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Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV) infection, chronic hepatitis follows acute hepatitis C in 50−70% of cases; chronic infection is common even in those with a return to normal in aminotransferase levels after acute hepatitis C, adding up to an 85% likelihood of chronic HCV infection after acute hepatitis C. Few clues had emerged to explain host differences associated with chronic infection until recently, when variation in a single nucleotide polymorphism (SNP) on chromosome 19, IL28B (which codes for IFN-λ3), was identified that distinguished between responders and nonresponders to IFN-based antiviral therapy (see below). The same variants correlated with spontaneous resolution after acute infection: 53% in genotype C/C, 30% in genotype C/T, but only 23% in genotype T/T. The association with HCV clearance after acute infection is even stronger when IL28B haplotype is combined with haplotype G/G of a SNP near human leukocyte antigen (HLA) Class II DBQ1*03:01.

In patients with chronic hepatitis C followed for 20 years, progression to cirrhosis occurs in about 20−25%. Such is the case even for patients with relatively clinically mild chronic hepatitis, including those without symptoms, with only modest elevations of aminotransferase activity, and with mild chronic hepatitis on liver biopsy. Even in cohorts of well compensated patients with chronic hepatitis C referred for clinical research trials (no complications of chronic liver disease and with normal hepatic synthetic function), the prevalence of cirrhosis may be as high as 50%. Most cases of hepatitis C are identified initially in asymptomatic patients who have no history of acute hepatitis C (e.g., those discovered while attempting to donate blood, while undergoing lab testing as part of an application for life insurance, or as a result of routine laboratory tests). The source of HCV infection in many of these cases is not defined, although a long-forgotten percutaneous exposure (e.g., injection drug use) in the remote past can be elicited in a substantial proportion and probably accounts for most infections; most of these infections were acquired in the 1960s and 1970s, coming to clinical attention decades later.

Approximately one-third of patients with chronic hepatitis C have normal or near-normal aminotransferase activity; although one-third to one-half of these patients have chronic hepatitis on liver biopsy, the grade of liver injury and stage of fibrosis tend to be mild in the vast majority. In some cases, more severe liver injury has been reported—even, rarely, cirrhosis, most likely the result of previous histologic activity. Among patients with persistent normal aminotransferase activity sustained over ≥5−10 years, histologic progression has been shown to be rare; however, approximately one-fourth of patients with normal aminotransferase activity experience subsequent aminotransferase elevations, and histologic injury can be progressive once abnormal biochemical activity resumes. Therefore, continued clinical monitoring and antiviral therapy are indicated, even for patients with normal aminotransferase activity.

Despite this substantial rate of progression of chronic ...

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