HIV coinfection is associated with decreased HCV quasispecies variability, which appears to be reversed by effective HAART. Although HIV- and HAART-related effects on host immune pressure are likely to play a role in the observed differences in HCV genetic heterogeneity, other mechanisms may be operative.

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...

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.

Hepatitis frequently recurs after liver transplantation for early recurrence is associated with a higher risk of disease progression. (HEPATOLOGY 1997;26:1646-1652.) hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis Hepatitis C virus (HCV) infection has become the leadcaused by chronic hepatitis C underwent liver transplantation ing indication for orthotopic liver transplantation (OLT) between January 1990 and December 1993. Hepatitis C geno-in the United States. Approximately 50% to 60% of patients type was determined, and liver biopsies were performed at develop recurrent liver disease in the first few years after frequent intervals posttransplantation. The median follow-up transplantation, whereas the remaining patients remain distime was 40.4 months. The cumulative rate of survival was ease-free despite persistent viremia. [1][2][3][4][5][6] Although recurrent no different in liver transplant recipients for hepatitis C than disease is often clinically mild, early graft failure and morin liver transplant recipients for other chronic liver diseases tality have been reported. 4,7 The reasons for the variation (P Å .62). Histological recurrent hepatitis C developed in 33 in disease expression remain uncertain. Studies of the relaof 50 patients assessable for disease recurrence; the median tionship between circulating viral levels and recurrent herecurrence-free survival time was 13.4 months. Histological patocellular injury have yielded conflicting results. [8][9][10][11][12] Paactivity and stage were mild in most cases. Only 2 patients tients infected with genotype 1b have been reported to have developed cirrhosis, and no patient required a second trans-a greater incidence of recurrent hepatitis and more severe plantation for recurrent disease. Patients with acute cellular liver disease. 3,11,13 It also has been suggested that immunorejection had a shorter recurrence-free survival (P Å .0141). In suppression for cellular rejection may play a role in disease patients with recurrent hepatitis, rejection also was correlated recurrence.14 Finally, a correlation between donor-recipiwith increased histological grade 2 years after transplantation ent matching and recurrent hepatitis has been shown in (P Å .0061). Recurrence-free survival was decreased in pa-some, but not all, studies (Unpublished data, September tients infected with genotype 1 (1a and 1b combined) com-1996). 13 Reports on rates of patient survival have also been pared with genotypes 2 and 3 combined (P Å .02), whereas conflicting. Although short-term survival appears to be there was no difference between genotypes 1a and 1b (P ú good, 2,5 preliminary data from one U.S. center suggest de-.80). Only patients infected with genotype 1a or 1b developed creased survival rates among patients undergoing liver bridging fibrosis or cirrhosis. In addition, patients who had an transplantation for HCV. 15 To date, only two centers ha...