International Notes Survey of Non-U.S. Hemophilia Treatment Centers for HIV Seroconversions Following Therapy With Heat-Treated Factor Concentrates

Until 3 years ago, non-heat-treated factor concentrates were used in treating congenital and acquired clotting factor deficiencies. At that time, heat-treated factor concentrates were introduced because the unheated concentrates had been epidemiologically linked with the exposure of large numbers of U.S. hemophilia patients to the human immunodeficiency virus (HIV) (1). There have now been a few reports of HIV seroconversion associated with heat-treated factor concentrates (2,3). Because several hemophilia treatment centers (HTCs) outside the United States began using heat-treated factor concentrates somewhat earlier, a sample of major non-U.S. HTCs identified by the U.S. National Hemophilia Foundation were contacted during November and December 1986 and asked to help estimate the continued risk of seroconversion among their patients deficient in factor VIII and factor IX. Patients with von Willebrand's disease and other clotting factor deficiencies were not included.

The directors of 13 HTCs located in western Europe, Canada, and Australia were asked to provide information concerning: 1) HIV antibody seroprevalence rates within their patient populations; 2) whether they were using, and when they had begun to use, heat-treated factor concentrate products (4-6); and 3) details regarding any HIV seroconversions occurring among their patients while receiving heat-treated factor concentrates. Most HTCs monitor the serologic status of their seronegative hemophilia A and B patients at approximately 3-month intervals and were confident of all these patients' serologic status as of late July 1986. Of the combined total of 2,370 hemophilia A patients and 434 hemophilia B patients served by the HTCs in this survey, over 1,300 were still seronegative when heat-treated factor concentrates became available. Approximately 50% of the seronegative patients were classified as severely deficient in factor VIII or factor IX; the remainder had either moderate or mild hemophilia*.

Of the 23 patients who had their first documented positive HIV antibody test after receiving heat-treated factor concentrate, 16 seroconverted within 6 months of last receiving untreated factor concentrates. The remaining seven individuals fell into three groups (Table 1). Group 1: Two patients were first found to be seropositive more than 6 months after starting to use heat-treated factor concentrate products (at 7 and 10 months, respectively). However, for both of these patients, the last seronegative test had taken place several months before their last treatment with unheated factor concentrates. Group 2: Two patients who were seronegative within the initial 6 months of heat-treated factor concentrate therapy (at 3 and 5 months, respectively) were not tested again until after the initial 6 months (at 8 and 10 months, respectively), at which time they were seropositive. Group 3: Three pediatric patients were seronegative at 8, 12, and 16 months after first receiving heat-treated factor VIII concentrate but had their first of many consistently seropositive tests at 10, 13, and 22 months after treatment, respectively.

The patients in Group 3 had no reported risk factors for HIV infection other than hemophilia and reportedly had received no other blood components during this time period. All three pediatric patients were severely deficient in factor VIII. One child, a 6-year-old, had received vials from four lots in the 10-month interim before seroconversion. He is presently asymptomatic and his reported T-cell values are normal; no HIV cultures have been attempted. The other two children, aged 4 and 13, had received large amounts of heat-treated factor VIII concentrates for extended periods either as therapy for an inhibitor or as routine care. The 4-year-old was found to be HIV culture positive in 1986 and now has AIDS. The 13-year-old had severe T-cell abnormalities by mid-1986 and now has lymphadenopathy and encephalopathy.

The many lots of concentrate received by each of the three patients in Group 3 had come from three different U.S. manufacturers. The plasma used by each of the U.S. manufacturers was collected before serologic screening of donors for HIV antibody became available. In addition, during the first 5 months of the 13-month interval before seroconversion, one of the three patients had also received extremely large amounts of heat-treated factor VIII concentrate prepared by a European manufacturer using a wet-heat process. The manufacturer had used unscreened plasma from U.S. donors.

The three patients who seroconverted (Group 3) represent 0.7% of the total 450 initially seronegative hemophilia A patients and 0.2% of the total 1,300 patients who were serologically monitored for 1 year after beginning to use unscreened, heat-treated factor. Since November 1985, no seroconversions have been observed among the patients included in the survey.

Although information on the transition to using unscreened, heat-treated factor in each HTC is readily available, the dates of subsequent transition to using donor-screened, heat-treated factor concentrate products by each HTC are not. One HTC reported beginning to use donor-screened, heat-treated factor therapy in August 1985; however, for most HTCs, this transition occurred between February and July 1986. No cases of seroconversion following the use of donor-screened, heat-treated products were identified through this survey.

Four percent (50) of the 1,300 seronegative patients in this survey were followed for 1 year while receiving donor-screened, heat-treated factor concentrates. Follow-up on the remainder is approaching 1 year. In early March 1987, supplemental information was obtained from eight of the 13 HTCs. These eight HTCs collectively have 60% of the seronegative patients; no further seroconversions have been found. Although over 600 patient-years of therapy with donor-screened product have elapsed without a recognized HIV seroconversion, the risk associated with unscreened, heat-treated product is so low that several more months of surveillance will be required before a statistically significantly further reduction of risk can be substantiated. Reported by M Blomback, MD, S Schulman, MD, Stockholm, E Berntorp, MD, Malmo, L Stigendal, MD, Goteborg, Sweden; EP Mauser-Bunschoten, MD, Bilthoven, Netherlands; T Lambert, MD, Paris, France; H Egli, MD, H Brackmann, MD, Bonn, Federal Republic of Germany; PM Mannucci, MD, Milan, Italy; PBA Kernoff, MD, London, P Jones, MD, Newcastle-upon-Tyne, CR Rizza, MD, Oxford, AL Bloom, MD, Cardiff, United Kingdom; MJ Inwood, MD, London, Ontario, Canada; KA Rickard, MD, Sydney, New South Wales, Australia; Div of Host Factors, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: Earlier published reports disclosed no seroconversions among selected hemophilia patients followed for up to 1 year after beginning therapy with heat-treated factor concentrates (7-10). However, during the past 12 months, published (2,3) and unpublished reports (personal communication, I Walker, MD, Hamilton, Ontario, Canada; FG Hill, MD, MRC Path, Birmingham, United Kingdom; G Mariani, MD, Rome, Italy) have described several hemophilia patients who had seroconverted after receipt of unscreened, heat-treated factor concentrates. In June 1986, one U.S. manufacturer (Armour Pharmaceutical Company) offered to exchange any remaining heat-treated factor VIII concentrates produced from plasma collected before the availability of a test for HIV antibody with the equivalent amount of antibody-screened product. Similar exchanges are now available through four other U.S. producers (Alpha Therapeutics, American Red Cross, Cutter Laboratories, Hyland Therapeutics).

The influence of previous exposure to allogeneic proteins and other infectious agents as well as the HIV inoculum size and differences in inoculum strain may alter the seroconversion intervals among hemophilia patients. For this reason, it is currently uncertain whether anecdotal reports that seroconversion in other risk groups occurs within 8 to 12 weeks after exposure can be generalized to hemophilia patients (11). One study suggests that the vast majority of hemophilia seroconversions would be detectable less than or equal to 26 weeks (12). The distribution of seroconversion latency periods for hemophilia patients is not yet known. Therefore, it is uncertain whether any of the three seroconversions in persons with a documented seronegative test greater than or equal to 6 months after beginning to use only heat-treated factor concentrates could be associated with the former source of exposure.

No cases of seroconversion among patients using only donor-screened, heat-treated products have been reported to date. With the exception of the HTC surveyed in Australia, less than a year has elapsed since most of the HTCs surveyed began administering donor-screened, heat-treated factor concentrates. Further longitudinal studies by several of the HTCs in this survey may substantiate the additional margin of safety provided by screening donated plasma for HIV antibody. Donor-screened, heat-treated factor concentrates remain the recommended therapy for patients requiring factor replacement.

References

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