3
History of the Controversy

INTRODUCTION

The events marking the emergence of HIV in the United States and its transmission through blood and blood products are best understood in four periods. (1) Through the end of 1982, people were struggling to understand an emerging disease and characterize the risk of infection. (2) In early 1983 official meetings took place and public and private decisions established the blood industry's early response to AIDS. (3) Meetings and other occasions for decisionmaking from mid-1983 through the end of 1983 provided many opportunities for blood banks, blood product manufacturers, regulatory organizations, and other agencies to reconsider the decisions of early 1983. (4) During 1982-1985, research on AIDS led to isolation of the virus and the development of a screening test. Concurrently, research efforts related to viral inactivation of the antihemophilic factor (AHF) concentrate, underway since the 1970s, were accelerated and completed. Table 3.1 provides a summary chronology of critical events.

The early 1980s were an unsettled time for the individuals and organizations responsible for blood safety in the United States. The public's confidence in government and public institutions generally was quickly eroding, and its hostility towards the involvement of government agencies in social matters was growing. The new Republican presidential administration had strong sentiments against government regulations, even those that addressed public health and safety.

In addition, the emergence of AIDS challenged every aspect of the country's public health infrastructure. It brought new focus to the importance of infectious diseases at a time when the attention and resources of both physicians and



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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking 3 History of the Controversy INTRODUCTION The events marking the emergence of HIV in the United States and its transmission through blood and blood products are best understood in four periods. (1) Through the end of 1982, people were struggling to understand an emerging disease and characterize the risk of infection. (2) In early 1983 official meetings took place and public and private decisions established the blood industry's early response to AIDS. (3) Meetings and other occasions for decisionmaking from mid-1983 through the end of 1983 provided many opportunities for blood banks, blood product manufacturers, regulatory organizations, and other agencies to reconsider the decisions of early 1983. (4) During 1982-1985, research on AIDS led to isolation of the virus and the development of a screening test. Concurrently, research efforts related to viral inactivation of the antihemophilic factor (AHF) concentrate, underway since the 1970s, were accelerated and completed. Table 3.1 provides a summary chronology of critical events. The early 1980s were an unsettled time for the individuals and organizations responsible for blood safety in the United States. The public's confidence in government and public institutions generally was quickly eroding, and its hostility towards the involvement of government agencies in social matters was growing. The new Republican presidential administration had strong sentiments against government regulations, even those that addressed public health and safety. In addition, the emergence of AIDS challenged every aspect of the country's public health infrastructure. It brought new focus to the importance of infectious diseases at a time when the attention and resources of both physicians and

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 3.1 Chronology of Critical Events Date Event July 16, 1982 CDC MMWR reports immune-suppressive disorder identified in three hemophiliac patients. July 16, 1982 FDA's Bureau of Biologic meeting to discuss opportunistic infections in hemophiliacs. July 16, 1982 Public Health Service Working Group on Opportunistic Infections in Hemophiliacs meeting to exchange information about the three cases of AIDS in hemophilia patients. July 27, 1982 Working Group on Opportunistic Infections in Hemophiliacs second meeting to determine if other groups with acquired immunodeficiency showed similar etiology and if blood products were risk factors for AIDS. December 10, 1982 CDC MMWR reports four additional cases in hemophiliacs, one suspect case in an infant who had received a blood transfusion. January 4, 1983 CDC public meeting to identify opportunities to prevent AIDS. March 4, 1983 Assistant Secretary for Health promulgates the first official PHS recommendations on the prevention of AIDS, including recommendations to avoid sexual contact with persons known or suspected of having AIDS and the increased probability of developing AIDS by having multiple sex partners. March 24, 1983 FDA notification of all establishments collecting source plasma and human blood for transfusion and manufacturers of plasma derivatives of steps to be taken to decrease the risk of blood or plasma donation by persons who might be at increased risk of transmitting AIDS. May 11, 1983 Baxter Healthcare recall of a lot of AHF concentrate when it discovers that the product was manufactured from pools containing plasma from an individual subsequently diagnosed as having AIDS. July 19, 1983 FDA Blood Products Advisory Committee (BPAC) meeting to discuss the criteria for deciding to withdraw lots of AHF concentrate.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Date Event December 15, 1983 FDA's BPAC meeting to consider implementation of the hepatitis B core antibody test as a possible surrogate screening test for HIV. April 1984 National Cancer Institute scientists report they have isolated a virus that causes AIDS. October 26, 1984 CDC MMWR reports information on the viral inactivation of HIV through the use of heat treatment. December 1984 First tests for detecting HIV developed and license application submitted to FDA. March 1985 FDA grants two licenses for commercial use of the HIV tests, and notifies all blood facilities of the test's availability and schedules a workshop on its use. public health officials was turning elsewhere. The AIDS epidemic called for emergency, focused, biomedical and behavioral research in a system based on investigator-initiated basic research. The exploding number of cases called for additional resources and new models of health care in a system increasingly concerned about costs. AIDS caused the nation to take note of homosexuality and drug use, which were easily avoided before these issues became such obvious matters of public health, and AIDS required clinicians and public health officials to address matters of personal behavior that had been heretofore taboo. Personnel changes at the highest levels of the Public Health Service may have influenced the federal government's response to AIDS, and to concerns about the safety of the blood supply. Between 1982 and 1986, the position of director of the Centers for Disease Control (CDC) and NIH, administrator of the FDA, and Assistant Secretary for Health all changed hands, and there were substantial intervals during which these positions were filled on an acting basis. Finally, the Committee was also struck by the way in which one historical event seems to have influenced individuals and organizational conduct and interpretations of the evidence about the HIV epidemic. This episode was the federal government's experience with the swine flu epidemic. In early 1976, at the urging of officials of the CDC, the federal government (with the visible participation of President Ford) engaged in a crash program to immunize every American against a disease that never materialized. Millions were vaccinated, however, and some died of complications that were attributed to the vaccine (Neustadt and Fineberg 1978). This episode seems simultaneously to have

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking reduced the self-confidence of the CDC and increased the skepticism with which other public health service organizations regarded its warnings. THE RISK OF AIDS From the introduction of HIV into the United States through the end of 1982, most efforts were oriented to understanding an emerging disease and characterizing the risk of infection in a variety of settings. Following standard epidemiologic procedures, CDC epidemiologists and scientists, in collaboration with others, analyzed the characteristic manifestations of the new disease—opportunistic infections such as Pneumocystis carinii pneumonia (PCP) and Kaposi's sarcoma—and identified groups at high risk for the disease. Starting with the identification of 26 homosexual men with the opportunistic infections in June 1981 (see below), the CDC's MMWR became the source for reports of the epidemic. (Table 3.2 summarizes the information on the number of AIDS cases and the evolving knowledge base as reported in the CDC's Morbidity and Mortality Weekly Report [MMWR]). Kaposi's Sarcoma and PCP in Homosexual Men The first cases of the disease that would come to be known as AIDS came to light as early as October 1980, when Kaposi's sarcoma (KS) was diagnosed in several young homosexual men in Los Angeles. These and similar cases (21 in all) were reported in the following year (CDC, MMWR, June 5, 1981). Shortly thereafter, on July 3, 1981, the CDC reported five new cases of PCP in homosexual men in New York City, Los Angeles, and San Francisco (CDC, MMWR, July 3, 1981). Both KS and PCP are opportunistic infections that occur in individuals with severely weakened immune systems. In addition to reported cases of these diseases, there was an unusual increase in requests made to the CDC for a drug called pentamidine that is used for the treatment of PCP. At the time, this drug could only be dispensed through a physician's request to the CDC (Curran, Evatt interviews). With the possible outbreak of a new infectious disease in the United States coming to the attention of public health officials, the CDC established a task force in July 1981 to monitor the cases of opportunistic infections, to investigate additional cases, to formalize a definition of the disease, and to design a case/control study to examine the prevalence and epidemiology of the disease. The task force was headed by James Curran, chief of CDC's Venereal Disease Control Division (Curran, Foege interviews).

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Table 3.2 Reported Cases of Opportunistic Infections and AIDS, Risk Groups Identified, and Evolving Knowledge Base: June 1981 Through May 1985 Date No. of Cases (cumulative) Risk Groups Fatality Rate (%) Knowledge of Disease and Modes of Transmission June 5, 1981 5 5 Homosexual men 40 ''The occurrence of pneumocystis in these 5 previously healthy individuals without a clinically apparent underlying immunodeficiency is unusual." (p. 1) July 3, 1981 26 26 Homosexual men 31 "The occurrence of this number of KS cases during a 30-month period among young, homosexual men is considered highly unusual. No previous association between KS and sexual preference has been reported." (p. 3) August 28, 1981 108 108 Homosexual men 40 "The apparent clustering of both Pneumocystis carinii pneumonia and KS among homosexual men suggests a common underlying factor. Both diseases have been associated with host immunosuppression, and studies in progress are showing immunosuppression in some of these cases." (p. 5) June 11, 1982 355 281 Homosexual and bisexual men 15 Heterosexual men 6 Heterosexual women 20 Men, unknown risk 33 IVDUs 43 "A laboratory and interview study of heterosexual patients with diagnosed KS, PCP or other OI is in progress to determine whether their cellular immune function, results of virologic studies, medical history, sexual practices, drug use, and life-style are similar to those of homosexual patients." (p. 9) July 9, 1982   (34 Haitians)* 50 "The in vitro immunologic findings and the high mortality rate (nearly 50%) for these patients are similar to the pattern recently described among homosexual males and IV drug abusers." (p. 13)

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Date No. of Cases (cumulative) Risk Groups Fatality Rate (%) Knowledge of Disease and Modes of Transmission July 16, 1982   (3 Hemophiliacs) 67 "Although the cause of the severe immune dysfunction is unknown, the occurrence among the three hemophiliac cases suggests the possible transmission of an agent through blood products." (p. 15) September 24, 1982 593 445 Homosexual men 77 IVDUs 36 Haitians 3 Hemophiliacs 32 Unknown risk 41 "CDC defines a case of AIDS as a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in a person with no known cause for diminished resistance to that disease.…; The eventual case-mortality rate of AIDS, a few years after diagnosis, may be far greater than the 41% overall case-mortality rate noted.…" (p. 18); "… The [case-mortality] rate exceeds 60% for cases diagnosed over a year ago." (p. 17) December 10, 1982   (1 Infant)   "If the platelet transfusion contained an etiologic agent for AIDS, one must assume that the agent can be present in the blood of a donor before onset of a symptomatic illness and that the incubation period for such illness can be relatively long." (p. 27) December 17, 1982   (4 Infants)   "Transmission of an 'AIDS agent' from mother to child, either in utero or shortly after birth, could account for the early onset of immunodeficiency in these infants." (p. 29) January 7, 1983   (16 Prison inmates)   "Since male homosexuals and IV drug abusers are known to be at increased risk for AIDS, the occurrence of AID among imprisoned members of these groups might have been anticipated." (p. 32)

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking March 4, 1983 1,200 No breakdown given Not stated "Over 450 persons have died from AIDS, and the case-fatality rate exceeds 60% for cases first diagnosed over 1 year previously. …" (p. 32)         "… The California cluster investigation and other epidemiologic findings suggest a 'latent period' of several months to 2 years between exposure and recognizable clinical illness and imply that transmissibility may precede recognizable illness." (p. 33) June 24, 1983 1,641 1,165 Homosexual men 279 IVDUs 16 Hemophiliacs 82 Haitians 98 Unknown risk 39 "The cause of AIDS is unknown, but it seems most likely to be caused by an agent transmitted by intimate sexual contact, through contaminated needles, or, less commonly, by percutaneous inoculation of infectious blood or blood products. No evidence suggests transmission of AIDS by airborne spread." (p. 38) August 5, 1983 1,972 No breakdown given 38 "… The ratio of male to female patients (14:1) has been almost constant over the last year." (p. 41) September 9, 1983 2,259 1,604 Homosexual men 384 IVDUs 113 Haitians 26 Hemophiliacs 26 Heterosexual women 26 Transfusion 80 Unknown risk 41 "The occurrence of AIDS cases among homosexual men, IV drug abusers, persons with hemophilia, sexual partners of members of these groups, and recipients of blood transfusions is consistent with the hypothesis that AIDS is caused by an agent that is transmitted sexually, or, less commonly, through contaminated needles or blood." (p. 45) January 6, 1984 3,000 2,130 Homosexual men 510 IVDUs 31 Transfusion 42 Pediatric 287 Unknown risk 43 "The 31 patients with 'transfusion-associated' AIDS include 18 men and 13 women who have no other known risk factor for AIDS and were transfused with blood or blood components within 5 years of their onsets of illness. These patients received transfusions between April 1978 and May 1983." (p. 50)

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Date No. of Cases (cumulative) Risk Groups Fatality Rate (%) Knowledge of Disease and Modes of Transmission June 22, 1984 4,918 3,541 Homosexual men 836 IVDUs 197 Haitians 49 Hemophiliacs 49 Heterosexual women 49 Transfusion 197 Unknown risk 45% "… More than 76% of patients diagnosed before July 1982 are dead." (p. 60) October 26, 1984   52 Hemophiliacs 58 "The possibility of blood or blood products being vehicles for AIDS transmission to hemophilia patients has been supported by the finding of risk of acquisition of AIDS for intravenous drug abusers and, subsequently, by reports of transfusion-associated AIDS cases. …" (p. 66)         "Although the total number of hemophilia patients who have thus far developed clinical manifestations of AIDS is small relative to other AIDS risk groups, incidence rates for this group are high (3.6 cases/1,000 hemophilia A patients and 0.6 cases/1,000 hemophilia B patients)." (p. 67) November 30, 1984 6,993 5,038 Homosexual men 1,190 IVDUs 249 Haitians 52 Hemophiliacs 54 Heterosexual women 93 Transfusion 263 Unknown/adult 54 Unknown/children 48 "Eighty-one adults and 12 children with transfusion-associated AIDS (TA-AIDS) have no other risk factors and were transfused with blood or blood components within 5 years of illness onset. TA-AIDS patients received blood from one to 75 donors (median 16 donors); interval from transfusion to diagnosis was 4 months to 62 months. …" (p. 72)

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking May 10, 1985 10,000 7,261 Homosexual men 1,685 IVDUs 71 Hemophiliacs 81 Heterosexual women 149 Transfusion 672 Unknown risk 81 Unknown/children 49 "Since 1981, the proportion of AIDS cases in transfusion recipients has increased significantly. …" (p. 91) "Because the time from infection with HTLV-III/LAV to onset of AIDS may be several years, persons exposed to the virus through transfusion before institution of the self-deferral guidelines for blood donors in 1983 and screening of blood for HTLV-III/LAV antibody in 1985 may remain at risk of AIDS." (p. 93) NOTE: CDC = Centers for Disease Control; HTLV-III = human T-cell lymphotropic virus, type III; IV = intravenous; IVDUs = intravenous drug users; KS = Kaposi's sarcoma; LAV = lymphadenopathy-associated virus; OI = opportunistic infection; and PCP = Pneumocystis carinii pneumonia. * Cases in parentheses indicate the occurrence of the disease in a new risk group. SOURCE: Centers for Disease Control. Reports on AIDS Published in the Morbidity and Mortality Weekly Report, June 1981 Through May 1986. Washington, D.C.: U.S. Government Printing Office, 1987.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Because the early cases appeared in the gay community, the new disease was first called "gay-related immunodeficiency disease" (GRID). Many scientists and public health officials initially hypothesized that behavioral elements of the homosexual lifestyle (multiple sex partners, for example) were the cause. Another early theory was that "poppers" (amyl nitrates), drugs frequently used by some gay men to enhance sexual pleasure, were the cause (CDC, MMWR, June 18, 1982). Opportunistic Infections Among Heterosexual Intravenous (IV) Drug Users and Haitian Immigrants In June 1982, the CDC reported 355 cases of opportunistic infections, with an increase in the number of heterosexual patients, particularly among IV drug users. According to the report, "a laboratory and interview study of the heterosexual patients [was] in progress to determine whether their cellular immune function, results of virologic studies, medical history, sexual practices, drug use, and lifestyle [were] similar to those of homosexual patients" (CDC, MMWR, June 11, 1982). One month later, the CDC reported 34 cases of opportunistic infections in Haitian patients. The pattern of infections was "similar to the pattern recently described among homosexual males and IV drug users" (CDC, MMWR, July 9, 1982). On July 16, 1982, the CDC reported the first three cases of PCP among individuals with hemophilia. All three were reported to be heterosexual males. At this time, the CDC postulated that the immune dysfunction symptoms were transmitted through blood and blood products: The clinical and immunologic features these three patients share are strikingly similar to those recently observed among certain individuals from the following groups: homosexual males, heterosexual IV drug users, and Haitians. Although the cause of the severe immune dysfunction is unknown, the occurrence among the three hemophiliac cases suggests the possible transmission of an agent through blood products [CDC, MMWR, July 16, 1982]. On the same date, the FDA's Bureau of Biologics convened a meeting to discuss opportunistic infections in hemophiliacs. The meeting included representatives from the CDC, the National Hemophilia Foundation (NHF), the American Red Cross, the American Blood Resources Association (ABRA) (who represented the plasma fractionators), and the National Institutes of Health (NIH). The CDC presented an update of the epidemic of opportunistic infections, noting that the one common thread among all groups affected (i.e., homosexual men, IV drug users, Haitians, and individuals with hemophilia) was the presence of markers for hepatitis in more than 90 percent of each group (Hansen 1982).

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking In conjunction with the first cases among hemophiliacs, CDC Director William Foege asked public health officials to inform physicians caring for patients with hemophilia about the three cases of PCP among patients with hemophilia. He wrote to inform state and territorial health officers, industry representatives, the Assistant Secretary for Health, the FDA Commissioner, the Director of NIH, and all CDC regional offices that the CDC was conducting surveillance of the new disease and gathering additional information to determine the significance of the incidence reports. In addition, he asked physicians to immediately report cases of opportunistic infections or suspected acquired immune deficiency through state health departments to the CDC (Foege 1982a). At the July 16, 1982, PHS meeting, a Committee on Opportunistic Infections in Patients with Hemophilia was established to exchange information about the cases, to characterize their similarity to other risk groups, and to conduct surveillance of both hemophilia cases and antihemophilic factor (AHF) concentrate (Public Health Service July 1982). The committee held its second meeting on July 27, 1982; representatives from the PHS, CDC, FDA, NHF, ABRA and NIH attended. The committee, chaired by Dr. Foege, adopted the term "acquired immunodeficiency syndrome" (AIDS), and decided to focus on two goals: to determine if the underlying immunodeficiency seen in hemophiliacs had the same etiology as in other groups with acquired immunodeficiency, and to determine if certain blood products were risk factors for AIDS (Foege 1982b) (see further discussion below). By September 1982, 593 cases of AIDS had been reported to the CDC. Of these cases, 445 of the patients were homosexual men, 77 were IV drug users, 36 were Haitians, 3 were hemophiliacs, and 32 had no defined risk; 41 percent had died (CDC, MMWR, September, 24, 1982). In an editorial note, the CDC defined AIDS as: … a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring in persons with no known cause for diminished resistance to that disease. Such diseases include Kaposi's Sarcoma (KS), Pneumocystis Carinii Pneumonia (PCP), and other serious opportunistic infections. … This case definition does not include the full spectrum of AIDS manifestations, which range[s] from absence of symptoms, to specific diseases that are insufficiently predictive of cellular immune deficiency to be included in incidence monitoring [CDC, MMWR, September 24, 1982]. The reference to an "absence of symptoms" suggests that as early as the autumn of 1982 researchers were beginning to establish that the new disease might have had an asymptomatic incubation period.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking an infectious agent transmitted sexually or through exposure to blood or blood products (CDC, MMWR, January 7, 1983). Summary By January 1983, epidemiological evidence from CDC's investigations strongly suggested that blood and blood products transmitted AIDS and that the disease could be transmitted through intimate sexual contact. The evidence that the AIDS agent was blood-borne was the result of two findings. First, AIDS was occurring in transfusion recipients who did not belong to any known high-risk group and in individuals with hemophilia who had received AHF concentrate. Second, the epidemiological patterns of AIDS was similar to that of hepatitis B, another blood-borne disease. IMMEDIATE RESPONSES TO EVIDENCE OF BLOOD-BORNE AIDS TRANSMISSION In the first months of 1983, the epidemiologic evidence that the AIDS agent was blood-borne led to official meetings and public and private decisions that set the pattern of the blood industry's response to AIDS, starting with a public meeting convened by the CDC in Atlanta on January 4, 1983. Later that month, the leading blood bank organizations and, separately, the National Hemophilia Foundation (NHF) and the plasma fractionation industry issued statements. In March 1983, the Assistant Secretary for Health promulgated the first official PHS recommendations for preventing AIDS, and the FDA codified safe practices for plasma collection. The CDC's Public Meeting The purpose of the public meeting on January 4, 1983, was to identify opportunities to prevent AIDS. The CDC's objectives for the meeting were to tell the blood services community about the evidence they had gathered; to enlist the help of other PHS agencies, especially the FDA; and to formulate recommendations for the prevention of AIDS. According to data presented by the CDC, the manifestations of AIDS appeared 4–17 months after transmission of infection (Foege 1983). The meeting produced a great deal of debate but no consensus on specific action (Bove, Curran, Evatt, Francis, Foege, McAuley, Sandler interviews). Donald Francis, assistant director for medical science of the Division of Virology at the CDC, recommended that the blood banks question donors

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking directly about their sexual behavior and run blood donations through a series of surrogate tests (the use of nonspecific laboratory markers), including a test for the hepatitis B core antibody, which showed an 88 percent correlation with patients who had AIDS (Foege 1983; Evatt, Foege, Francis interviews). Some meeting participants opposed this recommendation because of the cost of the tests and other reasons (see Chapter 5). Gay activist groups objected to screening measures, claiming that they were discriminatory toward their members. Many meeting participants were not convinced by the evidence that AIDS was transmitted by blood or blood products (Bove, Curran, Evatt, Foege, Pindyck interviews). Dennis Donohue, Director of the FDA's Division of Blood and Blood Products, stated that research on processes for inactivating viruses in blood products was under way. Oscar Ratnoff, a prominent hemophilia specialist, stated there was enough information about the danger of AHF concentrate to stop using it in favor of cryoprecipitate (Johnson 1983). Dr. Francis tried to establish a time frame for action or a minimum number of transfusion-related AIDS cases after which the FDA's Blood Products Advisory Committee would agree to take action to implement donor screening policies. The Blood Bank Community's Statement A week after the Atlanta meeting in January 1983, the American Association of Blood Banks, the Council of Community Blood Centers, and the American Red Cross issued a joint statement that ''direct or indirect questions about a donor's sexual preference are inappropriate." The statement recommended questions to detect possible AIDS exposure (i.e., a donor health history), but did not recommend any laboratory screening tests. At this time, the PHS agencies had not completed their own recommendations (Donohue, Foege interviews), and the FDA did not issue any recommendations. Position of the National Hemophilia Foundation The next day, the Medical and Scientific Advisory Council (MASAC) of the NHF met and recommended that cryoprecipitate (a blood product produced from the serum of a small number of donors), rather than AHF concentrate, be used for newborn infants and children under four, newly diagnosed patients, and those with mild hemophilia. According to the report, there was insufficient evidence to develop specific recommendations about blood product use (i.e., AHF concentrate or cryoprecipitate) in the treatment of severe hemophilia. Additional recommendations included delaying all elective surgical procedures and the use of a synthetic substance, DDAVP (desmopressin acetate), to elevate

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Factor VIII levels in patients with mild or moderate hemophilia A. MASAC also stated that it was important to screen and exclude all high-risk donors from the blood and plasma supply for the production of blood products used for treatment of hemophilia. The NHF directed their recommendations to treating physicians, regional and community blood collection centers, and plasma fractionators; in some instances, the NHF also told their chapters to distribute the information to the chapter members. Position of the Plasma Fractionation Industry On January 28, 1983, the American Blood Resources Association (ABRA), which represents the plasma industry, issued recommendations about donor screening and deferral to reduce the risk of AIDS. The recommendations focused on donor education, donor screening, and surrogate laboratory testing. The ABRA recommended issuing a brochure that would describe AIDS, tell how individuals in high-risk groups could reduce their risk of exposure, and discourage high-risk persons from donating. The ABRA also recommended that prospective donors, prior to donating, be required to read the information about AIDS and indicate that they were not members of a high-risk group. Individuals who identified themselves as members of high-risk groups or were unwilling to reply would be excluded from donating plasma (donor deferral). The ABRA recommended against large-scale surrogate testing of donated blood until ABRA had evaluated its feasibility. On December 17, 1982, prior to ABRA's recommendations, Alpha Therapeutics, one of the four commercial manufacturers of AHF concentrate, had begun excluding all plasma donors who identified themselves as having been in Haiti, having used IV drugs, or if male, having had sexual contact with another man. Alpha had notified all its affiliates that this policy was effective immediately and that unscreened plasma should no longer be sent to Alpha. By the early part of 1983, each of the companies had in place donor education and screening programs requesting members of high-risk groups to identify themselves and refrain from donating plasma (FDA, BPAC, 1983b). Federal Recommendations on the Prevention of AIDS In a March 4, 1983 report, the PHS promulgated its first official recommendations on the prevention of AIDS. The recommendations stated that the evidence suggested the disease was a severe disorder of immune regulation caused by a transmissible agent (CDC, MMWR, March 4, 1983). As evidence, the report indicated that the transmission routes of AIDS paralleled that of hepatitis B and that blood or blood products appeared to be responsible for

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking transmitting AIDS to hemophilia patients. Suspected cases of transfusion-associated AIDS had been reported, but none were yet proven. According to the report, the evidence suggested a latency period of two months to two years between exposure and onset of symptoms. Brandt noted that a significant proportion of individuals in high-risk groups had no symptoms of AIDS, suggesting that the pool of persons potentially capable of transmitting an AIDS agent may be considerably larger than the known number of AIDS cases. The PHS made the following recommendations for preventing AIDS transmission: Sexual contact should be avoided with persons known to have or suspected of having AIDS. Avoid sex with multiple partners or those who may have multiple partners. Members of groups at increased risk for AIDS should not donate plasma and/or blood products. Studies be conducted to evaluate screening procedures for their effectiveness in identifying and excluding plasma and blood with a high probability of transmitting AIDS—including lab tests and physical exams. Physicians should adhere strictly to medical indications for transfusions. Work should continue toward development of safer blood products for use by hemophilia patients. About three weeks later, on March 24, 1983, the FDA notified all establishments collecting source plasma and human blood for transfusion and all manufacturers of plasma derivatives of steps to be taken to decrease the risk of blood or plasma donation by persons who might be at increased risk of transmitting AIDS. These steps included implementing standard operating procedures to quarantine and dispose of any products collected from donors known or suspected of having AIDS. The FDA also advised the blood and plasma collection facilities to establish educational programs to inform persons at increased risk for AIDS that they should stop donating and to train personnel who screen donors to recognize the early signs of AIDS. The FDA also announced that it had approved a new heat treatment to inactivate viruses in AHF concentrate. The treatment was purported to help protect individuals with hemophilia from hepatitis B, and perhaps from AIDS (Petricciani 1984). Summary and Comment Government and private agencies identified, considered, and in some cases adopted strategies for dealing with the risk of transmitting AIDS through blood and blood products. The recommended safety measures were limited in scope,

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking which reflected a lack of consensus about the nature and magnitude of the threat (especially among physicians and public health officials who were unprepared for the unique epidemiological pattern of AIDS), and uncertainty about the costs, risks, and benefits of the proposed control strategies. RECONSIDERING THE EVIDENCE: FURTHER ATTEMPTS TO FORMULATE POLICIES In the interval between the decisions of early 1983 and discovery of the virus that causes AIDS in early 1984, public health and blood industry officials became more certain that AIDS was a blood-borne disease as the number of reported cases of AIDS among hemophiliacs and transfused patients increased. As their knowledge grew, these officials had to decide about recall of contaminated blood products and possible implementation of a surrogate test for HIV. Major opportunities to reconsider the policies of early 1983 arose at meetings of the FDA's Blood Product Advisory Committee (BPAC) in July and December 1983. On May 11, 1983, Hyland Therapeutics recalled a lot of AHF concentrate when it discovered that the product had been manufactured from pools containing plasma from an individual subsequently diagnosed as having AIDS. The NHF issued a medical bulletin and a chapter advisory in conjunction with the recall, stating: It is not the role of the NHF to judge the appropriateness of corporate decisions made by individual pharmaceutical companies. However, we urge that patients and treaters recognize the need for careful evaluation of blood products and note that such a recall action should not cause anxiety or changes in treatment programs. … The NHF recommends that patients maintain the use of concentrates or cryoprecipitate as prescribed by their physicians. If you have any questions regarding this matter, they should be directed to your treating physician and/or the NHF [NHF, 1983]. On June 22, 1983, the American Association of Blood Banks, the Council of Community Blood Centers, and the American Red Cross issued a second joint statement, stating that "it appears at this time that the risk of possible transfusion-associated AIDS is on the order of one case per million patients transfused. There is a risk that widespread attempts to direct donations, while not increasing the safety of transfusions, will seriously disrupt the nation's blood donor system." Directed donation is the process by which the patient in need of blood or blood components identifies persons (usually friends and family) to provide the needed units rather than utilizing blood from the hospital blood supply. The directed donation programs were an administrative and logistical

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking burden for blood banks, and blood bank officials were not convinced that these programs significantly increased the safety of the recipient (Bove, Perkins, Pindyck, Sandler interviews). The joint statement thus strongly recommended against conducting directed donation programs. On July 19, 1983, the FDA's Blood Products Advisory Committee (BPAC) discussed the criteria for deciding to withdraw lots of AHF concentrate, and recommended product withdrawal only if there was good evidence that plasma from a donor with AIDS had been present in the pooled plasma from which the lot had been manufactured. The Pharmaceutical Manufacturers Association expressed concern about the impact of a recall on the supply of AHF concentrate. The NHF's Medical and Scientific Advisory Council (MASAC) had stated that recall of a product should be automatic if a donor was either suspected of having or diagnosed with AIDS. Dr. Louis Aledort, medical director of the NHF, stated his personal view that the NHF/MASAC recommendation would adversely impact the continued supply of AHF concentrate (Aledort, Hoyer interviews). Because of concern about maintaining an adequate supply of AHF concentrate, and skepticism that blood products were a vector for transmitting AIDS, the BPAC advised the FDA to recommend a case-by-case decision rather than automatic withdrawal for each lot that included plasma from an individual who had AIDS or was suspected of having AIDS (see Chapter 6 for further discussion). On December 15–16, 1983, the BPAC met to consider all possible options of surrogate marker tests. The discussion focused on the implementation of the hepatitis B core antibody (anti-HBc) test as a possible surrogate screening test for HIV. Arguments against using the test in blood banks included (a) it would eliminate too many noninfected donors and would therefore threaten the adequacy of the blood supply; (b) the test was not useful in differentiating high-risk homosexuals (e.g., those with multiple partners) from other male homosexual donors; and (c) the prevalence of anti-HBc antibodies was high among certain ethnic groups (e.g., Asians) and would cause deferral of these donors. The BPAC did not recommend surrogate testing, but agreed with a suggestion to create an industry task force to consider the logistics of testing plasma for anti-HBc as a surrogate for AIDS. Summary and Comment Blood safety policies changed very little during 1983. Many officials of the blood banks, the plasma fractionation industry, and the FDA accepted with little question estimates that the risk of AIDS was low ("one in a million transfusions"), and they accepted advice that control strategies (such as automatic withdrawal of AHF concentrate lots containing blood from donors suspected of having AIDS, or a switch from AHF concentrate to cryoprecipitate

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking in less severe hemophiliacs) would be ineffective, too costly, or too risky. During this period, there were missed opportunities to learn from pilot tests to screen potentially infected donors or implement other control strategies that had been rejected as national policy. (These local attempts to screen are discussed briefly below, and in more detail in Chapter 5.) RESEARCH ACTIVITIES During 1983 through 1985, research on AIDS included epidemiological analysis to understand patterns of spread and etiology, methods to control or eliminate the disease, and evaluation of the efficacy of potential safety measures such as surrogate tests for the infection. Related research on methods to inactivate the hepatitis B virus in blood products that had begun in the 1970s came to fruition in the early 1980s (see Chapter 4 for a detailed discussion). The Public Health Service Effort As discussed earlier, the PHS Committee on Opportunistic Infections in Patients with Hemophilia held its second meeting on July 27, 1982. On the same date, the committee distributed two recommendations to the assistant secretary for health, the FDA commissioner, the NIH director, CDC regional offices, and state and territorial health officers. The first recommendation was to establish an active surveillance system at once to identify new suspected cases of AIDS occurring in individuals with hemophilia. In November, the CDC, the NHF, and the regionally based network of hemophilia treatment centers agreed to cooperate in this effort. The second recommendation called for (a) laboratory studies of the immunologic competence of individuals with hemophilia who had no symptoms of opportunistic infections, and (b) applied research to determine practical techniques for eliminating the risk of infection from AHF concentrate (Foege 1982b). The meeting summary also noted concerns about the adequacy of funding to support these activities, stating that existing federal grants and contract mechanisms were not "responsive to rapid funding of urgent problems" (Foege 1982b). The PHS committee also recommended studies to evaluate the effectiveness of screening procedures for identifying and excluding high-risk donors but did not propose a source of funding for the studies. Several blood banks did initiate pilot studies on safety measures such as anti-HBc as a surrogate for HIV (Irwin Memorial Blood Bank), the use of a reversed T-cell ratio test (a test indicating immune dysfunction) to exclude high-risk donors (Stanford University Blood Bank), and confidential unit exclusion to allow donors to self-defer (New York

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Blood Center). The results of the studies did not provide strong enough evidence to convince those who attended the December 15–16, 1983, BPAC meeting (discussed above) to recommend surrogate testing or other measures to reduce AIDS transmission. In March 1983 Assistant Secretary of Health Edward Brandt announced the formation of a PHS Executive Committee on AIDS. The purpose of the committee was to coordinate the activities of PHS agencies and share information on upcoming meetings, grant awards, and new developments. In addition, Assistant Secretary Brandt directed the NIH, in collaboration with the CDC and FDA, to support studies to evaluate screening procedures, including laboratory tests, for their effectiveness in identifying and excluding blood and plasma donors at increased risk for AIDS (Brandt 1983). In response to this request, the NIH director, Dr. James Wyngaarden, designated the National Heart, Lung, and Blood Institute (NHLBI) to lead NIH's effort in determining if any test "would merit experimental validation and possible preparation for an Request for Application (RFA)" (Wyngaarden 1983). In the following year, the NHLBI sponsored several conferences on AIDS. Early in 1983, NIH redirected some of its research budget ($165,000 in supplemental funding) to scientists working on studies of Kaposi's sarcoma (Thomas 1983; Panem 1988). In addition, the NHLBI established an interagency agreement with the CDC to evaluate immunologic changes in hemophiliacs and patients receiving blood and blood products (Sloand 1994). A total of $61,500,000 was allocated to the PHS budget in fiscal year 1984 for AIDS-related research; this represents a 114 percent increase from the $28,700,000 allocated in fiscal year 1983 (Stoto, et al. 1988). Isolation of the Virus and Development of a Screening Test Investigators at the Pasteur Institute in Paris reported the isolation of novel virus that they termed LAV from an individual with lymphadenopathy syndrome in 1983. These investigators suspected that LAV might be involved in the causation of AIDS, but due to difficulties they experienced in propagating the virus in large quantities and the lack of an effective serologic test to identify LAV-infected persons, this hypothesis could not be proved at the time. In April 1984, researchers at the National Cancer Institute of the NIH reported the isolation of a virus they called HTLV-III from a number of persons suffering from AIDS and from asymptomatic or moderately symptomatic persons from groups of persons at risk of AIDS (Popovic, et al., 1984). The NIH investigators described for the first time a method to prepare large quantities of HTLV-III in the laboratory and provided convincing evidence that this virus was the etiologic agent of AIDS.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking The discovery that a virus caused AIDS shifted some research efforts toward a focus on the biological aspects of transmission of the disease and its interactions within the human body. The public's reaction to the discovery of HTLV-III (later renamed HIV) included an increased fear of casual transmission and of infection through the act of donating blood (Fee and Fox 1988; Brandt 1987). As a result of the isolation of HTLV-III, blood and plasma collection organizations, anticipating the quick development of a direct test for the virus, did not implement any additional donor screening procedures until such a test was developed. Meanwhile, during 1982–1984, U.S. manufacturers were completing the development of a process for inactivating the hepatitis B viruses by heating AHF concentrate (see Chapter 4). In October 1984, the CDC announced that laboratory experiments showed that the heat treatment process also inactivated HIV. During 1984, however, researchers remained focused on developing a screening test for HIV. Once the virus was identified, several companies began developing tests to screen blood by detecting antibodies that would indicate exposure to the virus. In April 1984, NIH developed and patented a prototype screening test for antibodies to HIV, and by May it had solicited applications from companies interested in commercial use of the tests. Five companies were selected in June. The first tests used an enzyme-linked immunosorbent assay (ELISA), and the FDA received an application for licensure from a company in December 1984. By March 1985, the FDA had granted two licenses for commercial use of the tests; it also notified all blood facilities that the test was available, and it scheduled a workshop on its use [50 Federal Register 28477]. Subsequently, all blood banks and plasma collection centers implemented the ELISA. The first ELISA tests detected 96–98 percent of HIV-infected blood samples. However, despite a high degree of specificity, false seropositive results occurred. For this reason, a second, more costly, less sensitive, but more specific screening test called the Western Blot was used to confirm or refute the positive results of the ELISA test. Neither test could detect HIV antibodies during the six-to-eight-week window period (i.e., the time between HIV infection and the evidence of antibodies in a donor's blood). Since the implementation of the initial ELISA test, several more sensitive tests have replaced it because they reduce the length of the window period. Through the widespread use of this test, the current risk of HIV transmission through screened blood is estimated to be less than 1 in 420,000 units (Lackritz, et al. 1995; Busch, et al. 1995).

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Summary and Comment In the early 1980s, the CDC's surveillance program identified AIDS patients and characterized the disease swiftly and thoroughly. Dr. Gallo at the NIH isolated and characterized HIV in less than two years. Meanwhile, laboratories of the plasma fractionation industry were developing viral inactivation methods for AHF concentrate. The pace of virus inactivation research in the 1970s had been slow, but accelerated in the 1980s in response to hepatitis and was complete by 1984. Most of the PHS research effort was concentrated on identifying and characterizing the virus. Research into other potential ways to safeguard the blood supply, such as surrogate tests, was not pursued vigorously, and there was relatively little research on blood safety issues perse. REFERENCES Brandt, Allan. No Magic Bullet. Oxford University Press, New York, New York; 1987. Brandt, Edward, Assistant Secretary for Health. Memorandum to Agency Heads; March 2, 1983. Busch, et al. Presentation at the National Institutes of Health consensus conference; January 1995. Centers for Disease Control, Morbidity and Mortality Weekly Report , June 5, 1981. Centers for Disease Control, Morbidity and Mortality Weekly Report , July 3, 1981. Centers for Disease Control, Morbidity and Mortality Weekly Report , June 11, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , June 18, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , July 9, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , July 16, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , September 24, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , December 10, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , December 17, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , November 5, 1982. Centers for Disease Control, Morbidity and Mortality Weekly Report , January 7, 1983. Centers for Disease Control, Morbidity and Mortality Weekly Report , March 4, 1983. Fee, Elizabeth and Fox, Daniel, eds. AIDS: The Burdens of History. University of California Press, Berkeley, California; 1988. Foege, William H., M.D., Director, Centers for Disease Control. Letter to State and Territorial Health Officers; July 9, 1982a. Foege, William H., M.D. Summary Report on Open Meeting of Public Health Service Committee on Opportunistic Infections in Patients with Hemophilia; August 6, 1982b. Foege, William H., M.D. Summary Report on Workgroup to Identify Opportunities for Prevention of Acquired Immune Deficiency Syndrome; January 4, 1983a. Food and Drug Administration. Blood Products Advisory Committee; February 7, 1983b.

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HIV and the Blood Supply: An Analysis of Crisis Decisionmaking Food and Drug Administration. Blood Products Advisory Committee; July 19, 1983. Hansen, K.B. Armour Pharmaceuticals. Interoffice Correspondence to Bessler, et al.; July 19, 1982. Johnson, Robert. Letter to list [Armour Pharmaceutical interoffice correspondence]; January 12, 1983. Lackritz, et al., Presentation at the National Institutes of Health consensus conference; January 1995. Neustadt, R. and Fineberg, H. The Swine Flu Affair: Decisionmaking on a Slippery Disease. U.S. Department of Health, Education, and Welfare; 1978. National Hemophilia Foundation. Chapter Advisory #8; May 11, 1983. Panem, Sandra. The AIDS Bureaucracy. Harvard University Press, Cambridge, Massachusetts; 1988. Petricciani, John C. M.D., Food and Drug Administration, Director Division of Blood and Blood Products, Center for Drugs and Biologics. Letter issued August 8, 1984. Popovic, M., et al. Detection, Isolation, and Continuous Production of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and pre-AIDS. Science; 1984. Sloand, Elaine. Submission to the Institute of Medicine, "Chronology of Major NHLBI Intramural Activities on AIDS"; April 8, 1994. Stoto, et al. Federal Funding for AIDS Research: Decision Process and Results in Fiscal Year 1986. Reviews of Infectious Diseases, Vol. 10; March-April 1988. Thomas, R. Anne, Director, Division of Public Information, National Institutes of Health. Memorandum issued May 17, 1983. Wyngaarden, Director, National Institutes of Health, Memorandum to NHLBI Director; March 14, 1983.