Nobuo Takada

Clinical backgrounds of the patients having different types of hepatitis C virus genomes

Hepatitis C virus (HCV) genomes were recently detected in biological materials, and variations of nucleotide sequences were reported. In the present study, typing of the HCV genomes was performed in 91 HCV-RNA-positive patients and the clinical features of patients with different types of HCV were compared. From the nucleotide sequences of the cDNA fragments, HCV can be divided into at least two types: HCV-K1-PT and HCV-K2. All cDNAs amplified from 91 patients were hybridized with cDNA probes of either HCV-K1-PT or HCV-K2. HCV-K1-PT was found in about 80% of the patients, and HCV-K2 was found in about 20% of the patients. These results indicate that types of HCV are limited to two types, i.e., K1-PT and K2, and the major type is HCV-K1-PT, at least in Japan. Detection rate of antibodies to C-100-3 protein were not different between the patients having HCV-K1-PT and HCV-K2, indicating that the antibodies may develop in HCV-related patients without relation to the types of the HCV genomes. Prevalence of the two types of HCV were nearly the same in various forms of NANB-related liver disease. However, the prevalence was somewhat different in alcoholic liver disease. HCV-K2 was found in patients younger than the patients with HCV-K1-PT. Frequency of a history of blood transfusion tended to be lower and the initial response to interferon treatment was clearly better in patients having HCV-K2 versus patients having HCV-K1-PT. These results suggest the possibility that clinical features due to HCV-K1 may be somewhat different from those due to HCV-K1-PT. However, the number of patients examined was too small to allow a definite conclusion, indicating a necessity for further study with a larger number of patients.

Differences in the hepatitis C virus genotypes in different countries

We recently classified the hepatitis C virus (HCV) into 4 types (HCV-PT, -K1, -K2a and -K2b) according to differences in nucleotide sequences. It was found that HCV-PT, the prototype reported from the U.S.A., was rare in Japan, suggesting that distribution of HCV genotypes may be different in various countries. The prevalence of HCV genotypes was therefore compared in different countries. Genotyping of HCV was performed by slot-blot hybridization analysis using cDNA probes specific to each type of HCV or by restriction fragment length polymorphism analysis. In 121 Japanese non-cancer patients, the prevalence of HCV genotypes was 77.7% for HCV-K1, 16.5% for HCV-K2a and 5.0% for HCV-K2b. HCV-PT was detected in only 1 patient (0.8%). The prevalence in 43 Japanese hepatocellular carcinoma (HCC) patients was 74.4% for HCV-K1, 18.6% for HCV-K2a and 4.7% for HCV-K2b. HCV-PT was found in only 1 sample. In 19 European non-cancer patients, HCV-PT was found in 42.1% and HCV-K1 was found in 52.6%. HCV-K2 was not found. All 7 samples from European HCC patients were HCV-K1, indicating a significantly higher prevalence than in non-cancer patients. In 13 Brazilian non-cancer patients, the distribution pattern was similar to that of the Europeans. In 10 samples from the U.S.A., HCV-PT was found in 70% and HCV-K2 was found in 1 sample. In 18 Chinese non-cancer patients, HCV-K1 was found in 44.4%, HCV-K2a in 50.0% and HCV-K2b in 5.6% HCV-PT was not found. Two samples from Chinese HCC patients were HCV-K1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of genotypes of hepatitis C virus on interferon treatment for chronic type C hepatitis

SummaryInterferon is commonly used for treatment of type C hepatitis, but the effects are variable and many factors may be responsible. Hepatitis C virus (HCV) can be classified into 4 types, PT, Kl, K2a and K2b. Therefore, the responses to interferon treatment in patients with the different HCV genotypes were analyzed. Twenty-four patients with type C hepatitis were treated with 3 to 10 million units of various types of interferon for more than 8 weeks. HCV-RNA encoding the NS5 region (HCV-NS5) was positive in these 24 patients, 16 of which were classified with the Kl type and 8 with the K2 type of HCV. In all patients except for 2, HCV-NS5 became negative within 3 weeks of treatment without relation to the HCV genotypes. Serum alanine aminotransferase levels were normalized in 7 out of 8 patients in the K2 group and in 4 out of 16 patients in the Kl group at the end of 8 weeks. At the 24th week, ALT levels were normalized in 5 out of 6 patients in the K2 group, and in one out of 9 patients in the K1 group. The percentage of patients exhibiting a good response was significantly higher in the K2 group than in the K1 group at both observation periods. During the post-treatment periods, relapse following complete response was found in 3 patients in the K2 group and in one patient in the K1 group. The final effects of interferon were significantly better in the K2 group than in the K1 group. These results indicate that the effects of interferon were significantly better in patients in the K2 group than in patients in the K1 group. Normalization of serum ALT levels was found in two patients with cirrhosis in the K2 group, but in none of the cirrhosis patients in the Kl group, suggesting that effects of interferon may not be related to the progression of liver disease in patients in the K2 group. These results suggest that genotypes of HCV are one of the major determinants of the effect of interferon treatment.

Effects of interferon treatment for chronic type C liver diseases with different hepatitis C virus genotypes: a cooperative study in three hospitals

Abstract Effects of interferon (IFN) treatment on 91 patients with chronic HCV-related liver diseases in three hospitals were analyzed. HCV-RNA encoding the NS5 region of HCV was detected by the RT-PCR method, and HCV genotyping was performed by slot-blot hybridization using the type-specific cDNA probes on HCV-NS5. HCV titers in blood before treatment with IFN were determined by the multicyclic PCR method. HCV-NS5 was positive in 61 out of 91 patients and the HCV-K1 genotype was found in 40 patients, whereas the HCV-K2 genotype was found in 21. To summarize results from all three hospitals, 52.3% of patients recovered completely and 33.3% recovered partially in the K2 group, in each of these the percentage was significantly higher than in the K1 group. In addition, the percentage of the patients showing no response to IFN treatment was significantly higher in the K1 group than in the K2 group. In the HCV-NS5-negative group, the percentage of patients who did not respond was significantly lower than in the K1 group. In the K1 group, a complete recovery tended to be found more frequently in patients with lower titers of HCV. However, some patients with low titers of HCV did not respond to treatment. The differences of HCV titers between the groups showing different responses to IFN treatment was not statistically significant. In the K2 group, HCV titers were significantly lower than those in the K1 group; however, the effects of IFN were not related to the titers of HCV in K2 group. Two patients with liver cirrhosis in the K2 group had a complete or partial recovery, whereas four patients with liver cirrhosis in the K1 group did not respond to IFN treatment. These results indicate that the HCV genotype is the most important determinant of the effects of IFN treatment.

Hepatitis C virus RNA genome in plasma of patients with non-A, non-B hepatitis

SummaryRecently, the assay system of anti-hepatitis C virus antibody (HCV-Ab) was developed. However, there is no clinically useful method to detect hepatitis C virus (HCV) itself. The authors recently developed a method to detect the HCV-RNA genome in plasma using polymerase chain reaction (PCR). In the present study, the specificity of this assay in detecting HCV infection was investigated. Freshly obtained 1 ml plasma specimens from 100 patients with various liver diseases and from 11 control subjects were studied. In patients with non-A, non-B (NANB) hepatitis-related liver diseases, HCV-RNA was detected in 2 out of 7 cases of acute hepatitis, in 29 out of 31 cases of chronic hepatitis, in 17 out of 21 cases of cirrhosis and in 2 out of 6 cases of hepatocellular carcinoma. On the other hand, no HCV-RNA was detected in 15 cases of various types of alcoholic liver diseases, in 12 cases of hepatitis B related liver diseases, and in 11 controls. HCV-RNA was detected in 2 of 6 drinkers with chronic hepatitis. The prevalence of HCV-RNA was not closely related to a history of blood transfusions. These results suggest that our method for HCV-RNA is specific for HCV infection and HCV infection is the likely etiology of most chronic NANB hepatitis cases. The clinical usefulness of our method is illustrated by the fact that we were able to study 100 patients and needed only 1 ml plasma per HCV-RNA assay.

Nucleotide sequences and subtypes of hepatitis C virus genomes

ConclusionThese results indicate that there are at least two subtypes of HCV genomes and that the major type is HCV-K1, HCV-K2 is the minor type and the prototype HCV is scarcely found in Japan.