There are seven confirmed hepatitis C virus (HCV) genotypes, with whole-genome nucleotide sequences differing by Ͼ30%, and each can be further subdivided into related subtypes (67 confirmed), with nucleotide sequence divergence of between 15% and 30% (1).Genotype identification has long been used in clinical practice, because major genotypes have different response rates and require different doses and durations of pegylated interferon and ribavirin (PR) treatment. In contrast, until recently, subtype identification was mainly used in epidemiological studies. However, both in vitro studies and clinical trials with different classes of direct-acting antiviral (DAA) agents (NS3 protease, NS5A-, and nucleos[t]ide and nonnucleos[t]ide NS5B-polymerase inhibitors), given with PR or in interferon-free combinations, have shown lower response rates for HCV genotype 1a than for HCV genotype 1b (2-8). Moreover, at least for HCV genotype 1, both the frequency and the pattern of resistance to different DAA classes are subtype specific (9). A striking example is the NS3-Q80K polymorphism, naturally found in Ͼ30% of naive subtype 1a patients but in Ͻ1% of subtype 1b patients (10), which conveys 30%-to-40%-lower sustained-virologic-response (SVR) rates to the macrocyclic protease inhibitor simeprevir (2). Similarly, all subtype 1g sequences identified naturally carry a mutation conferring resistance to linear NS3 protease inhibitors (11).Subtype-specific differences in the genetic barrier to resistance appear to correlate to the RNA-dependent RNA polymerase mu-

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INTRODUCTIONAlthough there are many models for animal testing, the ideal model for chronic liver disease involving hepatic encephalopathy has not been described yet. Different problems associated with the models have led researchers to develop their own, sometimes unique experimental models, which makes difficult the comparison between the results of the conducted studies (1). Hepatic encephalopathy (HE) definition, nomenclature, diagnosis and quantification consensus were published in 2002 (2) where three types of HE were considered: type A, associated with acute liver failure, type B, associated with the existence of porto-systemic communication (by-pass) without intrinsic liver disease and type C, associated to liver cirrhosis. HE type C, in turn, is classified according to their form of presentation as spontaneous or episodic HE, in relation to precipitating factors, persistent HE is subdivided into mild (HE grade I), severe (HE II-IV) or treatment-dependent (early developed after abolition of treatment) and finally, the minimal HE, as the first manifestation of HE. HE type C is the most common form and from a clinical point of view, the episodic HE type because of liver cirrhosis decompensation is the most typical and relevant.