The role of viral factors in the pathogenesis of chronic hepatitis C is unknown. The objective of the present study was to characterize markers of hepatitis C virus (HCV) infection and replication in liver biopsy specimens obtained from 65 genotype 1-infected subjects, including 31 who were coinfected with human immunodeficiency virus (HIV), and to analyze associations between intrahepatic viral markers and hepatitis C disease severity. The percentages of liver cells harboring HCV genomes (%G) and replicative-intermediate RNAs (%RI) were evaluated using strand-specific in situ hybridization, while HCV core and NS3 antigens were assessed by immunocytochemistry. HIV-positive and HIV-negative subjects had similar mean grades and stages of liver disease and had similar indices of HCV infection and replication in liver, even though coinfected subjects had significantly shorter mean disease duration (P ؍ 0.0003). Multivariate analysis showed that %G was not associated with grade or stage of liver disease (P ؍ 0.5 and 0.4, respectively), while %RI was strongly associated with liver inflammation (P < 0.001), liver fibrosis (P < 0.001), and serum alanine aminotransferase levels (P ؍ 0.01). NS3 antigen (but not core) was more frequently detected in HCV RI-positive versus RI-negative specimens (P ؍ 0.028). These findings demonstrate a link between HCV proliferation and hepatitis C disease severity and suggest similar pathogenic mechanisms in HIV-positive and HIV-negative individuals.Hepatitis C is a chronic progressive disease of the liver that is caused by infection with hepatitis C virus (HCV) (9). Although 15 to 20% of individuals infected with HCV spontaneously clear the virus in the acute phase, up to 85% develop persistent viremia. Approximately 60% of those infected develop clinically overt chronic hepatitis, and in this group, the rate of liver disease progression is generally slow but variable (34a). Approximately 20% of patients with chronic hepatitis C develop cirrhosis within 20 years of infection, and those with cirrhosis are at risk of clinical decompensation and developing hepatocellular carcinoma. Finally, chronic hepatitis C occurs in up to 30% of individuals with human immunodeficiency virus (HIV) infection, and evidence to date suggests that HCVassociated liver disease is more severe in subjects with HCV/ HIV coinfection than in subjects with HCV monoinfection. The mechanisms driving HCV disease acceleration in coinfected subjects are presently unknown (17).As with other members of the Flaviviridae family, HCV replicates by enzymatically converting its positive-strand RNA genome into a complementary or minus-strand replicativeintermediate RNA (RI RNA) and then copying the minusstrand RNA to produce new progeny plus-strand RNA. Nascent HCV genomes are then packaged into virions that are released from infected cells by unknown mechanisms. For positive-strand RNA viruses such as HCV, the RI RNA is a highly specific index of active viral replication (26). Based on in vitro experiments using the HCV r...
Without dramatic reductions in injection risk behaviors, shattering of cohesive injection networks, and/or broad coverage of an effective vaccine, HCV will likely remain hyperendemic in drug injectors.
Approximately 20% of patients receiving liver transplants for end-stage hepatitis C rapidly develop severe allograph fibrosis within the first 24 months after transplant. Hepatitis C virus (HCV) variants were studied in 56 genotype 1-infected subjects with end-stage hepatitis C disease at the time before and 12-month after liver transplant, and post-transplant outcome was followed with serial liver biopsies. In 15 cases, pre-transplant HCV genetic diversity was studied in detail in liver (n=15), serum (n=15), peripheral blood mononuclear cells (n=13) and perihepatic lymph nodes (n=10). Our results revealed that pre-transplant HCV genetic diversity predicted the histological outcome of recurrent hepatitis C disease after transplant. Mild disease recurrence after transplant was significantly associated with higher genetic diversity, and greater diversity changes between the pre- and post-transplant time points (p=0.004). Meanwhile, pre-transplant genetic differences between serum and liver were related to a higher likelihood of development of mild recurrent disease after transplant (p=0.039).
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