Abstract
The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.
Highlights
Hepatitis C virus (HCV) is a significant human pathogen affecting nearly 3% of the world’s population, and is a leading cause of progressive chronic liver disease, potentially culminating in cirrhosis and hepatocellular carcinoma [1]
The clinical development of tegobuvir was recently halted; an in vitro study recently demonstrated the potential of tegobuvir as a Direct acting antivirals (DAA) due to its additive effect when examined with PIs or nucleoside inhibitors (NNI) in inhibiting replicon models and significantly hindering the development of resistance mutations [105]
Benzothiadiazines have been shown to cause the inhibition of phosphodiester bond formation in both primed and de novo [118]. These findings emphasize the importance of different RNA-dependent RNA polymerase (RdRp) conformations on the biochemical activity of the enzyme, and the differential effects HCV NNIs have on RdRp conformational changes
Summary
Hepatitis C virus (HCV) is a significant human pathogen affecting nearly 3% of the world’s population, and is a leading cause of progressive chronic liver disease, potentially culminating in cirrhosis and hepatocellular carcinoma [1]. Similar to other molecules binding to T1, P495 substitutions (Figure 3) were associated with increased resistance to beclabuvir [76,77] Another T1 RAV A421V, was identified upon treatment of GT1 patients with baclabuvir in a phase 2 trial [78]. Compounds that have been identified as Thumb II (T2) binders include thiophene-2-carboxylic acids [80] like lomibuvir (VX-222) and GS-9669 Both lomibuvir and GS-9669 have progressed to phase 2 clinical trials for the treatment of GT1 infections, lomibuvir was recently halted from further development. Resistance to T2 inhibitors, lomibuvir and filibuvir, has been demonstrated in vitro and most commonly associated with RdRp amino acid substitutions at L419, M423, M426 and I482 (Table 1) [85,87,88] These substitutions have been shown to cause a loss in the binding affinity of these molecules to the RdRp [87]. The clinical development of tegobuvir was recently halted; an in vitro study recently demonstrated the potential of tegobuvir as a DAA due to its additive effect when examined with PIs or NNIs in inhibiting replicon models and significantly hindering the development of resistance mutations [105]
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