* Abbreviations: HCV = : hepatitis C virus • NANB = : non-A, non-B hepatitis • RIBA = : recombinant immunoblot assay • HIV = : human immunodeficiency virus • ALT = : alanine aminotransferase • FDA = : Food and Drug Administration Ten years have elapsed since the identification of the viral agent (hepatitis C virus [HCV]) responsible for hepatitis C was first reported.1 This remarkable achievement occurred after >20 years of intense effort by investigators worldwide following the observation that at least 1 additional viral agent, other than hepatitis A and hepatitis B, was the major cause of posttransfusion hepatitis.2 Before the discovery of HCV, the term non-A, non-B hepatitis (NANB) was used to designate viral hepatitis for which there were no recognized serologic or virologic markers. Because most instances of NANB hepatitis were, in reality, hepatitis C, prospective studies and observations conducted in the 1970s and 1980s shed much light on the clinical features and natural history of HCV infection in adults. However, the discovery and characterization of the viral agent was a major leap forward and rapidly led to the development of assays to detect anti-HCV antibodies and more recently to the application of polymerase chain reaction assays that recognize minute amounts of circulating HCV genome (HCV-RNA). The development of these tests have made it possible to firmly establish a diagnosis of hepatitis C in the clinical setting and have led to a better understanding of the salient epidemiologic, clinical, biochemical, and histologic manifestations of HCV infection. In addition, they provide information essential for obtaining a more accurate assessment of the effects of both established and experimental therapeutic regimens on the course of infection. Moreover, the ability to screen potentially infectious materials, such as blood donated for transfusion, has had an important impact in preventing the spread of hepatitis C. HCV is an enveloped RNA virus with a genome that consists of ∼10 000 nucleotides.3 The virus is a member of the flavivirus family, which also includes other parenterally spread viruses, such as yellow fever and dengue. …

BACKGROUND: Testing for antibody to hepatitis B core antigen (anti‐HBc) as a surrogate for hepatitis C viremia is no longer needed for blood donor screening. Currently, the important question is how much its use supplements hepatitis B surface antigen (HBsAg) donor screening in preventing transfusion‐transmitted hepatitis B virus (HBV) infection. STUDY DESIGN AND METHODS: In a study conducted in the 1970s, 64 blood donors were associated with 15 cases of HBV (1.0%) in 1533 transfusion recipients. Sera from 61 donors at donation and 29 follow‐up visits were available for present‐day assays for HBsAg, HBV DNA, anti‐HBc, and antibody to HBsAg (anti‐HBs). RESULTS: HBsAg was found in four previously negative blood donors; HBV DNA was limited to three of these four. Anti‐HBc was detected in six HBsAg‐negative donors. Two other donors were negative in all assays at donation, but positive for anti‐ HBc and anti‐HBs 2 to 4 months later. The remaining donors were negative for all HBV markers, which left five recipient cases unexplained. No HBV transmission was observed when anti‐HBs sample‐to‐ negative control values were > or = 10. CONCLUSION: Some 33 to 50 percent of cases of hepatitis B that could be transmitted by transfusion of blood from HBsAg‐negative donors are prevented by anti‐ HBc screening. Anti‐HBc‐positive donors unequivocally positive for anti‐ HBs should be considered noninfectious for HBV and should be allowed to donate. Anti‐HBc screening of paid plasmapheresis donors, supplemented by anti‐HBs testing, would reduce the amount of HBV to be processed by virus inactivation and increase the content of anti‐HBs in plasma pools.

Objective-To investigate the possible interference with acute hepatitis B virus infection by coinfection with hepatitis C virus.Design-Analysis of stored sera collected for transfusion transmitted viruses study in 1970s.Setting-Four major medical centres in the United States.Patients-12 recipients of blood infected with hepatitis B virus.Main outcome measures-In 1970s, presence of antibodies in hepatitis B virus and raised serum alanine aminotransferase concentration; detection of antibodies to hepatitis C virus with new enzyme linked immunoassays.Results-Five of the 12 patients were coinfected with hepatitis C virus. Hepatitis B surface antigen was first detected at day 59 in patients infected with hepatitis B virus alone and at day 97 in those coinfected with hepatitis C virus (p=0.01); median durations of antigenaemia were 83 and 21 days respectively (p=0.05), and the antigen concentration was lower in the coinfected patients. Alanine aminotransferase patterns were uniphasic when hepatitis B virus infection occurred alone (range 479-2465 IU/l) and biphasic in patients with combined acute infection (no value >380 IU/l; p=0.0025). Four coinfected recipients developed chronic hepatitis C virus infection. The fifth patient was followed for only four months.Conclusions-Acute coinfection with hepatitis C virus and hepatitis B virus inhibits hepatitis B virus infection in humans, and onset of hepatitis B may reduce the severity of hepatitis C virus infection but not frequency of chronicity. Alanine aminotransferase concentration showed a biphasic pattern in dual infection.

BACKGROUNDThe causes of post-transfusion non-A, non-B hepatitis are still not fully defined, nor is it clear how accurate the tests are that are used to screen blood donors for hepatitis C virus (HCV) and to diagnose post-transfusion hepatitis caused by infected blood.METHODSWe used two first-generation enzyme-linked immunoassays (EIAs) and one second-generation immunoassay to test for anti-HCV antibodies in serum samples collected between 1976 and 1979 in the Transfusion-Transmitted Viruses Study (from 1247 patients who underwent transfusion and 1235 matched control subjects who did not receive transfusions). We tested serum collected before and after infection from the patients in whom non-A, non-B hepatitis developed, serum from their blood donors, and serum from 41 of the control subjects who had hepatitis unrelated to transfusion.RESULTSOf the 115 patients in whom post-transfusion non-A, non-B hepatitis developed, the initial serum samples of 111 were anti-HCV-negative; after hepatitis developed in these 111 patients, the first-generation EIAs detected anti-HCV in 51 (46 percent), and the second-generation assay detected anti-HCV in an additional 16 (14 percent), for a total of 60 percent. Of 40 controls, 37 were anti-HCV-negative initially, and none seroconverted after hepatitis developed. If the 3 percent rate of non-A, non-B, non-C hepatitis among the controls (37 of 1235) was applied to the 1247 transfusion recipients, only 74 of the 111 cases of hepatitis were attributable to the transfusion. Thus, 91 percent (67 of 74) of the cases of post-transfusion hepatitis were caused by HCV. Of the 99 donors, 60 were HCV-positive (9 on second-generation tests only) and 39 were not.CONCLUSIONSNearly all cases of non-A, non-B post-transfusion hepatitis are caused by HCV. Screening with a second-generation assay improves the rate of detection of HCV infection in patients with post-transfusion hepatitis and in blood donors. The use of this test showed a 3.6 percent risk of non-A, non-B, non-C hepatitis, which was not significantly different from the rate in the controls (3.0 percent).

BACKGROUND:The causes of post-transfusion non-A, non-B hepatitis are still not fully defined, nor is it clear how accurate the tests are that are used to screen blood donors for hepatitis C virus (HCV) and to diagnose post-transfusion hepatitis caused by infected blood. METHODS:We used two first-generation enzyme-linked immunoassays (EIAs) and one second-generation immunoassay to test for anti-HCV antibodies in serum samples collected between 1976 and 1979 in the Transfusion-Transmitted Viruses Study (from 1247 patients who underwent transfusion and 1235 matched control subjects who did not receive transfusions). We tested serum collected before and after infection from the patients in whom non-A, non-B hepatitis developed, serum from their blood donors, and serum from 41 of the control subjects who had hepatitis unrelated to transfusion. RESULTS:Of the 115 patients in whom post-transfusion non-A, non-B hepatitis developed, the initial serum samples of 111 were anti-HCV-negative; after hepatitis developed in these 111 patients, the first-generation EIAs detected anti-HCV in 51 (46 percent), and the second-generation assay detected anti-HCV in an additional 16 (14 percent), for a total of 60 percent. Of 40 controls, 37 were anti-HCV-negative initially, and none seroconverted after hepatitis developed. If the 3 percent rate of non-A, non-B, non-C hepatitis among the controls (37 of 1235) was applied to the 1247 transfusion recipients, only 74 of the 111 cases of hepatitis were attributable to the transfusion. Thus, 91 percent (67 of 74) of the cases of post-transfusion hepatitis were caused by HCV. Of the 99 donors, 60 were HCV-positive (9 on second-generation tests only) and 39 were not. CONCLUSIONS:Nearly all cases of non-A, non-B post-transfusion hepatitis are caused by HCV. Screening with a second-generation assay improves the rate of detection of HCV infection in patients with post-transfusion hepatitis and in blood donors. The use of this test showed a 3.6 percent risk of non-A, non-B, non-C hepatitis, which was not significantly different from the rate in the controls (3.0 percent).

Stored serum samples from the Transfusion-transmitted Viruses Study in the 1970s were tested for the presence of antibody to hepatitis C virus (anti-HCV). Single specimens from five control subjects who did not receive transfusions tested negative for anti-HCV. Of four control subjects who did not receive transfusions and who developed non-A, non-B (NANB) hepatitis after hospitalization, three remained anti-HCV negative; the fourth person with postoperative NANB hepatitis tested anti-HCV positive before the operation. Five transfusion recipients with posttransfusion hepatitis B virus infection remained seronegative; a sixth with NANB hepatitis as well as hepatitis B virus infection had seroconversion for anti-HCV. Five of nine transfusion recipients with NANB hepatitis had anti-HCV seroconversion. These results show that present anti-HCV testing demonstrates an etiologic basis for approximately half of the cases of transfusion-associated NANB hepatitis, particularly those that develop chronicity. Although cases of NANB hepatitis without seroconversion may be explained otherwise, they may be caused by another, presently unidentified, virus.

Patients who received transfusions and nontransfused control patients were followed to assess the incidence and cause of post-transfusion hepatitis and to identify donor factors that might relate to risk of hepatitis. We evaluated as risk factors in donors the presence of antibody to hepatitis B virus compared with elevated alanine aminotransferase (ALT) level. Units of blood that were positive for antibody to hepatitis B core antigen (anti-HBc) were associated with a twofold to threefold greater risk of non-A, non-B hepatitis in the recipients than were units without anti-HBc. In the absence of specific serologic tests for non-A, non-B agents, screening of donors for anti-HBc might be considered. Our data suggest that the incidence of non-A, non-B hepatitis might have been reduced by about one third by such screening. However, elevated ALT levels in donors had a similar association with non-A, non-B hepatitis in recipients but would have resulted in fewer units of blood being discarded than would screening for anti-HBc.

The authors studied the distribution of alanine aminotransferase (ALT) levels in 10,034 volunteer blood donors. The mean +/- SD ALT value was 21.4 +/- 19.3 IU/liter; 549 (5.5%) of the donors had a ALT value greater that 45 IU; 2.5 per cent had ALT values greater than 60 IU. In general, ALT levels were higher in males than in females, and were age related; peak values occurred in the third decade of life for males and between 50-60 years of age in females. ALT values greater than 45 IU were found significantly more often in males, in donors of both sexes 30-40 years of age, in married donors, in non-Caucasians, and in those whose education level was no higher than high school. Follow-up samples in donors with an initial ALT greater than 45 IU, revealed that 67% continued to have ALT values above 45 IU 2-8 weeks following initial sampling, and 40% had an ALT greater than 45 IU when tested again six months after entry into the study. ALT values greater than 60 IU were associated with a significantly increased prevalence of antibody of hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) occurring together. No statistically significant association was found between transaminase activity and the prevalence of anti-HBs or anti-HBc alone, or with hepatitis A antibody. These findings demonstrate that there are defined sociodemographic and serologic features of donors with elevated ALT values.

R. D. Aach. Adoption, more than 20 years ago, of Federal Regulations (Title 21, Section 640.3, C.F.R.) seemed to be a reasonable approach to minimizing the risk of posttransfision hepatitis based upon the state of the art at that time. The Regulations exclude individuals with a history of viral hepatitis, a history of close contact with an individual having had viral hepatitis within a 6-month period, and a history of having received, within 6 months of the time of donation, blood or a potentially infectious blood derivative. Although a history of prior jaundice was, and is still, not a specific cause for exclusion in the United States, it has been regarded as a natural extension ofexclusion on the basis of a history of hepatitis. Efforts to develop tests which could readily detect the infectious donor and hopehlly make available for donation the approximately 3 % of potential donors who give a positive history, were unsuccessful prior to the discovery ofthe Australian antigen (HBsAg). Therefore, although doubt existed as to the effectiveness of exclusion by history, even as early as the 1950s, a policy has been almost universally adhered to that is based more upon hypotheses than scientific observation. Two studies do shed some light on the validity of exclusion by history. Matthes and Riderer [I] in Freiberg, Germany, observed a 10.5 % attack rate of icteric posttransfusion hepatitis among recipients of blood from donors with a history of hepatitis within 3 months to 6 years of the time of donation compared with a rate of4.8 % from donors without a history ofprior hepatitis, and 3.7% among recipients whose donors had hepatitis

To evaluate the incidence of post-transfusion hepatitis and factors influencing its occurrence, the Transfusion-Transmitted Viruses Study prospectively followed 1513 transfusion recipients from 1974 through 1979. The attack rate for non-A,non-B hepatitis was 10 per cent. The incidence of hepatitis was directly related to the alanine aminotransferase (ALT) level in blood donors. In recipients of multiple transfusions of blood that had no donor-ALT level above 29 IU per liter the attack rate was 6 per cent or less; at higher donor-ALT levels the attack rate increased progressively, reaching 45 per cent in recipients of units with an ALT of 60 IU or greater. A similar relation was observed among recipients of single units of blood. Moreover, hepatitis developed in 10 of 11 recipients of two units with an ALT level of 45 IU or greater. These data indicate that screening blood for ALT levels would reduce the incidence of non-A,non-B post-transfusion hepatitis.