**2. Epidemiology**

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.

> **Nucleos(t)ide NS5B Polymerase Inhibitors**

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

*Boceprevir* Daclatasvir Mericitabine *Dasabuvir Telaprevir* Elbasvir *Sofosbuvir* Deleobuvir *Simeprevir Ledipasvir* VX-135 Lomibuvir *Parotaprevir Ombitasvir* Tegobuvir Asunaprevir Samatasvir ABT-072 Faldaprevir ACH-2928 BMS-791325 Danoprevir BMS824393 GS-9669

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

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

**Nonnucleos(t)ide NS5B Polymerase Inhibitors**

**NS3/4 Protease Inhibitors NS5A Inhibitors**

58 Recent Advances in Liver Diseases and Surgery

Grazoprevir PPI-461 Sovaprevir PPI-668 Vedroprevir GS-5816

Adapted from www.hepatitis.va.gov

Vaniprevir IDX320

In the most recent National Health and Nutrition Examination Survey (NHANES), the estimated prevalence of HCV infection is approximately 3.6 million in the United States alone, with an estimated 2.7 of these having chronic infection. Worldwide, the World Health Organization (WHO) estimates that nearly 150 million people have chronic HCV infec‐ tion. In both the United States and worldwide, estimates likely fall significantly short given that nearly half of all infected patients have never been tested for HCV. Additionally, the incidence among prisoners and the homeless are not known and in less developed nations are often not recorded [1]. HCV is thought to be the causal factor of up to one-third of cases of cirrhosis worldwide [2, 3].

In a study done by Shepherd *et al.* [4], analysis of positive HCV seroprevalence throughout some of the most populous nations of the world revealed an overall worldly prevalence rate of 2%, or roughly 123 million people. Given the limitations that widespread detection and recording pose, one would expect the actual prevalence to be larger. Individual analysis of many nations including China, Pakistan, and Egypt revealed estimated HCV seroprevalence well above this range. Disease transmission patterns again reveal that the majority of trans‐ mission of HCV is thought to be from unscreened blood donation, injection drug use, unsafe therapeutic injection, or other health care-related procedures. As medical practices become safer and blood screening continues to occur, the rates of HCV transmission from injection drug use will become the predominant mode of transmission as it has in developed countries like Australia, England, and the United States. Despite its success in the United States, several barriers to improving the safety of blood transfusions have remained throughout nations across the world [4-6]. As it stands, the WHO's global database estimates that among the 97 of 164 countries that provided data, 89% of donated blood is being screened following basic quality procedures [7].

HCV cirrhosis remains the primary indication for liver transplant (LT) in the United States with over 15,000 patients currently listed on the United Network for Organ Sharing (UNOS) list [8]. In year 2013 alone, over 6,400 patients underwent LT in the United States, increasing steadily from 1,700 in 1988 [9]. The United States leads in amount of deceased donor liver transplantations followed by China, with roughly 2,000 in 2010 [10].
