Shuhei Nishiguchi

Objective: This study was aimed at evaluating the effects of interferon (IFN)-α on survival rate after resection of hepatocellular carcinoma. Methods: In a randomized, controlled trial by the University Hospital, Medical Center and affiliated hospital in Osaka, Japan, 30 men were after surgery randomly allocated to an IFN-α group (15 patients) and to a control group. Patients in the IFN group received 6 MIU of IFN-α intramuscularly daily for 2 weeks, then three times a week for 14 weeks, and finally twice a week for 88 weeks. The incidence of recurrence and survival rate were then studied. Results: The response to IFN was sustained viral response (SVR) in 2 patients, biochemical response (BR) in 6, partial response (PR) in 5, and no response (NR) in 2. In the control, 8 of the 15 patients demonstrated continuous abnormally high levels of ALT. At the end point of the study, intrahepatic recurrence was detected in 9 of the IFN group and in 13 of the control (p = 0.065, log-rank test). The cumulative survival rate was higher in the IFN group than in the controls (p = 0.041). Conclusion: Postoperative IFN therapy improves the outcome after resection of hepatitis C virus-related hepatocellular carcinoma.

The response of chronic hepatitis C to interferon (IFN) treatment is classified as complete response (CR), biochemical response (BR), or no response (NR). Several studies have found no difference in prevention of hepatocellular carcinoma by IFN therapy between patients with CR and those with BR. We investigated whether specific human leukocyte antigen (HLA) alleles were associated with response to IFN, especially BR, in 138 patients with chronic hepatitis C. Comparing patients with and without CR, male, a low viral titer, genotype 2a or 2b, HLA-B55, and HLA-DRB1-0803 were more common in the group with CR. Multivariate analysis showed that age (adjusted odds ratio [OR], 0.95 by every year [95% confidence interval [CI] 0.90 - 0.99], p = 0.028), genotype 2a or 2b (5.21 [95% CI 1.63 - 16.6], p = 0.005), and low viral titer (8.58 (2.66 - 27.7), p < 0.001) were associated with CR. Comparing patients with BR and NR, the pretreatment alanine aminotransferase (ALT) level was lower in the BR group (p < 0.001). Both HLA-B7 and HLA-DRB1-0101 were more common in this group (p = 0.002). As the alleles HLA-B7 and HLA-DRB1-0101 were in linkage disequilibrium, the HLA-B7-DRB1-0101 haplotype may be associated with BR. Multivariate analysis indicated that a low ALT level (0.98 by every 1 IU/L [95% CI 0.98 - 0.99], p = 0.001) and HLA-B7-DRB1-0101 haplotype (32.3 [95% CI 1.50 - 693.1], p = 0.026) contributed significantly to BR. This study suggested that host HLA expression, but not viral factors, can influence BR.

DNA of free hepatitis B viruses (HBV) has been detected in the liver of patients infected with hepatitis C virus (HCV). It is unknown whether HBV DNA is integrated into such livers; if so, it may affect hepatocarcinogenesis. Hepatocellular carcinomas (HCCs) from 34 patients without HBV surface antigen (HBsAg) and with anti‐HCV, and from 7 patients with HBsAg and without anti‐HCV as controls, were examined, using the cassette‐ligation–mediated polymerase chain reaction and primers based on HBV DNA sequence. In the controls, HBV DNA had been integrated into human DNA of all HCCs. On the basis of HBV DNA in tumor tissue, 23 of the 34 patients with anti‐HCV had occult infection. Junctions between human DNA and HBV DNA were detected in 10 of the 34 patients without HBsAg and with anti‐HCV. HBV DNA was integrated into chromosome 11q in 4 of the 10 HCCs with junctions. The DNA to either side of the human‐viral junctions was sequenced. Clinically, the mean tumor size of these 10 HCCs was 39 mm; that of the 24 HCCs without integrated HBV was 25 mm. The surrounding tissue was cirrhotic in 2 of the 10 former HCCs and in 16 of the latter 24 HCCs. In conclusion, integrated HBV was detected in some patients with HCV infection; in these patients, the integrated DNA was associated with accelerated hepatocarcinogenesis. J. Med. Virol. 69:475–481, 2003.

Objective and Methods: Serum levels of hepatitis C virus (HCV), a predictor of the response to interferon (IFN) therapy, can fluctuate widely in patients with chronic hepatitis C, even without antiviral therapy. In order to increase the accuracy of predicting the response to therapy, serum samples from 134 patients with chronic hepatitis C were collected twice: 1.0–4.5 months before and just before the start of IFN therapy, and were tested for HCV core protein by a fluorescent enzyme immunoassay. Results: Forty-one (31%) patients had a complete response to IFN and 93 (69%) had no response. The most useful cutoff value between high and low viral loads for predicting the response to therapy was 40 pg/ml of HCV core protein. A complete response was obtained more frequently in 32 of 45 patients with persistently low viral loads than in those with persistently high viral loads (7 of 71) (p < 0.0001). In 2 of 18 patients with a low viral load at one time point but a high viral load at another, the rate of complete response was similar to that in patients with persistently high viral loads. Conclusion: Prediction of the response to IFN therapy based on HCV core protein measurement at two time points before therapy is more reliable than that based on HCV core protein measurement at only one time point.

Polyamines are essential for cell proliferation, differentiation, and transformation. Concentrations of polyamines are higher in some cancer tissue than in normal tissue. We examined erythrocyte-binding polyamines to evaluate the usefulness of polyamines as pathophysiological markers for hepatocellular carcinoma. We measured erythrocyte-binding polyamine levels in peripheral blood samples obtained from 51 normal adult controls, 136 patients with chronic viral hepatitis, 104 patients with viral hepatic cirrhosis, and 130 patients with hepatocellular carcinoma. We defined the concentration of spermidine plus spermine as the erythrocyte polyamine level, and designated the cut-off level for normal as the mean erythrocyte polyamine level +/- 2 SD in control. The erythrocyte polyamine level was abnormally elevated (positive) in 56 (43%) of 130 patients with hepatocellular carcinoma, 11 (8%) of 136 patients with chronic hepatitis, and 13 (13%) of 108 patients with cirrhosis. The level was higher in patients with a short tumor doubling time. In 27 patients with tumors, there was negative correlation between tumor doubling time and erythrocyte polyamine level (r = -0.46; P = 0.0147). We conclude that erythrocyte polyamine may be a useful tumor growth marker in patients with hepatocellular carcinoma.

The association of the newly identified viruses, GB virus C (GBV‐C) and TT virus (TTV), with autoimmune hepatitis remains to be elucidated. Sera from 20 Japanese patients with autoimmune hepatitis and 50 volunteer blood donors were assayed for GBV‐C RNA, antibodies to the GBV‐C second envelope protein (E2), and TTV DNA. GBV‐C RNA was examined by reverse‐transcription polymerase chain reaction (PCR). Anti‐GBV‐C E2 (a marker of past infection) was tested by an enzyme‐linked immunosorbent assay. TTV DNA was amplified by PCR using two different sets of primers: one derived from the original N22 sequence (Set A) and the other from the untranslated region (Set B). None of the patients or controls had GBV‐C RNA. Anti‐GBV‐C E2 was found significantly more often in patients with autoimmune hepatitis (3/20) than in controls (1/50; P = 0.034). The prevalence of TTV DNA detected by primers Set A and that detected with either Set A or B were similar among patients with autoimmune hepatitis (4/20 and 16/20, respectively) and controls (9/50 and 40/50, respectively). Clinical characteristics did not differ in association with any of these viral markers. Of the 13 TTV isolates amplified with Set A, seven were classified as genotype 1a, four as genotype 1b, and 2 as genotype 3; no particular strain was associated with autoimmune hepatitis. These findings provide no compelling evidence that GBV‐C or TTV has a pathogenic role in autoimmune hepatitis. J. Med. Virol. 66:258–262, 2002.