approximately 3%. 3,4 Early detection of HCC in cirrhotic pa-A prospective study was performed to establish tients can usually be achieved by screening with noninvasive whether infection with specific hepatitis C virus (HCV) techniques, such as ultrasound (US) scan and serum a-fetogenotypes was associated with an increased risk of protein (AFP) concentration. 5,6 development of hepatocellular carcinoma (HCC) in cirOver the years, several lines of experimental evidence indirhosis. A cohort of 163 consecutive hepatitis C virus anticated that male sex, age, and alcohol consumption 4,7,8 were body (anti-HCV)-positive cirrhotic patients was proclosely associated with the development of HCC in cirrhotic spectively evaluated for the development of HCC at patients. The identification of additional variables associated 6-month intervals by ultrasound (US) scan and awith an increased risk of developing HCC would be particufetoprotein (AFP) concentration. HCV genotypes were larly important to optimize preventive medical programs in determined according to Okamoto. Risk factors associthis setting. Recent studies suggested a possible role for HCV ated with cancer development were analyzed by univarigenotype in chronic liver disease outcome and, specifically, ate and multivariate statistics. At enrollment, 101 pa-HCV type 1 was more frequently found in advanced liver tients (62%) were infected with type 1b, 48 (29.5%) were disease, such as cirrhosis and HCC, 9-11 and was associated infected with type 2a/c, 2 (1.2%) were infected with type with a more rapid deterioration of liver histology in chronic 3a, 1 (0.6%) was infected with type 1a, 3 (1.8%) had a hepatitis. 12 We have studied the distribution of HCV genomixed-type infection, and, in 8 patients (4.9%), genotype types in a cohort of patients with cirrhosis prospectively folcould not be assigned. After a 5-to 7-year follow-up (melowed for early detection of HCC, and we performed multivardian, 68 months), HCC developed in 22 of the patients, iate analysis to evaluate the independent risk for tumor 19 infected with type 1b and 3 with type 2a/c (P õ .005).development associated with specific HCV types and with Moreover, HCC developed more frequently in males (P other variables, including interferon treatment, which has õ .01), patients with excessive alcohol intake (P õ .01), been recently reported to reduce the cancer risk in HCVthose over 60 years of age (P õ .02), and in patients who induced cirrhosis. ated with the development of cirrhosis. 1 HCV infection alone was also calculated. Aliquots of sera collected at entry were stored accounts for over 25% of all cases of cirrhosis in Italy, 2 a at 030ЊC for further serological and molecular analysis. When hepacondition that is associated with an increased risk of hepato-titis C virus antibody (anti-HCV) serology became available, sera cellular carcinoma (HCC), with a yearly incidence rate of from 472 of 501 patients were tested by second-generation enzyme immunoassay (Ortho Diagnostic Systems, Raritan, NJ), and 240 sub...

Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles. (HEPATOLOGY 1999;29: 1272-1279.)Hepatitis C virus (HCV) is the major cause of chronic liver disease in Italy and accounts for over 70% of cirrhosis and hepatocellular carcinomas. 1 HCV infection results in high rates of chronicization and in a broad spectrum of liver lesions, ranging from mild inflammation to liver failure.Mechanisms underlying viral persistence and liver damage in chronic HCV infection are marginally known, a complex interplay of viral and immunologic factors being likely involved. Immunomediated mechanisms are believed to play a major role, 2-4 as is suggested by the lack of evidence for a cytopathic effect of the virus, 2 the severe course of infection in immunosuppressed patients, 5 the frequent occurrence of immunologic disorders, 6 and the cytokine-mediated expression of immunoregulatory molecules in the infected liver. 7

No abstract

No abstract

No abstract

Hepatitis C virus (HCV) infection is a dynamic process during which molecular variants are continously selected as the result of virus adaptation to the host. Understanding the nature of HCV genetic variation is central to current theories of pathogenesis and immune response. We prospectively studied hypervariable region 1 (HVR1) variation in the E2 gene of 36 hepatitis C patients, including 10 asymptomatic carriers, followed up for 1 to 2 years. Sequence changes in single and consecutive serum samples were assessed and correlated with clinical and virological parameters of liver disease. A region of the E1 gene was sequenced for comparison in 3 subjects. HVR1 heterogeneity at single time points widely varied in individual patients, did not increase cumulatively over the follow-up period, and did not correlate with HVR1 evolutionary rates. Conversely, the process of HVR1 sequence diversification, although differed considerably among patients, was stable over time and directly correlated with infections by HCV type 2, lower alanine aminotransferase (ALT) levels, and absence of cirrhosis. HCV carriers showed the highest HVR1 variation rates. Our findings indicate that HVR1 variation has an adaptive significance and is associated with favorable features of liver disease and suggest that prospective, rather than static, observations are required to model the process of HCV variation. (HEPATOLOGY 1998;27:1678-1686.)Hepatitis C virus (HCV) shares with other eukaryotic RNA viruses considerable sequence diversity both among isolates from unrelated individuals and within the same individual, 1 in which the virus is not present as a single molecular species, but as a variable population of closely related genomes, 2 according to the model of the viral quasispecies. 3,4 HCV sequence diversity observed among isolates is relevant to the process of viral evolution as it occurred during the history of human populations 1 ; therefore, it has been largely exploited to classify viral variants showing different epidemiologic and pathogenetic features. 5 Conversely, genetic diversity within individuals is more pertinent to the long-term adaptation of the virus to the host and reflects the dynamics of viral populations and the selective mechanisms operating during the course of the infection. 4 Sequence diversity is unevenly distributed throughout the viral genome being highly concentrated at the N-terminus of the E2 envelope glycoprotein, in which an hypervariable region (HVR1) of 31 aminoacids has been identified. 6 This suggests that sequence changes within HVR1 do not simply reflect the intrinsic mutation rates of the virus, but rather indicates that viral variants are actively selected and that genetic variation in this region may have an adaptive significance. [7][8][9][10] The quasispecies nature of the RNA virus populations represents a formidable obstacle to the study of genetic variation; this is a problem further compounded by the lack of structural constraints within protein domains, such as the hypervariable regions of ...

No abstract

Several genotypes of hepatitis C virus (HCV) have been recently identified by phylogenetic analysis, but their clinical relevance in the liver transplant setting is unknown. We evaluated the incidence and course of recurrent hepatitis C after transplantation in 50 patients who underwent transplantation for HCV‐related liver disease. Liver biopsy specimens were obtained when clinically indicated and at yearly intervals; hepatitis was histologically graded and staged according to standard criteria. HCV‐RNA was detected by nested reverse‐transcription polymerase chain reaction (RT‐PCR). HCV genotyping was performed by primer specific PCR. Follow‐up was 6 to 62 months. HCV genotype distribution after transplantation of our 50 patients was as follows: 31 type 1b, 13 type 2a, 3 type 1a, 1 type 3a, 1 type 1b/2a, and 1 undetermined. Actuarial rates of recurrent hepatitis and of severe fibrosis or cirrhosis 5 years after transplantation were 56% and 20%, respectively, in patients infected by type 1b and 33% (P = .18) and 8% (P = .16) in those infected by 2a. In conclusion, this study provides evidence that in patients infected by HCV type 1b there is a trend for a more aggressive recurrent liver disease. Copyright © 1996 by the American Association for the Study of Liver Diseases.