Serum HCV RNA levels correlate with histological liver damage and concur with steatosis in progression of chronic hepatitis C

The role of HCV RNA levels and host factors in the severity of liver injury was studied. Enrolled were 298 consecutive liver biopsy-proven chronic hepatitis (CH) C patients (179 men; median age: 52 years, range 19–68; CH, 198; cirrhosis, 100) and 18 chronic hepatitis C with normal ALT. HCV genotypes were: 1a, 4.3%; 1b, 53%; 2a/c, 28%; 3a, 7%; 4, 1.3%, and mixed 6.4%. Serum HCV RNA levels were similar for all genotypes (median: 2.8 × 10⁶ eq/ml; range <0.2–69). In patients with chronic hepatitis without cirrhosis, the serum HCV RNA levels reflected the grade of liver necroinflammatory activity (R = 0.45; P < 0.001) and the stage of fibrosis (R = 0.51; P < 0.001), regardless of age, gender, HCV genotype, hepatic steatosis, and hepatic iron overload. Patients with high serum HCV RNA levels (3 × 10⁶ eq/ml) had higher ALT values (P < 0.002) than those with lower HCV RNA levels. Patients with normal ALT showed low HCV RNA levels (median: 0.82 × 10⁶ eq/ml) and histological features of minimal or mild chronic hepatitis. Cirrhotic patients showed significantly lower levels of viremia than those with chronic hepatitis with a similar HAI. The data of a subgroup of 62 patients with an established time of infection showed that for a similar duration of disease, patients with serum HCV RNA levels 3 × 10⁶ eq/ml had a significantly higher fibrosis score than those with lower levels. HAI and fibrosis score were significantly higher in patients with HCV RNA levels 3 × 10⁶ eq/ml and grade 3–4 steatosis than those with lower HCV RNA levels and steatosis grades. The data indicate that the liver damage is correlated with the HCV RNA levels and that a high viral load acts together with steatosis in accelerating the progression of liver injury.     

Hepatitis C virus serotypes and liver pathology

Abstract: The present study aimed to analyze the pathology of chronic hepatitis C in relation to HCV serotype, and to speculate on possible differences in the pathogenesis of liver injury. Liver biopsies were investigated from 59 consecutive patients in whom hepatitis C virus genotypes were determined by a serological genotyping assay that detects antibodies directed to epitopes encoded by the NS4 region. A morphological study was performed in each case, semiquantitatively scoring necro-inflammatory and fibrotic liver lesions. The prevalence of HCV serotypes was as follows: 26 of the 59 patients (44%) had type 1 infection, 11 (19%) had type 2 and 20 (35%) had type 3. A significant association between intravenous drug abuse and serotype 3 infection was observed. Patients with HCV type 2 proved significantly older than patients with infection types 1 or 3, and more frequently they showed a more active liver disease, but no differences were found in the quality and acinar topographic distribution of all the morphological lesions scored. In conclusion, in chronic hepatitis C a more active liver disease can be related to HCV serotype 2 but the spectrum of liver lesions is independent of HCV types. From a morphological point of view, a different pathogenesis of liver injury related to different HCV types is unlikely.     

Hepatitis C virus infection and genotypes in Japanese hemophiliacs

Abstract: Liver function and antibodies to hepatitis C virus and to human immunodeficiency virus-1 were examined in 195 Japanese patients with hemophilia. One hundred and seventy-three were positive for antibody to HCV and 61 for antibody to human immunodeficiency virus-1. In 63 patients, we examined HCV genotypes according to the double polymerase chain reaction method. Forty cases (63%) were infected with hepatitis C virus with a single genotype, including type 1a in five, type 1b in 21, type 2a in seven and type 2b in seven; 16 (25%) were infected with double genotypes, including types 1a+1b in 14, types 1b+2a in one and types 1b+2b in one; and four (6%) were infected with triple genotypes, including types 1a+1b+2a in two and types 1a+1b+2b in two. Genotype could not be determined in three patients by this method. In the 191 non-hemophiliac patients with chronic hepatitis C, HCV genotyping was as follows: type 1a in 0, type 1b in 121, type 2a in 40 and type 2b in 10 of 171 cases (89.5%) with single infection and types 1b+2a in five and types 2a+2b in one of six (5.5%) with double infection. In the remaining 14 patients, genotype could not be determined. Frequent transfusion of domestic and/or imported coagulation factor concentrates probably caused the high incidence of HCV infection with rare or mixed genotypes in Japanese hemophiliacs.     

Hepatitis C virus genotypes are not responsible for development of serious liver disease

Although hepatitis C virus (HCV) is known to have at least four kinds of genotypes, no clear relationship has yet been established between the genotype and the severity of liver disease. Therefore, we determined HCV genotypes in sera of 251 Japanese patients with type C chronic liver disease, using polymerase chain reactions with six independent primers. One set of primers and a probe derived from 5-noncoding region of HC-J1 was supposed to detect all four genotypes, while the other five were devised to detect each of the genotypes. Among the patients, the major genotype was type II (69%) and the second most common was type III (18%). Type IV was found in 7%, while none had type I genotype. There was no significant difference in the distribution of any genotype among different stages of liver disease, although the ratio of type II to type III tended to be higher in the group of cirrhosis and hepatocellular carcinoma than in the chronic hepatitis group (5.5 vs 3.0). The amounts of HCV RNA were significantly greater in patients with type II (P<0.001) compared with those with types III and IV. However, HCV concentrations of each genotype were not associated with the disease status. These results suggest that HCV genotypes are unlikely to be responsible for the development of more serious liver disease.     

Hepatitis C virus genotypes and severity of chronic liver disease in haemophiliacs

Summary. We studied the activity and stage of chronic liver disease in 45 HCV-seropositive/HIV-seronegative patients with severe haemophilia followed for at least 10 years. HCV-RNA was detected in serum in 36 patients (80%) Viraemic cases were further analysed for HCV genotypes: 10 (28%) were infected by type la, 10 (28%) by type lb, seven (19%) by type 2, four (11%) by type 3, four (11%) had mixed infections (one by la + lb, one by la 4- 2, one by type 2+3, and one by la + 2 + 3). ALT levels were within the normal range in 55% of the HCV-RNA negative patients but in only 11% of the viraemic cases. Results show a trend for higher levels of ALT in HCV-RNA-positive patients compared with those without viraemia (98 ± 56 v 60 ± 61), and particularly with patients with type 3 HCV infection (148 ± 44). We suggest that a slow progression of chronic liver disease occurs in haemophilic HCV-positive/HiV-negative patients and conclude that presence of HCV-RNA in serum correlates well with cytolitic damage but, in the time-scale of our follow-up period, commonly used clinical-laboratory parameters cannot predict the chronic evolution of liver infection or identify differences in disease progression in relation to specific HCV subtypes.     

Long-term treatment of chronic hepatitis C with ursodeoxycholic acid: influence of HCV genotypes and severity of liver disease

Abstract: Aims/Background: Current therapy for chronic hepatitis C virus (HCV) infection is based on the administration of interferon alpha (IFN) alone or in combination with other anti-viral agents. However, such therapy is effective in only a minority of selected patients. Long-term ursodeoxycholic acid (UDCA) treatment has been reported to improve liver function and structure especially in cholestatic disorders. We investigated the effect of long-term UDCA treatment on liver function in respect to the severity of chronic liver disease and HCV genotypes. Methods: Forty-five patients with non-cholestatic laparoscopy-biopsy proven HCV-associated chronic hepatitis (n=16) or cirrhosis (n=29) who had not responded to, or were unsuitable for IFN, were randomly assigned to receive UDCA (600 mg/day; n=23) or no therapy (n=22) for 12 months. At entry, all patients were evaluated by means of conventional and quantitative liver function tests (LFTs), including galactose elimination capacity and antipyrine clearance, HCV antibodies, HCV-RNA and HCV genotypes. LFTs were measured at 6 and at 12 months, whereas HCV-RNA was determined again after treatment. Results: Baseline characteristics were comparable in the two study groups. Long-term UDCA therapy was well tolerated. Based on the analysis of variance, there was a significant decrease in serum transaminase, LDH and GGT levels in UDCA treated patients. By contrast, the activities of these enzymes increased in untreated patients, with AST levels reaching statistical significance only. Statistical analysis also showed that the improvement in biochemical markers was more pronounced in UDCA treated patients with liver cirrhosis than in those with chronic hepatitis but was similar in patients with HCV genotype lb and non-1b. However, HCV-RNA was positive in all patients after treatment. Quantitative LFTs remained, on average, stable over the 12 months of the trial in all groups. Conclusions: Long-term UDCA treatment is well tolerated in patients with HCV-associated chronic liver disease. The effect appears to be greater in cirrhotics than in patients with chronic hepatitis but is independent of HCV genotypes. Thus, long-term UDCA treatment, despite the absence of an anti-viral effect, seems beneficial in reducing disease activity in patients with chronic hepatitis or cirrhosis who are unsuitable for IFN therapy.     

Hepatitis C virus genotypes in chronic hepatitis C of children

SUMMARY. Several hepatitis C virus (HCV) genotypes have been recently identified and genotype 1b has been correlated with severe liver disease and a poor response to interferon therapy. HCV infection in children is an interesting model for evaluation of the relationship between HCV genotypes and liver disease, because of its relatively short duration and the infrequent association with confounding cofactors. We have investigated HCV genotypes, using a dot-blot hybridization assay with genotype-specific probes, in 36 Italian children with chronic hepatitis C who were otherwise well and had no other underlying disease. Only four patients were symptomatic; liver histology, obtained in 3 3 patients, showed minimal hepatitis in 17 and mild chronic hepatitis in 16. Infection with HCV genotype Ib was found in 55.5% of patients, with a peak prevalence of 83% in children from southern Italy (P < 0.05 vs other regions). The remaining children were infected with HCV genotype la (16.6%), genotype 2 (11.1%). and mixed (10.9%) or undetermined (2.7%) genotypes. In one patient, HCV viraemia was never detected. There was no statistically significant correlation between genotype and age, sex, source of infection, alanine aminotransferase pattern and histological activity index. These results indicate that genotype 1b is widespread among Italian children with chronic hepatitis C, although with significant geographical variations. It is not associated with a more severe liver disease, therefore suggesting that the greater severity of liver disease recently reported in adults could reflect the cumulative effects of disease duration and of interfering cofactors.     

Prevalence of HCV genotype among patients with chronic liver diseases in the Tokyo metropolitan area

We examined 613 Toranomon Hospital patients with HCV RNA-positive chronic liver disease to elucidate the viral genotype in the Tokyo metropolitan area. An epidemiological and clinical study was conducted in the 565 patients whose HCV genotype could be determined. The HCV genotypes found were type II, in 414 patients (67.5%); type III, in 103 (16.8%); type IV, in 37 (6.0%); type V, in 4 (0.7%); mixed genotype II and III, in 5 (0.8%); and mixed genotype II and IV, in 2 (0.3%). The HCV genotype could not be determined in 48 patients. Type II was most prevalent. The HCV genotype I was not found at all. There were no significant differences between genotypes in relation to sex, age, history of blood transfusion, or the progression of the disease. It was uncommon to find a history of blood transfusion in the patients with mixed genotypes; however, a high incidence of hepatic disorders was noted among the family members of these patients. Ninety-two percent of the patients with HCV genotype II tested positive for C100-3, while 70.9% of those with type III, and 43.2% of those with type IV tested positive for this antibody. HCV genotype II was most prevalent, and the positivity rate for anti C100-3 in patients with this HCV genotype was significantly higher (P<0.00001) than that in patients with the other genotypes.     

Hepatitis C virus infection in chronic liver disease and hepatocellular carcinoma in Saudi Arabia

The prevalence of antibody to hepatitis C virus (HCV) was determined in 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC) during one year at the Riyadh Military Hospital, Saudi Arabia. The anti-HCV was detected in 36 of 96 (37.5%) HBsAg-negative patients with chronic liver disease and six of 43 (13.9%) HBsAg-positive patients with chronic liver disease. In addition, 11 (42.3%) HBsAg-negative hepatocellular carcinoma patients and two of 16 (12.5%) HBsAg-positive hepatocellular patients had antibody to HCV. The anti-HCV prevalence was 1.5% in 4818 healthy blood donors and 1% in 385 antenatal patients. The overall HCV seropositivity of 30.4% in 181 liver disease patients (CLD and HCC) in Saudi Arabia is lower than that reported from European countries.     

Hepatitis C virus genotypes in patients with chronic liver disease and haemodialysis patients from Saudi Arabia

Summary. The genotypes of hepatitis C virus (HCV) were investigated in 28 Saudi patients (21 males, seven females; age range 23–68 years; mean 45.0 years) with histologically proven chronic hepatitis (13 chronic active hepatitis and 15 liver cirrhosis) and in 32 Saudi patients with chronic renal failure maintained on haemodialysis (22 males, 10 females; age range 18–60 years; mean 40.0 years) who also had liver disease due to HCV. Among the 28 patients with chronic liver disease genotype 4 was the predominant one (60.7%), followed by types 1b (21.4%), 1a (14.3%) and 2a (3.6%). The distribution of genotypes was similar in patients with chronic active hepatitis to those with liver cirrhosis. Among the 32 patients with chronic renal failure and maintained on haemodialysis, genotype 4 was also the dominant type (55.0%), followed by 1a (25.0%), 1b (21.9%) and 2a (3.1%). In all categories studied the prevalence of genotypes between males and females was the same. As our patients were selected from various regions of Saudi Arabia, we believe that genotype 4 is the predominant one throughout the whole kingdom.     

Hepatitis C antibody in patients with chronic liver disease and hepatocellular carcinoma

Hepatitis C virus (HCV) is the major etiologic agent of parenterally transmitted non-A,non-B hepatitis. To determine whether there is a relationship between this virus agent and hepatocellular carcinoma (HCC), the sera of patients with HCC and chronic hepatitis were assessed using a sensitive immunoassay for HCV antibody. Anti-HCV was detected in 65% of 132 patients with HCC, without any relationship with the presence of the hepatitis B surface antigen (HB_sAg). The prevalence (74%) of anti-HCV was high, as expected in patients with putative non-A,non-B cirrhosis also. The prevalence of anti-HCV was less in patients with HB_sAg-positive cirrhosis (28%) and in patients with disease not related to viral hepatitis and healthy controls (8%). These data suggest, but do not prove, that HCV is an important factor associated with HCC.Presented at the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Are hepatitis G virus and TT virus involved in cryptogenic chronic liver disease?

BACKGROUND: Hepatitis G virus can cause chronic infection in man but the role of this agent in chronic liver disease is poorly understood. Little is known about the relation of another newly discovered agent, the TT virus, with chronic liver disease. AIM: To investigate the rate of infection with hepatitis G virus and TT virus in patients with cryptogenic chronic liver disease. PATIENTS: A total of 23 subjects with chronically raised alanine transaminase and a liver biopsy in whom all known causes of liver disease had been excluded, and 40 subjects with hepatitis C virus-related chronic liver disease. METHODS: Evaluation of anti-hepatitis G virus by enzyme immunoassay. Hepatitis G virus-RNA by polymerase chain reaction with primers from the 5' NC and NS5a regions. TT virus-DNA by nested polymerase chain reaction with primers from the ORF1 region. Results. Hepatitis G virus-RNA was detected in 4 out of 23 patients with cryptogenic chronic hepatitis and in 6 out of 40 with hepatitis C virus chronic hepatitis (17.4% vs 15% p=ns). At least one marker of hepatitis G virus infection (hepatitis G virus-RNA and/or anti-hepatitis G virus, mostly mutually exclusive) was present in 6 out of 23 patients with cryptogenic hepatitis and 16 out of 40 with hepatitis C virus liver disease (26. 1% vs 40% p=ns). T virus-DNA was present in serum in 3 subjects, 1 with cryptogenic and 2 with hepatitis C virus-related chronic liver disease. Demographic and clinical features, including stage and grade of liver histology, were comparable between hepatitis G virus-infected and uninfected subjects. Severe liver damage [chronic hepatitis with fibrosis or cirrhosis) were significantly more frequent in subjects with hepatitis C virus liver disease. CONCLUSIONS: In Southern Italy, hepatitis G virus infection is widespread among patients with chronic hepatitis, independently of parenteral risk factors. Its frequency in subjects with cryptogenic liver disease parallels that observed in hepatitis C virus chronic liver disease, thus ruling out an aetiologic role of hepatitis G virus. TT virus infection is uncommon in patients with cryptogenic or hepatitis C virus-related liver disease who do not have a history of parenteral exposure.     

Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV‐coinfected patients

Summary. The efficacy of current hepatitis C therapy in HIV/HCV‐coinfected patients is largely dependent on HCV genotype. The annual prevalence of HCV genotypes/subtypes and their influence on HCV clearance with antiviral treatment were examined in a dynamic cohort of HIV/HCV‐coinfected patients followed up in Madrid since 2000. Patients entered the cohort at first visit and left the cohort when HCV clearance was achieved with HCV therapy or when follow‐up was interrupted for any reason, including death. A total of 672 HIV/HCV‐coinfected patients constituted the cohort. The mean follow‐up time was 5.5 years, corresponding to 4108 patient‐years. Mean age at entry was 37 years, and 73% were men and 86% were intravenous drug users. Overall distribution of HCV genotypes was as follows: 57.1% HCV‐1 (1a: 29.2%, 1b: 20.4%, unknown: 7.6%), 1.3% HCV‐2, 25.4% HCV‐3 and 15.9% HCV‐4. A total of 274 (40.8%) patients were treated with peginterferon–ribavirin, of whom 116 (42.3%) achieved HCV clearance following 1–3 courses of therapy. The proportion of HCV‐1/4 rose from 71.7% in 2000 to 76.8% in 2008, whereas the proportion of HCV‐2/3 fell from 28.1% in 2000 to 23.2% in 2008. The yearly prevalence increased for HCV‐1 (R²: 0.92, b: 0.59, P < 0.001) and HCV‐4 (R²: 0.77, b: 0.33, P < 0.005) and conversely diminished for HCV‐3 (R²: 0.94, b: ?0.82, P < 0.001). In summary, the prevalence of HCV‐1 and HCV‐4 has increased over the last decade in HIV/HCV‐coinfected patients, whereas conversely it has declined for HCV‐3, in association with the wider use of HCV therapy (41%) in this population.     

Serotyping of hepatitis C virus in chronic type C hepatitis in Taiwan: Correlation with genotypes

To evaluate the usefulness of a new serologic assay to group hepatitis C virus (HCV), genotypes identified by this serotyping method were compared to those identified by a polymerase chain reaction (PCR) assay with type-specific primers in 71 Taiwanese patients with chronic type C hepatitis. The group-specific antibodies against different HCV genotypes were detected by using an enzyme-linked immunosorbent assay (ELISA) based on group-specific recombinant peptides (C14-1 and C14-2) within the NS4 region. Among 71 patients positive for current second-generation HCV antibodies, HCV RNA was detected in 55 patients by PCR with primers from the 5′ untranslating region, and in 52 by genotype-specific PCR. In 49 (89%) of 55 viremic patients, the results of serotyping by ELISA showed complete agreement with those determined by PCR genotyping, and none of the patients showed a group opposite to that of HCV genotype. The positive rate of group-specific antibodies (69/71;97%) was even better than that of the PCR (55/71;78%). We conclude that this new serotyping assay is highly sensitive and specific for the determination of HCV genotypes, and will be useful in future epidemiologic studies, as well for clinical application.     

Epidemiology of genotypes of hepatitis C virus in Japanese patients with type C chronic liver diseases: A multi-institution analysis

Sixteen medical institutions in Japan collaborated in this study of the epidemiology of hepatitis C virus (HCV) genotypes. A total of 4176 patients with type C chronic liver disease, from the four main islands of Japan, were evaluated. Of those evaluated, 2794 had chronic hepatitis, 727 had liver cirrhosis and 655 had hepatocellular carcinoma. The HCV genotype of the patients was determined by an enzyme-linked immunosorbent assay based on serological genotype 1- and 2-specific recombinant peptides (SG-1 and SG-2, respectively) of the NS4 region. The prevalence of SG-1 and SG-2 HCV was similar in the four main islands of Japan. SG-1 HCV predominated in each disease category (69–76%). The percentage of patients with SG-1 HCV increased by 7%, while that of patients with SG-2 HCV decreased by 7%, as liver disease progressed in severity from chronic hepatitis to carcinoma (P < 0.001). Patients with either SG-1 or SG-2 had a similar mean age and history of blood transfusion. In conclusion, SG-1 HCV was found to predominate in Japan, and the HCV genotype was found to be related to the stage of hepatitis C disease.