**Advances in HCV Therapy**

Eric Hilgenfeldt and Roberto J. Firpi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60986

#### **Abstract**

Hepatitis C is a devastating illness which has the potential in the majority of cases to lead to significant morbidity and mortality. Worldwide, the number living with chronic hepatitis C approaches 185 million. Up until recently, the regimen of peg-IFN and ribavirin stood as the standard of care and is still commonly used as first line therapy. This is rapidly changing. Direct acting antivirals have altered the landscape drastically. By understanding the genome of the hepatitis C virus, scientists and researchers have been able to exploit its mechanism of transmission by creating inhibitors against several of the nonstructural proteins that are integral to HCV replication and function [NS3/4 protease, NS5A polymerase, and NS5B polymerases (nucleoside and non-nucleoside)]. The previously reported 50%-70% SVR rates achieved with peg-IFN and RBV are no longer the standard of care. Thanks to direct acting antivirals, IFN free as well as "all oral" regimens are being used to treat HCV. In addition to this, ribavirin-free regimens are also available. These highly effective therapies also provide far less side effects and accomplish better results in less time, thus shortening treatment duration significantly. Additionally, even in the notori‐ ously difficult -to-treat populations, results have been promising.

**Keywords:** Hepatitis C Virus, Direct Acting Antiviral, Treatment, Sustained Viro‐ logic Response

### **1. Introduction**

Hepatitis C virus (HCV) infection is a devastating illness, which has the potential in the majority of cases to lead to significant morbidity and mortality. Worldwide, the number living

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with chronic HCV approaches 185 million. Until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care and is still commonly used as firstline therapy in some countries. This is rapidly changing. Direct acting antivirals (DAA) have altered the landscape dramatically. By understanding the genome of the HCV, scientists and researchers have been able to exploit its mechanism of transmission by creating inhibitors against several of the nonstructural proteins that are integral to HCV replication and function. Sustained virological response (SVR), which is commonly defined as a lack of HCV viral detection 12-24 weeks following treatment, with ribavirin and pegylated interferon alone, was marginal but has continued to improve. Despite the improvement, the introduction of DAAs has made the previously reported 50-70% SVR rates fall far short of rates achieved with DAAs.


Legend: Drugs in italics have received FDA approval as of January 2015

Adapted from www.hepatitis.va.gov

**Table 1.** FDA approved and investigated drugs by mechanism of action

As it currently stands, four classes of DAA exist, which can be categorized according to the protein they inhibit. These four include inhibitors of the NS3/4 protease, NS5A polymerase, and NS5B polymerases (nucleoside and nonnucleoside). The approval of two NS3/4 protease inhibitors, telaprevir (TEL) and boceprevir (BOC), occurred in 2011 and marked the beginning of the age of DAAs. This was followed 2 years later by the approval of sofosbuvir (SOF), a nucleoside NS5B inhibitor, and simeprevir (SIM), an NS3/4 protease inhibitor, further ex‐ panded the available treatment options. In 2014, a combination of IFN-free regimen utilizing SOF and an NS5A inhibitor, ledipasvir (LED), was approved. Closely following this, the fourdrug combination pack of an NS5A inhibitor, NS3/4A inhibitor, and a nonnucleoside NS5B inhibitor of ombitasvir (OMB), paritaprevir (PARr), and dasabuvir (DAS), respectively, gained Food and Drug Administration (FDA) approval in the United States. In addition to the DAAs in the four-drug combination pack, ritonavir has been added due to its potent inhibition of CYP3A4, increasing the effect of paritaprevir. Several other agents are currently undergoing late stage clinical trials and are expected to be approved in the near future (Table 1).
