Date: 05 Jun 94 09:58 PDT From: "John S. James" AIDS TREATMENT NEWS Issue # 200, June 3, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Antivirals and Immune Recovery: Interview with Michael S. Saag, M.D. D4T (Stavudine): Approval Recommended Government AIDS Research: the ACTG. Interview with Michael S. Saag, M.D. ***** Antivirals and Immune Recovery: Interview with Michael S. Saag, M.D. by John S. James Michael S. Saag, M.D., is Associate Professor in the Division of Infectious Diseases at the University of Alabama at Birmingham. He is both a laboratory scientist and a physician who treats patients. "I combine my laboratory experience and my clinical experience, and participate as a member of a dynamic scientific group here at the University of Alabama at Birmingham, where I help translate what's happening in the lab and what's happening in the clinic, so the clinical and laboratory groups can communicate efficiently. We are trying to coordinate new developments in the laboratory with clinical care and apply the developments to patients as soon as possible." Dr. Saag's group has done some of the earliest work with L- 524, the Merck & Co. protease inhibitor, a new anti-HIV drug which is now in small-scale clinical trials. He is finding evidence that the immune system can recover on its own to a surprising degree, even from late-stage AIDS -- if the virus can be suppressed enough, as measured by experimental blood tests. AIDS Treatment News: In a time of widespread pessimism, you have said that there are important grounds for hope. Dr. Saag: Much of the pessimism among HIV patients and their physicians accelerated a little over a year ago, as the Concorde data [questioning early use of AZT] started to be discussed. I saw people get hung up on the details of a single study, and lose sight of the big picture. In the big picture, this is a viral disease. The virus constantly wants to replicate, and the immune system tries to suppress replication. The use of antiretrovirals helps suppress the virus, but to date, the available agents are effective for a limited time. The good news is that we have learned a lot about HIV in less than a decade. We can target specific elements of its life cycle to attack with antiviral therapy. We can test new approaches [for example, protease inhibitors] in the laboratory and find that they work; now we are beginning to test them in people and find that they work quite well, at least so far. The fact that we can figure these things out is quite a testimony to basic sciences being applied to clinical medicine. This is unprecedented in the history of treating infectious diseases, where discoveries are usually made by lucky accident, rather than by a reasoned approach to drug development. And now we have newer techniques to measure how well these drugs work; we can follow the viral burden, as measured by circulating RNA levels of the virus. We need more research to be sure that tests not only tell us that the drugs are active, but also translate into clinical benefit. Then we can use the tests to tell us which drugs are working best in a specific individual. If we can achieve that, it will be a real step forward, and we will be great shape in the next two or three years. ATN: Is the P24 antigen test not very effective? Saag: It could be OK if someone has a level that is measurable. But for the majority who are not p24 positive, or for those who are marginally positive and convert to negative, you cannot tell how well the drugs are working and how long their effect lasts. I think the HIV RNA is a much more direct marker in people; I believe that ultimately it will be proven to be useful in day-to-day practice. ATN: What needs to be done to get more certainty, and to make these tests more widely available? Saag: We need to show that the tests correlate to clinical outcome. That is easy to say and hard to do. One approach would be a retrospective study -- a case- controlled evaluation of a known cohort. We could use stored specimens from previously conducted trials, and select specifically those individuals who had disease progression, and compare them with those who did well on the study. This might require several hundred patients over many time points. Then we will see if these tests can indeed predict who is going to do well. Other studies may prospectively evaluate the marker, allowing those with a poor prognosis to keep trying different treatments until the tests show that the prognosis has improved. It has been shown that CD4 counts (T-helper counts) can show indirectly whether or not an antiviral drug is working. But they are not good at telling us precisely what is going to happen to an individual clinically. That has always been a problem in comparing drugs; first, because existing drugs were not powerful enough to make profound changes in T-helper counts and immune system restoration, and secondly, because there is much variability in the measurement of the counts. T-helper counts are still useful, but not as good as they need to be. These new blood tests (for levels of HIV RNA) may fine-tune the measurement so we can predict how someone is going to do clinically. ATN: Has early experience with the protease inhibitor L-524 shown that, if you can suppress the viral load, there is evidence of immunological and clinical improvement? Saag: AZT seems to do this as well, but to a smaller degree. If you reduce viral burden by ten fold, with AZT, you'll see an increase in T-helper counts, but not a profound increase. They may go up from 50 to 100, for example, or 100 to 200. But it seldom does much better than that, and the durability of the increase is about six to 12 months, if you start later in the course of the disease. If you start earlier, for example with baseline counts of 400 to 500, the durability may be 18 to 36 months. With the protease inhibitor L-524, we have seen some examples of viral burden dropping around 100 fold. When we achieve that, we can see at least temporarily a substantial increase in T-helper counts -- in some cases from below ten, to around the 200 range, lasting for several weeks or months. This is important because it is proof of concept that the protease inhibitors indeed can work, and that they mirror what we hoped to see from the test-tube experience. Also, it shows that if you can suppress viral replication to a more profound degree than with AZT, then the immune system has some ability to reconstitute itself, at least as measured by the T-helper count. To a degree we knew that from AZT; now, with new agents which may be more potent than AZT, we are seeing more immune system reconstitution as a natural consequence of reduced viral replication. [So far the effect is temporary, however, since HIV develops resistance to the drug, and then the viral load increases.] The recent experience with L-524 and other antiviral drugs has been telling us a lot about viral pathogenesis. The virus is becoming easier to understand in terms of what it is trying to do -- to survive and replicate. It is constantly trying to infect new cells, and to turn itself over [replace the current virus with new generations]. This suggests that ideally we should be treating patients as early as possible. Whether people believe that AZT is good enough to begin therapy when T-helper counts are above 500 remains to be seen in clinical trials. But if we could imagine drugs that are two, three, or ten times better than AZT, then I don't think there would be much of a debate. If they are relatively nontoxic, we will be using the drugs as early as possible. ATN: We heard about one person who started L-524 with a T- helper count of 600, and had a large increase which continued even after the drug was stopped. Saag: One patient was in our earlier studies, when we just treated patients for 12 days. He had a T-helper count in the 600 range, and it did go up to over 1000. He only had 12 days of therapy, and he stayed around 1000; he is still there at this time (12 months later). I can't say that this was due to the L-524, but it is a possibility. If we consider that this is a virus that is constantly trying to replicate, when you give antiviral therapy, you're adding air support for the infantry; perhaps using a drug with that much activity early in the course of disease may have allowed his immune system to get a better handle on the viral infection, and gain better control -- having effects even long after the drug was present. The other possibility is that the T-helper increase would have happened anyway, due to variability in the expression of the disease. But usually one would expect that T-cell counts, left to their own devices, would continue to drift downward, not bounce up by 400 cells per cubic millimeter. ATN: It would make a lot of sense to try this treatment with a few more patients, and see if it happened again. Saag: I think so. We should do it in a controlled way, following people with that goal in mind. Remember that in the early studies with this compound, all we were really looking for was safety and the pharmacokinetic profile; what happened to the patients clinically was more of an incidental observation; we were certainly interested in it, but that was not an objective of the study. We need more research on earlier infection. Indeed there are some trials in development right now, not so much with protease inhibitors just yet, but with some of the nucleoside analogs [e.g. AZT, ddI] and non-nucleoside reverse transcriptase inhibitors [e.g. nevirapine, or delavirdine], looking at earlier interventions to see what antiviral effects we get in people with higher T-helper counts. ATN: The big interest now is combination treatments, for delaying or avoiding resistance; this has worked for other diseases. Is there anything you can add from your work? What combinations would make sense to test with L-524? Saag: The results so far with the Merck drug (L-524) are all with monotherapy [the drug alone, not in a combination]. Roche is finding some success with their protease inhibitor in combination with AZT. So the first approach would be to use the protease inhibitors with AZT. The rationale is that you're attacking two different areas of the viral life cycle; that is sound reasoning. Another approach would be to combine a protease inhibitor with other nucleoside drugs that have different toxicity profiles [for example, ddI], or perhaps with non-nucleoside drugs, such as nevirapine. We may also want to try combining different protease inhibitors. The resistance patterns for the different protease inhibitors are different. After growing HIV in cell culture in the laboratory [with low doses of a protease inhibitor, to deliberately produce resistant viruses], resistant or less susceptible viruses can be identified, and they have certain changes in their genetic structure that confer the resistance. If you do this with another drug, you get a virus which is less susceptible to that drug, but often not less susceptible to the first drug; there may be little or no cross resistance. The reason is that different changes in the genetic makeup of the virus give resistance to the different drugs. So if you have the two drugs together in the same patient, you might have broader coverage against the two types of genetic changes that could occur, just using protease drugs. That may work well in the future. But first we must prove that the new drugs are safe and well tolerated, and that the drugs being combined do not have harmful interactions. If they can be safely administered together, a combination test will be important. ***** Government AIDS Research: the ACTG. Interview with Michael S. Saag, M.D. by John S. James [Note: This interview was conducted as a continuation of "Antivirals and Immune Recovery," above.] Michael S. Saag, M.D., a researcher at the University of Alabama at Birmingham, is a new member of the Executive Committee of the AIDS Clinical Trials Group (ACTG), the main U.S.-government program for clinical trials of AIDS drugs. Among other responsibilities, Dr. Saag directs the subcommittee in charge of the ACTG's interaction with outside groups, including the pharmaceutical industry, community organizations, and government medical-research teams outside the ACTG. ATN: What is most important for our readers about the ACTG? Saag: I think the ACTG is a very valuable resource for the country. It has taken a lot of criticism, some of it fairly applied. But the success of the ACTG is not widely understood. If you think about what happens in clinical practice today in a doctor's office, and compare it to six or seven years ago, you will find that much -- perhaps 70 to 80 percent of the activities of a physician, in terms of new approaches to management of their HIV patients -- was initiated through the results of an ACTG trial. When you go to conferences, and hear discussions about patient care and trial results, you almost always hear references to ACTG studies. There have been many contributions, not only in the primary infection area [treating HIV itself], but especially in opportunistic infectious diseases. What types of prophylaxis work best, what is the best treatment for cryptococcal meningitis or pneumocystis pneumonia or CMV retinitis, these results have usually come from ACTG trials. People should recognize that the ACTG has made major contributions. Also, much that goes on behind the scenes at the ACTG helps pharmaceutical-industry studies. Consider the quality assurance program that assures that virology labs working with the ACTG all operate in a standardized way, and that the measurements of T-cell counts are standardized. All these spill over into industry trials. The sites that are ACTG funded also can do industry studies, and whenever a company goes to those sites, it is using the same laboratories that are ACTG certified. That's been a very important plus for studies that are not ACTG affiliated. In the future, due to a recent reorganization, the work of the ACTG will be based more directly on a foundation of its scientific agenda. In the past, an individual researcher at an ACTG site would come up with an idea, propose it as a concept sheet, and go through the system from the bottom up. While that is democratic and taps into the great resources of a number of very talented people, it can also be inefficient. In the future, all these researchers with their talents and ideas will first come together to brainstorm and come up with a scientific agenda, and then develop specific protocols to address that agenda. This should speed protocol development and the conduct of trials. ATN: We have heard of many cases where concept sheets don't go anywhere, probably because the leadership does not agree with them. This change might help to avoid that problem. Saag: I think it will. And I think the other problem is that some members of the ACTG, especially in leadership positions, get so inundated with paper, having to keep up, that it's hard to give every concept sheet a clean, fresh look every time. You never know when one is going to be coming in. So we will back up and say, "What are the big-picture issues that we should be addressing as a group?" We will define those questions, establish that agenda, prioritize, and then ask, "What kind of trials will help us answer this question?" I believe that the proposal I have seen will reduce protocol development time -- going from an idea to a protocol open for enrollment -- from over 230 days down to about 85 days. This is about to be implemented. Also, we also should keep in mind what would happen if the ACTG did not exist. Suppose it had never been created; what would people be saying about what ought to be done? They would say that we should get together some of the best scientists and clinical investigators in the country, and form a network where they could work together and study new approaches to treat the disease. Also, you would want to bring those people together, at least semi-annually, to talk about progress, discuss current issues, decide directions together, and then implement those new protocols and studies that they come up with. That is precisely what the ACTG is. The problem is that it has been inefficient in its ability to get things done quickly; it has been too bureaucratic in the past. I think that with the reorganization it will become more streamlined, and enable us to fulfill those desperately needed missions of having some of the better investigators in the country working together on joint projects. I'm very encouraged by what is happening. There is a dynamic interaction within the ACTG leadership, and a lot of dedication to making the organization run efficiently, and be as productive as possible. I'm optimistic that we can do that. But it will take much work to get us to that next level. ATN: Recently some leading scientists have called for a redirection of AIDS research. [See "AIDS Research Direction: New Scientific Approach?," AIDS Treatment News #199, May 20, 1994.] Some have interpreted Dr. Fields' recent paper as calling from a shift from clinical to basic research; but what he really seems to be saying is that there should be better communication between the laboratory studies and the clinical trials which test new drugs in patients. Where do you think we should focus now? Saag: There has been a fairly strong emphasis on basic science from NIAID [the U.S. National Institute of Allergy and Infectious Diseases, which runs the ACTG] over the last five or six years. In 1987, there was a project called Programs for Excellence in Basic Research on AIDS (PEBRA); our team at the University of Alabama was one of the recipients of that award, and that is what started us coordinating the clinical side and the basic science side. That's the kind of initiative we should continue with. NIAID has continued this approach, with the new SPIRATS grants, which encourage investigators to work together from the beginning of a new concept of treatment, to developing that approach in the laboratory, and carrying it through all the way to the initial clinical trials. [Note: SPIRATS stands for Special Program for Innovative Research on AIDS Treatments. The first five to eight SPIRATS grants are expected to be awarded in August 1994.] This is an important initiative that encourages creativity among investigators within different disciplines, having them work together. This kind of approach is where progress in HIV will come from. I think we do it at the University of Alabama about as well as it's done anywhere; it was the U.S. National Institutes of Health programs that got us going. The PEBRA, our Center for AIDS Research, and other government programs, have all been used to have scientists from different disciplines work together. This is the critical issue that should be emphasized, rather than segregating out more money for basic science, or for clinical science. We are trying to get money used in a way that maximizes the interaction between the different disciplines and different research groups. ***** D4T (Stavudine): Approval Recommended by John S. James The experimental anti-HIV drug d4T (generic name stavudine, brand name Zerit), now widely available in a "parallel track" program for patients who cannot successfully use either of the approved drugs AZT or ddI, was cautiously recommended for early approval by the Antiviral Drugs Advisory Committee, at an all-day public hearing on May 20. The FDA [U.S. Food and Drug Administration] must make the final decision on whether to grant approval on the basis of the data so far available; it does not have to follow the recommendation of its advisory committee, but usually does. There has been considerable confusion about this hearing and what it means. We believe that most of the confusion does not involve d4T itself. Rather, it arises from the difficulty of fitting the particular situation of this drug into the existing body of approval regulations, in such a way that a reasonable result is achieved. [Note: This writer did not attend the hearing. This report is based on discussions with people who were there.] Background A major clinical trial of d4T (known as the '019' study) is still underway in the U.S.; it is expected to finish at the end of 1994. After completion of this trial, it will take months to analyze the data and schedule another hearing of the Antiviral Drugs Advisory Committee; as a result, approval will be delayed for about a year if it is necessary to wait for the final data and its analysis. To avoid this delay, the developer of d4T, Bristol-Myers Squibb Company, asked for an earlier approval under the new "accelerated approval" regulations. These regulations allow the FDA to approve a drug for serious or life-threatening illnesses, when no other satisfactory treatment is available, on the basis of "surrogate markers" (for example, blood tests such as the T- helper count, which seems to provide a crude measure of a drug's effectiveness). But the pharmaceutical company must finish its clinical trials, in order to eventually obtain conclusive proof that the drug is clinically beneficial to patients. D4T Results The May 20 hearing focused on partial data from two human studies of d4T. One is the Bristol-Myers '019' study -- the ongoing clinical trial mentioned above. The other is the parallel track program, run by Bristol-Myers with FDA permission primarily for compassionate purposes, to make the drug available before approval for persons with no other therapeutic option. The '019' study includes 822 patients. All of them had been on AZT for at least six months (but often considerably longer). When they entered the study, each patient was randomly assigned to either continue AZT, or switch to d4T. The study is "blinded"; neither the patients nor their physicians were told who is getting which drug. At the May 20 hearing, data was available for 359 patients. Data from the other 463 patients could not be used, because their treatment is still blinded. (Researchers are very reluctant to break the blind prematurely, since doing so could bias the study.) About 14 percent of the patients in this study entered with a T-helper count under 100. About 50 percent were in the range of 100 to 300; and the other 36 percent were over 300. Only 10 percent had an AIDS diagnosis at entry. The data showed that: * Those assigned to d4T had an average rise to a maximum of about 20 to 25 in their T-helper count, compared to baseline (just before their d4T treatment began). Counts then declined, however, and by week 16, the average increase from baseline was only about 10. For those assigned to continue on AZT, T-helper counts decreased. According to Bristol-Myers, a difference of 50 in the T-helper count between groups was maintained for up to 60 weeks. * HIV titer (of PBMC-associated virus) dropped 53 percent from baseline, for those on d4T. For those on AZT, the titer increased 11 percent. * The d4T group also showed improvement in weight gain over the AZT group. The weight gain on d4T was small, however, and there was no significant weight gain for those with T-helper counts under 100. But the average difference between the d4T and AZT groups exceeded 2 kilograms (4.4 pounds). * In an interview with AIDS Treatment News, Lisa Dunkle, M.D., who presented some of the data for Bristol-Myers at the May 20 hearing, said that the d4T group showed hematologic improvements over the AZT group. She did not present the hematologic data at the hearing, however. * According to Dr. Dunkle, there was also a marked difference in favor of d4T in reduced side effects -- with the only adverse event being peripheral neuropathy in 12 percent of the patients after one year, and in only half of those was it serious enough to require discontinuation of the drug. (See other views of side effects, below.) The data now available from the parallel-track program was less clear. This program is only for patients who had already tried and failed both AZT and ddI. As would be expected, they tended to be at a more advanced stage of HIV infection; their median T-helper count at entry to the parallel track was 41, and 75 percent of these patients had a T-helper count under 100 (compared to only 14 percent for the '019' study, as reported above). In order to collect scientific data from this program, patients were randomly assigned to two different doses of d4T -- either the standard dose of 40 mg twice a day (the dose used in the '019' study), or half that dose, 20 mg twice a day. After a median time of 40 weeks, 79 percent of the patients were still alive. As a check to make sure that patients were not left on a dose known to be inferior, a group called the Data Safety Monitoring Board (DSMB) secretly unblinded the study and compared the two doses. It found that there was no survival difference between the doses, but that those taking the larger dose had a somewhat higher risk of peripheral neuropathy -- 21 percent of those receiving 40 mg twice a day, vs. 15 percent of those receiving 20 mg twice a day. As a result, the DSMB asked that the 40 mg dose be discontinued in the parallel track, and those who had been receiving it were switched to 20 mg. Since the survival rate was the same with the 40 mg and 20 mg doses, does this mean that the two doses both worked equally well -- or does it mean that the drug did not improve survival for those patients at all? We cannot tell from the parallel-track data. There was no placebo or no-treatment group (which would have been unethical in this situation); and it was also impossible to compare d4T with AZT or with ddI, since the patients had to fail both of those drugs as a condition for getting into the parallel track. (The '019' study is designed to look for a survival difference -- between switching from AZT to d4T, vs. continuing on AZT -- so we should have information after this study is completed.) Patients in the parallel-track program were not required to obtain regular T-helper counts. Somewhat fewer than half of them did choose to do so; and for them, T-helper counts tended to be stable for over a year. Regulatory Issues There has been some confusion about just what the May 20 hearing did decide, and what it means. To understand the current status of d4T, certain background should be kept in mind: * The studies are not comparing d4T against AZT (or against ddI or ddC, the other approved anti-HIV drugs) as a starting treatment. (Early, smaller studies evaluated d4T as a starting treatment in some patients, and found that the T- helper count rise appeared to last for a prolonged period -- but the large studies now ongoing are not designed to confirm this result, or to make sure that it translates into clinical benefit.) Also, there is no study comparing switching to d4T vs. switching to ddI, as a second treatment after AZT. Nor is there any comparison of d4T in combination with other anti- HIV drugs. These obvious question, that doctors would like to have answered, will not be addressed in the approval of d4T. * Despite the limited information, and the disappointment due to the small T-helper count improvement seen in the '019' study, there is a widespread feeling that, on balance, d4T should be approved -- without waiting an extra year for the final data from the '019' study. Everyone knows that existing HIV treatments are inadequate; and all the evidence suggests that some people do benefit from d4T. At the same time, the existing parallel track program restricts access to the drug, and limits the normal development of clinical experience by physicians. Bristol-Myers has provided this program as a public service, at a cost of millions of dollars which it may not be able to recover, instead of denying the treatment to thousands of people. (But there is increasing concern that as the overall process of drug development becomes more expensive, other companies will avoid developing potential AIDS drugs, and may even conceal important treatment leads.) * The regulatory complication about approving d4T now is the following. The FDA's new "accelerated approval" regulations would need to be used, since the data so far shows improvement in blood tests and in weight gain, but not in "clinical endpoints"; there is not enough data yet to provide statistical proof that, in the long term, certain patients treated with d4T will do better than those treated otherwise. The accelerated approval system was designed for just this situation. But the accelerated approval regulations require that no other treatment be available; the point is to allow the increased risk of approving a drug early, without clinical- endpoint data, in situations where the need for the drug is very urgent. This is the case with those in the parallel track program, as they have already failed standard treatments. The complication is that while accelerated approval does apply to one group of patients, the best data available are from another group, those with less advanced disease (who are in the '019' study). An additional complication is that the dose which generally appears best and will probably be approved, 40 mg twice a day, is the dose which the DSMB discontinued for those in the parallel-track program -- the patients that an accelerated approval will need to address. In other words, there seems to be a general consensus that d4T should be approved; but the factual situation of this drug does not exactly match what the regulations were designed for. The FDA staff seems to have sidestepped this potential red-tape gridlock by asking the Advisory Committee to answer particular questions which have the effect of leaving the situation open. This gives the FDA staff more freedom to make the right decision on the basis of all available data, as it comes in, without needing to wait a year for the '019' study to be completed. The FDA asked the Antiviral Drugs Advisory Committee to vote on the following questions: "1. Does there exist a population for whom stavudine [d4T] will provide meaningful therapeutic benefit over existing therapies? If the answer is yes please comment on the characteristics of that population. "2. Has the applicant provided evidence from adequate and well-controlled clinical trials establishing that stavudine has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit?" The Advisory Committee answered yes to both questions, by majority vote. This is considered a recommendation in favor of approval. Side Effects Controversy Over a year ago ACT UP/Golden Gate, a San Francisco-based activist group, started a series of public forums for people in the d4T parallel-track program, independently of Bristol- Myers or anyone else involved. ACT UP also developed a survey, and its own computer database to record peoples' reports, and was in phone contact with patients around the country. In July 1993 ACT UP/Golden Gate reported that more than half of the patients in its database had some degree of peripheral neuropathy or other side effect that they thought might be drug related. The organization presented an updated version of its report at the May 20, 1994 hearing on d4T. [Note: This writer usually attends the weekly meetings of the ACT UP/Golden Gate Treatment Issues Committee. We were not involved in the d4T study, however.] A practical result from the ACT UP study is the suggestion that, if people have sleep disturbances while taking d4T, the problem can often be corrected by not taking the second dose at bedtime, but taking it earlier in the day. In addition, the Conant Medical Group in San Francisco did a retrospective study of the case reports of about 100 of its patients who participated in the d4T parallel track program; it found that more than half of them reported adverse effects which might have been drug related. While this study has not yet been published, the Conant Medical Group sent a summary report to the FDA before the May 20 meeting. These numbers are considerably higher than those reported by Bristol-Myers, and also by the DSMB. No one knows why there is this difference. Self-selection may have had a large effect on the ACT UP numbers, since those who have problems during a treatment may be more likely to come to a meeting and be recorded in the database. But self selection would not be expected to have affected the Conant study. The differences might also have occurred if Bristol-Myers and the DSMB made more effort to screen out minor side effects or those which appeared not to be drug related, while the other reports counted everything. The major side effect of d4T is peripheral neuropathy, which can also be caused by HIV itself. This makes it hard to interpret reports of side effects -- especially since the patients in the parallel- track program usually had advanced AIDS or HIV infection, which would have caused a number of cases of peripheral neuropathy that were not due to the drug. The issue of side effects should be kept in perspective. ACT UP/Golden Gate, which first reported seeing a larger number of side effects, still supported approval of d4T at the May 20 hearing -- but asked for neuropsychiatric studies focusing on possible adverse effects of the drug. And the Conant Medical Group is continuing to use d4T through the parallel- track program. The issue of side effects will affect medical management of d4T use, but it has not changed the belief that the drug can be useful and should be available. Comment At the May 20 meeting, the FDA also asked the Advisory Committee to meet again, on the subject of "surrogate markers" in AIDS drug approval (for any drug, not focusing only on d4T). This concerns the ongoing controversy of whether we can trust blood tests such as T-helper counts, or clinical indications such as weight gain, as proof that an AIDS drug is really a benefit to patients. On this issue, we believe it is time for AIDS community as a whole -- as well as the FDA, and its advisory committee -- to step back and take a look at the big picture. And the big picture, we believe, is that far too much effort is being spent agonizing over the details of marginal drugs which will never work very well. Instead, we should quickly approve the drugs when there is good safety data and some indication of benefit. Then we can re-focus research attention and resources on the discovery and development of fundamentally better treatments. AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS Treatment News reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. 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