Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis.

The influence of the hepatitis C virus (HCV)-genotype on liver disease severity was evaluated in 429 consecutive patients with chronic hepatitis C, including 109 with cirrhosis who were followed up prospectively, allowing for the assessment of the role of the HCV-genotype on disease outcome and on the development of hepatocellular carcinoma (HCC). HCV-1 was detected in 147 (46%) patients without cirrhosis and in 47 (43%) with cirrhosis (P: not significant), being mainly HCV-1b. HCV-2 was found in 103 (32%) cases without cirrhosis and in 30 (27.5) with cirrhosis (P: not significant), being mainly HCV-2a. HCV-3 was detected in 32 (10%) patients without cirrhosis and in 2 (2%) with cirrhosis (P < 0.005). Infection with more than one genotype (HCV-1/HCV-2 and HCV-1/HCV-3) was observed only in cirrhotic patients (6 of 109; 5.5%). During a mean follow-up of 67 +/- 22 months, 21 (19%) patients with cirrhosis showed worsening in Child's stage, 5 (4.5%) underwent liver transplantation, 23 (21%) developed HCC, and 24 (22%) died of complication of liver disease; the overall incidence of at least one of these events was 38.5%. By the Kaplan-Meier method and log-rank test, the cumulative probability of developing each or at least one of the above events did not differ in relation to the genotype of infecting HCV, apart from patients with mixed genotype infection who showed a significantly higher incidence of death (P < .05). These data indicate that HCV-genotypes do not have a significant effect on the severity and outcome of liver disease in patients with chronic HCV-infection. Patients with cirrhosis who are also infected by HCV-1 and HCV-2 had a similar prognosis and progression to HCC, while patients infected by more than one genotype showed the most unfavorable course of disease.

Hepatitis C virus infection and liver failure in patients undergoing allogeneic bone marrow transplantation.

The role of hepatitis C virus (HCV) infection in severe liver failure (LF) following bone marrow transplantation is still uncertain. We therefore decided to determine the presence of HCV-RNA in 31 patients who died of severe LF after BMT and in 26 matched BMT controls who did not develop LF. HCV-RNA was identified by polymerase chain reaction and anti-HCV by second generation enzyme-linked immunoassay and by 4-band recombinant immunoblotting assay in serum samples obtained before and after BMT. Biochemical and clinical parameters of liver disease were obtained by reviewing clinical records. LF developed at a median interval of 80 days (20-570) from transplantation and was clinically assessed as VOD (n = 7), liver GVHD (n = 5) or hepatitis (n = 19). HCV-RNA was detected, respectively, in 15/31 (48%) and in 12/26 (46%) of LF patients and controls (P = 0.9). Conversely, the risk of dying of LF was 62% and 53% (P = 0.5) respectively, for HCV-RNA positive and negative patients. Anti-HCV profile did not correlate with viremia, nor with type of liver disease. These findings indicate that, despite a 47% prevalence of HCV infection in our series, HCV-RNA positivity was neither a predictor of VOD nor a marker for life-threatening liver disease.

Evidence against the role of hepatitis C virus in severe liver damage occurring early in the course of acute leukemia in children.

Severe liver damage revealed by a sharp transaminase elevation may be seen in patients with leukemia. This may be due to several possible causes, including viral hepatitis, chemotherapy-induced hepatotoxicity and leukemic infiltration. HCV infection may be suspected to play a relevant role as these patients are often heavily transfused after the onset of their hematologic disorder. We have therefore examined the role of HCV in 15 children with leukemia who developed severe liver damage shortly after the diagnosis of leukemia. All patients were tested for HCV-RNA by the polymerase chain reaction at the time of peak SGPT elevation and for anti-HCV on serial serum samples taken thereafter. Only one patient (6.6%) showed hepatitis C viremia and none developed confirmed anti-HCV positivity during follow-up, suggesting that HCV had not played a major role in causing these severe episodes of liver necrosis. This is in agreement with observations made in non-immunocompromised patients in whom fulminant hepatitis is only exceptionally due to HCV.

Hepatitis C virus serum markers and liver disease in children with leukemia during and after chemotherapy.

The pattern of hepatitis C virus (HCV) serum markers and liver disease was investigated in 11 leukemic children showing anti-HCV reactivity at least once during long-term observation to define the role of HCV infection and the behavior of HCV serologic markers in this patient cohort. Antibodies to HCV by first- and second-generation enzyme-linked immunosorbent assay (ELISA) and by second-generation (four antigens) recombinant immunoblotting assay (RIBA) and HCV-RNA by nested polymerase chain reaction (PCR) were serially examined in serum. Liver disease was defined according to transaminase levels. Seven of 11 patients were found HCV-RNA positive during chemotherapy and after blood transfusion, 3 of 11 became viremic during follow-up, and 1 of 11 was always HCV-RNA negative. Seroconversion to anti-HCV positivity by second-generation ELISA occurred in all the HCV-RNA positive children either during or after chemotherapy. Alanine aminotransferase (ALT) levels were elevated in all the HCV-RNA positive patients during antileukemic treatment and normalized in seven of them after therapy withdrawal, despite persisting viremia. These results indicate that HCV-RNA testing by polymerase chain reaction is required to correctly identify HCV infection in patients with leukemia while on chemotherapy. Viremia did not correlate with ALT levels and anti-HCV patterns.

Patterns of antibodies to hepatitis C virus in patients with chronic non-A, non-B hepatitis and their relationship to viral replication and liver disease.

Patients with hepatitis C virus infection may have circulating antibodies to various structural and nonstructural antigens of the virus. To assess whether the antibody profile is related to epidemiological or clinical features of chronic infection or to viral replication, sera from 172 consecutive patients with biopsy-proven chronic non-A, non-B hepatitis were studied for antibodies to nonstructural and structural hepatitis C virus antigens and for serum hepatitis C virus RNA with the polymerase chain reaction using primers derived from the 5' noncoding region. Three subgroups could be identified on the basis of their seroreactivity to hepatitis C virus: 133 cases (77.3% [group A]) were positive on first- and second-generation assays and had antibodies to C100-3 and to C22, C33c or both identified on recombinant immunoblot assay; 23 cases (13.4% [group B]) were positive only on second-generation assay and reacted with C22, C33c or both but not with C100-3; and 26 cases (9.3% [group C]) were negative for all hepatitis C virus antibodies. Mean age and sex distributions were similar among the three groups; a history of transfusion was more frequent among cases in group B (p = 0.06). These patients also had the highest serum aminotransferase values (p = 0.001). Liver histological studies showed active necroinflammatory changes in 69.2% of patients in group A and 52.2% of those in group B but only in 25% of cases in group C. Serum hepatitis C virus RNA was frequently detected in patients of groups A and B, independent of their recombinant immunoblot assay profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment with interferon(s) of community-acquired chronic hepatitis and cirrhosis type C. The TVVH Study Group.

Two hundred and thirty-four patients with chronic non-A, non-B hepatitis, 86% positive for anti-HCV by ELISA, were treated with recombinant interferon-alpha 2a or with natural (human-leukocytes-derived) interferon-alpha using different dosage and periods of administration. Interim analysis of follow-up data indicate that 65-70% of patients treated initially with 6 MU, thrice weekly, of recombinant interferon-alpha 2a achieved a complete biochemical response (normalization of alanine aminotransferase: ALT) during therapy compared to 56-58% of those treated with 3 MU, thrice weekly, of recombinant or natural interferon-alpha. A 12-month schedule of interferon administration appeared superior to a 6-month schedule in reducing the probability of reactivation of liver disease after therapy withdrawal, although further data are needed to confirm such a conclusion. The probability of response to interferon in terms of maintaining normal ALT after withdrawal did not appear to be influenced by sex, while it was significantly higher in patients aged below 45 years and in those without cirrhosis.

Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV.

There is controversy about clinical management of patients who persistently have antibodies to hepatitis C virus (anti-HCV) but who have no symptoms and signs of liver disease. We have taken liver biopsy samples from 23 such patients (16 of whom had normal alanine aminotransferase [ALT] values) to assess prevalence of liver disease and to see whether anti-HCV and HCV-RNA correlated with histological findings. 16 patients had histological evidence of chronic hepatitis, which was not predicted by serum ALT or by the pattern of specificity of anti-HCV. All 16 cases with hepatitis C viraemia (HCV-RNA detected by polymerase chain reaction), including 9 with normal ALT, had chronic hepatitis on biopsy (p less than 0.001), whereas 7 HCV-RNA-negative cases had normal liver histology. These findings indicate that serum HCV-RNA is a sensitive and specific marker of liver disease in anti-HCV-positive subjects, independent of ALT values, and challenge the idea of the existence of "true" healthy carriers of HCV.

Hepatitis C virus infection in hemodialyzed patients detected by first and second generation assays.

A prospective study of liver disease has been conducted among patients entering our Dialysis Unit between 1987 and 1990. On entry, 7 patients had a history of blood transfusions but none had clinical or biochemical features of liver disease. During follow-up, 13 further patients were transfused; 1 case developed acute resolving hepatitis B and another acute non-A, non-B hepatitis progressing to chronicity. Eleven other cases showed transient or fluctuating ALT abnormalities. On entry, anti-HCV was negative by both 1st and 2nd generation ELISA assays (Ortho-Diagnostic Systems) in all cases. During follow-up, a positive reaction was detected in 17 cases: 4 patients were positive by both assays and 13 only by 2nd generation test (p less than 0.01). HCV was implicated in 66% of cases with liver disease of the non-A, non-B type and in 50% of transfused as compared to 23% of nontransfused cases (p = n.s.). These findings suggest that HCV could play a major etiological role in liver disease of hemodialysis patients and that anti-C100 reactivity is more affected by immunosuppression associated with chronic uremia.

Antibody to hepatitis C virus in cryptogenic chronic liver disease.

The prevalence of antibody to hepatitis C virus (HCV) was studied in 207 patients with chronic liver disease of unknown etiology, in relation to clinical, epidemiological and histological features. Serum antibody to C-100 epitope of HCV was detected by ELISA in 82.6% of patients, with a significant difference compared with a group of patients with primary biliary cirrhosis (10%). The presence of anti-HCV antibody in serum did not correlate with age, sex, histological diagnosis, and activity and duration of the disease, nor with serum anti-HBc, used as a marker of exposure to hepatitis B virus infection. These results strongly support the view that most cases that were previously defined as cryptogenic forms of chronic liver disease are in fact related to HCV infection. There was a correlation between serum anti-HCV antibody and history of risk for parenteral exposure or of acute hepatitis. This correlation was particularly evident for transmission by parenteral route, suggesting that HCV infection may be transmitted often by this route (36.8% among anti-HCV antibody-positive patients and 11.1% among anti-HCV-negative patients). Liver disease in patients without risk factors for parenteral transmission and with lower prevalence of anti-HCV antibody may be caused by other as yet unidentified non-A, non-B (non-C) agents or may be of nonviral origin.

Hepatitis C virus infection and chronic liver disease in children with leukemia in long-term remission.

Antibody to the recently identified hepatitis C virus (HCV) was investigated in sera of 50 leukemic children who had chronic liver disease (CLD), observed for 1 to 12.6 years after therapy withdrawal. All patients were tested for anti-HCV at regular intervals: Ortho-enzyme-linked immunosorbent assay (ELISA) test was performed in all cases. Reactive sera were also tested by recombinant immunoblotting assay to define the specificity of the results obtained by ELISA. Twelve cases (24%) were persistently positive (group A), 11 (22%) were transiently anti-HCV+ positive (group B), and 27 (54%) were negative. Mean SGPT peak during follow-up was significantly higher in group A (P = .014, A v B and P less than .00001, A v C). SGPT normalized off-therapy in 1 of 12 cases (group A), 10 of 11 (group B), and 19 of 27 (group C) (P = .0004, A v B and P = .012, A v C). Accordingly, liver histology, available in 37 patients, showed signs of chronic hepatitis in all patients in group A while most patients in group B and C had less severe liver lesions. These results indicate that HCV plays a significant role in the etiology of chronic hepatitis in leukemic patients and that persistent anti-HCV activity correlates with a more severe CLD, which could jeopardize the final prognosis of children cured of leukemia.

Antibody to hepatitis C virus and liver disease in volunteer blood donors.

OBJECTIVE: To evaluate the specificity of antibodies to hepatitis C virus (anti-HCV) and their relation to liver disease in blood donors. DESIGN: Case series of consecutive blood donors found positive for anti-HCV by enzyme-linked immunosorbent assay (ELISA). Patients were evaluated for antibody specificity using a recombinant immunoblotting assay (RIBA) and were evaluated for biochemical evidence of liver disease. Patients showing increased alanine aminotransferase (ALT) levels had a liver biopsy. SETTING: University hospital. PARTICIPANTS: Fifty consecutive blood donors found to be anti-HCV positive on both an initial and repeat ELISA. Inclusion criteria were as follows: an absence of hepatitis B surface antigens and non-organ-specific autoantibodies; a daily alcohol intake of less than 50 g; no history of recent hepatotoxic drug use; and normal serum levels of alpha 1 antitrypsin, ceruloplasmin, and copper. MAIN RESULTS: Anti-HCV positivity was confirmed by RIBA in only 13 of 50 donors (26%) who had positive ELISA results. These 13 donors had an elevated ALT level and histologic evidence of chronic hepatitis, which was active in 8 patients (62%) and had already produced cirrhosis in 2 patients (15%). In contrast, the 17 donors with an intermediate RIBA pattern had only mild and often nonspecific histologic liver abnormalities. The 20 patients with a negative RIBA result had normal ALT levels. CONCLUSION: In blood donors, the anti-HCV RIBA is not only more specific than the anti-HCV ELISA, but is also useful in identifying patients who have an underlying chronic liver disease.

Fine specificity of human antibody response to the PreS1 domain of hepatitis B virus.

The preS1 domain of hepatitis B virus envelope proteins contains a site of attachment to the hepatocyte membrane that has been shown to evoke virus-neutralizing antibodies. Using synthetic peptides, we have examined kinetics and specificity of the anti-body response to preS1 during acute and chronic HBV infection. Antibodies against two continuous B cell epitopes, p (21-32) and p (32-47), which overlap with the virus receptor for hepatocytes, were detected in 17 (28%) and 28 (47%) patients, respectively, of 60 patients who were tested during acute hepatitis B. Serial testing demonstrated these anti-preS1 specificities in more than 50% of patients who became virus free. By contrast, five patients with chronic evolution of hepatitis B and 61 of 66 patients with an established chronic HBV infection were negative, independent of serological profile and liver disease activity. Fifteen (22.7%) patients with chronic hepatitis B were positive for antibody to the C-terminus p (94-117) preS1 sequence that, unlike the acute-phase anti-(21-32) and anti-(32-47) reactivities, did not behave as a virus-precipitating antibody. Acute-phase sera were found to also contain virus-precipitating antibodies directed against conformational preS1 epitopes. These results indicate that the preS1 site, which contains the binding activity for the hepatocyte membrane, elicits an early antibody response during acute hepatitis B. A defect in such antibody repertoire may participate in the chronicity process as a result of continuing reinfection of hepatocytes by circulating virions.

Expression of preS1 and preS2 in the liver of chronic hepatitis B virus carriers.

Using monoclonal antibodies we have studied the expression and distribution pattern of preS1 and preS2 proteins in the liver of 25 patients with chronic hepatitis B virus infection. Both preS1 and preS2 were detected in the liver of most cases, independently of viral replication and of the state of the viral genome in the liver. In fact, preS1 and preS2 were present in the liver of 14 out of 15 patients with HBV-DNA in the serum as well as of 7 out of 10 cases with no evidence of viral replication, including 2 with integrated HBV-DNA sequences in the liver and 5 patients with no evidence of liver damage. The pattern of distribution of preS proteins was identical to that of hepatitis B surface antigen, with exclusive cytoplasmic staining in cases without viral replication and cytoplasmic and membranous positivity in those with viral replication. These results clearly indicate that translation of preS proteins is independent of viral replication and is not necessarily associated with liver damage.

Antibody response to pre-S2 and hepatitis B virus induced liver damage.

Antibodies to the pre-S2 encoded sequence of the hepatitis B virus (HBV) envelope were detected in 83% of patients recovering from acute hepatitis B. Such antibodies were absent in cases showing chronic evolution and were found in less than 10% of chronic hepatitis B cases, with no relation to liver disease activity. In acute infection anti-pre-S2 became detectable when maximum liver damage had already occurred and was still detectable in 30% of the cases tested 5-7 years after recovery, as well as in 40% of healthy individuals with naturally acquired immunity to HBV. 10 out of 20 recipients of a plasma-derived, pre-S2-containing, HB vaccine acquired anti-pre-S2 and had no evidence of concurrent liver damage or of autoimmune reactions to human albumin or of suppression of the anti-HBs response. These findings indicate that the antibody response to pre-S2 is a marker of HBV clearance and has no role in the pathogenesis of HBV-related liver damage.