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The Concorde Study




 

GMHC Treatment Issues 1993 May 1; 7(4): 1

Preliminary results from the long-awaited European trial of "immediate" vs. "deferred" AZT treatment were released in a letter to The Lancet on April 3, 1993. The study, dubbed Concorde, was conducted in England, France, and Ireland. And like the jet plane that shares its name, Concorde set off sonic booms across the Atlantic.

BACKGROUND Concorde began in October 1988 and was organized by the British Medical Research Council and the French National AIDS Research Agency. The trial was the largest randomized, double-blinded, and placebo controlled AZT study ever conducted. Neither the clinicians nor the participants knew who was given AZT and who was given placebo.

In the study, 1,749 patients were followed for an average of three years. At enrollment, all patients were HIV-positive and asymptomatic (no AIDS or ARC) with a broad range of CD4 counts (59 percent had less than 500, 6 percent had less than 200). A total of 877 individuals were randomized to receive 1000mg per day of AZT (the "immediate treatment" arm) and 872 were given placebo (the "deferred treatment" arm). The immediate treatment arm commenced AZT whatever their CD4 levels were, while the deferred treatment arm was given placebo until they developed symptomatic disease (AIDS or ARC). The characteristics of the two groups were similar in age, sex (15 percent were women), and immunological markers.

Since all patients began AZT once they became symptomatic, the trial was designed only to show whether it is beneficial to begin AZT treatment before symptoms appear. The trial was not designed to provide information on the usefulness of taking AZT for symptomatic HIV disease.

TRIAL MODIFICATION In 1989, a U.S. study, ACTG 019, was halted after one year when it found that AZT seemed to delay progression of disease in people with less than 500 CD4 cells. The Concorde study was modified on ethical grounds to allow participants with less than 500 CD4 cells to begin taking AZT open label. Those who chose to begin AZT once their CD4 cells fell below 500, along with those who began AZT because they developed symptomatic disease, were included in the preliminary analysis published in The Lancet.

PRELIMINARY RESULTS After an average follow-up of three years, the research team reports that survival rates did not differ significantly. The death rate was 8 percent in the immediate treatment group and 7 percent in the deferred treatment group. In addition, there was no significant difference in disease progression. After three years, 18 percent in both groups progressed to AIDS or death. However, there was a statistically significant difference in CD4 levels between the two arms. After three months, the immediate group had, on average, about 30 more CD4 cells than the deferred group. This difference was sustained up to three years.

No new or unexpected toxicities were seen. Of those who had to stop the treatment because of anemia or a drop in white blood cells, sixteen were in the immediate group and three were in the deferred group. An additional 82 in the immediate and 37 in the deferred withdrew because of other events, mostly nausea and vomiting.

STUDY CONCLUSION The authors of the study conclude that "Concorde has not shown any significant benefit from the immediate use of zidovudine (AZT) compared with deferred therapy in symptom-free individuals in terms of survival or disease progression, irrespective of their initial CD4 counts. The discrepancy between this result and the significant effect of immediate zidovudine on CD4 cell counts casts doubt on the value of using changes over time in CD4 count as a predictive measure for effects of antiviral therapy on disease progression and survival." CRITICISMS OF CONCORDE The protocol change in 1989, which allowed open label use of AZT for those with less than 500 CD4 cells, may have skewed the results by causing a significant number of those in the deferred arm to receive the same therapy as those in the immediate treatment arm. Therefore, some argue, it is not surprising that there is no significant difference between the two arms. The Concorde researchers respond "that a valid comparison was still possible because of the large number of patients in the study and the marked difference in the amount of zidovudine taken; in the first eighteen months of the trial, participants in the immediate group spent 85 percent of the total time before they developed AIDS or ARC on zidovudine, compared with only 7 percent of the deferred group." The dose of AZT used in Concorde (1000mg per day) is significantly greater than that now used in the U.S. (500-600mg per day). Since Concorde did not use what is believed to be the optimum dose of AZT, some suggest the results do not provide an accurate indication of the potential benefits of AZT.

Concorde was a monotherapy study of AZT and does not reflect the use of combination therapy which, some claim, may provide the most beneficial results in antiretroviral therapy.

Perspectives on Concorde Treatment Issues surveyed a number of leading AIDS researchers and physicians in the U.S. for their thoughts on the preliminary results of Concorde and whether it has affected their treatment recommendations for their HIV-positive patients. We did not use scientific methods to select the participants. Consequently, this survey does not necessarily represent the opinions of all AIDS researchers and physicians in the U.S. Rather, we solicited responses from the researchers who conducted previous U.S. clinical trials of AZT, private physicians with large AIDS practices, community-based researchers, and prominent critics of previous AZT studies. We are grateful to all who participated in this survey.

1. At what CD4 level do you presently recommend your HIV-positive patients take AZT? Donald Abrams, M.D., San Francisco General Hospital: I have never adopted a rigid cutoff point at which I recommend AZT. I generally initiate therapy when a patient requests it, although I discourage people with more than 500 CD4 cells from beginning drug. Over the years I have followed, and continue to do so, a cohort of people who have chosen not to initiate drug regardless of CD4 count.

Lynn Besch, M.D., Louisiana Community AIDS Research Program: 500+1-100, or when patients feel strongly they should be on antiretroviral drug at any CD4 cell count.

Richard E. Chaisson, M.D., Director, AIDS Service, Johns Hopkins Hospital, Baltimore: Less than 500.

Deborah Cotton, M.D., Ph.D., Harvard Medical School: I have always felt that a CD4 of 500 was not the appropriate cutoff at which to initiate AZT. However, I have tended to initiate AZT in asymptomatics with a CD4 of 350 or lower. Concorde may change my practice: to wait until the patient has symptoms or reaches a CD4 of 200. In other words, I was already conservative about early intervention with AZT and am likely to become more so. The caveat, of course, is that like everyone else I really would like to see the complete data report.

Lawrence R. Crane, M.D., Medical Director, HIV/AIDS Programs, Detroit Medical Center: Less than 500 CD4 cells.

Margaret Fischl, M.D., University of Miami School of Medicine; Principal Investigator for many AZT efficacy studies: We still initiate AZT at 500 CD4 cells. Data from David Cooper will appear soon. His data, in patients with 400-750 CD4 cells, gave patients AZT or placebo. Apparently, there was delayed progression to advanced disease and/or a CD4 count below 350. Data from 019 should also be available early next year. We are beginning to implement early intervention starting at 750 CD4 cells.

Howard Grossman, M.D., New York City: I begin discussions when CD4 counts decrease to less than 500 on two occasions but do not really encourage patients strongly unless CD4 counts are obviously dropping or the patient has symptoms.

John D. Hamilton, M.D., Professor of Medicine, Duke University; Principal Investigator, Veterans Administration AZT Study: I have no definite preset CD4 level at which I recommend AZT. Below 200, however, I nearly always suggest it. Above that level, I base my recommendation on the presence of symptoms, their level of severity, and a frank discussion with the patient about the other potential treatment incentives and disincentives.

N. Patrick Hennessey, M.D., New York City: It depends entirely on the individual, i.e., the chronological course of CD4 numbers and the relationship to change in CD8 and clinical symptoms. There has never been a set number at which I suggest treatment.

Martin S. Hirsch, M.D., Harvard Medical School: Less than 500 CD4 cells.

Roberta Luskin-Hawk, M.D., Principal Investigator, Chicago Community Program for Clinical Research on AIDS (CPCRA): 2 CD4 counts under 500.

Ronald Mitsuyasu, M.D., Director, UCLA Center for Clinical AIDS Research and Education: CD4 at or below 500.

Joan Priestley, M.D., Director, Center for 21st Century Medicine; Holistic AIDS Specialist: I do not prescribe AZT.

Robert R. Redfield, M.D., Chief, Dept. of Retroviral Research, Walter Reed Army Research Institute; Principal Investigator, gp160 Therapeutic Vaccine Study: I recommend that patients consider AZT when their mean CD4 cell count is less than 300, particularly patients who are also anergic. I recommend combination antiretroviral therapy for patients whose CD4 count mean value is less than 200. Although there is a risk of additional side-effects when using both AZT and ddI and lack of definitive proof related to the impact of this approach on viral resistance, I recommend combination therapy (AZT/ddI) rather than a single agent. I believe this represents a common sense approach.

Joseph Sonnabend, MBBCh, MRCP. Medical Director, Community Research Initiative on AIDS/New York: I have never been guided by CD4 levels. As you may know, I believe that endogenous alpha-interferon may play an important role in pathogenesis, and as our work has shown, AZT can promptly remove interferon from the circulation. I therefore recommend AZT for eight to twelve weeks for patients who have indications of elevated interferon, such as increased beta-2 microglobulin, fever and weight loss. I believe that the recommendation for uniformly prescribing at less than 500 CD4+ cells was inappropriate, particularly given that no data other than a press release was made available to prescribing physicians.

Paula Sparti M.D., Medical Director, Community Research Initiative of South Florida: Less than 500 CD4 or higher if persistent decline over six month period of time.

Paul Volberding, M.D., Director, AIDS Program, San Francisco General Hospital; Principal Investigator, ACTG Study 019: I would continue to recommend AZT initiation in HIV infected persons with CD4 counts at or below 500 cells.

2. Will Concorde change your recommendation? Please explain.

Abrams: No, I will continue the above. The Community Consortium is piloting a large simple trial, entitled comPACT I in order to determine the best time to intervene with antiretroviral therapy in asymptomatic people. The pilot, funded by AmFAR, will test the methodology of the LST. Ultimately we hope to enroll 20,000 people nationwide to answer the question. Concorde, for some, will increase their uncertainty and make randomization to immediate versus deferred treatment a more attractive option.

Besch: No, have seen too many symptomatic patients get good to excellent benefit from AZT. If asymptomatic patients want to wait, I already agree with that and continue to monitor them. Also, Concorde has not presented their data. Study population more varied than ACTG study populations and design changed during the course of the trial. Therefore, need to see more information.

Chaisson: No. The analysis was an intention to treat analysis. The protocol was changed and patients with two CD4s less than 500 could go on open label AZT. Thus, the study showed that AZT was no better than placebo when open label use is permitted for CD4 less than 500.

Cotton: My reasoning has always been that to justify the long-term toxicities, including resistance of AZT, early intervention should result in clear-cut benefits: i.e. improved survival, real increases in time to AIDS, etc.

Crane: Not at present. The letter did not provide sufficient information to make an informed decision. I await the full paper. Additionally, a significant change was made in study design during the study. We need to know how this might have influenced outcome.

Fischl: Concorde will not change my recommendation to patients for a couple of reasons: a.) We need a lot more information from the study before we should change clinical practice. b.) My interpretation of the Concorde data is different from the study investigators. I believe the data shows that immediate AZT resulted in a significant delay in development of AIDS, but did not prevent it. AZT and other nucleosides lose their effectiveness over time. We need to know how long they work and what other markers we should use to indicate drug efficacy. We need to know what to do once AZT loses its effect--should we switch to ddI or add a combination. Rather than throwing AZT out, I believe the real question is how do we maximize and prolong its effect. c.) Concorde may not be analyzed correctly; we need a lot more analysis of the data. For instance, about 30 percent of patients under 500 CD4 cells elected to take AZT. The figures in The Lancet imply this was not significant. However, we need to see the data to be sure. For instance, what was the self-withdrawal rate from the study? What was the effect of the cross-over on the study results? We also need a center by center analysis. In America it is common practice to examine the data provided by each center to ensure there is no bias. This was not provided in The Lancet. Since Concorde enrolled patients in three countries with different medical systems and differing availability of drugs, this analysis is crucial.

Grossman: No. So far, we have been given next to no data and yet are, once again, being asked to make significant clinical decisions. I want release of all the data. Secondly, I think it is clear that AZT has an effect for at least several years, and no one seriously suggests now that single agent therapy be used for longer than that with AZT. So, I'm not sure we'll need to change course even if the study pans out.

Hamilton: Certainly not until after I have seen the complete analysis and commentary on the study, and perhaps not then.

Hennessey: No. It does justify in some respects my treatment of some individuals with CD4 counts of 650 and my not treating other individuals with CD4 counts of 350.

Hirsch: Insufficient data are available currently to indicate whether any change is indicated. Detailed analysis of Concorde data will be required, and the study conduct and results compared with other related studies (ACTG 019, 016, 036 and the VA study.) Luskin-Hawk: Certainly for patients who don't tolerate AZT well, I would stop it readily, since the only thing we may gain is quality of life if AZT is well tolerated. I need to see the complete analysis.

Mitsuyasu: At this point, no. The weight of evidence from several other large randomized studies suggest an advantage to early antiretroviral therapy in those with CD4 below 500. The Concorde study results do not contradict this. It speaks to the fact, however, that with long term use, viral resistance or host resistance may occur and limit the long term effectiveness of prolonged AZT use.

Priestley: If anything, Concorde does not alter my recommendation; in fact, it strengthens my opinion that AZT is not a useful and cost-effective therapy.

Redfield: No, it confirms my previous interpretation of the available data. AZT provides limited clinical benefit of limited duration in a subgroup of patients with HIV infection. In my opinion, this benefit should be reserved for patients as they develop symptomatic or late stage disease and combination therapy should be seriously considered when initiating dideoxynucleoside intervention. I also believe greater attention should be applied to determine which patients benefit from AZT, which patients are potentially harmed by AZT treatment, and which patients demonstrate no effects.

Sonnabend: No. Although these are preliminary results, they are reassuring to me in confirming my decision not to routinely prescribe AZT to asymptomatic patients.

Sparti: No, I believe that reverse transcriptase inhibitors do delay progression of disease, and although the effect is rather short lived, it will be prolonged by combination therapy.

Volberding: I would not change my recommendations based on the preliminary analysis of Concorde. I would, of course, be inclined to reconsider after the final analysis is available for careful review, although I suspect that limitations in the Concorde design will, even so, leave my recommendations as they currently are. Concorde included only about half as many patients with a baseline CD4 count of under 500 when the study began. Also, there are suggestions in the preliminary report that in fact AZT use did delay the onset of clinical AIDS. If this is true in the final analysis, it could well still argue for initiation at an asymptomatic phase of disease hoping that second and third line therapies with non-cross resistant nucleosides or other combinations may allow a prolongation of the clinical benefit induced by zidovudine.

3. What do you now say to your asymptomatic HIV-positive patients who have taken AZT for a significant period of time? Abrams: I generally say, if it's not broken, don't fix it. Others say the results of recent trials suggest that people should switch, say to ddI, after a time. That trial also failed to demonstrate a survival advantage for those who switched. Still others say monotherapy is clearly inadequate and combinations are the way to go. Large trials designed to answer the question are currently maturing. I think it would be worthwhile to see some of the data before jumping on the "more is better" bandwagon.

Besch: What I have been saying previously will--not make any major changes until can more critically evaluate Concorde data.

Chaisson: Stay on it if it's working.

Cotton: I always tell patients everything I know and assure them that there are no right answers. In other words, this is a situation where patient preference is very important. We have no data that stopping nucleosides is bad, so I would feel comfortable with a patient on AZT with under 200 CD4 cells stopping it, especially if they had any side-effects. In general, however, I am switching patients from AZT to ddI after about one year.

Crane: Continue drug as along as clinically stable, no major changes in laboratory parameters such as CD4, beta-2, HIV antigen.

Fischl: For this group, the question is how long does the effect of AZT last. John Phair will be presenting an abstract in Berlin from the MACS study which says that AZT is effective for about 2.5 years. Drs. Volberding and Lagakos examined patients in ACTG 019 who continued on long-term follow-up. They found that AZT is effective for 36 months. I believe you should switch to a new nucleoside after the presence of syncytia inducing variants of HIV and CD4 count drops. You should probably switch to ddI. I am reluctant to switch to combination therapy in advanced disease, because the efficacy may be limited. For example, we see a very limited impact on viral burden with combination therapy. Perhaps early intervention with combination nucleoside therapy will keep viral burden low enough to prevent the development of resistance.

Grossman: What's a significant period? I recommend combination therapy to all patients who have been on AZT for more than one to two years or who show progression, and switch therapies if progression continues.

Hamilton: Depending on how long the patient has been on AZT, his/her stage of disease, and the nature of the discussion and expectations at the time of the initial discussion, I would tend to persevere with the present regimen, certainly until the impact of Concorde has been assessed.

Hennessey: If they were started on AZT in our offices, I review the study as well as the earlier U.S. studies of asymptomatics and I reiterate the rationale we used in starting that individual on meds at the time we did.

Hirsch: This depends on CD4 count. At the higher end of the scale (e.g. 400-500), I would recommend no change. At the lower end of the scale (e.g. under 300), I would recommend switch to ddI or ddC, particularly if the slope of the CD4 counts is precipitously downward. Ongoing studies, e.g. ACTG 175, should help answer some of these questions.

Luskin-Hawk: Continue AZT if tolerated.

Mitsuyasu: The study suggests that the effect of AZT long-term does dissipate with time and that alternate or combination therapy will be needed as time progresses, even in those who have remained relatively stable on AZT alone.

Priestley: I recommend that current users of AZT slowly taper off taking the drug--drop 200mg from your daily dose each week until you are down to nothing.

Redfield: Since I have not recommended early AZT therapy, I have few patients in this situation. However, if asked, I would review their clinical course on treatment, evaluate the tolerance of drug in terms of side effects, consider testing patient's virus for sensitivity to AZT, ddI, and ddC and adjust therapy based on this information. If a patient lacks side effects and clinical course is stable (i.e no evidence of CD4 decline or increase in immunological dysfunction) it is reasonable for this subgroup to consider continuation of single agent AZT treatment. However, if CD4 decline has continued despite AZT and/or defects in functional immunity development (i.e. anergy), I would consider viral sensitivity testing and combination antiretroviral therapy (based on results) or encourage the individual to consider other experimental options.

Sonnabend: I don't have many patients in this category. For the few I have, I would reiterate my recommendation that they consider other approaches.

Sparti: If they are tolerating AZT well, I advise continuing medication, with a low threshold for making the decision to add ddI or ddC.

Volberding: With asymptomatic patients who have taken AZT for a significant period of time, I would recommend that they continue the use of zidovudine until there has been some laboratory or clinical evidence of disease progression. If, for example, the CD4 cell count is less than 50 percent of what it was when they began zidovudine, or if they developed clear symptoms or signs of HIV disease, I would urge that they either add ddI or ddC or switch to one of these drugs based on the results from ACTG trials 116A and 116B/117.

4. What are your thoughts on the CD4 data from Concord? Abrams: I am becoming more concerned about what CD4 changes in response to drugs really means. Intuitively, one would love to believe increased counts translate into clinical benefit--decreased progression and prolonged survival. More and more studies bring this into question. Concorde, the VA study, 116B/117, and our recent CPCRA ddI versus ddC study. In the CPCRA trial, a CD4 response was appreciated in the ddI recipients, but there was a trend towards increased survival in those initially treated with ddC. We really need to see some mega meta-analysis of all CD4/survival data presented at some forum somewhere to help clarify the issue. We may be discarding agents that could have some potential benefit for lack of a CD4 response and approving others with little effect other than a small transient CD4 cell increase.

Besch: No surprise--I think most researchers view CD4 counts as available but imperfect surrogate markers--not many studies have correlated CD4s or drug treatment with survival.

Chaisson: CD4 is a reliable surrogate marker. I do not accept the published conclusion of the Concorde study, thus maintain my opinion about CD4.

Cotton: The CD4 data is critical to analyze carefully when it comes out. We have pinned a lot on CD4 as surrogate marker; we need to constantly reassess this decision as new data becomes available. (By we I mean the ACTG, FDA, advocates, patients.) Crane: I think that clinical parameters more important and agree that CD4 is not a "perfect" surrogate marker.

Fischl: I was disappointed in these comments. CD4 is not perfect, as statistical modeling has shown. However, the Concorde team may not have modeled CD4 correctly. CD4 is a two dimensional marker --you have to account for increases and the duration of response. When CD4 is modeled correctly, it becomes more predictive.

Grossman: a). Showing beginning and ending levels without looking at intervening data points is not useful. b). What about other markers, such as CD4 percent, Beta 2 microglobulin, anti-p24 antibody, etc? c). I would imagine that if one- third of delayed treatment group actually took AZT for the last two to three years of the study, it would have a large impact on the results, especially when progression rates are so low. Hamilton: I have no thoughts about the data until I have had the opportunity to review the details of Concorde. Generally, my use of CD4 in guiding decisions is somewhat limited in any case.

Hennessey: When the Concorde study was not stopped at the evaluation point that stopped ACTG 019 and the other U.S. studies, it was apparent that dramatic differences were not being seen between the groups and results similar to those just published in the Concorde study were expected. I have some questions as to composition of the European/U.S. studies in terms of just how "asymptomatic" the participants were. Conclusion, the data is not a surprise but the clarification of the letter will be difficult as best.

Hirsch: Initial impressions are that AZT raises CD4 counts early, but that this effect is lost over time, confirming earlier studies. More definitive interpretation will require more detailed analysis of the data. Conclusions about the prognostic value of CD4 changes, based on the available data from Concorde, appear premature.

Luskin-Hawk: This study underscores the importance of using clinical endpoints and survival to evaluate antiretroviral therapy and not to rely too heavily on surrogate endpoints. Since patients on the deferred arm could start AZT if two CD4 counts were under 500, how different were the two groups? Severe drug toxicity was an endpoint in Concorde and a higher dose (1000mg/day) was used.

Mitsuyasu: The finding merely confirms the fact that benefits from small changes over the short run in CD4 counts are perhaps overshadowed by other variables (such as development of viral resistance, etc.) over the long run. Better prognostic markers are clearly needed to predict overall prognosis for individual patients and to assess benefit of therapy. CD4 change is a good, but not perfect surrogate marker.

Priestley: I believe this study will renew interest in CD8 cells, and concentrate on therapies that raise them.

Redfield: I believe this is possible. What I would like to know is was there a disparity between treatment arms in terms of functional immunity (i.e. skin test reactivity) and clinical outcome. I suspect that maintenance or lack of functional immunity and outcome will correlate. The difference reported in CD4 cell counts are marginal, and even of less importance to me if these differences reflect differences in single values rather than mean values.

Sonnabend: Again, although the results are preliminary, they seem to justify the unease that some of us felt over the decision to use CD4+ levels as a measure of therapeutic efficacy.

Sparti: I strongly believe that CD4 count is predictive of outcome. Survival is much better in 50-100 CD4 group than those persons close to zero. The Concorde data will need to be evaluated closely. Were they using multiple prophylaxis? Probably not! Volberding: The CD4 data from Concorde are obviously still extremely preliminary. As I understand it, there was, in fact, a significant CD4 benefit from the use of zidovudine in the immediate therapy group. The investigators concluded that CD4 wasn't of value because they felt there wasn't an ultimate clinical value but again I think we shouldn't be willing to concede that point until we see the final data. If there was, in fact, a clinical benefit from our way of thinking, then their study may in fact reinforce the use of CD4. Obviously, none of us believe that CD4 is a very good marker of the disease or especially of its response to therapy but I think that it would be dangerous to immediately abandon this marker given that that might force us to use only clinical endpoints which would require that drug development take much longer than it already does. I am very hopeful that HIV quantitation, using a variety of new methodologies, may be able to resolve this dilemma quickly by giving us a surrogate marker that is more central to the actual disease process.

Excerpt from a letter to Treatment Issues by Ian Weller M.D., University College London Medical School; Principal Investigator, Concorde Study: At the moment, I do feel strongly that physicians and patients should not change what they are on until the final report is published...If a patient with CD4 levels at 350, and who had been on AZT for two years, wanted me to decide for them then I would recommend that they stop (taking AZT). However, I am one of the few that has seen many of the analyses that will make up the final report of Concorde, and outside of the trial I have been very conservative in the use of zidovudine monotherapy in asymptomatic patients and my patients have been comfortable with this but of course they may self-select in terms of coming to see me.

Excerpt from the statement of the National Institute of Allergy and Infectious Diseases: Daniel F. Hoth, M.D., Director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), says, "The Lancet letter is based on a preliminary analysis, with many important details to be clarified. We look forward to meeting with our European colleagues and reviewing this data in detail. However, at this time we see no basis for changing the recommendation to initiate antiretroviral therapy for HIV-infected persons whose CD4+ T-cell count falls below 500 per cubic millimeter of blood." Excerpt from the statement of the Food and Drug Administration: FDA believes this report clearly shows the need for continued studies of AZT and other AIDS products to ensure that the usefulness of the drugs is fully understood. It will be important to explore what factors, such as viral resistance, may be responsible for decreases in benefits of the drugs over time.

The Concorde study documents the need for trials that include clinical outcome data-the effect of the drug on the course of disease--and the need for postmarketing surveillance for drugs approved on the basis of surrogate markers such as CD4 cell counts.

FDA is looking forward to reviewing the data referred to in The Lancet letter, particularly those pertaining to the use of surrogate markers to predict clinical outcome. Careful review and discussion with expert consultants will allow the agency to place the study in perspective and will indicate whether any changes in labeling for AZT are warranted.

Excerpt from the statement of Project Inform: The bottom line: Far more data and analysis are required before any final conclusions should be drawn about the meaning of this study. The overall rate of disease progression seen in this study, both on and off drug, should be extremely encouraging to HIV-infected people.

The relevance of these findings may or may not be relevant to the way this drug is used in the US. If one assumes they are basically accurate, then the prudent course of action is not to abandon therapy, but to seek to improve upon it, especially if one is still using AZT as a sole therapy after a year or more of use.

If the findings are relevant, they would seem to back up conclusions drawn earlier in the US that, at most, people should remain on a single drug therapy for no longer than one year, or that small doses of a combination of drugs is likely to be both more effective and longer lasting because of the inhibition of drug-resistant strains of virus.

The study provides clear evidence that long-term antiretroviral, even using a dose two times higher than standard, for four years, does not augment disease progression.

Different and more appropriate statistical models must be employed or enforced in future studies to guarantee that assessment will reflect the actual behavior of study participants, rather than an idealized course of treatment abandoned in the course of study.

Excerpt from the statement of Burroughs Wellcome, the manufacturer of AZT: CD4 cell counts were significantly higher for people who received immediate treatment with AZT compared to CD4 counts for people who received deferred treatment with AZT after a variable time on placebo.

It shows an encouraging low rate of adverse reactions associated with 1g AZT for up to four years. This dose is higher than the currently recommended dose.

The study reports no difference in benefits in terms of disease progression or mortality between immediate and deferred AZT treatment. However, during the trial approximately 40 percent of people who received placebo initially changed to AZT.

There was a surprising discrepancy between the benefit observed for CD4 cell counts related to immediate use of AZT and the lack of difference in benefit measured by disease progression, as specified in the protocol. The Concorde team concludes that there are doubts about the value of CD4 cell counts as a measurement of the benefit of therapy.

Copyright (c) 1993 - Gay Men's Health Crisis, New York City, NY Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. http://www.aegis.com



 


Copyright © 1993 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in May 1, 1993. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.