Clinical Aspects of and Therapy for Hemophilia A. Incidence. Clinical Severity, страница 12

Both HCV and HBV are difficult to inactivate. Heating the lyophilized concentrate at 60–68єC for 30–72 hours does not inactivate HCV, although raising the temperature to 80єC for 72 hours does eliminate HCV. MLID94054272  66 Heating the concentrate in solution (60єC for 10 hours of "pasteurization") appears to kill HCV, although there are anecdotal reports that hepatitis B and C have still occurred after pasteurization methods were used. MLID87144520 MLID89013554  75,76

Solvent/detergent-treated concentrates appear to be free of HCV. MLID88287648  77 Of note is that solvent/detergent methods do not inactivate viruses without lipid envelopes. Thus, parvovirus, for example, may not be killed. In Ireland, Italy, Germany, and Belgium a recent outbreak of hepatitis A occurred in 84 hemophilia patients infused exclusively with solvent/detergent-inactivated concentrates purified by ion exchange chromatography. MLID92194930  78

HIV appears to be easily inactivated by any of the current viral inactivation procedures. In all viral safety trials in which HIV antibody status was studied, which include over 300 subjects, no seroconversions occurred. MLID89274385  64 However, 18 cases of HIV seroconversion have been reported with heat-treated factor VIII concentrate not associated with viral safety trials. 79 Most cases used concentrate that was dry heated at 60єC, a methodology that is no longer used. "Dry heat" at high temperatures for longer periods of time (80є for 72 hours), vapor treatment, or heat treatment in solution ("pasteurization") appear to be efficacious in killing HIV. The solvent/detergent methods, as well as purification by affinity chromatography, also appear safe, vis-а-vis HIV infection.

Purity of Factor VIII

It is our opinion that for previously untreated and  infrequently treated hemophiliacs and for others who are free  of HIV infection, a concentrate that is pasteurized,  treated with solvent/detergent, or immunoaffinity  purified can be used. It should be virus free, but not  necessarily highly purified. For HIV-seropositive patients, highly  purified concentrates that are virally inactivated offer  theoretical benefits.

Highly Purified Concentrate

Concentrates purified using affinity chromatography (Monoclate, Hemophil M) have a final specific factor VIII activity of approximately 3,000 U/mg protein. MLID88264483  67 The purity is significantly higher than previously available products, and most extraneous human proteins have been removed. These products are efficacious and appear to be free of hepatitis viruses and HIV.

Since extraneous proteins such as immune complexes, aggregated immunoglobulins, and the killed viruses may be additionally suppressive to the immune system of a hemophiliac, concentrates containing only factor VIII and albumin may be less immunosuppressive. This would theoretically be beneficial not only to previously untransfused patients, but to HIV-seropositive patients as well.

An early nonrandomized study of 14 HIV-1-seropositive patients compared the initial seven patients on high-purity factor VIII concentrate with seven patients on intermediate-purity concentrate (specific activity 1–3 U/mg protein); in the first group CD4 cell counts stabilized over the 3-year course of the study, while the second group had a decrease in CD4 counts. MLID89229428  80 There are now three randomized prospective trials comparing the effects of intermediate-purity versus high-purity concentrates on the immune system of HIV-1 seropositive hemophiliacs. 81 Two studies, using immune affinity-purified factor VIII, have shown independently that HIV-1-seropositive hemophilia patients have a slower decline of CD4 cell counts on the very high-purity concentrate versus the intermediate-purity concentrate. 82,83 In a third study using a less high-purity concentrate, no difference between the two groups could be seen. MLID92351359  84 All studies were performed with small numbers of patients.