Ideal oral combinations to eradicate HCV: The role of ribavirin

Hézode, Christophe; Bronowicki, Jean–Pierre

doi:10.1016/j.jhep.2015.09.009

Cited by 41 publications

(37 citation statements)

References 56 publications

(80 reference statements)

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“…This is, particularly, a tremendous problem for chronic viral infections requiring a long-term antiviral therapy. The common practice to reduce the selection of drug resistance is combination therapy with antivirals targeting multiple viral functions (63,64). However, although drug-resistant viruses usually exist in inocula and pretreated individuals at a very low frequency and can be selected during antiviral therapies, a drug-resistant mutation first occurs in an infected cell in the presence of many drug-susceptible genomes.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Zhao

Zhang

et al. 2017

J Virol

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Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein.Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.IMPORTANCE HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.KEYWORDS antiviral agents, capsid assembly, hepatitis B virus

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Section: Discussionmentioning

confidence: 99%

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Zhao

Zhang

et al. 2017

J Virol

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“…The effects of genotype 3 and of genotypes other than 1 or 3 were both assumed to be of ‘uncertain direction’ (prior odds ratio (OR) 1.0, 95% credible interval (CI) 0.25 to 4.0); no prior treatment was assumed to be ‘possibly beneficial’ (prior OR 1.5, 95% CI 0.38 to 6.0); and no or stable cirrhosis was assumed to be ‘probably beneficial’ (prior OR 2.0, 95% CI 0.5 to 8.0) [16, 17]. There is clinical interest in the value of including ribavirin in treatment combinations but limited information [18, 19]. Given adequate data were collected on the use of daclatasvir and sofosbuvir both with and without ribavirin, the fourth model was extended to include an additional covariate for ribavirin use, with its effect assumed to be of ‘uncertain direction’ (prior OR 1.0, 95% CI 0.25 to 4.0).…”

Section: Methodsmentioning

confidence: 99%

The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease

et al. 2017

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BackgroundThere is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options.MethodsA retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling.ResultsThe 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis.ConclusionsDaclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-2106-x) contains supplementary material, which is available to authorized users.

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“…At this time, guidelines do recommend the use of ribavirin in combination with DAAs, depending on genotype and presence or absence of cirrhosis. For example, there is evidence to support the use of ribavirin in specific situations, such as patients using sofosbuvir-based regimens who are either HCV genotype 1, treatment-experienced, and cirrhotic, or HCV genotype 3 with cirrhosis [25]. SVR rates tend to be lower among HCV genotype 3 patients with advanced liver disease (as low as 62% in patients with cirrhosis who were null responders to IFN-RBV therapy) [26].…”

Section: Role Of Ribavirin In the Era Of Direct-acting Antiviralsmentioning

confidence: 99%

A Brief Update on the Treatment of Hepatitis C

Austria¹,

Ninčević²,

Wu³

2017

Update on Hepatitis C

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Hepatitis C virus was discovered nearly 30 years ago, and for the first two decades, treatment was limited to agents with low response rates and substantial side effects. Since the introduction of direct-acting antivirals, there have been rapid advances made toward even higher sustained virologic responses (SVRs) and fewer side effects. This chapter provides a review of the newer agents for treatment of hepatitis C and highlights special populations, including those coinfected with HIV or hepatitis B, previously treated patients, and post-liver transplant patients.

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Ideal oral combinations to eradicate HCV: The role of ribavirin

Cited by 41 publications

References 56 publications

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly

The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease

A Brief Update on the Treatment of Hepatitis C

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