Safety of Therapeutic Immune Globulin Preparations with Respect to Transmission of Human T-Lymphotropic Virus Type III/ Lymphadenopathy-Associated Virus Infection
Publication date: 04/11/1986
Table of Contents
POINT OF CONTACT FOR THIS DOCUMENT:
Immune globulins produced by plasma fractionation methods approved for use in the United States have not been implicated in the transmission of infectious agents. Nevertheless, because immune globulins manufactured before 1985 were derived from plasma of human donors who were not screened for antibody to human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), CDC and the U.S. Food and Drug Administration (FDA) have received inquiries concerning the safety of immune globulin (IG), hepatitis B immune globulin (HBIG), and intravenous immune globulin (IVIG). Current epidemiologic and laboratory evidence shows that these preparations carry no discernable risk of transmitting HTLV-III/LAV infection and that current indications for their clinical use should not be changed based on such concerns.
The IG, HBIG, IVIG, and other special immune globulins used in the United States are produced by several manufacturers using the Cohn-Oncley fractionation process (1,2). This process involves a series of precipitation steps performed in the cold with addition of varying concentrations of ethanol. Production lots of IG and IVIG are made from plasma pools from at least 1,000 donors; HBIG and other specific immune globulins (e.g., varicella-zoster IG) may be prepared from plasma pools from fewer donors.
Before 1985, donors were screened only for hepatitis B surface antigen but not by other tests for specific diagnosis of viral infections. Since April 1985, all donor units also have been screened for antibodies to HTLV-III/LAV, and all repeatedly reactive units have been discarded. Tests conducted at FDA and CDC have shown that as many as two-thirds of HBIG lots, as well as some lots of IG and IVIG, produced between 1982 and 1985 may have been positive for HTLV-III/LAV antibody. The question of safety arises out of concern that some immune globulins currently available were prepared from plasma pools that included units from donors who may have had HTLV-III/LAV viremia.
Several studies have shown that recipients of HBIG and IG, including recipients of lots known to be positive for antibody to HTLV-III/LAV, did not seroconvert to antibody to HTLV-III/LAV-positivity and have not developed signs and symptoms of acquired immunodeficiency syndrome (AIDS) or other illnesses suggesting HTLV-III/LAV infection.
Since August 1983, CDC has enrolled 938 individuals who have had parenteral or mucous-membrane exposures to blood or body fluids of AIDS patients in a prospective surveillance study. To date, 451 entrants have been followed and tested for HTLV-III/LAV antibody. Of these, 183 persons received IG and/or HBIG as prophylaxis against hepatitis B infection; 100 (55%) received only IG; 65 (36%) received only HBIG; and 18 (10%) received both. One of the 183 HBIG recipients is now positive for HTLV-III/LAV antibody, but no preexposure serum was available for this individual, and seropositivity may have predated the needlestick exposure and IG prophylaxis. Further, heterosexual transmission of HTLV-III/LAV infection in this individual cannot be ruled out. No documented seroconversions have occurred in any of the 183 health-care workers who received IG or HBIG. Studies have been reported of 16 subjects who received HBIG that was strongly positive for HTLV-III/LAV antibody (3). Each patient had been given one to five ampules. A total of 31 doses were administered to 16 individuals. Low levels of passively acquired HTLV-III/LAV antibody were detected shortly after injection, but reactivity did not persist. Six months after the last HBIG injection, none of the 16 individuals had antibody to HTLV-III/LAV.
In a study of prophylaxis against cytomegalovirus (CMV) infections among kidney-transplant patients, 16 patients received CMV-specific IVIG preparations subsequently found to contain HTLV-III/LAV antibody. After 10 months or longer of follow-up, none of the 16 recipients developed antibody or other evidence of HTLV-III/LAV infection.
In studies of a group of IVIG recipients, most of whom had idiopathic thrombocytopenia, none of 134 patients developed antibodies or other evidence of HTLV-III/LAV infection.
Information regarding past therapy with immune globulins is available from 10,227 of 17,115 AIDS patients reported to CDC. Three hundred fifty-eight (4%) reported receipt of an IG preparation. All but seven of these patients also were members of groups known to be at high risk for developing AIDS. The percentage of patients with no recognized risk factors for AIDS was not significantly different among those who received immune globulins (7/358 (2%)) than among those who did not (358/9,869 (4%)).
Scientists at FDA recently evaluated the basic fractionation processes (1,2) used for production of immune globulins to determine effectiveness of those procedures in eliminating HTLV-III/LAV infectivity (4). Six sequential steps in a typical process were evaluated. The study was designed so that efficiency of eliminating HTLV-III/LAV at each step was measured. The degree to which HTLV-III/LAV was reduced by partitioning or inactivation at individual steps ranged from 10))-1)) to more than 10))-4)) of in vitro infectious units (IVIU)/ml. The effectiveness of virus removal in the entire process by partitioning and inactivation was calculated to be greater than 1 x 10((15)) IVIU/ml.
Concentrations of infectious HTLV-III/LAV in plasma of infected persons have been estimated to be less than 100 IVIU/ml. Further, FDA scientists have shown that the geometric mean infectivity titer of plasma from 43 HTLV-III/LAV infected persons was 0.02 IVIU/ml (4). Thus, the margin of safety based on the removal of infectivity by the fractionation process is extremely high.
Scientists at CDC and FDA also cultured 38 lots of HBIG, IVIG, and IG, most of which contained HTLV-III/LAV antibody. HTLV-III/LAV was not recovered from any lot tested.
Reported by J Bossell, MD, Cornell University, New York City; Central Laboratories Swiss Red Cross Blood Transfusion Svc, Berne, Switzerland; Immuno A.G., Vienna, Austria; KabiVitrum AB, Stockholm, Sweden; Massachusetts Public Health Biologics Laboratories, Boston, Massachusetts; Miles Laboratories, Inc., Berkeley, Travenol Laboratories, Inc., Glendale, California; Center for Drugs and Biologics, U.S. Food and Drug Administration; Center for Infectious Diseases, CDC.
Editorial Note:The laboratory and epidemiologic studies referred to have shown that concern about HTLV-III/LAV infection associated with the use of immune globulins available in the United States is not warranted. Strategies for using immune globulins recommended by the Immunization Practices Advisory Committee should be followed (5). Recently, concern has been expressed that patients who received IG prepared from plasma of donors not screened for HTLV-III/LAV antibody may have a passively acquired false-positive reaction for antibody (6). Passively acquired HTLV-III/LAV antibody from HBIG known to contain high levels of antibody has been reported (3). Based on the estimated half-life of globulins in plasma, it can be calculated that passively acquired antibodies might be detected in sera of recipients for as long as 6 months after administration of immune globulins. It is important to recognize this possibility when attempting to determine the significance of HTLV-III/LAV antibody in a person who has recently received immune globulins, especially HBIG.