From: sbharris@ix.netcom.com(Steven B. Harris) Subject: The Facts About the Concorde AZT Trial (was: AZT in Pregnant Women) Date: Sat, 16 Aug 1997 Newsgroups: misc.health.aids,misc.health.alternative,sci.med,sci.med.nutrition, sci.med.pharmacy In <01bcaa0f$8778bf00$LocalHost@crown.crown.icongrp.com> "Kathy Gorny" <gornyk@mail.icongrpns.com> writes: >Steven B. Harris <sbharris@ix.netcom.com> wrote in article ><01bcaa07$f7b29460$a3b496ce@crown.crown.icongrp.com>... >> In <01bca98b$bcd8bbc0$LocalHost@crown.crown.icongrp.com> "Kathy Gorny" >> <gornyk@mail.icongrpns.com> writes: >> >> >The thing about Concorde (and what is a hell of a lot more relevant in >> >comparing it to this case) is that they found HIV positive people who >> >took AZT tended to convert to full blown AIDS faster then those who >> >did not. Which did dispute the original study. > >> This is false. Feynman didn't say it was okay to comment on studies >> you haven't read. >> Steve Harris, M.D. > >This is serious... I'm not joking here... but I am beginning to think >there are two Concorde Studies? For I remember reading a review of the >results of the study (back when it first came out) [...] Then I remember >hearing they was a big dispute over these findings... there was talk the >authors were going to change "something" I can't remember - and I >remember thinking they succumbed to the drug company... and that's it. Comment: The Concorde trial, which is larger than all other AZT vs. placebo trials combined, has been greatly misunderstood and misused. The design was simple: take 1749 people who were HIV positive and fairly healthy clinically, and randomize them to high dose AZT, or placebo. Those who got sick or developed low CD4 counts could be put on AZT later, if it turned out that they had gotten AIDS or low counts while on placebo. Half of those who got AIDS turned out to be on placebo, unfortunately. The abstract below shows what happened after 3 years of study: AZT started early didn't affect total deaths, total AIDS deaths, or total numbers of progression to AIDS. These were the same in both groups, despite the fact that one group got AZT from the beginning, while the other one got the drug late or not at all (still consisting of more than half "AZT virgins" who still hadn't gotten the active drug, after 3 years). Thus, the first important conclusion of Concorde: AZT use is causing little or no AIDS in HIV-positive people, a conclusion opposite to that which Duesberg and Lauritsen and many others had been (and still are) asserting. On the contrary, Concorde demonstrates once and for all that clinically healthy HIV- positive people develop AIDS just fine without AZT, and do so at the same rate as people getting AZT. In fact, in the Concorde trial almost 20% of the HIV-positive AZT deferred group managed to get AIDS or AIDS related complex (ARC) in three years on placebo alone--- no AZT at all. So much for the idea that without AZT, the AIDS plague would not be with us. The deferred group, which had less than half as many people who EVER got AZT at any time, should have had less than half as much AIDS and AIDS death, *IF* AZT was a major cause of AIDS. They didn't-- they had the same AIDS rate and AIDS death rate. In fact, the people who got sick in the "immediate AZT" group had been on AZT 5 times longer than those in the deferred group had been on it, before they got sick. Again, if AZT was the basic cause of the sickness, these times would naturally have been about the same. A poison should take about the same time to poison, no matter if given early or held until later, after all. Note also that the AZT dose in Concorde is high-- about twice what is standard today. The second important conclusion of the Concorde is that AZT alone doesn't do any good if started too early in HIV disease. This does not mean that AZT doesn't do any good for any HIV- positive group of people-- merely that when it is given early in HIV disease, before HIV-positive people would naturally be ill with AIDS, the virus has 6-12 months to develop resistance to the drug before there is much damage done to the immune system. So the AZT grace period is wasted if the drug is given before it is needed, and AZT is thus best saved for later in the disease when the immune system is failing. Again, Concorde (and other studies) suggest that AZT fails quickly against the virus when used alone. The Concorde did not contradict earlier studies in which AZT had been used later in HIV disease, and there shown to improve survival during the 6-12 months it was active (and the immune system was failing). Concorde has now been run out to 5 years, though I don't think these results have been published yet. They show basically the same-- still the same AIDS rate and AIDS death rate in both groups. However, later analyses of the Concorde now show that total death rate is statistically higher in the group which was started immediately on AZT, suggesting some long term toxicity of this drug which overwhelms any benefit, but only after many years of monotherapy (the trend does not become significant until after more than 3 years into the trial). Again, however, there is no evidence in Concorde that this toxicity manifests itself as AIDS-- rather the excess deaths in the early drug intervention group appear due to auto accidents and suicides, if you look at trends already apparent at 3 years. Thus, while it seems likely that high dose AZT used as monotherapy after many years may exact a price in depression and incoordination, it does not do so in opportunistic infections. Finally, it needs to be remembered that the death numbers in both groups were still within 90% of each other, so the extra AZT is (again) NOT responsible for most of the deaths in HIV-positive people the Concorde trial. Statistically, it could not be, statistically. AIDS, which had nothing to do with AZT, still overwhelmed the death statistics in Concorde, and was independent of AZT use. Over the years, it has been interesting to see what the AIDS skeptics have had to say about Concorde. This trial is a litmus test for honest use of evidence. There is no support in Concorde for early use of AZT, but on the other hand, Concorde does pretty well prove that AZT is not the cause of the AIDS plague. Nevertheless, rather incredibly, you will see AIDS skeptics arguing the opposite, and citing this study. Thus, the AIDS/AZT debate is not one between rational people making honestly different interpretations of the same evidence. Rather, it is a debate too often between people using the evidence of trials like Concorde, and other people simply ignoring, mis-citing, or straight out *lying* about such evidence, which they are never willing to discuss in detail. Periodically it is necessary to review the evidence to show which side is being dishonest in use of this study, and which is not. Let the reader judge. I have the paper and will be glad to argue details with any skeptic so inclined. -- Steven B. Harris, M.D. TI - Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Concorde Coordinating Committee [see comments] AB - Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31, 1992 (total 5419 person-years; median 3.3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% CI 90-94%) in Imm and 94% (92-95%) in Def (log-rank p = 0.13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p = 0.18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups.(ABSTRACT TRUNCATED AT 400 WORDS) CM - Comment in: Lancet 1994 Apr 9;343(8902):866-7 ; Comment in: Lancet 1994 May 28;343(8909):1355; discussion 1358 ; Comment in: Lancet 1994 May 28;343(8909):1355-6; discussion 1358 ; Comment in: Lancet 1994 May 28;343(8909):1356-7; discussion 1358 ; Comment in: Lancet 1994 May 28;343(8909):1357; discussion 1358 ; Comment in: Lancet 1994 May 28;343(8909):1357-8 ; Comment in: ACP J Club 1994 Nov-Dec;121(3):73 SO - Lancet. 1994 Apr 9;343(8902):871-81. |
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