Assessing safety and efficacy of sofosbuvir for the treatment of hepatitis C

D’Ambrosio, Roberta; Aghemo, Alessio; Colombo, Massimo

doi:10.1517/14740338.2015.1009035

Cited by 9 publications

(6 citation statements)

References 41 publications

(22 reference statements)

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“…However, the EC 50 of sofosbuvir against H118R, E333G, N335S, or E333G/N335S mutant virus was not increased when compared with that against the WT HCV ( Table 3 , Figures 2(b) , 2(c) , 2(d) , and 2(e) ). This agrees with our results detected in the newly infected Huh7.5 cells ( Figure 1(b) ), and the result suggested that sofosbuvir is a drug with high genetic barrier to drug-resistance [ 26 ].…”

Section: Resultssupporting

confidence: 93%

A Simple but Accurate Method for Evaluating Drug-Resistance in Infectious HCVcc System

Cheng

et al. 2017

BioMed Research International

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Use of direct-acting antivirals sometimes causes viral drug resistance, resulting in inefficiency in treated patients in real-world practice. Therefore, how to rapidly and accurately evaluate drug resistance is an urgent problem to be solved for rational use and development of antivirals in the future. Here, we aim to develop a new method by which we can evaluate easily but effectively whether a drug will still be efficient in the future treatment in infectious hepatitis C virus cell culture system. HCV-infected Huh7.5 cells were treated with drugs and the culture supernatants were replaced with fresh culture media containing the same drugs at 24 hours. The supernatants were harvested at 48 hours and incubated with naïve Huh7.5 cells. Intracellular HCV RNAs or proteins in the newly infected cells were extracted and analyzed at 48 hours or longer. Results showed that after being treated with telaprevir mutant viruses were easily detected which were resistant to telaprevir, while after being treated with sofosbuvir drug-resistant viruses did not emerge. In conclusion, the new method is simple and quick but accurate to evaluate whether a drug will be still efficient in the forthcoming therapeutic regimen and whether drug resistance will occur after long-term treatment with drugs.

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Section: Resultssupporting

confidence: 93%

A Simple but Accurate Method for Evaluating Drug-Resistance in Infectious HCVcc System

Cheng

et al. 2017

BioMed Research International

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“…Unphosphorylated nucleosides were used to maximize intracellular uptake. ddC was used as a positive control and sofosbuvir (Sovaldi ® ) (25,30) was used as a negative control.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, 2′-F-pyrimidines have been already extensively de-risked in prior long-term studies in woodchuck and rat (28), where no evidence of mitochondrial toxicity was observed. Another 2′-F-nucleoside-based drug, Sofosbuvir (Sovaldi ® ), a prodrug of 2′-fluoro-2′-C-methyluridine-5′-monophosphate, is widely used for the treatment of chronic hepatitis C and has an excellent safety record (25,30). FIAU, which has been associated with severe toxicity in clinical studies and in woodchucks (18,23,24), carries a 2′-F modification but in the arabino (up) configuration as well as a 5-iodo modification on the uracil base; it is thus quite structurally distinct from Sofosbuvir and the 2′-F-nucleosides present in siRNA conjugates.…”

Section: Discussionmentioning

confidence: 99%

Safety evaluation of 2′-deoxy-2′-fluoro nucleotides in GalNAc-siRNA conjugates

Janas

Zlatev

Liu

et al. 2019

Nucleic Acids Research

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For oligonucleotide therapeutics, chemical modifications of the sugar-phosphate backbone are frequently used to confer drug-like properties. Because 2′-deoxy-2′-fluoro (2′-F) nucleotides are not known to occur naturally, their safety profile was assessed when used in revusiran and ALN-TTRSC02, two short interfering RNAs (siRNAs), of the same sequence but different chemical modification pattern and metabolic stability, conjugated to an N -acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Exposure to 2′-F-monomer metabolites was low and transient in rats and humans. In vitro , 2′-F-nucleoside 5′-triphosphates were neither inhibitors nor preferred substrates for human polymerases, and no obligate or non-obligate chain termination was observed. Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2′-F-nucleosides, typically not attained in vivo . No apparent functional impact on mitochondria and no significant accumulation of 2′-F-monomers were observed after weekly administration of two GalNAc–siRNA conjugates in rats for ∼2 years. Taken together, the results support the conclusion that 2′-F nucleotides can be safely applied for the design of metabolically stabilized therapeutic GalNAc–siRNAs with favorable potency and prolonged duration of activity allowing for low dose and infrequent dosing.

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“…Thus, PegIFNα + RV regimen is not optimal therapy for CHC particularly for G1&4 (where SVR was ~50%) among that cohort. The advent of Direct Antiviral agents that target the nonstructural enzymes of HCV involved in viral replication processes has led to the development of IFNα‐free regimens with a potential wider applicability than regimens based on IFNα . It will be important to extend these benefits to children, and to ensure that affordable treatment can be provided to areas where the disease is prevalent but mean incomes are low …”

Section: Discussionmentioning

confidence: 99%