Hepatitis C virus (HCV) represents a major worldwide public health problem. The search for the key molecular biomarkers that may provide insight on the basis of the differences in disease progression, severity, and response to therapy is crucial for understanding the natural history of HCV, for estimating the burden of infection and for developing preventive interventions. Initially, molecular epidemiology studies have focused on studying the viral genetic diversity (genotypes, genetic variants, specific nucleotide and amino acid substitutions). However, the clinical heterogeneities of HCV infection and the imperfect predictability of the response to treatment have suggested the need to search for host genetic biomarkers. This led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as in treatment response and adverse effects, such as IL-28B, ITPA, and IP-10. As a consequence, nowadays the focus of molecular epidemiology studies has turned from the viral to the human genome. This paper will cover recent reports on the subject describing the most relevant viral as well as host genetic risk factors analyzed by past and current HCV molecular epidemiology studies. 1. Introduction HCV represents a major health problem with approximately 3% of the world population—that is, more than 170 million people—infected. While only 20–30% of individuals exposed to HCV recover spontaneously, the remaining 70–80% develop chronic HCV infection (CHC) [1]. Moreover, 3–11% of those people will develop liver cirrhosis (LC) within 20 years [2], with associated risks of liver failure and hepatocellular carcinoma (HCC) [3] which are the leading indications of liver transplantation in industrialized countries [4]. The socioeconomic impact of HCV infection is therefore tremendous and the burden of the disease is expected to increase around the world as the disease progresses in patients who contracted HCV years ago. Since the discovery of HCV more than 20 years ago [5], epidemiological studies have described complex patterns of infection concerning not only the worldwide prevalence of this virus but also its clinical presentation and its therapeutic response. HCV presents highly variable local prevalence rates between countries and within countries [6]; for example, in Argentina the overall prevalence of HCV infection is close to 2%, but higher rates have been reported in different small rural communities (5.7–4.9%) [7, 8]. The outcome of HCV infection is—as previously stated—heterogeneous ranging from an asymptomatic self-limiting
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