Susumu Takano

Resolution of acute hepatitis C after therapy with natural beta interferon

To test whether interferon can prevent acute non-A, non-B hepatitis from becoming chronic, a prospective controlled trial was conducted in 25 patients; 11 were treated for an average of 30 days with a mean of 52 megaunits of interferon and 14 acted as controls. 4 patients in the treatment group who continued to have raised serum aminotransferase concentrations after a years follow-up were given a second course of interferon. Follow-up at 3 years has revealed that all but 1 of those treated showed normal serum aminotransferase, whereas only 3 controls showed such change (p less than 0.02). Serum hepatitis C virus RNA became undetectable in 10 of 11 treated and in only 1 of 12 control patients, which suggests that interferon prevents the progression of acute non-A, non-B hepatitis to chronicity by eradicating HCV.

Histological changes of the liver by treatment of chronic non-A, non-B hepatitis with recombinant leukocyte interferon alpha

We have treated 17 patients with non-A, non-B chronic hepatitis by recombinant interferon alpha (0.3–9 megaunits for 4–28 weeks). In six patients, serum aminotransferase levels fell to normal or near-normal range during treatment. The mean levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 17 patients fell from 156±80 (mean±sd) and 213±135 at the beginning of treatment to 94±49 and 112±71, respectively, at the end of treatment. In 12 patients, liver biopsies were performed before and after (or during) the treatment, and histological activity indices (HAI) were blindly examined by two independent observers. For comparison, we examined histological changes of pre- and posttreatment liver biopsies of 19 patients who were treated by recombinant interferon for chronic hepatitis B. Mean HAI scores improved from 10.0 to 5.4 after treatment in non-A, non-B chronic hepatitis. The most marked reduction was noted in scores of portal inflammation and hepatocellular degeneration and/or necrosis. No such reduction was observed in B- viral chronic hepatitis. These data indicated that rapid biochemical resolution by the treatment was related to histological improvement of the liver in our patients with non-A, non-B hepatitis.

Randomized, double-blind, placebo-controlled trial of eight-week course of recombinant α-interferon for chronic non-A, non-B hepatitis

Forty-nine Japanese patients were enrolled in a randomized, placebo-controlled, doubleblind trial of α-interferon for chronic non-A, non-B hepatitis: 24 patients received 3 million units of recombinant human alpha α-interferon (α-2a) thrice weekly for eight weeks, and 25 patients received placebo in a similar schedule. The mean serum alanine aminotransferase (ALT) dropped from 155±91 (sd) to 69±72 during interferon treatment, but remained unchanged (158±140 to 147±130) during placebo treatment (P<0.001). Serum ALT level fell to the normal range in 29% of interferon-treated patients, but in only 4% of placebo-treated patients. Pre- and posttreatment liver biopsies were obtained in all but one case. Average histological activity indices (HAI) were markedly improved in the interferon-treated group (9.5±3.7 to 7.0±4.3), but were unchanged in the placebo group (8.5±4.3 to 8.5±4.9). In addition, we compared the efficacy of interferon treatment between anti-hepatitis C virus (HCV) antibody positive and negative groups. Biochemical and histological improvements were similar and statistically significant in patients with and without antibody to hepatitis C virus. These data indicate that a eight-week course of α-interferon induces biochemical and histological improvement in more than half the patients with chronic non-A, non-B hepatitis.

Posttransfusion hepatitis in Japan.

The incidence of posttransfusion hepatitis and the rate of chronicity were investigated in a program devised at our hospital in December, 1982. Out of 2,596 blood recipients between January, 1982, and December, 1987, 451 (22.7%) developed posttransfusion hepatitis. Seventy‐seven patients out of 217 (35.3%) whose course was closely followed progressed to chronicity. The incidence of posttransfusion hepatitis increased with the volume of transfused blood without any evident limitation. Recipients of elevated‐ALT donor blood (> 26 Karmen units) were found to be more susceptible to posttransfusion hepatitis than those who had received only normal‐ALT donor blood. Packed red blood cells, whole blood and fresh whole blood were high‐risk components, and fresh frozen plasma a low‐risk component of blood. The carrier rate of non‐A, non‐B hepatitis agents in Japanese healthy blood donors was determined to be 1.2% using the Frost‐Reed model of infectious diseases. Anti‐hepatitis C virus was detected in 62% of the cases of posttransfusion hepatitis 1 year after transfusion.

Prospective assessment of incidence of fulminant hepatitis in post-transfusion hepatitis: A study of 504 cases

The incidence of posttransfusion hepatitis and “fulminant” hepatitis was investigated by a plan devised at our hospital in December 1982. Of 2959 blood recipients between January 1982 and December 1988, 504 (22.5%) developed posttransfusion hepatitis, with a mean transfusion volume of 10.2 units. Of the 504 cases of posttransfusion hepatitis, “icteric” (T-Bil>2.0 mg/dl) and “overt icteric” hepatitis (T-Bil>5.0 mg-dl) developed in 111 cases (22.0%) and 28 cases (5.6%), respectively. Of the 28 overt icteric hepatitis cases, 13 (2.8%) were thought to be true overt icteric posttransfusion hepatitis because the icterus was caused by other reasons in the other 15 cases (seven neonatal jaundice, four hemolytic anemia, one radiation hepatitis, one halothane-induced hepatitis; two other cases were excluded because chronic liver disease was diagnosed by imaging procedures despite serum ALTs in the normal range before transfusion). The anti-HCV serostatus was investigated in five of the 13 true overt icteric posttransfusion hepatitis patients using blood specimens taken 180 days or more following the onset of posttransfusion hepatitis. Anti-HCV seroconversion occurred in three of the five cases (60%). HCV seroconversions were not seen in the cases in which the icterus was due to other reasons.

A Randomized, Controlled Trial of Interferon-β Treatment for Acute Hepatitis C

To investigate whether interferon can prevent acute non-A, non-B hepatitis from becoming chronic, a prospective controlled trial was conducted in 25 patients: 11 were treated for an average of 30 days with a mean of 52 MU of interferon, and 14 acted as controls. Four patients in the treatment group with continuing serum aminotransferase elevation after a year’s follow-up were given a second course of interferon. Follow-up at 3 years revealed that all but 1 of those treated showed normal serum ALT levels, whereas only 3 controls showed such a change (P < 0.02). Serum hepatitis C virus (HCV)-RNA fell below detectable concentrations in 10 of 11 treated and in only 1 of 12 control patients, which suggests that interferon prevents the progression of acute non-A, non-B hepatitis to chronicity by eradicating HCV. Early diagnosis of acute hepatitis C was demonstrated using the second-generation anti-HCV assay.

Occurrence of hepatocellular carcinoma in chronic viral hepatitis

In the general population of Japan, the carrier rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) are in the same range (1.3% and 1.5%, respectively) [16]. However, HBV and HCV carriers account for 20% and 70% of hepatocellular carcinoma (HCC), respectively (original data, not shown). According to the data reported by the Ministry of Health and Welfare of Japan, 17,000 HCV antibody-positive and 7,000 HBV surface antigen (HBsAg)-positive HCC patients die each year. Therefore, the relative risk of developing HCC in HCV carriers should be larger than that in HBV carriers. On the other hand, the relative risks of developing HCC in cirrhotic patients is about the same, regardless of the etiology [3, 17]. However, the relative risk of developing HCC in patients with chronic hepatitis of various etiologies has not yet been evaluated. The occurrence of HCC was investigated in 251 patients with hepatitis B (127 patients) and hepatitis C (124 patients) with an average follow-up period of about 70 months. All patients were diagnosed by liver biopsy, and the histological diagnoses were chronic persistent hepatitis and chronic active hepatitis. Patients were followed at outpatient clinics on the basis of the ultrasonographic findings and the serum alpha-fetoprotein (AFP) level. When mass lesions were detected or the serum AFP level increased, additional diagnostic procedures were added, including enhanced computed tomography, angiography, and ultrasound-guided biopsy of neoplastic lesions. As a result, HCC was detected in 10.4% of the 124 Cviral chronic hepatitis patients and 3.9% of file 127 B-viral chronic hepatitis patients. Thus, the relative risk of developing HCC was 2.7 times higher in chronic hepatitis C patients than in chronic hepatitis B patients. According to liver biopsy specimens of nonneoplastic lesions taken on the same day of ultrasound-guided liver biopsy of neo-

Prospective assessment of donor blood screening for antibody to hepatitis C virus and high-titer antibody to hepatitis B core antigen as a means of preventing post-transfusion hepatitis

SummarySince November 1989, the Japan Red Cross has been screening blood donors for hepatitis C virus antibody (anti-HCV) with 1st generation assay and high-titer antibody to hepatitis B virus core antigen (HBcAb). To clarify the effectiveness of the new screening tests for the prevention of post-transfusion hepatitis, the incidence of post-transfusion hepatitis after the introduction of new tests (December 1989 to September 1990) was compared with the incidence before the in introduction (January 1982 to December 1987). The incidence of “definite” post-transfusion hepatitis was 10.3% (205/1991) with a mean transfusion volume of 10.2 units before the screening, and 3.9% (11/282) with a mean transfusion volume of 14.6 units after the introduction of the new screening tests. Statistical analysis revealed a significant decrease of post-transfusion non-A, non-B hepatitis after the introduction of new tests (χ2=10.9, P< 0.01). The incidence of “probable” post-transfusion hepatitis was 12.4% (246/1991) and 11.7% (33/282) respectively. No significant change was observed between the rates of “probable” posttransfusion hepatitis before and after the introduction of the new tests. It was concluded that anti-HCV and high-titer anti-HBc screening of volunteer blood donors could contribute to the prevention of the post-transfusion non-A, non-B hepatitis in Japan.