Edward Tabor

TRANSMISSION OF NON-A, NON-B HEPATITIS FROM MAN TO CHIMPANZEE

Non-A, non-B hepatitis was transmitted to four colony-born chimpanzees by intravenous inoculation of human sera. Two chimpanzees were inoculated with serum from a patient with a clinical and serological diagnosis of chronic non-A, non-B hepatitis whose blood appeared to transmit this disease to a nurse following accidental needle-stick, and the other two chimpanzees were inoculated with serum from either of two former blood-donors whose HBsAg-negative blood appeared to transmit clinically recognisable hepatitis, and who were found to have raised serum-aminotransferase levels 1 1/2 and 5 years later. Serum-aminotransferase levels rose in all four chimpanzees, beginning 2--4 weeks after inoculation: peak alanine-aminotransferase values were 210 to 328 I.U./l. Evidence of hepatitis was present in liver biopsy specimens from all four chimpanzees, beginning 8--10 weeks after inoculation. None showed serological evidence of infection with hepatitis A virus, hepatitis B virus, cytomegalovirus, or Epstein-Barr virus.

Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection

BACKGROUND: A study was designed to estimate relative analytic sensitivity and window‐period (WP) closure and to project incremental yield of newer HBsAg tests, pooled‐sample NAT, and single‐sample NAT, compared to currently licensed HBsAg tests.

THE EPIDEMIOLOGY OF VIRUS TRANSMISSION BY PLASMA DERIVATIVES: CLINICAL STUDIES VERIFYING THE LACK OF TRANSMISSION OF HEPATITIS B AND C VIRUSES AND HIV TYPE 1

During the past 50 years, most US-licensed plasma derivatives have maintained an impressive record of not transmitting HBV, HCV, or HIV Albumin (50-year history) has never transmitted these viruses. PPF (40-year history) transmitted HBV on only one occasion, which was associated with a design flaw in one manufacturing plant. IGIM has never transmitted any of these viruses since the requirement of sensitive serologic screening tests for HBV (24 years). IGIV (17-year history) transmitted HCV in only one outbreak involving the product of one manufacturer. Even AHF and FIX have not transmitted these viruses since effective virus-inactivation processes in manufacturing were developed. In summary, there has been no transmission of HBV, HCV, or HIV by US-licensed plasma derivatives since the introduction of effective virus-inactivation procedures. This means, essentially, that there has been no transmission of these viruses since the end of 1987; the sole exception is IGIV, by which there has been no transmission since 1994.

Chronic non-A, non-B hepatitis carrier state: transmissible agent documented in one patient over a six-year period.

NON-A, non-B hepatitis is a major health problem, present in up to 89 per cent of patients with post-transfusion hepatitis1 and 25 per cent of hospitalized patients with sporadic hepatitis.2 Experi...

Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: Relative expression of transforming growth factor-α and its receptor in the different areas of tumor

Expression of transforming growth factor-alpha (TGF-alpha) and its receptor, the epidermal growth factor receptor (EGFR), in hepatocellular carcinomas (HCCs) and adjacent nontumorous livers from 25 Japanese patients were examined using immunoperoxidase staining of paraffin-embedded sections. TGF-alpha was detected in 24 of 25 (96%) HCCs and 23 of 24 (96%) available adjacent nontumorous livers. EGFR was detected in 16 of 25 (64%) HCCs and 17 of 24 (71%) adjacent nontumorous livers. TGF-alpha and EGFR were not detected by immunohistochemical staining in normal livers. Fifteen of 25 HCCs contained an apparent area of a second tumor (two of the 15 also contained a third tumor) that had a less-differentiated histological grade developing within or adjacent to the first tumor. In those cases, staining in the less-differentiated area of tumor was usually less intense than in the more highly differentiated area (80% of cases for TGF-alpha; 91% for EGFR). These data confirm that increased expression of TGF-alpha and EGFR occur frequently in human HCC. Furthermore, the detection of greater staining in more highly differentiated portions of the tumors suggests that increased expression of TGF-alpha and EGFR may be events of the early stages of human hepatocarcinogenesis.

Transforming growth factor‐alpha in human hepatocellular carcinoma and coexpression with hepatitis B surface antigen in adjacent liver

Background. Hepatitis B virus (HBV) infection is closely associated with the development of hepatocellular carcinoma (HCC) in many patients, but the mechanisms by which HBV contributes to HCC are not known. Transforming growth factor‐alpha (TGF‐α), a regulator of growth and regeneration in rat liver that can be found in high levels in some human cancers, theoretically could play such an intermediate role in the development of HCC.

Studies of Donors Who Transmit Posttransfusion Hepatitis

Sera and questionnaires were evaluated retrospectively from 128 volunteer blood donors whose blood had been implicated in cases of clinically recognized posttransfusion hepatitis in recipients of one‐ or two‐unit blood transfusions between 1971 and 1977. Serologic markers of hepatitis B virus (HBV) infection were found in 23 per cent, compared to 9.7 per cent of 3,230 prospective blood donors. The prevalence of antibody to hepatitis A virus was similar among implicated donors (44%), prospective donors (58%), and among those implicated donors with (41%) and without (44%) HBV markers. Among implicated donors, none had a history at the time of donation of having had clinically recognizable hepatitis, 93 per cent had no history of prior blood transfusion, and 80 per cent had normal hepatic enzymes. Data from this study confirm that non‐A, non‐B hepatitis has been a common form of posttransfusion hepatitis in recent years, since 77 per cent of these implicated donors had no HBV serologic markers. In addition, these donors could not be distinguished by age, race, sex, history of clinical hepatitis or of prior blood transfusion, or in most cases by hepatic enzyme levels.

NAT screening of blood and plasma donations: evolution of technology and regulatory policy

N AT for screening blood and plasma for viruses have been rapidly developed and implemented for the detection of HCV and HIV-1. The US FDA has had to develop regulatory policies under conditions not previously encountered, namely the development, improvement, and application of new test technologies occurring at such unprecedented speed that nearly all blood and plasma donations would need to be tested while the methods were still in clinical trials. This rapid pace of development can be clearly seen to extend into the future; NAT procedures for additional viruses and modifications of NAT for greater sensitivity and the rapid detection of many viruses simultaneously are currently under development. It had been clear for several years that the increased sensitivity for detecting HCV and HIV-1 by NAT would give an added level of safety to the nation’s blood and plasma supply and that widespread use at the earliest possible date, even if conducted under investigational exemptions before approval of licenses for NAT systems, would be desirable. Furthermore, the expectation in the late 1990s that NAT screening of plasma for HCV would be required by European regulatory authorities, and the fact that substantial volumes of plasma collected in the United States were being exported to Europe, drove the efforts to initiate such testing in the United States. In the end, NAT for HCV was required in Europe for all plasma used for fractionation after July 1, 1999. The processing of blood and plasma collected in the United States includes screening for antibodies and antigens of HCV, HIV-1, and HBV by sensitive immunoassays (such as EIA). These immunoassays already had been in use for many years before NAT was introduced, and their use led to a high degree of safety. Nevertheless, some infectious units still escaped detection by these immunoassays. (However, plasma derivatives are subjected to procedures that would remove or inactivate all HCV, HIV-1, and HBV, if done appropriately.1) The development of the “minipool” concept made such NAT testing feasible; these minipools range from pools of 16 to 24 donations each for whole blood donations and 512 to 1200 donations each for source plasma donations. The use of minipools, accompanied by an algorithm for identifying an infected unit if a minipool tested positive, made the labor-intensive NAT screening affordable for the first time. Many of the few remaining infectious units can be identified by NAT and excluded from transfusion use. Today, NAT conducted on minipools can detect as few as 5 to 6 copies per mL of these viruses in the pool; depending on the minipool size, this is equivalent to 80 to 7200 copies of the virus per mL in the donor blood or plasma.2 Most of these infectious units are from donors in the “window period” of infection, when they are infectious but before they have serologic markers that can be detected by immunoassays. NAT screening can identify most of these donors, as well as the rarer cases of infectious atypical carriers of the viruses. For instance, NAT can detect HCV RNA in stored samples from anti-HCVnegative, NAT-positive donors who previously transmitted HCV to recipients over a long period of time, indicating that they were atypical carriers of HCV.3 Similarly, NAT can detect HIV-1 RNA in stored samples from antiHIV-negative, p24 antigen-negative individuals who had previously transmitted HIV-1.1 Beginning in 1997, discussions were held between the US FDA and representatives of the fractionation community concerning the development of NAT screening to ABBREVIATIONS: BLA = Biologics License Application; IND(s) = investigational new drug application(s).

Concomitant Hepatitis B Surface Antigen and Antibody in Thirteen Patients

Both hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs) were found in 13 patients. Nine patients had HBsAg subtype ad, and 7 had anti-HBs monotypic subtype anti-y. Nine patients had HBsAg before detectable levels of anti-HBs were present. Of the 6 patients whose serum contained subtypes of both HBsAg and anti-HBs, 4 had HBsAg before development of the monotypic antibody. All patients have remained positive for HBsAg and anti-HBs (mean duration, 55.5 weeks). Nine patients were positive for HBeAg, and 7 had renal disease. Six of these seven patients are on hemodialysis. Because of the differing subtype specificities of the circulating HBsAg and anti-HBs, we conclude that HBsAg and anti-HBs occur concomitantly. The presence of HBeAg, which indicates infectivity, is common in our study group, suggesting that these patients are a reservoir for transmission of hepatitis-B-virus infection. Therefore, the presence of anti-HBs alone does not indicate a noninfectious serum. Concomitant HBsAg and anti-HBs seems to be particularly common in patients with renal disease who are on hemodialysis.

Transmission of Hepatitis B Virus Infection by Transfusion of Frozen-Deglycerolized Red Blood Cells

Chimpanzees were used to determine the ability of prior freezing of red blood cells to prevent the transmission of Type B post-transfusion hepatitis. Four units of human whole blood were each inoculated with 10(6) infectious doses of hepatitis B virus. Although all units became HBsAg negative after freezing and deglycerolization, hepatitis B virus infection developed in all four chimpanzees when these units were transfused. Two of these chimpanzees had only serologic evidence of infection, including the development of HBsAg and antibody to both the hepatitis B surface and core antigens; in these animals, the incubation periods were prolonged (24 to 25 weeks). In contrast, the other two animals also had elevated serum glutamic pyruvic transaminase (peaks of 190 and 461 IU per liter) and had a more rapid onset. There was no hepatitis B virus infection in two nontransfused controls. Our results do not support the use of frozen red blood cells for the prevention of post-transfusion hepatitis.