Hugo E. Vargas1 and Andrew W. Tai2 1 Mayo Clinic, Scottsdale, AZ, USA 2 University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA Hepatitis C virus (HCV) is an enveloped positive‐sense, single‐stranded RNA virus of the genus Hepacivirus in the family Flaviridae (Figure 49.1). Among the 10 mature viral proteins are several that are targets for antiviral therapeutic agents, including the NS3/4A serine protease, the NS5A nonstructural protein, and the NS5B RNA‐dependent RNA polymerase. HCV infects hepatocytes (Figure 49.2), leading in many chronically infected individuals to a typical histopathological pattern of a mononuclear portal tract infiltrate with interface hepatitis (Figure 49.3). In many individuals, chronic HCV infection leads to progressive hepatic fibrosis and ultimately cirrhosis, which is associated with an elevated risk of hepatocellular carcinoma and liver failure (Figure 49.4). In the United States, populations with increased HCV seroprevalence have been identified (Box 49.1) and should be offered anti‐HCV antibody testing. An individual with a positive anti‐HCV antibody test should be evaluated to determine whether chronic infection is present and, if so, antiviral therapy should be offered (Figure 49.5). Table 49.1 summarizes diagnostic tests for HCV infection, including anti‐HCV antibody testing, HCV RNA testing, and HCV genotyping. Several classes of direct‐acting antiviral (DAA) drugs targeting viral proteins (Figure 49.6) have led to interferon‐free regimens for the treatment of most chronically infected patients. These new regimens have been quickly simplified into ones that have increased the ease of treatment (Table 49.2). Figure 49.1 Genetic and polyprotein organization of HCV. HCV is encoded by a single‐stranded, 9.6 kb RNA genome flanked by 5′ and 3′ noncoding regions (NCRs), depicted at the top of the diagram. A single large polyprotein precursor (middle) is generated by translation of the positive‐sense RNA; translation initiation occurs at an internal ribosome entry site (IRES) located at the 5′ NCR. The HCV polyprotein is then cleaved by the endoplasmic reticulum signal peptidase (black diamonds), signal peptide peptidase (open diamond), and HCV NS2 and NS3/4A viral proteases (arrows) to release the 10 mature viral proteins (bottom). Numbers indicate the amino acid position relative to the HCV H strain (genotype 1a, GenBank accession number AF009606). Source: Moradpour D., Penin F., Rice C.M. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5:453. Reprinted with permission of Springer Nature. Figure 49.2 Life cycle of HCV infection. Cell entry of HCV (a) requires the host receptors CD81, scavenger class B type 1 receptor (SR‐B1), claudin‐1, and occludin. After virus internalization and uncoating (b), the positive‐sense RNA genome is translated at the endoplasmic reticulum to a single polyprotein, which is processed to release the 10 mature viral proteins (c). HCV induces the formation of an altered host membrane compartment called the membranous web (d), where a negative‐sense RNA intermediate is transcribed and used as a template for the production of positive‐sense HCV genomes. HCV virions are then assembled at or in the vicinity of cellular lipid droplets (e), followed by secretion of assembled virions through the endoscopic reticulum and Golgi apparatus (f), where the envelope proteins E1 and E2 become glycosylated. Source: Moradpour D., Penin F., Rice C.M. Replication of hepatitis C virus. Nat Rev Microbiol 2007;5:453. Reprinted with permission of Springer Nature. Figure 49.3 Typical histology of HCV‐infected liver. This micrograph (×100) of a hematoxylin and eosin‐stained liver biopsy specimen depicts the typical mononuclear portal tract infiltrate seen in chronic HCV infection. The mononuclear infiltrate is composed predominantly of lymphocytes, which often form aggregates or even distinct lymphoid follicles with germinal centers, and occasional plasma cells and eosinophils. There may be evidence of interlobular bile duct damage. Interface hepatitis, formerly known as “piecemeal necrosis,” is characterized by chronic inflammation extending beyond the limiting plate of the portal tract and is also seen in this micrograph. Lobular activity can consist of acidophil bodies, chronic inflammation, and occasional epithelioid cell granulomas; confluent necrosis is not typically seen. An increase in stainable iron is often found, although hepatic iron content is not quantitatively elevated in the majority of cases. Another common finding in chronic HCV infection, not well seen in this micrograph, is hepatic steatosis, particularly with genotype 3 infection. Source: Courtesy of Dr Joseph Misdraji, Massachusetts General Hospital, Boston, MA. Figure 49.4 Natural history of HCV infection. This figure illustrates the possible outcomes of HCV exposure. Up to 30% of exposed individuals may spontaneously clear their infection, while 70–80% develop chronic HCV infection. The estimated risk of progression to cirrhosis varies significantly depending on the population studied; some of the cofactors believed to accelerate fibrosis progression are shown. Once advanced fibrosis/cirrhosis develops, then the patient is at increased risk of developing hepatocellular carcinoma and/or liver failure, which is manifested clinically by decompensated cirrhosis (e.g., ascites, portal hypertensive gastrointestinal bleeding, jaundice, and/or hepatic encephalopathy).
CHAPTER 49
Chronic hepatitis C
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