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OBJECTIVES: Sera of patients with acute hepatitis non-A, non-B prospectively followed for a mean of 11.4 years (range 9 to 15 years) were assayed for anti-hepatitis C virus (HCV) by first- and second-generation enzyme-linked immunosorbent assay (ELISA) and second-generation recombinant immunoblot assay (RIBA) to study the patterns of antibody response in relation to the outcome of disease. METHODS: From 1974 through 1981, 112 patients with acute hepatitis non-A, non-B were enrolled in a prospective study. Sera of 45 patients taken during the acute phase of hepatitis, as well as taken during follow-up in 1983 and 1990 were still available for evaluation. Sera were assayed by first- (ELISA-1) and second-generation (ELISA-2) anti-HCV ELISA, second-generation RIBA (RIBA-2) and HCV RNA by RT-polymerase chain reaction (PCR). RESULTS: Based on anti-HCV seropositivity by RIBA-2 in acute hepatitis and/or during follow-up, a total of 22/45 patients with HNANB (48.8%) were considered to have confirmed HCV infection. By ELISA-1, 11/22-patients with HCV infection (50%) were positive for anti-HCV within 6 weeks of the onset of illness, 18/22 sera (82%) were reactive by ELISA-2. Confirmation by RIBA-2 was obtained in 12 (55%) cases, while one additional patient was RIBA-2 indeterminate. In 1983, a disappearance of anti-HCV tested by RIBA-2 was observed in 7/12 resolved patients but in none of the patients with chronic hepatitis (p = 0.0018) while loss of anti-HCV was observed in 2/12 cases with resolved hepatitis and none with chronic hepatitis by ELISA (not significant). In 1990, all patients with chronic hepatitis were still positive by either ELISA or RIBA-2 but 9/12 (75%), 6/12 (50%) and 10/11 (91%) patients with resolved hepatitis had lost anti-HCV seropositivity tested by ELISA-1 (p = 0.0004), ELISA-2 (p = 0.0124) or RIBA-2 (p < 0.0001), respectively. Mostly, RIBA-2 reactivity was lost prior to ELISA-2 reactivity during follow-up. Rates of antibody loss as detected by ELISA-1, ELISA-2 and RIBA-2 were 4.1, 2.9 and 5.8 per 100 person years, respectively. CONCLUSIONS: This study shows that the continuing presence of HCV is necessary to maintain anti-HCV seropositivity. In contrast, anti-HCV reactivity is progressively lost over time in resolved patients. In addition, albeit more specific, the RIBA-2 is less sensitive than the ELISA and RIBA seroconversion to negative seems to be the earliest serological marker of a resolved HCV infection.

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Orthotopic liver transplantation (OLT) was performed for liver failure related to hepatitis non-A, non-B (HNANB) or hepatitis C (HCV) infections in 12 patients. Of those, 8 patients had chronic and 4 acute hepatic failure. To determine the incidence of recurrent infection, the clinical course, histological findings and serological HCV markers (HCV-RNA and detection of anti HCV antibodies, respectively) were comparatively studied in these patients. Recurrent infection was apparent in 5 of 6 patients transplanted for liver cirrhosis attributable to chronic HCV infection and with HCV-RNA detectable in serum. The clinical course of infection after OLT varied considerably. Chronic active hepatitis, progressing to liver cirrhosis 13 months postoperatively and an acute hepatitis, resolving spontaneously were seen in one case each. Recurrent infection led to chronic persistent hepatitis in the remainder. None of the patients with acute liver failure experienced recurrent infection. HCV-RNA was detectable in all the patients after OLT, with HCV-RNA present pretransplant, however the presence of HCV-RNA in serum was not necessarily associated with clinical illness.

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Of 32 patients with non-A, non-B hepatitis, 10 (31%) were still anti-HCV-positive 12.8 years after the acute phase of the disease. Seven of the patients (21.9%) still had elevated ALT levels, and among these, 5 out of 5 patients who had been subject to parenteral risk were anti-HCV-positive. In contrast, none of the patients who had not been subject to parenteral risks were positive.

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To study the immunogenicity and reactogenicity of an inactivated hepatitis A vaccine, 204 healthy individuals were randomized into three equal groups, each to receive a different vaccine lot. Each subject received a total of three doses, each of 720 ELISA units of hepatitis A vaccine HM175, according to a 0 and 1 month primary vaccination schedule, with a booster dose given at month 6. Side effects were low and were < 30% after the second injection. All subjects but one had antibodies to hepatitis A virus two months after the first dose of vaccine. At month 6 all vaccinees had seroconverted. There were no differences between the three vaccine lots with respect to side effects, seroconversion rates and geometric mean titre of antibodies. We conclude that the three lots of inactivated hepatitis A vaccine are safe, well tolerated and equally immunogenic.

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We investigated immunogenicity, reactogenicity and consistency of three consecutive lots of an inactivated hepatitis A vaccine in 204 seronegative volunteers. Each volunteer received a total of three doses of vaccine (720 EIU) according to a 0, 1 month primary vaccination schedule with a booster dose given at month 6. Mild, moderate and mostly local side effects were reported in 49.7% after the first and in less than 30% after the third injection. Seroconversion rate after one vaccine dose was as high as 91%. All subjects but one had already seroconverted by 1 month after the second injection, corresponding to a seroconversion rate of 99%. The geometric mean titres (GMT) increased with each dose of vaccine administered. Our results show that this inactivated hepatitis A vaccine is highly immunogenic, safe and well tolerated. Furthermore, there were no significant differences between the three vaccine lots in respect to seroconversion rate, size of antibody titre or reactogenicity.

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To investigate biliary secretion in liver-transplanted patients on cyclosporine treatment we used duodenal perfusion with a nonabsorbable marker. After an overnight fast, 4 women and 5 men were studied for 6 hr at least 6 weeks after orthotopic liver transplantation. The data were compared with those obtained in 6 healthy controls. All transplanted patients received immunosuppressive therapy (corticosteroids, azathioprine, and cyclosporine). Biliary secretion rates of healthy controls were: bile acids 1.58 +/- 0.67 mmol/hr, phospholipids 0.27 +/- 0.11 mmol/hr, cholesterol 0.11 +/- 0.01 mmol/hr, and bilirubin 18 +/- 0.7 mumol/hr (mean +/- SEM). Liver-transplanted patients excreted 2.60 +/- 0.4 mmol/hr bile acids, 0.56 +/- 0.08 mmol/hr phospholipids, 0.18 +/- 0.04 mmol/hr cholesterol, and 22.0 +/- 4.5 mumol/hr bilirubin. Analysis of individual bile acids revealed that in the bile of liver transplant patients the percentage of cholic acid was elevated, whereas that of deoxycholic acid was reduced as compared with controls. These findings indicate that in the transplanted liver under immunosuppressive therapy with cyclosporine biliary secretion of bile acids, lipids, and bilirubin is not reduced.

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Due to frequent parenteral contact with blood transfusions hemodialysis patients are prone to acquire hepatitis C virus (HCV) infection. To determine the role of HCV infection we investigated the prevalence of antibodies to HCV in 188 hemodialysis patients. The prevalence of antibodies to HCV was 7.4%. As compared to anti-HCV-negative patients, anti-HCV-positive patients had slightly elevated transaminases which were independent of the presence of markers for hepatitis B virus infection. We conclude that HCV infection is common among dialysis patients.

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The C gene of hepatitis B virus (HBV) codes for at least two different proteins (p 21c and p 17e). To investigate the expression of C-gene-encoded proteins in vivo, serum and liver samples from HBsAg-positive patients as well as serial serum samples from an HBV-transfected chimpanzee were studied. Antibodies directed against bacterially synthesized C-fusion proteins were used in Western blots to test for the presence of p 21c and p 17e. In serial serum samples from the chimpanzee, p 21c and p 17e were detected concomitantly during the acute phase of the infection. When sera of patients with chronic HBV infection were studied, all sera containing p 17e were found to be positive also for p 21c. Sera positive for HBV DNA but negative for HBeAg were only positive for p 21c, indicating that HBeAg/p 17e is not an absolutely reliable marker for infectivity. In liver tissue specimens from 20 patients with HBV-related liver diseases, p 21c was detected in five cases, indicating viral replication. The p 17e antigen, however, was present only in low amounts in three of these five, suggesting that synthesis of p 21c and p 17e is not strictly coupled. C/Pol-gene-encoded fusion proteins were found in the liver tissue of only one patient with cirrhosis, supporting our previous finding that detectable levels of these proteins are expressed rarely.

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To evaluate the importance of antibodies directed against pre-S1 proteins (anti-pre-S1) of hepatitis B virus (HBV) in human sera, an enzyme-linked immunosorbent assay (ELISA) for their detection in human sera was established, using a bacterially synthesized pre-S1 fusion protein. Using this ELISA, it was found that anti-pre-S1 was present in sera from 10 of 11 patients with acute HBV infection who recovered completely, but only present in 1 of 8 patients where the infection was prolonged. In chronic HBV carriers anti-pre-S1 was present in only 3 out of 8 patients and titers were low. In addition, in 5 out of 17 individuals who had recovered from previous HBV infection, anti-pre-S1 was also detected. Individuals immunized with recombinant HBsAg-vaccine and healthy controls were all negative for anti-pre-S1. It is suggested that presence of anti-pre-S1 in sera of patients with acute HBV infection correlates with rapid recovery.

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Sera from 191 long-term hemodialysis patients and from 115 renal transplant patients were studied for the presence of HBsAg and other HBV markers. In 19.1% of the hemodialysis patients and 28.7% of the transplant patients, the sera were positive for HBeAg.HBV DNA in sera was detected by molecular hybridization. HBV DNA was present in the sera of 15 out of 16 hemodialysis patients positive for HBeAg, and in one hemodialysis patient positive for anti-HBe. All renal transplant patients positive for HBeAg were also positive for HBV DNA. Twelve transplant patients were positive for HBV DNA, but negative for both HBeAg and anti-HBe. Determination of HBV DNA was the most sensitive marker of infectivity in patients with end-stage renal disease, and in renal transplant patients.

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A protein of 154 amino acids, predicted to be encoded by the X-open reading frame of the hepatitis B virus (HBV) genome, was synthesized in an in vitro translation system from SP6 transcripts containing the X-coding sequence. As characterized by SDS-PAGE and immunoprecipitation this X-protein possesses the expected molecular weight of 17 kDa and reacts specifically with rabbit antisera directed against a fusion protein from Escherichia coli that contained 145 of the 154 amino acids from the X-sequence. The X-protein, radiolabeled with [35S]methionine, provided a sensitive and specific antigen to screen for anti-X antibodies in sera from HBV patients. Positive signals were obtained preferentially in subjects suffering from HBV-induced liver cirrhosis or primary hepatocellular carcinoma (PHC), i.e., individuals that had been exposed for an extended time period to HBV gene products. Carefully controlled experiments failed to reveal the presence of X-related proteins specific to liver specimens from HBV patients.

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Infection with the hepatitis Delta virus results in a reduction in hepatitis B virus replication. To study the question as to whether expression of large surface (pre-S1) protein is changed in patients with previous and chronic hepatitis Delta virus infection, sera of 25 HBsAg- and anti-HD-positive patients were analyzed by the Western blot technique using an antibody directed against a pre-S1 fusion protein. Pre-S1 proteins were present only in 3 of the 25 sera. This finding suggests that the expression of pre-S1 proteins and HBsAg is regulated independently, and that pre-S1 proteins are not necessarily required for the envelope of hepatitis Delta virus.

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Pre-S1 (large S) proteins are components of the envelope of HBV. The presence of pre-S1 proteins is correlated with viral replication. To test sera of patients with HBV infection for the presence of antibodies against pre-S1 proteins (anti-pre-S1), an E. coli extract containing a pre-S fusion protein covering the greater part of the pre-S1 region was subjected to Western blotting and probed with sera of patients. Anti-pre-S1 was present in the sera of all 4 patients with acute self-limited HBV infection and in the sera of 3 patients with a fulminant course. The antibodies could not be detected in the sera of 6 patients with acute HBV infection entering chronicity, in the sera from 10 HBsAg carriers or in the sera of 25 patients with chronic liver disease, positive for HBsAg and antibodies to hepatitis Delta virus. In an additional study, anti-pre-S1 could not be found in 11 sera from 12 patients with previous HBV infection, positive for anti-HBs and anti-HBc. Antibodies to pre-S1 proteins appear at the early stage of acute resolving HBV infection and seem to play a role in the elimination of the virus. The antibodies are absent in the sera of patients with acute HBV infection entering a chronic course and in the sera of chronic HBsAg-carriers.

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