlight the importance of the cholesterol biosynthetic pathway in HCV production and implicate SQS as a potential target for antiviral strategies against HCV. IMPORTANCEHepatitis C virus (HCV) is known to be closely associated with host cholesterol and its metabolism throughout the viral life cycle. However, the impact of targeting cholesterol biosynthetic enzymes on HCV production is not fully understood. We found that squalene synthase, the first committed enzyme for cholesterol biosynthesis, is important for HCV production, and we propose this enzyme as a potential anti-HCV target. We provide evidence that synthesis of free cholesterol is more important than that of esterified cholesterol for HCV production, highlighting a marked free cholesterol dependency of HCV production. Our findings also offer a new insight into a role of the intracellular cholesterol pool that is coupled to its biosynthesis in the HCV life cycle.

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confidence: 99%

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Saito

Shirasago

Suzuki

et al. 2015

J Virol

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“…The HCV genotype (and to a lesser extent, the subtype) must be determined prior to initiation of antiviral treatment because the genotype affects the choice of agents and the duration of therapy, as well as the prognosis for eradicating the virus (8,9). HCV typing and subtyping can be performed using various methods, including direct sequence analysis, reverse hybridization, and genotype-specific reverse transcription (RT)-PCR.…”

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confidence: 99%

Sequencing Assays for Failed Genotyping with the Versant Hepatitis C Virus Genotype Assay (LiPA), Version 2.0

Larrat

Poveda²,

Coudret

et al. 2013

J Clin Microbiol

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dFor optimal antiviral therapy, the hepatitis C virus (HCV) genotype needs to be determined, as it remains a strong predictor of sustained viral response. In this study, we assessed the number of HCV genotyping results that could not be determined using the commercially available line probe assay (LiPA) (Versant hepatitis C virus genotype 2.0 assay) in a large international panel of samples from 9,874 HCV-positive patients. In-house sequencing assays targeting the 5= untranslated region (UTR), core region, NS3 region, and NS5B region of the HCV genome and phylogenetic analyses were used to resolve these LiPA failures. Among all cases, the genotypes of 51 samples (0.52%) could not be determined with the LiPA. These undetermined results were observed more frequently among samples from non-European regions (mainly the Arabian Peninsula). The use of sequencing assays coupled with phylogenetic analysis provided reliable genotype results for 86% of the LiPA failures, which exhibited higher rates of genotypes 4, 5, and 6 than did LiPA-resolved genotypes. As expected, the 5= UTR was not sufficiently variable for clear discrimination between genotypes 1 and 6, but it also resulted in errors in classification of some genotype 3 and 4 cases using well-known Web-based BLAST programs. This study demonstrates the low frequency of genotyping failures with the Versant hepatitis C virus genotype 2.0 assay (LiPA) and also underlines the need for a complex combination of sequences and phylogenetic analyses in order to genotype these particular HCV strains correctly. Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and affects approximately 120 million to 210 million people worldwide (1, 2). Each year, over 250,000 people die from HCV-related chronic liver diseases, such as end-stage cirrhosis and hepatocellular carcinoma (3, 4). Most infections with HCV can be cured if treatment is available, and the emergence of new antiviral drugs that directly target HCV will greatly improve treatment outcomes.The HCV genome is characterized by extremely high sequence diversity and HCV strains are classified into genetically distinct groups, which are known as genotypes when differences at the nucleotide level range from 31% to 33% or as subtypes when differences range from 20% to 25%; genetic difference below these values define quasispecies (5-7). The HCV genotype (and to a lesser extent, the subtype) must be determined prior to initiation of antiviral treatment because the genotype affects the choice of agents and the duration of therapy, as well as the prognosis for eradicating the virus (8, 9). HCV typing and subtyping can be performed using various methods, including direct sequence analysis, reverse hybridization, and genotype-specific reverse transcription (RT)-PCR. Several regions of the HCV genome can be analyzed to classify strains accurately into specific genotypes. The 5= untranslated region (UTR) is the region of choice for detecting and quantifying HCV RNA, due to its high level of conservation. For t...

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“…The additional effectiveness of the HCV protease inhibitors boceprevir, telaprevir and simeprevir added to PEG-IFN and ribavirin has been described elsewhere [16,17]. In light of simpler, safer direct-acting antiviral therapies (DAAs), WHO conditionally recommended the addition of boceprevir or telaprevir with PEG-IFN and ribavirin.…”

Section: Recommendations On Hcv Treatmentmentioning

confidence: 99%

Global policy and access to new hepatitis C therapies for people who inject drugs

Doyle

Aspinall

Hutchinson

et al. 2015

International Journal of Drug Policy

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People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV). This review outlines policy recommendations made in the 2014 World Health Organisation (WHO) Guidelines on Screening, Care and Treatment of HCV and their relevance to PWID. It also canvasses issues that will affect translation of these global guidelines into practice. The first global HCV guidelines released by WHO have recently advocated targeted HCV testing for PWID, assessment of liver disease and support for alcohol reduction during care. They also strongly advocate treatment using currently licensed direct-acting antiviral agents for all individuals, in particular PWID as a key affected population. New HCV treatment regimens have the potential to cure more than 90% of treated individuals. Scaling-up treatment among PWID has the potential to improve individual and population health by reducing HCV transmission, improving quality of life and supporting behaviour modifications that lead to less risk-taking over time. PWID face several barriers to accessing HCV care and treatment that need to be overcome. Testing services need re-orientation toward PWID, individuals need to be informed of their results and provided with direct linkage to ongoing care. Health services need to provide care in the community using simpler, cheaper and more accessible modes of delivery. Healthcare costs and pharmaceutical costs need to be minimised so PWID, who are highly marginalised, can access HCV treatment. Sustained scale-up of treatment for PWID could simultaneously improve individual health and achieve the goal of eliminating HCV transmission among this high-risk and vulnerable group.

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Current and emerging antiviral treatments for hepatitis C infection

Cited by 47 publications

References 81 publications

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Sequencing Assays for Failed Genotyping with the Versant Hepatitis C Virus Genotype Assay (LiPA), Version 2.0

Global policy and access to new hepatitis C therapies for people who inject drugs

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