**8. Predictors of treatment response to HCV**

Several patient and viral-related factors that can affect the severity of the disease, its progres‐ sion, and treatment outcome have been identified. The chronicity rate in HCV infection appears to be lower in young individuals, and several studies highlight that young age (age <40 years) is associated with more sustained virological response (SVR) [33,48]. The female sex is associated with a higher SVR rate than that of males, using the standard peg-IFN and RBV dual therapy [49]. Obesity is also a relevant predictor of disease progression, and prospective studies report that a body mass index of 25 kg/m2 was associated with significant progression in the extent of fibrosis [50]. Furthermore, insulin resistance is extremely common in patients with chronic HCV infection and has been associated with increased disease severity, extrahe‐ patic manifestations, and decreased response to antiviral therapy [51]. Many epidemiological studies showed an association between chronic HCV infection and the risk of developing type 1 and type 2 diabetes mellitus [52]. Taking into account the viral factors, HCV genotype is the strongest baseline predictor since there is a close correlation between the different genotypes and sensitivity to IFN-based therapies. GT-1 and GT-4 are intrinsically more resistant to IFNα than GT-2 and GT-3, and for this reason, the viral clearance in patients who are IFN res‐ ponders occurs much slower in GT-1 and 4, as compared to 2 and 3 [53]. Although viral load does not correlate with the severity of liver injury or the progression of the disease, a low baseline viral load (<600,000 IU/mL) is related with the SVR and the treatment outcome [54].

risk of complications, as well as the need for expert histological interpretation, transient ultrasound elastography (Fibroscan) is now used to assess liver disease severity prior to therapy at a safe level of predictability [42,43]. Fibroscan is a noninvasive method of measuring the mean stiffness of hepatic tissue, with hepatic rigidity considered a marker of progressive fibrosis. There are different scoring systems for assessing the severity of chronic liver disease. The major approach to classify CHC involves three separate considerations: (1) the etiology, which is determined on the basis of histological appearance and laboratory tests; (2) the severity and distribution of necroinflammatory activity; and (3) the degree of fibrosis [44]. The most common scoring methods to interpret a liver biopsy include the Metavir, the histologic activity index (HAI), also known as Knodell score, and the modified hepatic activity index

Metavir is a scoring system used to assess inflammation and fibrosis by histopathological evaluation of a liver biopsy of patients with HCV. The scoring from A0 to A3 represents a grading system that gives an indication on the activity and degree of inflammation. The amount of inflammation is relevant since it is considered a precursor of fibrosis (Table 2). Metavir also includes a staging system that indicates the amount of fibrosis or scarring [46]. The Knodell score is a semiquantitative and reproducible histological scoring of liver biopsies, also commonly used for staging liver disease, that includes three categories of necroinflam‐ matory activity: periportal injury with or without bridging necrosis, lobular injury, and portal inflammation. Lesions are assigned weighted numeric values that resulted in a combined

In the last years, the Knodell score has been partially replaced by the Ishak score, in which the major changes concern the modification of the HAI and the further division of necroinflam‐

**Fibrosis stage** F0 F1 F2 F3 F4

Several patient and viral-related factors that can affect the severity of the disease, its progres‐ sion, and treatment outcome have been identified. The chronicity rate in HCV infection appears to be lower in young individuals, and several studies highlight that young age (age <40 years) is associated with more sustained virological response (SVR) [33,48]. The female sex is associated with a higher SVR rate than that of males, using the standard peg-IFN and RBV dual therapy [49]. Obesity is also a relevant predictor of disease progression, and prospective

Portal fibrosis with few septa

Numerous septa without cirrhosis

Cirrhosis

**Activity grade** A0 A1 A2 A3 *Definition* No activity Mild activity Moderate activity Severe activity

> Portal fibrosis without septa

(Ishak-modified Knodell score) [45].

30 Recent Advances in Liver Diseases and Surgery

score, the hepatic activity index (HAI) [47].

matory assessment in four categories [45].

*Definition* No fibrosis

**Table 2.** Metavir liver biopsy scoring system

**8. Predictors of treatment response to HCV**

Genetic variations have long been sought to explain the differences in host antiviral response, and it is now well established that host genetics plays a role in the response to IFN-based therapy in HCV infection [55]. A number of polymorphisms related to the IFN gene (IL28B) have been involved in the immune response to HCV and appear to be strongly associated with SVR in all groups of patients [56]. There are three IL28B distinct genotypes known as CC, CT, and TT, which are strongly associated with race/ethnicity. People with the CC genotype have a stronger immune response to HCV infection than people with the CT or TT genotypes (called non-CC genotypes), and this polymorphism is strongly associated with a greater likelihood of spontaneous viral clearance [57]. In the context of peg-IFN/RBV therapy, the IL28B genotype could assist clinical decision making for the treatment of HCV infection. The first generation of DAAs, including nonstructural NS3/4A protease inhibitors, has shown promising outcomes when used in combination with peg-IFN/RBV in several clinical trials on GT-1-infected patients, with an SVR higher than the dual therapy [58,59]. The SVR rates in the SPRINT-2 and ADVANCE trials were higher in patients with CC (80% and 90%, in the two trials, respectively) compared with CT (71% and 71%) or TT (59% and 73%) [60–62]. It is not yet clear if IL28B polymorphism could still affect the treatment outcome with the interferon-free regimen since larger cohort sizes will be required to confirm its influence.
