Virus Safety of Pasteurized Clotting Factor Concentrates

During the last century, the life expectancy of hemophilic patients was about 11 years, and up to 1960 it had slowly improved to 25 years. Between 1961 and 1980, after the introduction of clotting factor concentrates, many hemophiliacs reached the age of 60 years and their quality of life improved dramatically[1] as effective treatment of joint or cranial bleedings became available. Later, the introduction of home treatment provided a virtually normal lifestyle for many hemophiliacs. However, infection with hepatitis B virus, and in particular non-A, non-B hepatitis, in hemophilia patients became a serious problem because the prevalence of non-A, non-B hepatitis in hemophiliacs was between 80 and 100%.[2] [3] [4] [5] Since 1975, it has been possible to test all blood donors for hepatitis B surface antigen (HBsAg), and the risk of acquired hepatitis B infections by blood or plasma products has been markedly reduced. However, non-A, non-B hepatitis remained a serious complication, leading possibly to liver cirrhosis and in some patients to hepatocellular carcinoma.

Taking into account the bad prognosis of non-A, non-B hepatitis, Heimburger and coworkers[6] set as their goal the development of a virus-safe clotting factor concentrate, and in 1979 to 1980, a pasteurized factor (F) VIII:C (FVIII:C) preparation (Factor VIII HS^℗, the Behringwerke, Marburg, Germany) passed into clinical trials. It was the first effective virus-inactivated FVIII:C worldwide, treated by heating it at 60°C over 10 hours in aqueous solution. In 1981, the preparation was licensed in Germany. Other preparations that were virus inactivated by the same procedure followed, such as Factor IX HS^℗ (Behringwerke) in 1985 and Factor VIII:C HS^℗ (Behringwerke) in 1990.[7] [8] [9]

In 1984, the International Committee on Thrombosis and Hemostasis (ICTH) proposed guidelines for studies on the safety of clotting factor concentrates with regard to virus transmission; they were modified by the Scientific Subcommittee (SSC) in 1989.[10] [11] According to these guidelines, all studies on virus safety had to be designed with the following criteria in mind. Patients should not have received blood or blood products in the past (previously untreated patients [PUPs]). Liver damage must be excluded. Alanine aminotransferase (ALT) levels should be less than 2.5 times the upper normal range, and any drugs with influence on ALT levels should be excluded. Thus, the diagnosis of non-A, non-B hepatitis was made when the ALT levels were more than 2.5 times the upper normal range on two subsequent occasions. All hepatitis B markers must be negative except in patients who have been successfully vaccinated against hepatitis B. In addition, negative results have been mandatory for the anti-HIV enzyme-linked immunosorbent assay (ELISA) since 1985 and the anti-hepatitis C virus (HCV) ELISA since 1990.

REFERENCES

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