**5. Natural history of HCV infection**

hours to days after infection, the adaptive immune response against HCV is not detectable before 6–8 weeks and involves all components of the adaptive immune system, i.e., humoral

associated with viral clearance. A well-coordinated interaction of the different immune cells might be essential for a successful immune response against HCV; however, little is known about the precise dynamic of this cross-talk [15]. HCV-specific T cells are recruited to the liver, and the viral replication is inhibited by both noncytolytic and cytolytic mechanisms. In about 20% of patients, the immune reaction during acute hepatitis C is strong enough to eliminate the infection. Immunocompetent HCV-infected individuals produce antibodies against epitopes within the structural as well as nonstructural proteins. Most of them, however, have no relevant antiviral activity, and only a small fraction of antibodies is able to inhibit virus binding, entry, or uncoating. These "neutralizing antibodies" target linear as well as confor‐ mational discontinuous epitopes mainly located within the envelope glycoproteins E1 and E2. While strong data indicate the neutralizing activity of these antibodies *in vitro*, their efficiency *in vivo* is less understood [10,15]. HCV elimination is associated with strong and sustained

 and CD8+ cell responses that target multiple epitopes within the different HCV proteins and that remain detectable long after resolution of infection [10,16,17]. They act noncytolyti‐ cally, by secreting antiviral cytokines such as IFN-γ, as well as cytolytically, through perforin secretion and by engaging the FAS/FAS-L pathway [15]. Despite the intervention of both innate and adaptive immune response in CHC, the virus is able to escape from these barriers through

HCV infection is one of the main causes of chronic liver disease worldwide, and according to recent estimates, until now more than 185 million people around the world have been infected. In addition, annually there are three million of new infected people, and among them 350,000 die every year due to HCV-related disorders [18–21]. The prevalence of HCV varies greatly, depending on the geographical area and the population considered: in Western Europe, it ranges from 0.4% to 3%; in Eastern Europe and the Middle East, it is higher but not precisely known [22]. The majority of the infected people reside in Asian countries (Taiwan, Mongolia, and Pakistan), sub-Saharan Africa (Cameroon, Burundi, and Gabon), and the Eastern Medi‐ terranean (Egypt), which holds the highest frequency, with more than 20% [18]. HCV is a major global public health issue due to its high prevalence, long-term unpredictable disease pro‐ gression, and low diagnosis and treatment response rates. Despite the fact that HCV infection rates are decreasing, the clinical and economic impact of chronic HCV infection is expected to considerably grow in the next decade since a large population of individuals that acquired the virus in the 1960s developed disease-associated health issues through to the 1980s [23]. The dual therapy, based on the administration of peg-IFN and RBV, is successful only in 40–50% of patients infected with the GT-1, while untreated individuals or who failed treatment are at risk of developing severe liver injuries such as cirrhosis, liver transplantation, and hepatocel‐ lular carcinoma (HCC) [24]. In Europe, there are 30,000 people on the transplant waiting list but only 12,000 procedures per year, and the average cost of liver transplant in the United States varies between \$139,000 and \$400,000 [25]. Although HCV can be successfully treated

T cells [10]. All these three components were shown to be

antibodies, CD4+ T cells, and CD8+

26 Recent Advances in Liver Diseases and Surgery

CD4+

yet unknown mechanisms.

**4. Epidemiology and world impact of HCV**

HCV transmission primarily occurs via parenteral routes. Before the 1990s, the main routes of transmission were unsafe blood transfusion procedures and injecting drug use. Currently, new infections are mainly due to the use of drugs and, to a lesser extent, to unsafe medical and surgical procedures, tattoos, and piercings. Distinctive HCV genotype distribution and prevalence worldwide are due primarily to differences in transmission routes and clinical care (Table 1) [29,30].


**Table 1.** Populations with high HCV prevalence or who have a history of HCV risk exposure/behavior

Acute HCV infections are often oligo- or asymptomatic. The long incubation period makes difficult to link related cases to the source of infection, and despite the high prevalence of disease, most infected people are unaware of their infection. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis and cirrhosis with or without HCC [31]. Spontaneous clearance in the chronic phase of the infection is rare and occurs only in 15–25% of cases. In 70–80% of infected patients, the virus persists and the infection becomes chronic. In most patients, CHC leads to different degrees of liver fibrosis, and one third (15–25%) of them could develop liver cirrhosis and HCC at a rate of 2–4% after 10 to 40 years (Figure 1) [10,18]. The progression of liver disease occurs over decades and is accelerated by alcohol consumption, diabetes/obesity, coinfections (human immunodeficiency virus [HIV] and hepatitis B virus), old age at the time of infection, cumu‐ lative exposure to hepatotropic viruses, and environmental hepatotoxins [32,33]. The extra‐ hepatic manifestations of HCV infection include cryoglobulinemia, membranous glomerulonephritis, and some non-Hodgkin lymphomas [34]. In Europe, about 1/4 of HIVinfected patients have an HCV coinfection. Patients coinfected with HIV/HCV have a higher risk of cirrhosis and AIDS and a higher overall mortality [35]. Thanks to the growing knowl‐ edge on the pathophysiology of the disease, the development of diagnostic procedures, and the improvements in therapy and prevention, the clinical care for patients with HCV-related liver disease has considerably advanced during the last years.

**Figure 1.** Natural history of HCV infection. In patients with HCV infection, the spontaneous clearance after the acute phase occurs only in 15–25% of cases; during the chronic phase, extrahepatic manifestations might occur. For patients who progress to decompensated cirrhosis, the survival rate at 5 years is about 50%, and among them, 2–4% per year develop hepatocellular carcinoma
