266-5191-1648a by wuzhengqin


									 1                                  REVIEWING THE DATA–IV                                                                                        been injecting for a mean of 7.6 and 9.1            66
 2                                                                                                                                               years, respectively. When the duration of           65
     Could Drugs, Rather Than a                                                                                                                  drug use was controlled, there was a clear
                                                                                                                                                 difference between the two groups in CD4
                                                                                                                                                 status. Among those not infected with
     Virus, Be the Cause of AIDS?                                                                                                                HIV, the base line CD4 count was 914,
                                                                                                                                                 within the normal range. Among those in-
 8                                                                                                                                               fected with HIV, however, the base line was         59
 9   In March 1988, the headline of a news ar-           among both HIV-positive and HIV-negative                                                only 395, well outside the normal range. Be-        58
10   ticle in Science called Peter Duesberg a “rebel     drugs users, T cell reactivity decreased as the                                         tween 1989 and 1994, CD4s remained stable           57
11   without a cause of AIDS.” But Duesberg says         frequency of injection increased; Duesberg                                              in the HIV-negative group but declined              56
12   he’s a rebel with several causes of AIDS—it’s       cites this among his evidence that drug use                                             steadily among those infected with the virus.       55
13   just that none of them happen to be the             can cause AIDS.                                                                         And death from AIDS was associated with             54
14   consensus favorite, HIV. Among the causes              But critics of Duesberg’s work say the                                               HIV status but not with drug use alone.             53
15   he favors (at least for homosexuals and users       study actually undermines his case. First,                                              Among HIV-positives, there were 25 deaths,          52
16   of injectable drugs, the groups hardest hit by      they say, he does not mention that among                                                10 attributable to AIDS; among HIV-nega-            51
17   AIDS in the United States and Europe) are           the drug users in the study who were HIV-                                               tives there were eight deaths, none due to          50
18   drugs. Specifically, he thinks the disease is       negative, the chief indicator of the immune                                             AIDS-defining diseases.                             49
19   due to the use of illicit drugs such as heroin,     deficiency seen in AIDS—CD4 count—was                                                       Other checks of the theory that drug use        48
20   cocaine, and amphetamines, as well as to the        well within the normal range. The 49 HIV-                                               can cause AIDS raise just as many questions.        47
21   first drug approved for treating AIDS, AZT.         negative users who injected themselves more                                             For example, there is evidence that heroin          46
22       “AIDS is new because the drug epidemic          than 50 times a month had a mean of 990                                                 can cause immune abnormalities—but not              45
23   is new,” argues Duesberg. “We’re in the middle      CD4s (the normal range is from 600 to                                                   the type seen in AIDS. According to                 44
24   of giving 200,000 people AZT for a hypoth-          1200); the 55 users who injected from one to                                            Rockefeller University’s Mary Jeanne Kreek,         43
25   esis that’s at best unproven. … We’re telling       49 times a month had 910 CD4s. The HIV-                                                 who studies immune responses in heroin ad-          42
26   250 million Americans to use clean needles          positive drug users, on the other hand, had a                                           dicts, heroin users do not experience a de-         41
27   to inject cocaine and heroin. … What we             mean CD4 count of 450, less than half the                                               cline in CD4 counts unless they are infected        40
28   should do is point out it’s not just against the    CD4 count among the HIV-negative group                                                  with HIV. Indeed, in 1989 Kreek reported in         39
29   law to use drugs, it may be against your health.”   (although typically not low enough to cause                                             the Journal of Pharmacology and Experimental        38
30       To make his case that drug use causes           clinical symptoms). This study, say Dues-                                               Therapeutics that 11 long-term heroin users         37
31   AIDS, Duesberg points out that drug use (in         berg’s critics, shows that the decline of CD4                                           had a mean of 1500 CD4s—a significant el-           36
32   particular, use of nitrite inhalants known as       cells—the hallmark of AIDS—is associated                                                evation from the norm and the opposite of           35
33   “poppers”) has been high among some sub-            with HIV status and not with drug use.                                                  what is seen in AIDS. “Heroin is a blessedly        34
34   groups in the homosexual population. AIDS              Duesberg counters that this study does not                                           untoxic drug,” concludes Kreek.                     33
35   researchers agree. But beyond that, his con-        report lifetime dosages of drugs—only cur-                                                  If Duesberg’s effort to show that AIDS          32
36   tention that illicit drugs cause AIDS has pro-                                                                                              can be caused by drug use alone elicits sharp       31
                                                                                                           PETER C. HOWARD/JOHNS HOPKINS UNIV.

37   voked heated disagreement. Showing how                                                                                                      criticism, his critics say that his attempt to      30
38   heated the conflict between Duesberg and                                                                                                    find AIDS-defining illnesses among those            29
39   the majority of AIDS researchers has become,                                                                                                not infected with HIV is also problematic.          28
40   last year Duesberg charged that the authors                                                                                                 One piece of research Duesberg cites to             27
41   of a study in Nature showing that only HIV-                                                                                                 show that HIV-negative drug users have              26
42   positive drug users developed AIDS had fab-                                                                                                 AIDS-defining illnesses is a 1992 study from        25
43   ricated data; the charge was found to be                                                                                                    Johns Hopkins University. In his 1992 paper         24
44   groundless by an independent panel at the                                                                                                   in Pharmacology and Therapeutics Duesberg           23
45   University of California, Berkeley.                                                                                                         says that in the Hopkins study, the fraction        22
46       Duesberg builds what he calls his “drug-                                                                                                of the 160 HIV-negative people with AIDS-           21
47   AIDS” hypothesis using a variety of studies                                                                                                 defining diseases was roughly equal to the          20
48   he says show that “a critical lifetime dosage                                                                                               fraction of the 590 HIV-positives with              19
49   of drugs appears necessary in HIV-positives         Screen test. Alvaro Muñoz and Duesberg dis-                                             AIDS-related conditions.                            18
50   and sufficient in HIV-negatives to induce           agree about Munoz’s findings.                                                               Duesberg refers to a table in the paper         17
51   AIDS-indicator and other diseases.” To                                                                                                      listing “clinical symptoms,” which are defined      16
52   make the case that drugs are sufficient to          rent frequency of injections. “Thus the fre-                                            in a footnote as oral thrush (a mouth infec-        15
53   cause AIDS in HIV-negatives, Duesberg               quent injectors may include more newcom-                                                tion caused by the fungus Candida albicans),        14
54   highlights data he argues show AIDS-like            ers than the less frequent injectors,” he says.                                         fatigue, chronic diarrhea, weight loss, and         13
55   immune abnormalities and diseases in long-          In other words, the frequent injectors who                                              shortness of breath. But Hopkins epidemiolo-        12
56   term drug users.                                    were HIV-negative may actually have lower                                               gist Alvaro Muñoz, the study’s first author, says   11
57       For example, Duesberg cites a study of          lifetime dosages, and so their drug-caused                                              “None of these clinical symptoms were AIDS.”        10
58   drug users, both HIV-negative and HIV-              immune deficiency has not shown up yet.                                                     Muñoz says his statement is based on the         9
59   positive, in which a Dutch group examined               To test Duesberg’s hypothesis, one of                                               definition of AIDS developed by the Centers          8
60   the ability of the drug users’ T lymphocytes        the co-authors of the Dutch study, Roel                                                 for Disease Control and Prevention (CDC).            7
61   to kick into action when stimulated. T lym-         Coutinho of Amsterdam’s Municipal Health                                                That definition is specific about the type of        6
62   phocytes are an important set of immune-            Service, has compared HIV-positive and                                                  weight loss that is considered AIDS-defin-           5
63   system cells that circulate in the blood; CD4       HIV-negative drug users while controlling                                               ing. A weight loss of greater than 10% com-          4
64   cells, the group whose progressive decline is       for the length of time the two groups injected                                          bined with at least two loose stools per day for     3
65   the hallmark of AIDS, are a subset of T lym-        drugs. Coutinho compared 86 HIV-negative                                                30 days constitutes the AIDS-defining “HIV           2
66   phocytes. The Dutch group found that,               and 70 HIV-positive drug users who had                                                  wasting syndrome.” The patients in the Hop-          1
     1648                                                SCIENCE • VOL. 266 • 9 DECEMBER 1994
                                                                                                                                         SPECIAL NEWS REPORT
 1   kins study did not meet this definition.                                                                                 But gloomy as those conclusions are, the              66
 2   When Science asked Duesberg about                                AMSTERDAM DRUG STUDY                                    Concorde’s principal investigators disagree           65
 3   Muñoz’s claim, Duesberg said: “These are                    Characteristic HIV positive HIV negative                     sharply with Duesberg’s hypothesis that               64
 4   HIV-free drug users. How do you think                                                                                    AZT, rather than HIV, causes AIDS. The                63
                                                                 Total                          70                 86
 5   they lost weight, even if it’s 9.8% or 10%?                                                                              Concorde data in “no way argue in favor of            62
 6   How do you think they got diarrhea?”                        Female                         18                 24         the hypothesis that AIDS is caused by AZT,”           61
 7       Nor did Duesberg accept CDC’s defi-                     Mean age                       31.9               31.4       Concorde’s French principal investigator,             60
 8   nition of another AIDS-defining illness:                    Mean years regularly 9.1                            7.6      Maxime Seligmann of Paris’ Hopital Saint-             59
 9   esophageal candidiasis. This illness is                      injecting drugs                                             Louis, wrote Science in response to a query.          58
10   caused by the same agent as oral thrush,                    Recent injecting                                                 Duesberg, however, does not accept this           57
                                                                  Not injected                  18                 23
11   but it occurs in the esophageal passage, a                   < daily                       20                 18         conclusion. In his written response to questions      56
12   distinction Duesberg characterizes as                        ≥ daily                       32                 45         from Science, Duesberg wrote: “The Concorde           55
13   arbitrary: “I know, 10 centimeters down                     Total deaths                   25                   8        data exactly prove my point: The mortality            54
14   the throat is candidiasis, and 11 centime-                   AIDS                          10                   0
                                                                                                                              of the AZT-treated HIV-positives was 25%              53
15   ters is AIDS.”                                                                                                           higher than that of the placebo group.”               52
                                                                  Overdose                        4                  3
16       But clinicians who specialize in treat-                                                                                  But the method he uses to arrive at that          51
17   ing AIDS patients say the distinction is                     Suicide                         1                  3        figure is sharply disputed by experts in clini-       50
18   not arbitrary. Science asked Joseph Sonna-                   Pneumonia/sepsis                3                  1        cal trials. Duesberg notes that there were 96         49
19   bend, a New York clinician specializing in                   Other                           7                  1        total deaths in the Imm group and only 76 in          48
20   treating AIDS patients, whether the dis-                  SOURCE: R. COUTINHO, M. LANGENDAM, H. VAN HAASTRECHT,          the Def group. He therefore concludes that            47
                                                               AMSTERDAM MUNICIPAL HEALTH SERVICE
21   tinction is clinically well founded. Son-                                                                                the mortality rate among those given AZT              46
22   nabend, an early Duesberg sympathizer                                                                                    immediately is 25% higher than among                  45
23   who now says he thinks Duesberg has not                       from Science.                                              those who take it later. One problem with             44
24   been open enough to evidence that HIV is                           While mainstream AIDS researchers say                 this analysis, say experts familiar with the          43
25   involved in causing AIDS, says: “Oral thrush                  Duesberg is correct in noting that AZT is                  Concorde data, is that it includes 22 deaths          42
26   occurs in people who are relatively immuno-                   toxic because it interrupts DNA synthesis                  from events such as traffic accidents and sui-        41
27   logically intact. Esophageal candidiasis is                   generally, that contention, they say, is a far             cides. Subtracting deaths that were not relat-        40
28   more or less confined to people who are                       cry from claiming that the drug causes AIDS.               ed to AZT or AIDS yields 81 Imm deaths and            39
29   much worse off, immunologically speaking.”                    And researchers who have conducted large-                  69 Def deaths.                                        38
30   When the definitions established by CDC                       scale studies of the drug’s effects say that it                In addition, say the critics, there is a deeper   37
31   are used, the Hopkins study reveals that                      does not cause the fatal illness.                          flaw in Duesberg’s analysis: He does not take         36
32   none of the HIV-negative patients had                              The most comprehensive data on AZT                    account of the total number of people in the          35
33   AIDS-defining illnesses, while 47 of 590                      come from the “Concorde”—the largest,                      Imm and Def groups. His reasoning for ignor-          34
34   HIV positives did.                                            longest running study of the drug. This 3-                 ing the denominator is, as he told Science in         33
35       In addition to heroin and cocaine, Dues-                  year, British-French study included 1749                   an interview, that “it was the same in the two        32
36   berg argues that AZT, the very drug designed                  HIV-positive people who initially showed                   groups.” But National Institute of Allergy and        31
37   to treat AIDS, can, in fact, cause it. And                    no AIDS symptoms. Because of its large                     Infectious Diseases Director Anthony Fauci            30
38   even his severest critics concede that AZT                    numbers, Concorde has more statistical                     says this type of analysis means “ignoring an         29
39   is no wonder drug. Although it is one of the                  power than the seven other major AZT trials                important part of a calculation.” Specifically,       28
40   few drugs approved for fighting AIDS, AZT                     to date combined. The main conclusion of                   there were 96 total deaths out of 877 in the          27
41   can be severely toxic,                                                                                                   Imm group, implying that 10.9% of the people          26
42   and there is compelling                                   CONCORDE RESULTS                                               who were immediately treated with AZT                 25
43   evidence that the drug                                                                                                   died. In the deferred treatment group, there          24
44   probably doesn’t help in-                                     “Imm” group “Def” group                                    were 76 deaths among 872 people, or 8.7%.             23
                                                                      (n = 877)           (n = 872)         Log rank p***
45   fected people live long-                                                                                                     The appropriate conclusion, say the au-           22
46   er unless they already           Total deaths                          96                 76                 0.13        thors of the Concorde study, is that the dif-         21
47   have full-blown AIDS.            HIV-related deaths*                   81                 69                 0.34        ference in mortality between Imm and Def              20
48   Yet those reservations           AIDS or death**                      176                171                 0.94        groups is not 25% but 10.9% minus 8.7%—               19
49   pale next to the posi-           ARC§, AIDS, or death** 267                              284                 0.18        or 2.2%. Subtracting the deaths from causes           18
50   tion of Duesberg, who            Advanced ARC, AIDS,                                                                     unrelated to AZT or AIDS, the difference              17
51   contends AZT is “AIDS              or death                           191                186                 0.91        drops to 1.3%. As the Concorde paper notes,           16
52   by prescription.”               §
                                       ARC is AIDS-related complex, a pre-AIDS condition.                                     neither difference (2.2% or 1.3%) is statisti-        15
                                     * Includes six deaths (4 Imm, 2 Def) possibly HIV-related or drug-related and excludes
53       Duesberg attacks AZT          22 (15 Imm, 7 Def) unlikely to be HIV-related or drug-related.                         cally significant.                                    14
54   on several different lev-       ** As first event.
                                     ***A measure of statistical significance.
                                                                                            SOURCE: CONCORDE COORDINATING         “If the Concorde study showed anything,           13
55   els. His most sweeping                                                                                                   it showed that AZT’s benefit is of limited            12
56   attack is on the ratio-                                                                                                  duration,” says Fauci, referring to the fact          11
57   nale for using AZT in AIDS therapy. AZT                       the Concorde’s investigators was that pa-                  that the Imm group had fewer AIDS-related             10
58   interrupts synthesis of viral DNA, and in so                  tients treated with AZT soon after entering                illnesses during the study’s first year. Dues-         9
59   doing prevents HIV from replicating, which                    the study (the “Imm” group) fare no better                 berg replies that “according to my analysis of         8
60   AIDS researchers say is necessary for the vi-                 than those who defer use or do not take the                this paper, this paper shows that AZT is               7
61   rus to cause disease. But Duesberg notes                      drug (the “Def ” group). The study did show,               harmful … 25% more people die in the AZT               6
62   that AZT is not specifically targeted against                 however, that the Imm group had fewer                      group than in the placebo group. That mat-             5
63   the DNA of the virus but against DNA syn-                     AIDS-related diseases during the first year of             ters to me. Because even a single life seems to        4
64   thesis. “Since DNA is the central molecule                    the study than the Def group did.                          matter to me. Maybe not to you. You like to            3
65   of life, AZT treatment is not compatible                           That wasn’t a very hopeful finding: AZT               normalize that. To me it does. Period.”                2
66   with life,” he wrote in response to questions                 clearly isn’t a very effective anti-AIDS drug.                                                  –Jon Cohen        1
                                                                  SCIENCE • VOL. 266 • 9 DECEMBER 1994                                                                     1649

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