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Hepatitis C
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
Current medication regimes consist of DAAs. The antivirals are directed against specific sites in the genome—there are protease inhibitors (also called NS3/NS4A inhibitors) glecaprevir and grazoprevir, NS5A inhibitors velpatasvir, elbasvir, pibrentasvir and ledipasvir, and NS5B inhibitor sofosbuvir. Treatment with DAAs is associated with significantly improved survival and overall improvement in morbidity in hepatitis C positive patients, whether or not they are cirrhotic. These new antivirals are generally very well tolerated and need to be taken for a duration of 8–16 weeks usually, depending on the treatment chosen.
Ribavirin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Emily Woolnough, Amanda Wade, Joe Sasadeusz
After these treatment successes with serine protease inhibitors, attention turned to novel therapeutic targets important for hepatitis C viral assembly and replication. NS5A inhibitors, including daclatasvir and ledipasvir, act against a protein critical to both of these processes. In the COMMAND phase II trials, daclatasvir was combined with peginterferon–ribavirin for the treatment of HCV genotypes 1, 2 and 3. SVR rates were 83–88% at 12 and 16 weeks for genotype 2 but lower for genotypes 1 and 3 (Hezode et al., 2012; Dore et al., 2013). Further innovation in this field led to the development of NS5B inhibitors, which target the RNA-dependent RNA polymerase responsible for viral replication. Although there are several agents in various stages of development, sofosbuvir recently became the first NS5B inhibitor to be licensed for clinical use. In one large phase III study, 327 treatment-naive patients with genotype 1, 4, 5, or 6 demonstrated SVR rates of 90% when sofosbuvir was used in combination with peginterferon–ribavirin (Lawitz et al., 2013). The efficacy of triple therapy with sofosbuvir and peginterferon–ribavirin has also been established in patients with genotype 2 or 3 disease, including those with compensated cirrhosis (Lawitz et al., 2013).
Hepatitis C Virus and Its Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Animal models of viral infections have played a central role in studying various aspects of host–pathogen interaction, with applications ranging from histopathology to vaccine development. In the case of HCV, chimpanzees are the only animal species that are known to be susceptible to virus replication (Choo et al. 1989). These animals present an attenuated form of infection, manifested by low virus titers and lack of liver cirrhosis (Bukh 2004; Boonstra et al. 2009). In addition, their prohibitive cost and the fact that they are an endangered species have limited their use as an efficacy model. Nucleoside and nonnucleoside analogs have been used to treat HCV-infected chimpanzees (Chen et al. 2007; Carroll et al. 2009, 2011). In these studies, the NS5B inhibitors were able to significantly reduce viral loads by four to five orders of magnitude. In addition to chimpanzees, severe combined immunodeficiency (SCID) or irradiated mice transplanted with human liver tissue can also support HCV infection (Ilan et al. 2002; Mercer 2011). One of the main limitations to these models is the low viremia and transient replication of HCV in a host that has lost its normal immune system. These issues have been addressed by expressing human CD81 and occluding genes used as receptors for entry to the liver cells (Dorner et al. 2011). The use of “humanized” mouse models for antiviral efficacy studies has recently been validated with an experimental combination therapy including NS3 and NS5B inhibitors (Ohara et al. 2011). At the highest therapeutic dose, all of the infected animals had undetectable viral load after only one week of treatment.
Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors
Published in Xenobiotica, 2018
Xiaoliang Zhuo, Ying-Zi Wang, Kap-Sun Yeung, Juliang Zhu, Xiaohua Stella Huang, Kyle E. Parcella, Kyle J. Eastman, John F. Kadow, Nicholas A. Meanwell, Yue-Zhong Shu, Benjamin M. Johnson
During lead optimisation and selection, metabolism studies in vitro help to characterise metabolic liabilities and provide critical information that aid in the design of compounds with improved metabolic and PK profiles. Thus, in this study, we investigated the metabolism and bioactivation of six NS5B inhibitors. Four of them exhibit pan-genotypic HCV inhibition and bear either a 2-cyclopropylpyrimidine (1, 2) or a 2-isopropylpyrimidine (3, 4) element with a C6-subsitutued core scaffold (Figure 1). Also studied was the metabolism of 5 and 6, which feature a 2-cyclopropylpyrimidine element but no core C-6 substitution. The results from these studies revealed a novel bioactivation site that guided work towards optimising the structures of these compounds to avert the formation of reactive metabolites while maintaining pan-antiviral potency.
Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options
Published in Expert Review of Anti-infective Therapy, 2018
Elisabetta Loggi, Ranka Vukotic, Pietro Andreone
The emergence of NS5B RASs such as S282T, L320F C316N, and L159F has been described in the relapse to sofosbuvir [19,20]. However, a pooled analysis of sofosbuvir/ledipasvir phase 2 and phase 3 trials on a large number of patients showed that the emergence of S282T, the most important sofosbuvir-RASs, identified for all HCV genotypes is rare (<1%) in patients failing sofosbuvir-based regimens [21]. On the contrary, the emergence of dasabuvir-specific RASs is frequent and includes several substitutions at different positions. Among them, S556G is the most prevalent one [6,19]. Similarly to the NS3 RASs, the NS5B RASs seem to be rapidly replaced by the wild-type sequence [22], making the NS5B inhibitors suitable for the re-treatment of patients who failed a previous treatment. Because of these considerations, nucleosides inhibitors’ RASs have little impact on the treatment outcome and sofosbuvir (or other future nucleoside analogs) can be used for the re-treatment. As for dasabuvir, this is the only approved non-nucleoside and no others of such kind are in pipeline. Resistance to non-nucleosides is, therefore, not of clinical importance. Thus, based on these evidences, there is no major role for NS5B RASs testing.
NS5B polymerase inhibitors in phase II clinical trials for HCV infection
Published in Expert Opinion on Investigational Drugs, 2018
Guglielmo Borgia, Alberto Enrico Maraolo, Salvatore Nappa, Ivan Gentile, Antonio Riccardo Buonomo
Inhibition of NS5B polymerase is a key antiviral mechanism. Both nucleoside and non-nucleoside NS5B inhibitors co-exist in the anti-HCV armamentarium: the first have, when compared with the latter, higher genetic barrier resistance more antiviral potency. Apart from the combination Grazoprevir/Elbasvir, all the regimens recommended by the most recent European and American guidelines include a NS5B polymerase inhibitor, namely Sofosbuvir or Dasabuvir [4,5]. Another drug belonging to this class and having completed a phase 3 trial is Beclabuvir [51], which, combined with other DAAs, turned out to be effective in GT1-infected Japanese patients [52], and it is also under investigation as part of complex regimens to shorten anti-HCV treatment duration until to just 4 weeks [53]. So, is there still room for other members of this class? This is neither a mere moot point nor a quixotic attempt to pursue the development of a ‘perfectovir’ [54]. At the threshold of the ‘precision medicine’ [55], it is mandatory to guarantee a tailored treatment to HCV patients, possibly RBV-free, as some of the new regimens promise [56], and especially when first-line regimens fail [57]. Novel NS5B polymerase inhibitors may serve as backbone of future ‘salvage’ therapies, particularly in patients that exerted the rare S282 mutation conferring resistance to Sofosbuvir or Y93 NS5A mutations the ones that confer resistance to the majority of now available NS5A inhibitors [58].