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GB virus C (GBV-C) is related to hepatitis C virus (HCV) and has a similar genomic structure. Some predictors for the efficacy of interferon (IFN) therapy on HCV have been reported: genotype, viral load, IFN dose, and the amino acid substitutions in the NS5A region, designated as the interferon sensitivity determining region (ISDR). To evaluate the correlation between the amino acid substitutions in the GBV-C NS5A region and the response to IFN therapy, single-strand conformation polymorphism (SSCP) analysis was performed in the 12 concomitantly GBV-C–and HCV–infected patients who received IFN therapy at three time points: before, endpoint, and after the IFN therapy. The region in the GBV-C NS5A studied includes the amino acids that exhibit some homology to the ISDR and the various substitutions. By SSCP analysis, amplicons were separated into 1–4 bands, which indicated the existence of heterogeneity in each host. However, the deduced amino acid sequences in these bands exhibited no characteristic differences among these strains irrespective of response to IFN therapy. Of the 32 strains separated by SSCP, 7 strains were responders, and 25 were nonresponders. The mean amino acid substitution, compared with the consensus sequence of nonresponders, was 1.00 ± 0.93 among responders, and 1.40 ± 0.85 among nonresponders (P = NS). No correlation between the amino acid sequence in the GBV-C NS5A region and response to IFN therapy was found, indicating that the GBV-C NS5A region dose not act as the ISDR. J. Med. Virol. 57:376–382, 1999. © 1999 Wiley-Liss, Inc.

GB virus C/hepatitis G virus (GBV-C/HGV) is related distantly to hepatitis C virus (HCV). HCV has a hypervariable region (HVR), and exists as quasispecies in vivo. Although GBV-C/HGV also has replaceable amino acids in the presumed antigenic region, the existence and fluctuation of population of heterogeneous virus have not been evaluated. In this study, the heterogeneity of GBV-C/HGV and HCV was investigated by the single-strand conformation polymorphism (SSCP) analysis in six concomitantly infected patients. Two patients were observed for 4 years without any treatment, and four were treated with interferon-α (IFN). By SSCP analysis, amplicons of GBV-C/HGV RNA were separated into 1–5 bands on gels for each patient. The amplicons had different nucleotide but the same amino acid sequences in the presumed antigenic region. The amplicons of HCV RNA, separated into 1–4 bands, had different nucleotide and amino acid sequences in the HVR. In the two patients without treatment, the predominant strain of GBV-C/HGV was unchanged for the 4 years. In the four patients administered IFN, some strains of GBV-C/HGV disappeared after IFN therapy, whereas other strains persisted. The mean genetic distance among GBV-C/HGV strains represented by SSCP analysis was significantly lower than that of HCV (P < 0.05). The data indicate that: 1) GBV-C/HGV can be devoid of antigenic drift unlike HCV; 2) GBV-C/HGV has no HVR as seen in HCV in the presumed antigenic region; and 3) the sensitivity to IFN differs among GBV-C/HGV strains in the same hosts, as with HCV. J. Med. Virol. 55:109–117, 1998. © 1998 Wiley-Liss, Inc.

Interferon induces remission in about 50% of patients with chronic hepatitis C, but it is difficult to predict which patients will respond. Host and viral factors were evaluated for correlation with response to interferon in patients with chronic hepatitis C. Recombinant interferon alpha-2b with a total dose of 480-560 million units was given to 136 patients, of whom 74 (54%) responded. Genotypes of hepatitis C virus (HCV) in sera, I, II, III, IV, and V, were determined by polymerase chain reaction (PCR) with type-specific primers. In 72 patients, pretreatment levels of HCV RNA were titrated by PCR in serial tenfold dilutions of RNA extracted from serum. Response to interferon occurred in 34 (40%) of 85 patients infected with HCV of genotype II, less frequently than in 22 (85%) of 26 with genotype III (P0.001) or in 7 (70%) of 10 with genotype IV. Of 51 patients with genotype II HCV, 6 of 8 (75%) with HCV RNA titers10(6) responded, more frequently than 4 of 43 (9%) with titersor = 10(6) (P0.001). Responders were younger than non-responders (45.7 +/- 11.7 vs. 50.3 +/- 9.6 yr) and had received transfusions less frequently (26/74 or 35% vs. 37/62 or 60%, P0.01). Response to interferon correlated inversely with the severity of liver histopathology. These results indicate that response to interferon is influenced by HCV genotypes and pretreatment levels of HCV RNA in serum.

Genotypes of hepatitis B virus (HBV) were determined in 145 patients with acute hepatitis B from various districts in Japan to establish their geographic distribution and evaluating the influence on the clinical illness and outcome. Genotypes were A in 27 (19%) patients, B in 8 (5%), C in 109 (75%) and mixed with B and C in the remaining one (1%). Genotype A was more frequent in metropolitan than the other areas (21/69 (30%) vs. 6/76 (8%), P < 0.001). On phylogenetic analysis, seven of the nine (78%) HBV/A isolates selected at random clustered with those from Europe and the United States, while the remaining two with those of subgroup A' prevalent in Asia and Africa. Maximum ALT levels were lower (2069 +/- 1075 vs. 2889 +/- 1867 IU/L, P = 0.03) and baseline HBV DNA titers were higher (5.90 +/- 1.45 vs. 5.13 +/- 1.36 log genome equivalents (LGE)/ml, P = 0.002) in patients infected with genotype A than C. Hepatitis B surface antigen persisted longer in patients infected with genotype A than C (1.95 +/- 1.09 vs. 1.28 +/- 1.42 months, P = 0.02). HBV infection became chronic in one (4%) patient with genotype A and one (1%) with genotype C infection. Fulminant hepatic failure developed in none of the patients with genotype A, one (13%) with genotype B and five (5%) with genotype C. The point mutation in the precore region (A1896) or the double mutations in the basic core promoter (BCP) region (T1762/A1764) were detected in none of the patients with genotype A, two (25%) with genotype B and 27 (26%) with genotype C. In conclusion, genotype A is frequent in patients with acute hepatitis B in metropolitan areas of Japan, probably reflecting particular transmission routes, and associated with longer and milder clinical course than genotype C.

To determine the virological factors associated with a favorable long-term response to interferon-alpha (IFN) therapy in chronic hepatitis C virus (HCV) infection, 61 Japanese patients with chronic HCV infection were treated with IFN for 24 weeks (780 million units in total) and followed for 8 to 16 months after cessation of therapy. Ten patients dropped out because of severe side effects. Of the 51 patients who completed IFN therapy, 23 showed complete and sustained response (CR --SR), 13 complete response with early relapse (CR --Rel), and 15 no response to IFN (NR). For the pretreatment serum HCV RNA level, 20/23 who had CR --SR had10(6) eq/ml compared to 3/13 CR --Rel and 1/15 NR (P0.01). Serologically defined HCV type 2 infection was also associated with a better opportunity to develop CR --SR compared to CR --Rel of NR (P0.01). Loss of serum HCV RNA at week 4 of IFN therapy was also associated with a more favorable long-term response [17/19 CR --SR were HCV RNA negative compared to 3/11 CR --Rel (P0.01) and 2/13 NR (P0.01)]. In contrast, normalization of serum alanine aminotransferase (ALT) levels at week 4 was found in 9/19 CR --SR compared to 8/11 CR --Rel (P = NS), and 0/13 in NR (P0.01). Six months after cessation of IFN therapy, 3/25 CR --SR patients were HCV RNA positive despite normalization of serum ALT levels. These data indicated that in addition to pretreatment serum HCV RNA levels and HCV type, the kinetics of response to IFN (at week 4) were also predictive of subsequent long-term response to IFN in patients with chronic HCV infection.

The seroprevalence of hepatitis C virus (HCV) infection in Lanzhou, Western China was studied. HCV genotypes in 20 patients with HCV infection was determined by genotype-specific primer for polymerase chain reaction (PCR) based on HCV core region and compared with the genotype assigned by sequence comparison and molecular evolutionary analysis based on the same region. Antibody to HCV (anti-HCV) was present in 2.5% of volunteer blood donors and in 35.0% of paid blood donors (P < 0.01). HCV infection is uncommon in patients with liver disease who attended liver clinics in this locality; 4.0% with acute hepatitis and 4.0% with chronic hepatitis, 10.0% with liver cirrhosis, and none with hepatocellular carcinoma were seropositive for anti-HCV. Genotype 1b and 2a were both found to be prevalent. Together, they accounted for 19 of 20 (95%) patients with HCV infection. Sequencing of the HCV core region from two patients showed that the assignment of HCV genotype by genotype-specific primers for PCR matched well with the genotyping results based on sequence comparison and molecular evolutionary analysis. These data showed that HCV is present in Western China, HCV infection is more common in paid blood donors, and HCV genotypes 1b and 2a are both prevalent in Western China. © 1995 Wiley-Liss, Inc.

Viremia in hepatitis A viral (HAV) infection is said to be limited to pre-symptomatic period. However, it is not clear how long viremia lasts in human infection due to the lack of a simple and sensitive detection system. In an attempt to find HAV genome in patients' sera, we used the RT-PCR method by setting a pair of primers in the 5' non-coding region. While in most cases HAV-RNA was detected only before alanine aminotransferase (ALT) reached peak levels with this sensitive system, the viral genome was observed in some patients' sera even after ALT reached peak levels. Some patients also had HAV viremia after seroconversion to HAV antibody. These results show that viremia in HAV infection lasts longer than has been previously thought, and give a warning of possible secondary blood-borne infection.