[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 4 April, 1993 Gay Men's Health Crisis: Treatment Issues > The Concorde Study > Treatment Briefs >> d4T Survey >> Thalidomide for Painful Oral Ulcers >> Gingivitis: An Early Sign of HIV? >> NIAID Fact Sheets on AIDS and STDs >> Imuthiol Results Published; Drug Worse than Placebo >> Corticosteroids May Increase Risk for CMV >> Reports of Rapid CD4 Decline After Interferon Therapy >> Vegetables, Angiogenesis, and KS >> New PCR Test For HIV Reported >> New AMFAR NYS Clinical Trials Directory > On the Edge: Gene Therapy In AIDS > Washington Watch ================================= ================================= The Concorde Study by David Gold 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 cut-off 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 the 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 cut-off 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 pre-set 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. Editorial After Concorde The release of the Concorde data was a significant and rare event. It has caused thousands of HIV-infected people to reconsider their own treatment decisions. Additionally, the study and the controversy that surrounds it are already influencing many of the current debates in AIDS research. The news media understood that Concorde was important; however, they did not fully explain the many nuances in the discussion. For instance, the media coverage contained few scientists or patients. Lead stories on the networks and headlines in The New York Times and The Washington Post questioned the efficacy of AZT and reported on the falling stock price of the company that manufacturers the drug. However, for the most part, the stories did not explain the impact Concorde is having on people with HIV, prescribing physicians, and AIDS researchers. Due to the importance and complexity of the study, Treatment Issues offers coverage of it in a slightly different way. Rather than publish one comprehensive article, we asked leading AIDS researchers and physicians in the U.S. to comment on the significance of the Concorde data. All responses appear in their complete form. Brief excerpts from the public statements of the Food and Drug Administration (FDA), the National Institutes of Health (NIH), Burroughs Wellcome, and Project Inform are included for a sense of the initial institutional response. Additionally, this editorial is presented to help provide a preliminary context for the discussion. Treatment Issues encourages written responses to any of the issues discussed. Although skeptical scientists have yet to scrutinize Concorde, flaws have already become apparent. As more data are released and analyzed, different conclusions may well be made. However, to say Concorde contains flaws is not enough at this point to dismiss outright its conclusions. Every scientist realizes that clinical research never runs with textbook efficiency. Nor are there ever any perfectly designed or implemented clinical trials. In fact, many have argued that the American studies which suggest a benefit to early AZT use, such as ACTG 019, contain their own methodological errors. The limitations of Concorde, therefore, must be balanced against its statistical power, relative size, and length. Concorde is, by far, the largest, most powerful, and longest-running AZT study ever. Many in the media suggest that Concorde disproves other AZT studies. This is not entirely true. Concorde addresses a different question than previous AZT studies. It examined the long-term effect of AZT on the survival of asymptomatic patients. ACTG 019 examined only the effect of AZT on disease progression (i.e., the occurrence of opportunistic infections) in this population up to one year. It was too small and too short to examine the ultimate survival of the study participants. To knowledgeable AIDS researchers, Concorde was no big surprise. Many have recognized for some time that the effect of early AZT on survival is unresolved. In fact, in the September 1992 Treatment Issues, we noted that Sam Broder, M.D., the highly respected Director of the National Cancer Institute, had urged researchers at the International AIDS Conference in Amsterdam last summer to design studies to answer this fundamental question: Does early AZT therapy truly prolong the lives of asymptomatic people? So why all the fuss? Concorde underscores the uncertainty many AIDS researchers and clinicians feel. A few years ago, many physicians believed that the nucleoside analogs (the class of compounds which include AZT, ddI and ddC) would transform AIDS into a so-called "chronic manageable" condition. There is now a deep and growing sense among many that some of the basic assumptions underlying AIDS drug development need to be reexamined. From the criteria used to approve new drugs rapidly to fundamental ideas of how HIV causes immune collapse, researchers have lost consensus on the central questions in AIDS research. An open discussion on the approval criteria for early intervention drugs is clearly needed. While no one disputes the necessity of rapid approval for AIDS treatments, Concorde raises the question about the applicability of the same expedited approval criteria to treatments for asymptomatics. Many now ask if it is wise to approve treatments for asymptomatics based on small CD4 cell increases which growing data suggest do not indicate ultimate clinical benefit in this population. As more and more companies take advantage of early approval regulations to develop new therapeutic vaccines, new antiretrovirals, and immunomodulators for asymptomatics, the problem has become more acute. The benefit of early intervention with nucleoside analogs is not clear anymore. While hardly anyone believes that AZT should be pulled from the market, the official government recommendation that all healthy, asymptomatic people with less than 500 CD4 cells take AZT must be reexamined. Ongoing trials of combination nucleosides for early intervention are now much more critical. However, like other U.S. AIDS studies, the combination studies have been criticized for a heavy reliance on surrogate marker data, in particular CD4 cell changes. Although the CD4 data from Concorde surprises no one -- other studies, including ACTG 116b/117, the Alpha study, the VA study, and the CPCRA ddI/ddC study, all suggest that small CD4 changes are independent of clinical outcome -- clinical researchers are unsure what to do next. There are no obvious, well-defined surrogate markers available to replace CD4. Already some in the media suggest that Concorde's ultimate effect will be to lengthen the drug approval process by forcing a return to traditional trial designs using clinical endpoints. On a broader level, Concorde raises disturbing questions regarding the U.S. AIDS research effort. More studies of the nucleosides are likely to provide some additional information to doctors and their patients. Yet, how do we design future clinical trials of these drugs to give us the answers we need? Moreover, have we reached the point of diminishing returns with the nucleosides? Are we better off using the limited AIDS research dollars to develop and test new, more promising classes of compounds? Is there anyone who is presently developing an overall strategy and program for developing anti-HIV therapies? Are the President and the Secretary of Health and Human Services really using the powers of their respective offices to get the best and the brightest to lead our AIDS research effort? The blizzard of press releases responding to Concord reveals the extent of the personal and professional investment many U.S. researchers have in AZT's efficacy. While one should expect a profit- driven corporation like Burroughs Wellcome to interpret the data favorably, U.S. government agencies should be held to a different standard. Sadly, many researchers and government bodies appear to have participated in "spin control" of Concorde. We believe that Concorde researchers have a responsibility to release complete data from the study without delay, and that U.S. government officials, researchers, and doctors must let the science and the study speak for itself. No one really understands the effect of the multiple drug combinations many people with HIV and AIDS take. Many patients, particularly those with advanced AIDS, are often treated with a dozen drugs a day. The risks, and also the costs, of multiple drug treatment can seem remote when the stakes are so high. However, there are real risks. One recent example is the discovery of azole- resistant fungi in those treated with fluconazole primary prophylaxis. If azole-resistant fungi become common, it could have immense negative effects on all people with AIDS. Additionally, the possibility of adverse drug interactions cannot be eliminated and, therefore, must also be acknowledged. Finally, physicians must ensure patients clearly understand that many of the treatments they receive offer no documented chance of ultimate clinical success. Prescribing physicians have had to ask themselves very difficult questions about their personal relationship to their patients. Unquestionably, doctors prefer to cure disease rather than comfort the dying. Accordingly, a knowledgeable and compassionate AIDS doctor told Treatment Issues privately that he would continue to prescribe AZT for his asymptomatic patients even if it did not work. He said there was nothing else for him to do. This doctor's candor highlights the real context within which physicians and patients alike make treatment decisions -- the relentless progression of disease and death. The role hope and fear play in designing and interpreting clinical research must be discussed openly. ================================= ================================= treatment briefs by David Gold ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ d4T Survey ACT UP/Golden Gate is coordinating a survey of individuals taking d4T through the parallel track expanded access program set up by Bristol-Myers Squibb. According to Treatment Agenda, the group's newsletter, a public forum on d4T was held on March 10, 1993 in San Francisco. Of the 44 people on the access plan who have already filled out the survey, the most common side effect mentioned was sleep disturbance, primarily problems in falling back asleep during the night. According to the newsletter, "The consensus of those at the March 10 meeting was that waking occurred at a set time after drug administration, and people taking the drug at mealtime rather than bedtime were having fewer problems." Some participants also reported experiencing "cold hands and feet, that were not peripheral neuropathy" and "increased anxiety and emotional and mood changes." ACT UP/Golden Gate will be publishing more detailed survey results shortly. To participate in the survey or get more information, call ACT UP/Golden Gate at 415/241-8800. Thalidomide for Painful Oral Ulcers Ulcers of the oral cavity (aphthous ulcers) can be a severe and debilitating HIV-related condition. A report in the Journal of the American Academy of Dermatology (February 1992, 271-2) notes that thalidomide, a drug banned in the United States since the 1960s, may be effective in the treatment of oral ulcers. This is one of several anecdotal reports of the efficacy of thalidomide for HIV- related oral ulcers. A randomized, double-blinded clinical trial comparing thalidomide to prednisone (a steroid commonly used to treat aphthous ulcers) would be quite helpful. Gingivitis: An Early Sign of HIV? A recent report in Clinical Infectious Diseases (February 1993, 233- 36) studied patients entering a hospital emergency room in Britain who complained of severe gum pain. Of the 20 individuals tested for HIV, seven (35 percent) were seropositive and three of these seven were previously unaware of their serostatus. The authors conclude that painful gingivitis may be an early sign of HIV infection and that regular dental exams must be part of any HIV treatment regimen. NIAID Fact Sheets on AIDS and STDs The National Institute of Allergy and Infectious Diseases (NIAID) offers fact sheets and brochures on specific AIDS-related treatment topics to the public. Fact sheets about AIDS clinical trials, vaccines, AZT therapy, women and HIV, TB, toxoplasmosis, and PCP are available, as is a brochure about the human immune system. NIAID also offers a set of eleven fact sheets about sexually transmitted diseases. The STD fact sheets are designed for sexually active individuals. They summarize what is known, including ongoing research, about twenty of the most common viral and bacterial STDs. Free copies of these materials are available by calling the NIAID Office of Communications at 301/496-5717. Imuthiol Results Published; Drug Worse than Placebo The long awaited results of a placebo-controlled, multicenter trial of Imuthiol (Ditiocarb) have finally been published in AIDS Research & Human Retroviruses (Jan. 1993, 83-89). Of 2,333 participants, 1,669 received Imuthiol and 664 received placebo. Patients were asymptomatic or minimally symptomatic HIV-positive individuals. After 24 months, AIDS developed in 106 patients on treatment and 68 in the placebo. The risk of progression to AIDS was significantly higher in the Imuthiol arm. Smaller studies had shown benefits to the use of Imuthiol in HIV infection. Yet, because of the results from the larger study, patients are urged to discontinue drug. The manufacturer withdrew the drug from further studies. Imuthiol was once approved in New Zealand and imported into the U.S. by some buyers' clubs. The results from this study underscore the need for caution when making conclusions about the effectiveness of a particular therapy based on small initial studies. Corticosteroids May Increase Risk for CMV Corticosteroids are commonly used for a number of HIV-related conditions including PCP, aphthous ulcers, idiopathic thrombocytopenic purpura, lymphoma, and toxoplasmosis. However, a recent study in AIDS (March 1993, 375-378) suggests that corticosteroid use in PWAs may be associated with a higher risk of developing CMV disease. The study followed 130 PWAs (median CD4 count of 80) who received systemic corticosteroids and found that elevenof the 120 developed CMV disease within one month. The researchers compared this group to a similar cohort (median CD4 count of 87) who did not take corticosteroids. They found that in the group not taking corticosteroids, only two of 130 developed CMV within one month. In addition, those in the corticosteroid group had a mean survival period of CMV of 3.5 months compared with a six- month mean survival time after CMV diagnosis in another similar cohort. The most common corticosteroids used are prednisone, prednisolone, dexamethasone, and methylprednisolone. Reports of Rapid CD4 Decline After Interferon Therapy A letter in The Lancet (April 10, 1993, 958-959) reports three cases of HIV-positive individuals experiencing a rapid, profound decline in CD4 cells after therapy with alpha interferon (IFN-A). Two of the three were given recombinant IFN-A (Roferon) and one was given lymphoblastoid IFN-A (Wellferon). IFN-A is approved for Hepatitis B and C and some suggest it as a therapy for HIV. The authors suggest that IFN-A may induce specific autoimmune reactions in certain HIV-positive individuals which cause a rapid decline in CD4 counts. This report points to how little is known about the effects of cytokine therapy on people with HIV. Vegetables, Angiogenesis, and KS A recent article in The Proceedings of the National Academy of Sciences reports that researchers have isolated genistein, a compound found in soybeans and vegetables in the cabbage family that, in the test tube, blocks angiogenesis. Angiogenesis is the process of new blood vessel growth. Tumors stimulate angiogenesis to supply themselves with blood. Scientists hypothesize that blocking angiogenesis may inhibit the growth of tumors such as Kaposi's sarcoma. People on a traditional Japanese diet were found to have concentrations of genistein 30 times higher than those who eat a Western diet. Among the angiogenesis inhibitors presently being tested as potential KS treatments are SP-PG, Fumagillin, and Platelet Factor-4 (see Treatment Issues, January 1993). A synthesized version of genistein successfully blocked angiogenesis in the test tube. Genistein is the first compound found in vegetables that has anti-angiogenesis properties. A recent article in The New York Times ("Chemists Learn Why Vegetables are Good for You," April 13, 1993, C1) points to the need for well-designed, rigorous clinical trials that can provide clear answers as to the possible benefits of maintaining specific nutritional and vitamin regimens. New PCR Test For HIV Reported A new type of PCR (polymerase chain reaction) test may be a more accurate measure of HIV in the blood. The test, QC-PCR (QC is "quantitative competitive"), is being developed by GeneLabs, Inc. In an article in Science (March 19, 1993), researchers evaluated 66 HIV-positive individuals in various stages of disease and found that those with more advanced disease and lower CD4s had higher levels of circulating virus, according to the QC-PCR test. Additionally, changes in viral load correlated with antiviral therapy and progressive infection. New AMFAR NYS Clinical Trials Directory The New York State AIDS/HIV Clinical Trials Directory Guide for Winter/Spring 1993 is now available. Copies of the directory, which is published by AmFAR, can be obtained by calling 212/682-7440. Free Booklet on Nutrition & HIV Available The Physicians' Association for AIDS Care (PAAC) has produced HIV Disease Nutrition Guidelines: Practical Steps for a Healthier Life, a 21-page booklet which offers easy-to-read nutritional guidelines for people living with HIV/AIDS. The booklet was authored by registered dieticians under the medical peer review of the PAAC Nutrition Committee. It is available, free of charge, through an educational grant from Stadtlanders Pharmacy. To obtain a free copy, call 800/238-7828. ================================= ================================= On the Edge This article inaugurates a new, occasional series in Treatment Issues about experimental directions in AIDS treatment. Part two of this article will appear in a subsequent issue. Gene Therapy in AIDS by Michael Ravitch An expanding number of researchers believe that medicine is on the threshold of a revolution. Using the tools of molecular biology, researchers hope to manipulate directly an individual's deoxyribonucleic acid (DNA) to cure many diseases, including inherited genetic disorders like sickle cell anemia, many forms of cancer, and viral diseases, such as AIDS. While some dismiss "gene therapy" as a distant frontier of medicine, over thirty clinical trials are ongoing, start-up companies are developing gene therapy commercially, and the NIH has devoted a large share of its research spending to this field. Gene therapy could contribute to HIV treatment within the foreseeable future. DNA is the master plan of life. DNA contains approximately 50,000 to 100,000 genes, each of which controls the production of one protein. Proteins form the basic building blocks of life -- they control the structure, functioning, and reproduction of cells. Genetic diseases occur when a mutation alters a gene, resulting in the production of an unwanted protein, or the lack of an essential protein. It is a common misconception that all genetic diseases are inherited. Many diseases, including some forms of cancer and AIDS, originate in genetic mutations acquired after birth. What Is Gene Therapy? Gene therapy does not refer to a specific substance, but to a distinct and emerging branch of medicine, in which new, manufactured genes are inserted into patients to fight disease. Gene therapy includes a wide variety of approaches. While the basic aim is to insert genes which create proteins that fight disease, these proteins can perform many functions. They can compensate for other deficient proteins, inhibit abnormal cellular functioning, or regulate the expression of another gene. Approximately 1-2 percent of infants in the U.S. are born with a genetic birth defect caused by the absence, or in some cases even the presence, of a single gene. Inherited genetic disorders of this sort provide the clearest example of gene therapy's potential. ADA- deficient Severe Combined Immunodeficiency (SCID) is a disease of profound immune suppression similar to AIDS in symptoms, but not in cause. ADA-deficient SCID results from the lack of the gene which produces adenoside deaminanse (ADA), a protein crucial to the workings of the T-cell, an important immune cell. Scientists implanted the ADA gene into the T-cells of children with the disease. Since 1990, two little girls with the disease have been transfused with their own gene-corrected T-cells. There is yet to be a controlled clinical study; no real evidence of benefit can be garnered so far. However, it is very encouraging that the gene seems to perform inside the body and the T-cells function normally. This indicates that, despite many technical hurdles, gene therapy is feasible. The optimism engendered by the ADA work has to be tempered by the profound technical hurdles which remain. The greatest technical challenge thus far is how to insert the right genes into the right cells in the body. Disabled viruses are the most commonly used delivery method. One way to understand this is to remember how a virus works. A virus is essentially a piece of genetic material which survives by integrating itself into DNA of other organisms. Scientists can immobilize a virus, such as an adenovirus (a family of viruses which cause disease in the respirtory tract and eyes), and insert new genes into it. The immobilized virus does not have the ability to replicate itself, or cause disease, but does retain its capacity to infect cells and transmit the synthesized gene. However, there are serious safety concerns with the use of viruses as delivery methods. It is possible that a defective virus can recombine in the body and create new, pathogenic viruses. Last year, investigators at the NIH reported that three monkeys in a gene therapy protocol developed malignant lymphomas after receiving a contaminated viral preparation. For this reason, the NIH and FDA have developed strict, and some say time-consuming, regulations to govern gene therapy experiments. Technical Problems Another dilemma is that, in order for these viruses to target specific cells, they can only be inserted into cells outside the body. Researchers must first extract the designated cells from the patient's blood, expand those cells in the test tube, and infect them with the viruses carrying the desired gene. Subsequently, the gene- modified cells are reintroduced into the patient. This is a cumbersome and expensive process, with many technical difficulties. There are other technical problems as well. Into which cells should the therapeutic gene be implanted? And how can the right cells be targeted without damaging them? Some raise the concern that random insertion of new genes could cause changes in host cell DNA and thereby cause disease. Theoretically, this may be possible, but it has yet to occur in any gene transfer experiments to date. Other options for delivering genes into cells are also emerging. One of the most exciting is the prospect of "naked DNA" injections, whereby DNA is directly injected into the target cells. In some experimental models, DNA is packaged in a liposomal complex (a fatty covering) to help it bypass the cell walls. Other researchers are successfully injecting DNA directly into muscle tissue. In one notable experiment, patients with advanced melanoma (a type of skin cancer) are receiving DNA injections directly into their tumors. Scientists at the NIH are considering direct injection of therapeutic DNA into the lymph nodes of people with AIDS. Gene Therapy in AIDS HIV, like all viruses, can be described as an acquired genetic disease. HIV integrates itself into human DNA to transform cells into factories for creating copies of itself. HIV-infected cells produce viral proteins and then assemble them into new viruses. Ultimately, viral infection and replication destroy the host cell. Scientists have identified many of the proteins which play a part in the replication of HIV. These include enzymes such as reverse transcriptase, protease, and tat. Anti-HIV drugs function by attacking these proteins. For example, drugs like AZT, ddI, and ddC are aimed at the reverse transcriptase enzyme; the protease inhibitor is aimed at the protease enzyme. The great disadvantage of this approach is that it does not halt the production of these malignant proteins at their source. The drug must be given in high doses, to disable every copy of the protein, and must be given for the lifetime of the patient. Gene therapy, on the other hand, acts against the origin of the disease, the malignant HIV genome. Many strategies are being considered to fight HIV at the genetic level. Some scientists seek to engineer genes which protect a cell from infection; others create genes which regulate HIV into harmlessness. Although there are encouraging words from initial test tube models, none of these approaches has been tested in humans. Theoretically, gene therapy has at least one great advantage over current therapies; by implanting the mechanism for fighting disease within our genetic code, the treatment would last as long as the host cell. There is great hope for the future that if researchers can manage to implant therapeutic genes into stem cells (the progenitor cells of all blood cells), every blood cell could be immunized against HIV infection. To help understand the future direction of AIDS gene therapy, it's useful to examine the first two ongoing AIDS gene therapy protocols. The two clinical studies attempt to bolster the immune systems of people with AIDS through insertion of new genes. This approach attempts to marshall the natural defenses of the body against HIV. Researchers at Viagene, a San Diego-based biotechnology company, have developed a gene therapy intended to work like a gp160 therapeutic vaccine. They plan to insert a gene expressing the HIV envelope protein gp160 into cells from patients' arms. The production of this protein is expected to induce specific and potent immunological responses against HIV in a way similar to the well- known gp160 vaccine. In vitro and animal studies show no evidence of toxicity. The significant difference between the gene therapy product and the therapeutic vaccine is that the viral protein would be produced inside the cell, rather than introduced from outside. Viagene scientists claim that this method stimulates a better immune response than the conventional vaccine product. For information about Viagene's trial, and future protocols, call 619/452-1288. The other ongoing gene therapy trial in HIV takes place at the Fred Hutchinson Cancer Center in Seattle. Dr. Phil Greenburg is conducting a trial in HIV-infected individuals with lymphoma (cancer of the lymph system). This is a significant protocol, not only because it offers a radical option for people with terminal lymphoma, but because of how it might advance our knowledge. It is quite a complex trial. Patients receive high-dose radiation and chemotherapy to destroy the lymphoma. Then the patients are given a bone marrow transplant from a gentically similar sibling (not necessarily an identical twin). At that point, the recipient should generate an entirely new immune system. In order to prevent reinfection with HIV, the patient will be given AZT as well as gene- modified HIV-specific Cytotoxic T Lymphocytes (hereafter CTLs). CTLs are a type of immune cell involved in fighting viral infection. The gene that has been added to the CTLs serves only one purpose: a safety precaution. If the patient is unable to tolerate such a massive introduction of CTLs, the implanted gene allows the researchers to kill off all the new cells and save the patient. If the gene is successfully expressed in the re-implanted cells, it confirms the validity of this approach. Once scientists learn if gene therapy can be used to alter CTLs, more powerful CTLs can be produced which do not need to be extracted from the patient. Conclusion Gene therapy is rapidly expanding right now. Money is pouring in, interest and publicity increasing. Some researchers fear that disappointment will inevitably follow the hype, and the tide of support will recede. Furthermore, safety concerns about gene therapy are grave, and research is proceeding slowly and cautiously. The doubts about gene therapy are not all scientific. Some worry that gene therapy researchers are playing god. They fear that it will inevitably be used to damage (or, worse yet, improve) future generations. These arguments must be taken seriously, for they are significant. However, one must recognize a distinction between genetic manipulation of the genes which control reproduction and gene therapy directed at genes which only function after birth. Modification of genes which function after birth would, as a medical treatment, not affect the human gene pool any more significantly than an organ transplant. But then there is the enormous cost, possibly reaching $200,000 per patient at the present time. This is a legitimate concern, especially when so few have basic health care. Furthermore, it is difficult to imagine bone marrow transplants and ex vivo gene transfer becoming available to the projected 100 million HIV-infected people around the world. Yet gene therapy in such forms as naked DNA could be quite simple and inexpensive. Moreover, gene therapies that now are extremely expensive may become less so as technology advances. Also, knowledge from gene therapy experiments today may help to develop entirely new approaches in the future. Nevertheless, it is still likely that researchers will have to overcome very complex and cumbersome technical problems before a safe, effective, and affordable gene therapy arrives. ================================= ================================= Washington Watch by Derek Hodel How much do we currently spend on AIDS research? Is it enough? Too much? Just right? How does what we spend on AIDS compare to what we spend on research on other diseases? These questions are currently being posed in the House of Representatives as the Congress considers President Clinton's first budget proposal for fiscal year 1994, which begins on October 1. In his first FY94 budget, President Clinton requested a total of $1.3 billion for AIDS research, an increase of $227 million, or 21 percent more, over FY93. This increase, if approved by Congress, would be the largest percentage increase for AIDS research since FY90, and the largest dollar increase ever. Unfortunately, the President's budget does not include proportional increases for other NIH programs. In fact, while the AIDS budget will see substantial growth, the overall NIH budget will increase by a paltry 3.8 percent, less than the biomedical inflation rate of 4.1 percent. Some programs will, for the first time, be subject to cuts. (Women's health programs, primarily breast cancer, and the Human Genome Project will also see significant increases, however.) Of course, the President's budget request does not necessarily determine what will be appropriated by Congress. In fact, prior to 1990, Congress, in response to a hostile administration, uniformly appropriated substantially more funding for AIDS research than requested by then-President Reagan. Beginning in 1990, however, the increases began to subside, and in 1991, the Congress for the first time appropriated less than requested by the President. The net result: for the past three years, AIDS research funding has been essentially flat. AIDS research now accounts for approximately 10 percent of the overall NIH budget, a proportion that has remained consistent even as real increases in AIDS funding subsided, illustrating the diminishing support for biomedical research in general. This year, the NIH will spend $1.077 billion on the AIDS research conducted at the 21 institutes, centers, and divisions that comprise the agency. The National Institute for Allergy and Infectious Diseases receives the greatest proportion of that money ($460 million) followed by the National Cancer Institute ($175 million), and the National Institute for Mental Health (NIMH) ($127 million). Even the smallest institutes conduct AIDS research; the National Institute on Aging (NIA) receives $1.1 million. The budget for each fiscal year takes nearly 24 months to develop, so at any given time, no less than three budgets are in the picture: the current year, plus two future budgets. Initially, each institute proposes its own budget, split into AIDS and non-AIDS. The total AIDS budget is then reviewed by the Office of AIDS Research (OAR) and the Director of the NIH, who attempt to eliminate redundancies among the institutes. The final NIH research budget is referred to as a professional judgement budget and reflects what the agency feels are 1) scientifically justified and 2) doable, with sufficient resources. The professional judgement budget is then reviewed (and usually cut) at each layer of the bureaucracy between the NIH and the President. (The layers: Director of NIH, Director of the Public Health Service, Secretary for Health and Human Services, Director of the Office of Management and Budget, and finally, the President.) Next year, if the NIH Revitalization Act of 1993 passes successfully, this process will be a little different. Instead of 21 separate budgets being passed up the ladder, a single AIDS budget will be developed by the Director of the Office of AIDS Research. This "bypass budget" will then be submitted directly to the President for review and transmittal to Congress. In addition, a separate discretionary budget is expected to be authorized for $100 million to fund emergency research programs or take advantage of emerging breakthroughs. The President's budget, which is informed by a combination of department advice and politics, is then submitted to Congress. It is reviewed first in the House and then separately in the Senate. Finally, the two versions are combined into an appropriations bill that is sent to the President for signature. In both the Senate and the House, the appropriations committee is divided into thirteen separate subcommittees, each of which processes a separate appropriations bill. The Labor/Health and Human Services/Education subcommittees are responsible for the bulk of AIDS spending (excluding FDA and the Department of Defense). Each subcommittee conducts hearings to solicit both public and administrative branch input before marking up the bills. Once marked up, the bills must be voted on by the full House (or Senate). Each bill is accompanied by a committee report to clarify Congress' intentions, not always apparent in the statute. The report language may contain (sometimes controversial) earmarks that require specific spending. In past years, earmarks have been the mechanism whereby Congress insured that monies were spent on AIDS when the administration was disinclined to do so. In fact, in years past, the entire AIDS research budget was protected by an earmark. More recently, however, earmarks have directed program efforts without providing the necessary extra funding, sometimes skewing ongoing research. (One example is the $40 million pediatric research earmark that caused a substantial shift in funding away from ongoing projects.) As the House, and then the Senate, consider the President's budget request, the pressure will be on appropriators to diminish the percentage increase for AIDS and to shift money back toward other diseases. Although competing lobbyists on the Hill don't usually come right out and say "take it out of AIDS," the underlying message is pretty clear. With AIDS research getting the lion's share of the new money directed toward the NIH, it sticks out like a sore thumb. Traditional lobbying approaches including visits with congressmen and senators are being employed to ensure that legislators preserve the President's request. AIDS Action Council, the Treatment Action Group, and AmFAR urge concerned individuals to contact their representatives in Congress through letters and phone calls. They believe that now is the time to act and that constituent pressure can influence the amount ultimately allocated for AIDS research.