**3. Virology**

HCV induces chronic infection in up to 80% of infected individuals. One third of those who become chronically infected are predicted to develop cirrhosis or hepatocellular carcinoma. Despite its high prevalence, most people infected with the virus are unaware of their infection.

The purpose of this chapter is to give an overview on HCV and existing treatments and to outline recent innovations in the treatment of HCV patients. To do this, a broad search of the published literature has been undertaken. The search included epidemiology of HCV, its natural history, the risk factors involved, as well as the diagnosis and treatment of HCV, all of which have been graded on the best available evidence. The ultimate purpose is to improve HCV patient care and to promote and encourage the multidisciplinary care required in the

In most countries, surveys undertaken to establish the prevalence of HCV have focused on specific groups of individuals, for example, drug users, those indulging in high-risk sexual behavior, and blood donors who are not representative of the general population. Conse‐ quently, global estimates of HCV prevalence in the year 2008 are still not accurate [2].

Overall, the available data suggest that 130-170 million individuals are infected with HCV (approximately 2.2-3.0%) worldwide, with its highest prevalence occurring in Eastern Medi‐

Previously undertaken analyses on global, regional, and country levels have mostly failed to estimate the correct HCV disease burden with studies based on age distribution and active infection. Most country-level studies have been carried out on the adult population; however, when these estimates were applied to a country's entire population, the disease burden was probably overestimated. In addition, studies focused on anti-HCV (antibody positive) testing overestimated the disease burden because they often included those subjects who have been

Globally, genotype 1 (G1) has been found to account for 46% of all anti-HCV infections among adults, making it the most common, followed by G3 (22%), G2 (13%), G4 (13%), G6 (2%), and G5 (1%). Undefined or combination genotypes accounted for 3% of total HCV infections [4]. Genotype 1b was the most common subtype, accounting for 22% of all infections. However, significant regional, country, and local variations were found to exist. Infections in North America, Latin America, and Europe were predominately G1 (62-71%), with G1b accounting for 26%, 39%, and 50% of all cases, respectively. North Africa and the Middle East had a large G4 population (71%), which was attributable to the high prevalence of G4 in Egypt. When Egypt was excluded, genotype 4 accounted for 34% of all infections, and the genotype distribution of this region was dominated by G1 (46%). Asia was predominately G3 (39%) followed by G1 (36%), largely driven by the HCV infections in India and Pakistan. G1b accounted for 25% of all infections in this region. In Australasia, G1 dominated (53%), followed

treatment of these patients.

80 Recent Advances in Liver Diseases and Surgery

terranean and African regions [2,3].

cured, either spontaneously or after treatment [4].

by G3 (39%). G1b was present in 16% of cases [4].

**2. Epidemiology**

The hepatitis C virus is a hepatotropic RNA virus of the genus *Hepacivirus* in the Flaviviridae family, originally cloned in 1989 as the causative agent of non-A, non-B hepatitis [5,6,7]. HCV is a positive-sense, single-stranded enveloped RNA virus approximately 9600 nucleotides in length. Approximately 1012 viral particles are generated daily in chronically HCV-infected patients [5,8]. The genome is organized to include nontranslated RNA segments (NTRs) at 5 and 3 ends and a single large open reading frame (ORF) encoding a giant 327 kDa polyprotein that is processed by cellular and virally encoded proteases into three structural proteins (core, E1, E2) and seven nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) [9].

The HCV 5 NTR contains 341 nucleotides located upstream of the coding region and is composed of four domains (numbered I to IV) with highly structured RNA elements, including numerous stem loops and a pseudoknot. The 5 NTR also contains the internal ribosome entry site (IRES), which initiates the cap-independent translation of HCV genome into a single polyprotein by recruiting both viral proteins and cellular proteins such as eukaryotic initiation factors (eIF) 2 and 3 [5].

The core protein is the viral capsid protein with a length of 191 amino acids (p21c). It can be further cleaved to generate a smaller 179-amino-acid core protein (p19c). The core protein has numerous functionalities involving RNA binding, immune modulation, cell signaling, oncogenic potential, and autophagy [5,9,10]. E1 and E2 are the two viral envelope proteins that surround the viral particles. p7 contains two transmembrane domains and is required for viral assembly and release. NS2 is the viral autoprotease that likely contains at least four trans‐ membrane domains and plays a key role in viral assembly, mediating the cleavage between NS2 and NS3 [5,9,11,12]. NS3 protease plays a critical role in HCV processing by cleaving downstream of NS3 at four sites (between NS3/4A, NS4A/4B, NS4B/NS5A, and NS5A/NS5B) [5,9]. NS4A is a cofactor for the NS3 protease, and NS5B is the viral RNA polymerase. The functions of NS4B and NS5A are not totally clear, but they are probably involved in viral RNA replication and pathogenesis. All of these HCV proteins are believed to form replication complexes on intracellular membranes for either viral morphogenesis or RNA replication [5,9,13-15].
