SPECIAL NEWS REPORT

1 REVIEWING THE DATA–I the Multicenter Hemophilia Cohort Study 66 2 (MHCS) sponsored by the National Cancer 65 3 Institute (NCI), follows 2000 hemophiliacs 64 4 Duesberg and Critics Agree: at 16 centers in the United States and West- 63 5 ern Europe. In 1989, the New England Journal 62 6 Hemophilia Is the Best Test of Medicine published a study from the 61 7 MHCS comparing 242 HIV-infected hemo- 60 8 philiacs who received high, medium, or low 59 9 Peter Duesberg and his critics in the com- addition, some researchers contacted by Sci- doses of factor VIII. If exposure to contami- 58 10 munity of AIDS researchers disagree vio- ence say Duesberg has drawn incorrect con- nants in factor VIII were the cause of the 57 11 lently about the cause of AIDS. But they clusions from their work. immune suppression seen in AIDS, it would 56 12 agree on one thing: Hemophiliacs provide a In making his argument that hemophili- be expected that those who received higher 55 13 good test of the hypothesis that HIV causes acs suffer from AIDS independent of HIV, doses of the factor would be more likely to 54 14 AIDS. Hemophiliacs offer a unique window Duesberg cites 16 studies showing that HIV- develop AIDS, says NCI’s James Goedert, 53 15 on the effects of HIV infection because there negative hemophiliacs have abnormal ratios the principal investigator of MHCS. But the 52 16 are solid data comparing those who have of two types of critical immune-system cells: study, says Goedert, found no association 51 17 tested positive for antibodies to HIV—and CD4 and CD8. The normal ratio of CD4s to between dose levels and the likelihood of 50 18 are presumably infected—with those who CD8s is about 2, but the studies Duesberg coming down with AIDS. 49 19 have tested negative. In addition, the health cites indicate that hemophiliacs who are not Duesberg, however, thinks studies such as 48 20 status of hemophiliacs has been tracked for HIV-positive have ratios closer to 1. He con- 47

21 more than a century, providing an important cludes that even in the absence of HIV, he- DEATHS IN HEMOPHILIA /NCI 46 22 base line. And unlike homosexual groups, mophiliacs suffer immune deficiencies—and COHORT SINCE 1985* 45 23 hemophiliac cohorts are not riddled with hence that some factor other than HIV is 44 24 what Duesberg thinks are confounding vari- responsible for AIDS among them. Factor VIII Dose HIV+ HIVÐ 43 High 10/29 0/0 25 ables, such as illicit drug use. But researchers familiar with these data JAMES GOEDERT 42 26 Where AIDS researchers argue that HIV say the abnormal ratio Duesberg cites is not Moderate 103/264 0/17 41 27 causes AIDS in hemophiliacs, Duesberg indicative of AIDS—and may not even indi- Low 40/103 1/49 40 28 points to another cause: contaminants of fac- cate immune deficiency. The chief impact of *Groups are based on cumulative dosages of factor 39 29 tor VIII, a clotting factor derived from do- AIDS on the immune system is a progressive VIII from 1978 to 1984. 38 30 nated blood that is used to treat hemophilia. decline in the number of CD4 cells. A 37 31 Factor VIII is frequently contaminated with change in the CD4/CD8 ratio doesn’t in it- MHCS aren’t sufficient for establishing 36 32 foreign proteins from blood donors, and self say anything about the number of CD4 AIDS causality. He says more research is 35 33 Duesberg suggests that these contaminants cells, AIDS researchers say, as it could be due needed—specifically, a study that doesn’t 34 34 cause the immunodeficiency seen in AIDS. to an elevation of CD8 cells alone. “Any- combine hemophiliacs into groups such as 33 35 In his view, HIV is a harmless passenger that thing that would give your CD8s an eleva- “high, medium, and low dosage” and that 32 36 serves as an index of the number of blood tion could give you a ratio of 1,” says immu- instead includes records of exactly how much 31 37 transfusions. “Since HIV is a rare contami- nologist Michael Ascher, an AIDS re- factor VIII each patient has received during 30 38 nant of factor VIII, it is a marker of the num- searcher with the California Department of his or her lifetime. “We would need a study 29 39 ber of immunosuppressive transfusions re- Health Services. People with a ratio of 1 comparing 100 hemophiliacs—and it’s very 28 40 “could have more CD4s—and that may be doable; it’s probably in the computer—hav- 27 1.50 41 70 Median Age at Death immuno wonderful,” adds Ascher. ing received 2 million lifetime units [of factor 26 42 1.25 60 When asked about this point in relation VIII] to 100 guys having received exactly the 25 43 to a specific paper he cites, Duesberg re- same number of units, HIV positive and 24 50 44 1.00 sponded: “Look, why don’t you call [the negative. And then compare [the diseases in 23 40 45 0.75 paper’s author] and ask the fool, ‘Why did each group]. Not this type of stuff.” 22 46 30 you idiots describe your paper as immunode- In spite of Duesberg’s contention that 21 0.50 47 20 ficiency in patients with hemophilia?’ ” such a study is “very doable,” researchers 20

48 Deaths per million 0.25 Pediatrician Donald Kaufman of Michi- working with hemophilia databases say it is 19 SOURCE: TERENCE CHORBA/CDC 10 49 gan State University, who co-authored the impossible, because hemophiliacs do not 18 0.00 0 50 ’68 ’70 ’72 ’74 ’76 ’78 ’80 ’82 ’84 ’86 ’88 study in question, says Duesberg’s interpreta- keep track of each factor VIII treatment. 17 51 Year tion of their data is “erroneous.” In Kauf- “There’s no place that would even begin to 16 52 Crossing pattern. Death rates for hemophili- man’s 1989 study, CD4 counts of HIV-nega- have cumulative lifetime dosages,” says the 15 53 acs rose sharply in the 1980s. AIDS research- tive hemophiliacs showed no significant dif- University of Southern California’s James 14 54 ers disagree with Duesberg on the cause. ference from normal controls. The number Mosley, who heads the other large study of 13 55 of CD8 cells, however, was higher in hemo- hemophiliacs, the Transfusion Safety Study 12 56 ceived,” argues Duesberg. He contends that philiacs—regardless of whether they re- Group (TSSG), which has tracked 1200 he- 11 57 hemophiliacs infected with HIV are simply ceived factor VIII treatment. The treated pa- mophiliacs at six U.S. sites. “It’s sort of like 10 58 the ones who have received the most factor tients did show some immune deficiencies that trying to count grains of sand on the beach.” 9 59 VIII—with the accompanying contaminants. Kaufman thinks may be related to factor VIII, Although Mosley and others say precise 8 60 AIDS researchers interviewed by Science but he emphasizes that these were nothing lifetime dosages of factor VIII for large study 7 61 contend that this view is contradicted by two like what is seen in AIDS, and indeed, none groups are impossible to obtain, they say it is 6 62 large studies of hemophiliacs. Those studies, of these nine patients has developed AIDS. possible to do less ambitious studies that look 5 63 say AIDS researchers, show that being HIV Other AIDS researchers cite additional at cumulative dosages of factor VIII for spe- 4 64 positive is the key variable associated with data from the two large epidemiologic studies cific periods, such as when hemophiliacs are 3 65 the disease and death that accompany that they argue show factor VIII has little to being monitored in a study. NCI’s Goedert 2 66 AIDS—not contaminants of factor VIII. In do with causing AIDS. One of these studies, did such an analysis using his MHCS data- 1

SCIENCE • VOL. 266 • 9 DECEMBER 1994 1645 1 165, or 31%, of the 519 HIV-positive hemo- 66 2 philiacs had developed AIDS. In the HIV- 65 3 The Transfusion Studies positive group there were 176 deaths, and of 64 4 those, 135 were from AIDS. 63 5 Although science has produced no AIDS cure or vaccine, AIDS researchers like to For many “HIV dissenters,” Duesberg’s 62 6 point to one dramatic victory: the blood test that prevents people from being infected most compelling argument against HIV as 61 7 during transfusions. According to the Centers for Disease Control and Prevention the cause of AIDS in hemophiliacs is his 60 8 (CDC), as of mid-1994, 6888 AIDS cases had been linked to blood transfusions. But observation that the median age of hemo- 59 9 those people were almost all infected before screening began, and the blood test has philiacs has increased in spite of high HIV 58 10 essentially eliminated the risk of AIDS from transfusions—only 29 cases stem from infection rates. As Duesberg notes, studies 57 11 blood that was screened for HIV. This dramatic decrease has been invoked by AIDS have reported that the median age of hemo- 56 12 researchers as evidence that HIV causes AIDS. philiacs in the United States has risen from 55 13 Peter Duesberg says these data are meaningless. He argues that AIDS is not caused by 11 years in 1972 to more than 25 years by the 54 14 HIV in transfused blood but by the disease that required transfusion in the first place. early 1980s. “Thus,” he says, “one could 53 15 And, he says, the drop in AIDS cases after HIV was removed from the blood supply has make a logical argument that HIV, instead 52 16 a “trivial explanation.” Because the standard definition of AIDS requires the presence of of decreasing the lifespan of hemophiliacs, 51 17 HIV, when the virus was removed from the blood supply, people were no longer has in fact increased it.” 50 18 categorized as having AIDS—although their diseases had not changed. “Without HIV Researchers who study health patterns 49 19 antibodies,” contends Duesberg, “the diseases are called by their old names.” among hemophiliacs agree that life-span in 48 20 Proof that AIDS has vanished along with HIV, Duesberg says, would be a decrease in this group has increased over the last two 47 21 AIDS-defining diseases among transfusion recipients and a corresponding decrease in decades. But if were not for HIV, they say, 46 22 transfusion-associated mortality. In an interview with Science he criticized CDC scien- the increase would have been far higher. 45 23 tists—whom he described as “officers of the U.S. Army who are paid to find HIV is the What is more, they argue that life-span among 44 24 cause of AIDS”—for not providing that data. Harold Jaffe, head of the CDC’s Division hemophiliacs has actually been sharply de- 43 25 of HIV/AIDS, said “I don’t believe there’s national mortality data for all who have been creasing recently. 42 26 transfused.” Jaffe added that he doesn’t think such figures would be “particularly useful” That conclusion is supported by a study 41 27 in relation to AIDS causality “because the overall mortality in people who are transfused from the Centers for Disease Control and 40 28 is high, and AIDS has contributed relatively little.” Prevention (CDC), published this year in 39 29 Duesberg also argues that mainstream AIDS researchers attribute death among the American Journal of Hematology, evaluat- 38 30 transfusion recipients to HIV “without considering HIV-free controls.” But in 1990 the ing two decades of death certificates from 37 31 Transfusion Safety Study Group (TSSG) published just such a report. The TSSG hemophiliacs. CDC’s Terence Chorba and 36 32 compared HIV-negative and HIV-positive recipients who had been given transfusions his co-workers concluded that, because of 35 33 for similar diseases. Approximately 3 years after transfusion, the mean CD4 count in 64 the introduction in the 1960s of clotting 34 34 HIV-negative recipients was 850 (the normal adult range is 600 to 1200). In contrast, treatments that prevent death from hemor- 33 35 111 HIV positives had an average of 375 CD4s. By May 1993, there were 37 AIDS cases rhage, death rates dropped from 0.5 to 0.4 32 36 in the HIV-infected group, says TSSG Director James Mosley of the University of per million from 1968 to 1978. But from 31 37 Southern California. In contrast, there has not been a single AIDS-defining illness in 1979 to 1989, the period when most U.S. 30 38 the HIV-negative transfusion recipients, says Mosley. hemophiliacs became infected with HIV, 29 39 Duesberg says these data neatly fit his theories. HIV, he says, is a rare contaminant of the death rate among hemophiliacs in- 28 40 blood transfusions and therefore indicates the volume of transfusions received. “HIV- creased dramatically—to 1.3 per million. 27 41 positive transfusion recipients have received more blood because they had more severe The same study provides other perspec- 26 42 underlying diseases than HIV negatives,” he wrote in response to questions from Science. tives on the sharp increases in death rates 25 43 “The more severe the underlying disease, the more likely are subsequent AIDS diseases.” among hemophiliacs due to AIDS. The me- 24 44 –J.C. dian age at death of all U.S. hemophiliacs 23 45 fell from a high of 63 in 1983 to 38 in 1989. 22 46 That change was due to the increase in deaths 21 47 base. Goedert analyzed which was better cor- the moderate-dose group, there were 264 among HIV-positive hemophiliacs, the au- 20 48 related with a hemophiliac’s risk of death: HIV positives. Of that total, 103 have died. thors note, which soared from 19.9% in the 19 49 cumulative dosage of factor VIII or having In comparison, among 17 HIV negatives period 1983–1985 to 55.1% in the period 18 50 tested positive for HIV. (He did not use there were no deaths. In the low-dose group, 1987–1989. Chorba and his colleagues con- 17 51 AIDS as an endpoint because since the mid- there were 103 HIV positives, of whom 40 clude that the spread of HIV “significantly 16 52 1980s, when the medical community ac- have died; among 49 HIV negatives there disrupted the progress in mortality statistics 15 53 cepted HIV as the cause of AIDS, clinicians has been only one death. Dosage of factor for this population.” 14 54 have primarily diagnosed AIDS in people VIII, says Goedert, “had absolutely nothing Duesberg replies that this study “confirms 13 55 who test positive for HIV.) whatsoever” to do with a person’s risk of dy- very much everything I have said.” He argues 12 56 To make the comparison, Goedert di- ing. Being HIV positive, however, increased that the life-span dropped between 1987 and 11 57 vided hemophiliacs of similar age into HIV- a person’s risk of dying almost 20-fold. 1989 because of “the large-scale administra- 10 58 positive and HIV-negative groups. He then Goedert’s counterpart, TSSG Director tion of AZT to American hemophiliacs.” He 9 59 divided the two groups into those who had Mosley, offers additional data that he says calls the drop “an iatrogenic artifact.” 8 60 received high, moderate, or low cumulative link HIV to disease and death, specifically For researchers such as TSSG’s Mosley, 7 61 dosages of factor VIII. Dosages were totaled illnesses associated with AIDS. Data from however, the hemophilia data leave no ques- 6 62 from 1978 to 1984; the study analyzed the the TSSG reported in the New England Jour- tion that HIV causes AIDS. Indeed, says Mos- 5 63 hemophiliacs’ survival from 1985 on. nal of Medicine in 1993 show that none of the ley, in the face of the data on hemophiliacs 4 64 The 29 people in the highest dose cat- 419 HIV negatives from that large study had he has a hard time understanding why Dues- 3 65 egory were all infected with HIV and there- AIDS-defining diseases. In contrast, Mosley berg continues to stick to his arguments. 2 66 fore could not be used in the comparison. In says, by May 1993, the most recent analysis, –Jon Cohen 1

1646 SCIENCE • VOL. 266 • 9 DECEMBER 1994