What Are the Promising New Therapies in the Field of Chronic Hepatitis C After the First-Generation Direct-Acting Antivirals?

Abstract

A number of promising new hepatitis C virus (HCV) antiviral regimens have emerged during the last few years, with a trend toward increased efficacy, safety, and tolerability, when compared with currently available therapies. The focus of recent HCV antiviral drug development has been on inhibition of HCV replication, largely by targeting specific components of the HCV replication complex itself. A significant effort has been put into generating drugs that inhibit the NS5B polymerase. A number of such drugs have been developed, and NS5B polymerase inhibitors can be divided into nucleoside polymerase inhibitors and nonnucleoside polymerase inhibitors, with each group carrying specific pharmacologic and clinical characteristics. Additional research has explored the efficacy of drugs that inhibit the HCV replication complex via other mechanisms. Second-generation NS3-4A protease inhibitors have been developed, which have generally improved on the efficacy of the currently available FDA-approved first-generation agents. NS5A inhibitors have also been studied. These medications impede HCV replication and viral particle assembly and enhance host immune activation via novel mechanisms. Alternatively, medications that target a host protein, cyclophillin B, are under evaluation. These medications block HCV replication via modification of the effects of NS5B and via other poorly understood mechanisms. Detailed below are the most important HCV antiviral agents under development, many of which show promise for use within the next few years.

Community-based HCV screening: knowledge and attitudes in a high risk urban population

“…Furthermore, knowledge of one’s disease allows opportunity to seek out health insurance (something that may become easier under the Affordable Care Act), resulting in access to therapies at an earlier stage of liver disease, which is associated with better treatment response rates and less risk of long term liver complications [20-22]. As newer medical therapies with improved efficacy and side effect profiles become increasingly available, early identification of disease by HCV screening will have greater potential to reduce poor outcomes [23-25]. …”

Chronic hepatitis C: This and the new era of treatment

“…In addition, second-generation PIs also appear to have increased efficacy against genotype 1 HCV [83] ; as treatment options have progressed and improved, HCV-1, HCV-2 and HCV-4 are considered to be easy to treat [84] but HCV genotype 3 infection has become the most difficult to treat.…”

Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients

“…PegIFN/RBV treatment failure is mainly attributed to its low efficacy against genotypes 1 and 4, but also, to some extent to its side effects [3,4]. Recently developed direct-acting antiviral agents (DAAs) are predicted to have a major impact both in combination with PegIFN/RBV, as well as in IFN-free regimens and telaprevir and boceprevir have now been approved as standard of care treatment [5]. Targets for DAA include HCV NS3 protease, NS5B polymerase and NS5A protein which are essential for virus replication.…”