Perspectives in Disease Prevention and Health Promotion Safety of Therapeutic Products Used for Hemophilia Patients

On January 11, 1988, CDC sponsored a meeting in Atlanta, Georgia, for health-care providers and consultants concerned with hemophilia. The purpose of the meeting was to share current epidemiologic and clinical trial data, to address therapeutic issues, and to review the safety of products used for treating hemophilia patients. Participants included CDC attendees; consultants from the Food and Drug Administration, National Institutes of Health, Canadian Federal Centre for AIDS, and other public health agencies; and experts in hemophilia treatment or infectious diseases. This report summarizes information discussed at that meeting concerning the safety of therapeutic products used for treating hemophilia patients, specifically with regard to the transmission of human immunodeficiency virus (HIV) and non-A, non-B hepatitis (NANBH) viruses.

The treatment of hemophilia patients includes the use of manufactured blood components (factor concentrates) that are heat-treated or otherwise treated to reduce the risk of the transmission of infectious agents. The safety provided by various heat-treated products depends upon the heating temperature, the duration of heating, and the moisture content of the product during heating. Other factors unique to the production method for each concentrate may also affect the margin of safety, including the use and nature of stabilizers and other proteins present in the factor VIII preparation.

Human Immunodeficiency Virus

Pools of source plasma used for producing factor concentrates may contain units of plasma that were collected from donors who are infected with HIV but who are HIV-antibody-negative.* However, cases of HIV seroconversion associated with the use of heat-treated products are now rare. Since 1985, CDC has evaluated more than 75 reports, worldwide, of HIV seroconversion possibly associated with heat-treated products. Of these, 18 met CDC's operational criteria for a probable association with heat-treated factor concentrates (Table 1). Fourteen of the 18 patients had received products made by one manufacturing process: heat treatment in the lyophilized state (dry) at 60 /SDC for 30 hours. Nine additional reports are still under investigation.

Six seroconversions involved patients without any previous exposure to unheated products or to other blood components from HIV-untested donors; they included four of eight Canadian seroconverters, one of four U.S. patients, and one of six Europeans. The other 12 patients had received at least some earlier treatment with unheated concentrates. For some of these patients, the seroconversions--though considerably delayed--may have been attributable to previous therapy with unheated products.

A review of the products received by the 18 patients during the relevant period defined by the CDC operational criteria indicated that eight patients had received exclusively U.S.-manufactured factor VIII concentrates made from HIV-antibody-negative plasma. These concentrates had been heated in the dry state, in accordance with approved procedures, at 60 /SDC for either 24 hours or 30 hours.

One of the eight seroconversions occurred in a U.S. patient who had received, during the 10 months before seroconversion, five lots of one U.S. manufacturer's factor VIII concentrate, which had been heated for 24 hours. The patient was being monitored monthly for HIV antibody as part of an immune tolerance induction protocol for factor VIII inhibitor (3). The other seven patients whose seroconversions were associated with donor-tested concentrates were residents of Western Canada; their seroconversions were noted during testing in mid-1987.

The Canadian seroconverters had received products from at least two manufacturers. Some of the administered lots (from one manufacturer) had been made from plasma collected before HIV-antibody testing became available. These lots had been heated in the dry state at 68 /SDC for 72 hours. However, an epidemiologic investigation showed a strong statistical association between seroconversion and receipt of one or more of three lots of heat-treated (60 /SDC, 30 hours) factor VIII concentrates made by another company from one plasma pool (4). All plasma donations to this pool had been tested (ELISA) and found to be negative for HIV antibody. Retrospectively, 11 of the 4,200 donations contained in the pool were from seven donors for whom a subsequent donation was tested (ELISA) and reported to be positive; results of confirmatory tests are not available. These 11 donations were collected between 6 and 16 weeks after the antecedent donations to the pool (CDC, unpublished data). The three lots made from this pool and received by these Western Canadian seroconverters were voluntarily withdrawn from Canadian and U.S. markets by December 1987.

Hepatitis Viruses

Products heated in the lyophilized (dry) state at less than 80 /SDC, including one heated in an immiscible (N-heptane) solvent suspension, are at higher risk of transmitting NANBH viruses than are most of the newer products (described below). However, estimates of the risk of NANBH virus transmission associated with the newer products are less precise than estimates of the risk associated with older products. The small number of patients receiving newer products and studied in accordance with criteria such as those proposed by the International Committee on Thrombosis and Hemostasis (ICTH) (5) affects the precision. These criteria emphasize that detection of infection will be inaccurate if patients receiving new products have been exposed to NANBH virus through previously received blood products or if they are being tested for transient liver-function abnormalities at irregular or infrequent intervals. The ICTH criteria require that the patients be tested for alanine amino- transferase every 2 weeks for the first 4 months after therapy begins and at months 5 and 6.

The ICTH criteria were met by 26 patients studied prospectively while they were receiving products heated in aqueous solution (pasteurized); none contracted hepatitis (5). In another study of 28 patients who met these criteria but received a product heated in the presence of steam, four of 14 unvaccinated patients showed evidence of hepatitis B (HB) infection 8-24 weeks after the first infusion; none of the other 24 showed evidence of NANBH (6). In a prospective study of 32 British patients who received concentrates dry-heated at 80 /SDC for 72 hours, 13 met the ICTH criteria; none contracted hepatitis (J.K. Smith, 1988). The products used in the latter two studies, however, are not available in the United States.

In three other trials meeting the criteria, none of the patients contracted viral hepatitis during follow-up periods of 3-21 months of therapy. In the first two studies, 12-20 patients were treated, respectively, with concentrates exposed to solvent/detergent inactivation with tri-n-butyl phosphate (TNBP)/cholate (M. Horowitz, 1988) or with affinity column-purified products subjected to solvent/detergent inactivation by using TNBP/Triton X-100 (E. Gomperts, 1988). In the third study, 25 previously untreated patients were treated with affinity column-purified products subjected to dry-heat treatment at 60 /SDC for 30 hours (J. Lusher, 1988) (Table 2). Reported by: RS Remis, MD, MV O'Shaughnessy, PhD, Federal Centre for AIDS; Bureau of Biologics, Health Protection Br, Dept of National Health and Welfare; L Poffenroth, MD, Laboratory Centre for Disease Control; Canadian Red Cross Society, Ottawa; C Tsoukas, MD, McGill Univ; Canadian Hemophilia Society, Montreal; GH Growe, MD, Hemophilia Treatment Centre; M Schechter, MD, Univ of British Columbia, Vancouver, Canada. JK Smith, PhD, Churchill Hospital, Oxford, United Kingdom. PM Mannucci, MD, Milan, Italy. SL Dietrick, MD, JW Mosley, MD, Transfusion Safety Study, Univ of Southern California, Los Angeles; E Gomperts, MD, Children's Hospital of Los Angeles, California. JP Scott, MD, Milwaukee, Wisconsin. J Lusher, MD, Detroit, Michigan. K Hoots, MD, Houston, Texas. P Levine, MD, Worcester, Massachusetts. J Bouhasin, MD, St. Louis, Missouri. P Haas, PhD, A Brownstein, MPH, MSW, National Hemophilia Foundation; M Horowitz, PhD, New York, New York. Div of Blood and Blood Products, Center for Biologics Evaluation and Research, Food and Drug Administration. National Heart, Lung, and Blood Institute; National Cancer Institute, National Institutes of Health. Div of Host Factors, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Epidemiologic and laboratory data indicate that processed plasma derivatives currently available in North America, Europe, and Australia have a high degree of safety with regard to HIV transmission (7). The data on in-vitro inactivation of HIV purposely inoculated (in laboratory culture systems) into factor concentrates (8-10) must be supplemented by surveillance for seroconversions in recipients of factor concentrates. Seroconversion data provided to CDC come from a combination of prospective surveillance, ongoing cohort studies, and anecdotal reports. However, concerns regarding these sources of information include: 1) the completeness of surveillance systems, 2) the representativeness of specific cohort studies, and 3) the numbers of seronegative patients who receive each type of virus-inactivated product reportedly associated with seroconversions. Any seroconversion reported to CDC is thoroughly investigated to rule out the following: 1) a source of infection other than receipt of virus-inactivated concentrates, 2) flaws in the manufacturing processes, and 3) errors in donor screening or in HIV-antibody testing procedures.

Estimates for the annual rate of HIV seroconversions associated with donor- screened, virus-inactivated, clotting-factor products have been based on data from several sources, including the National Cancer Institute-coordinated multicenter study, the Transfusion Safety Study, the National Hemophilia Foundation (NHF)/Food and Drug Administration collaborative project, and CDC projects and surveillance. With the products now in use (Table 2), the annual rate appears to be less than one per 1,000. For example, of 1,489 seronegative, predominantly European patients followed through CDC-coordinated surveillance (11), none have seroconverted even though, collectively, they have received approximately 75 million units of American- or European-manufactured, virus-inactivated, donor-tested factor concentrates during the past 2 years (12). The proportion of products treated according to more rigorous procedures was higher for these 1,489 patients than the proportion typically received by U.S. and Canadian patients during the same period.

The inactivation of HB and NANBH viruses in factor concentrates has been less satisfactory than that of HIV. The potential for the newer types of factor concentrates to transmit hepatitis viruses is still being studied. Anecdotal cases are often more difficult to evaluate than prospectively studied patients. NANBH reportedly has been associated with concentrates heated in the lyophilized (dry) state at 60 /SDC for 72 hours (13), at 68 /SDC for 72 hours (14), and at 60 /SDC for 20 hours in a solvent suspension (15). Encouraging developments (16-19) include newer processes for reducing or eliminating contaminating viruses, for enhancing the purification of clotting factors from source plasma, for increasing viral inactivation, and for developing practical methods for manufacturing factor VIII through recombinant DNA techniques. Compared with older processes, most of the newer processes produce fewer units of factor activity per unit of source plasma collected. Pending procedural improvements, this less efficient recovery of clotting factor reduces the supply of available concentrates.

Presently, the only U.S. product for which dry heating is the primary method of virus inactivation is one heated at 68 /SDC for 72 hours. The average annual cost of therapy with the newer products represents a threefold increase compared with the cost of the formerly widely used materials treated with dry heat (17).

After reviewing the data presented at the CDC-sponsored meeting, the Medical and Scientific Advisory Committee of the NHF established and published recommendations for U.S. physicians treating hemophilia patients. The Committee addressed the following points regarding currently available concentrates (20): Summary of Recommendations for Physicians Treating Patients with Hemophilia National Hemophilia Foundation

1. General Recommendations The risks of withholding factor treatment far outweigh the risks of treatment, but health-care providers should educate patients to use appropriate doses of clotting factor to minimize overuse and to contain costs.

2. For Patients with Factor VIII Deficiency Desmopressin (DDAVP) should be used whenever possible by patients with mild or moderate hemophilia A. When feasible, an alternative to concentrates may be the use of cryoprecipitate prepared from one well-screened and repeatedly tested donor or from a small number of such donors.

1. Prevention of HIV. Products that are heated in aqueous solution (pasteurized), treated with solvent/detergent, purified with monoclonal antibody, heated in suspension in organic media, or dry heated at high temperatures for long periods are preferred. These products are at substantially reduced risk of transmitting HIV.

2. Prevention of Hepatitis. HB vaccination is essential for uninfected patients with hemophilia. Preliminary data suggest that products that are heated in aqueous solution (pasteurized), solvent/detergent treated, or monoclonal-antibody purified are at reduced risk of transmitting hepatitis viruses. C. For Patients with Factor IX Deficiency For patients with severe factor IX deficiency, NHF continues to recommend the use of virus-inactivated factor IX concentrate. For patients with mild or moderate factor IX deficiency, when feasible, an alternative would be the use of fresh, frozen plasma prepared from one well-screened and repeatedly tested donor or from a small number of such donors.

References

1. Simmonds P, Lainson FA, Cuthbert R, Steel CM, Peutherer JF, Ludlam CA. HIV antigen and antibody detection: variable responses to infection in the Edinburgh haemophiliac cohort. Br Med J (Clin Res) 1988;296:593-8.

2. Ranki A, Valle S-L, Krohn M, et al. Long latency precedes overt seroconversion in sexually transmitted human-immunodeficiency-virus infection. Lancet 1987;2:589-93.

3. Transfusion Safety Study Group. HIV transmission by anti-HIV donor-screened, heat-treated clotting factor concentrates (Abstract no. 7742). In: Final program and abstracts of the IV International Conference on AIDS. Book 2. Stockholm, Sweden: Swedish Ministry of Health and Social Affairs, National Bacteriological Laboratory, Karolinska Institute, World Health Organization, 1988:360.

4. Remis RS, Tsoukas C, Schechter MT, et al. Case-control study of a cluster of HIV seroconversions among hemophilia patients implicating heat-treated donor-screened factor concentrates (Abstract no. 7740). In: Final program and abstracts of the IV International Conference on AIDS. Book 2. Stockholm, Sweden: Swedish Ministry of Health and Social Affairs, National Bacteriological Laboratory, Karolinska Institute, World Health Organization, 1988:359.

5. Schimpf K, Mannucci PM, Kreutz W, et al. Absence of hepatitis after treatment with a pasteurized factor VIII concentrate in patients with hemophilia and no previous transfusions. N Engl J Med 1987;316:918-22. 6-20. Available upon request. Contact Dale N. Lawrence, M.D., Division of Host Factors, Center for Infectious Diseases, Mailstop D02, CDC, Atlanta, GA 30333. *The period between HIV exposure and seroconversion is usually less than 14 weeks (1); rarely, it may exceed 6 months (2).

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