Drug Administration Drug contamination

In the past, plasma factor VIII products have exposed patients with hemophilia to foreign proteins as well as blood-borne viruses, including hepatitis B, hepatitis C, human parvovirus B19, and human immunodeficiency virus (11,12). Before the introduction of heat-treated concentrates in 1985, about 20% of patients with hemophilia in the UK became infected with HIV (13) and virtually all patients with hemophilia who were exposed to large-pool coagulation factor concentrates before the introduction of viral inactivation procedures developed hepatitis C (14). Studies using a second-generation enzyme-linked immuno-sorbent assay showed 89% anti-HCV positivity in a heterogeneous group of patients in the USA and in 98% of Dutch patients with hemophilia who had been exposed to large-pool, non-virally inactivated coagulation factor concentrates (14). In the UK and the Netherlands increased mortality due to liver disease in patients with hemophilia has been reported (14). In patients co-infected with HIV, liver disease was more severe, probably because of higher amounts of hepatitis C viral RNA (13). In addition, patients infected with hepatitis C virus genotype 1 had a more rapid course of disease due to HIV (14).

Since viral inactivation methods, such as solvent detergent and heat pasteurization, were implemented in the production process, the risks of HIV and hepatitis have virtually been eliminated. Dry heating at 60oC is insufficient to eliminate all hepatitis C virus, which requires dry heating at 80oC, pasteurization, or treatment with mixtures of solvents and detergents (14). Nevertheless, many viral inactivation methods currently used do not completely eliminate certain (non-enveloped) viruses, for example parvovirus and hepatitis A (11,15); removal of the small, non-lipid-enveloped parvovirus B19 requires 15 nm nanofiltration. HIV appears to progress more rapidly in patients co-infected with hepatitis B and cytomegalovirus (11). In addition, hepatitis C replicated more rapidly in patients infected with HIV (11).

In a mortality study amongst patients with hemophilia in the UK in 1977-91, AIDS was far the commonest cause of death, and liver disease ranked as the third commonest cause of death (15).

It has been postulated that transfusion-transmitted virus (TT virus) can be transmitted through heat-treated blood products (16). Transfusion-transmitted virus is a common DNA virus in healthy Japanese, and it lacks a lipid envelope, similar to parvovirus B19 (16,17). Transmission of transfusion-transmitted virus often occurs with blood transfusion and it can cause post-transfusion hepatitis with high postoperative peak alanine transaminase activity (17). No patients with hepatitis due to transfusion-transmitted virus have clinically apparent hepatitis (17). The incidence of transfusion-transmitted virus viremia in patients with hemophilia was 43% of those who received only virus-inactivated concentrates and 78% in those who received non-inactivated products before 1984 (16).

Bacterial growth in infusion bags has not been detected, and complications such as infections during the postoperative period have not been observed (18).

Although transmission of classic Creutzfeldt-Jakob disease has never been observed, manufacturers have withdrawn plasma-derived products prepared from plasma obtained from donors who were subsequently found to have classic Creutzfeldt-Jakob disease (19). Although leukocytes are believed to play a key role in the patho-genesis of variant CJD, there may also be a theoretical risk of transmission by plasma products. However, various steps used in the manufacture of plasma-derived factors also contribute to reduced infectivity by bovine spongiform encephalopathy (20). The risk of transmission of nvCJD by recombinant products is unknown, as the cell cultures used for manufacturing them sometimes contain bovine proteins (21).

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