&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1992 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #142, January 3, 1992 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Tat Inhibitor Update Clinical Trials: Asking the Right Questions -- Interview with Lewis Sheiner, M. D. AIDS TREATMENT NEWS Volume 2 Now Available AIDS TREATMENT NEWS Selected Index ***** Tat Inhibitor Update by John S. James In our last issue (December 20), we listed the tat inhibitors as the most important potential AIDS/HIV treatment at this time, and said that Hoffmann-La Roche, which developed the only tat inhibitor now in human trials, was expected to announce that it had sold rights to the drug, code-named Ro-24-7429, to another pharmaceutical company. Such an announcement had been widely expected; but on December 19 (after our issue had gone to press), Hoffmann-La Roche announced it had decided to keep the drug and develop it itself. Apparently the company decided that this drug was too good to sell -- especially in view of the disappointing results with the competing class of non-nucleoside reverse-transcriptase inhibitors (including Merck's L-661 and Boehringer Ingelheim's BI-RG-587), which are not promising because HIV develops resistance to them very rapidly. As we reported in our December 20 issue, both theory and data suggest that HIV may never develop resistance to tat inhibitors. (A San Francisco newspaper report last week that L- 661 and BI-RG-587 are tat inhibitors was erroneous.) On December 20, a technical article on Ro-5-3335 (a tat inhibitor which is an earlier version of Ro-24-7429, but apparently was abandoned because of toxicity in animal tests) appeared in Science (MC Hsu and others, "Inhibition of HIV Replication in Acute and Chronic Infections in Vitro by a Tat Antagonist," pages 1799-1802). This article reports that the experimental drug was effective against all of the many HIV variants against which it was tested, and that it was equally effective against AZT-resistant and AZT-susceptible viral isolates. It did not include the key information, reported in our last issue, that extensive attempts to develop a virus resistant to Ro-5-3335 had failed to do so -- while the same technique succeeds very easily in producing virus resistant to L-661 and BI-RG-587. The new Science article does note the concern about possible toxicity of Ro-5-3335 -- reinforcing the important point that our attention should be on the entire class of potential tat- inhibitor drugs, not only on the one drug now in human trials. ***** Clinical Trials: Asking the Right Questions -- Interview with Lewis Sheiner, M. D. by John S. James Lewis Sheiner, M. D. is Professor of Laboratory Medicine, Medicine, and Pharmacy at the University of California San Francisco. He is active in the AIDS Clinical Trials Group (ACTG) of the U. S. National Institute of Allergy and Infectious Diseases (NIAID), and a member of the Antiviral Advisory Committee of the U. S. Food and Drug Administration (FDA). Dr. Sheiner has a particular interest in how to obtain the best possible information from clinical trials when real-world circumstances do not allow ideal study design. We asked him for his recommendations on how existing trials might be made more useful and more efficient. In the following edited text of our interview, some technical supporting information was omitted; we added clarifying comments in [brackets]. Dr. Sheiner: We spend about a hundred million dollars on clinical testing of a major new drug, and I doubt that we get even one million dollars worth of information. We are immensely inefficient. I think the problem can be traced to the fact that we are asking the wrong question. The whole process has to be revamped. The problem, as I see it, is like that of an academic scientist whose main motivation becomes earning money -- instead of to understand the universe better, which is what a research scientist should be doing. Such an academic might engage in research which was most remunerative, or might try to get promoted by getting a lot of papers published without a lot of thought about what was in the papers. To some extent the system would regulate this behavior; for example, it would not be easy to publish papers that had no content. But there's still a spectrum -- subjects that lead to papers more quickly, papers that record just new information as opposed to new understanding, and which can be published in other than the best journals. So the system might keep a person producing a product that looked something like what an academic should produce. It wouldn't be high quality and would therefore be wasteful. To be productive, scientists need to keep their eye on the ball, on the problem, which is understanding the subject matter better or teaching students better. Then everything else falls out; they become successful as a researcher, or successful as a teacher, and get the rewards. But they should not keep the rewards in mind as the reason for it. The problem is that the drug industry is not keeping its eye on the ball. The drug industry is concerned, properly (because we've assigned coming up with drugs to the private sector) with, "How do I make money." And that translates into, "How do I get my drug approved?" So when they're doing clinical testing of drugs, the question is, "What do we need to do to get the FDA to approve the drugs." They're not asking, "What does a doctor (and the patient) need to know, in order to use this drug sensibly." If everybody kept their eye on that ball, everything else would fall out fine. But the drug companies have their eyes on the ball of "What do I have to do to satisfy the FDA." Therefore the FDA has to come up with rules that will cause people who are not actually addressing the problem, but rather are trying to get the drug approved, to behave in ways that sort of address the actual problem. It's a tough business to make a set of rules that will cause the behavior to come out one way when the motivation is another. We see this all over society. What you want to do is get people engaged in the real question, and then they use their ingenuity to answer it. This is an underlying structural problem, since we've assigned this major contribution to the public health [new drug development] to private industry. I'm not sure we could do any better. I do know that the set of rules the FDA has come up with has been determined largely by the legislation they have been given, which is that you have to have safety and efficacy, and by conservatism having to do with the process by which drugs are approved -- peoples' impression is that essentially you get one shot. You get to hold the manufacturer ransom from earning any money on their product for a while, while they supply information on the drug. Once you decide that the company has supplied enough information to warrant marketing, then you don't have much opportunity to learn more from that source. Other sources start to kick in [after the drug is approved]: physicians, academic people will pursue research on the use of various drugs for their own reasons, we may get the answers eventually. But there's no organized search for information, except in the few instances where the FDA requires additional studies after approval. Or where the public, through the NIH or others, decides we need a large trial for certain conditions because we don't know the answer; we've seen that in coronary disease and certain other areas. What are the questions that are being asked when clinical trials are designed? And what kinds of answers can we expect? The question that's being asked, even in those large trials done under government auspices, is primarily, "Does a drug work"? You control things, give a group of patients a new therapy, another group an old therapy or a placebo, look at the outcome, and ask if there is a difference. But that is an empirical [observational] result; it doesn't tell you anything scientific. Science is understanding the world. We focus on the question, does it work or not? That's a mistake. Because the important question is, "What do we need to know in order to use this treatment sensibly." The question is not, "Does it work," but "How does it work in different patient groups, in combinations with other drugs, and so on." The second thing we do wrong, after deciding to answer what I think is a limited question, is that we then optimize the way in which we do an experiment to answer that question. That's a serious mistake. When you optimize a system to do one thing, it's almost certain that you make it inefficient to do anything else. Whereas if you are a little robust, and say, "I'll do the best I can with respect to one question, but I'll also spread my energies around and do OK with other questions," it turns out that you can do lots of things with the data. It's like biology; when you get highly specialized evolution of the animal it's great, but only if the environment doesn't change at all. The epistemologic paradigm we are using is that we're going to find a counterexample to the claim that the drug doesn't work. So we set up a "null hypothesis" which is that the drug does not do anything, and then we look for a circumstance in which we can gather evidence which refutes that. The randomized controlled trial essentially functions as a counterexample that disproves the null hypothesis. And then we try to make that example as strong as possible by magnifying the treatment difference -- by giving one group zero dose, and the other group as large a dose as safely possible. We try to maximize the "signal" and minimize the "noise." So we get a homogeneous group of patients, and treat them, in respect to everything except the drug of interest, very homogeneously. We treat them by protocol, which in general doesn't look like real medical therapy. It's standard practice in clinical trials to reject a minimum of 80 percent of people who are potentially qualified. It's a rare trial that uses 20 percent. For example, when testing a drug for high blood pressure, at least 80 percent of those who come in with high blood pressure are usually rejected because they are the wrong age, or the wrong size, or they are taking some other drug, or they had some unusual test result, etc. The first problem is because of the optimization: how can we extrapolate from this highly select sample to the whole patient population? [We can't] -- but we do it [wrongly] all the time. By trying to minimize noise [the variation among patients], we put ourselves in a situation where we don't have a representative patient sample. If you really had your eye on the ball of what do we need to know to use this drug, you would want to study lots of different kinds of patients, with lots of different regimens, and look at various outcomes. But the randomized controlled trial usually looks at a very homogeneous group of patients, with just two doses, zero and some large dose, and usually looks at only a restricted set of outcomes. [Therefore it doesn't give you the information you need to use the drug in real medical practice.] So when the trial is done, we have proved that there is some group in which the drug does something -- so we can deny the "null hypothesis" that it does nothing. But we are not very far ahead of the game. And it costs us millions, doing these extremely rigid studies. [What makes the problem even worse is] that we want the sense of assurance, that we're absolutely sure the answer is right, that we're not making a mistake. The kind of mistake we seem to fear the most is holding that a drug is active when it's not. So we design our studies in a very rigid way, and analyze them according to very low-assumption models -- one group vs. one other group, and simple statistics essentially based on the fact that we randomized. That way of testing is very demanding in stringency of design; you have to make sure that nothing else is going on. You can't deal with the fact that patients are different. Consequently, we have to generate an experiment that does not resemble real life, and is almost useless for answering any other question [than whether the drug works in some situation, however artificial]. Even if we get a good estimate of what is happening to one kind of patient, that does not help us much with other patients [who are different from those in the study]. But if you designed the study to spread the doses out, to spread the kinds of patients out, you would be forced to analyze it with a model which took into account more variability -- which means a model with many more assumptions. In this kind of model [which Dr. Sheiner proposes] there would be randomization of doses. The "noise" level is allowed to be higher, since variation among patients is allowed. You would have to average this out by having larger patient groups, but larger groups would be easier to get, since you would be using designs in which you treat people much more like you treat them in real life. Why not randomize to ranges of doses, but allow the physician to adjust the dose in that range, depending upon what they observe in their patients, which is what physicians do? Then you make it easier to enroll more people, as the trial deviates less from what we would call good treatment. If you look at the expanded access for ddI, for example, there was no problem to get ten thousand people for this program, because entry criteria were less stringent than for clinical trials. From those ten thousand people we learned very little, unfortunately, because we did not have an appropriate design. But if you put a bit of design in that kind of study -- if you randomize the doses into ranges, and then gather data on what actually occurs -- you can get good information. There are models to deal with this sort of variation [among patients], certainly better than ignoring it, which is what we do now. Because we ask the wrong question, and optimize our study design to answer it, we learn little about the questions we do need answered. You need to understand this in terms of the process of drug approval and use. People today are designing drugs that we know have pharmacologic action; that is not the important question. The real issues are two: toxicity, which can always be unpredictable, and ultimate efficacy (clinical benefit). Those are the questions that need to be answered. The societal question is, for life-threatening diseases, do we have to answer that second question [ultimate clinical benefit] before we allow a drug to be used? The answer seems to be clearly no -- we've decided that we will use a drug when a prudent person believes that the probable benefit is greater than the probable harm. We can base that on the known pharmacology, on the biology, that the drug ought to be helpful. We may make mistakes -- but we do act before we are sure. What we need, then, is a mechanism for checking whether we made the right decisions. But it doesn't have to be pre-marketing [before the drug is approved]. So the view I'm proposing is, "Present us with enough evidence to make us believe that using this drug is a sensible thing to do at the present time. But understand that we're going to have to gather more evidence, and if the drug really is not efficacious, we have to be able to take it off the market." That's the fundamental change that I believe we need to make. Then the approval risk -- the risk the FDA takes when it approves a drug, the risk that it may turn out to be harmful -- is lower [than now, when the drug usually will not be tested further by the manufacturer, and usually cannot be recalled]. Let's lower the approval risk, so we don't have a biased approval process. If the FDA has a chance to correct a decision if it turns out to be wrong, it can approve drugs much earlier, because it will not have to worry about a mistake forever. That's the overall view. [We asked about the "large simple trial" design, which is now generating interest for community-based AIDS research.] Dr. Sheiner: The large simple trials come in at the stage of checking to see if the drug works. You take all comers, and perhaps randomize them to dose vs. no dose; dose is anything the doctor wants to give, and may be adjusted. Or look at dose-range groups for analysis. Within the large simple trial it is very easy to pull out more information about the response, by knowing exactly what dose everybody gets, by using pharmacokinetics [e.g. blood levels of the drug] to see what the actual exposure was, by measuring area under the curve, or by using explicit protocols for dosage adjustment, so that you know why doses were changed. Allowing a mechanism whereby drugs that do not prove to have efficacy can be removed from the market should be attractive to pharmaceutical companies. They can start making money while they are still testing -- so the price of those studies is being paid while they are making money, not out of pocket. But this isn't a free ride; companies cannot market their drugs and then leave it to somebody else to figure out whether they work. Drug companies will hope that they can do this, can do less work to make money. We have to tell them that's wrong. But studies could be done for less money, if we were clear about how well we needed to know what. A lot of the money that is being spent on drug trials is being spent to do studies extremely stringently to get very objective evidence, where a few assumptions would allow us to get perfectly adequate information to allow us to proceed for a lot cheaper. For example, in hypertension [although not in AIDS], what happens to moderate hypertensives treated for three months with placebo has not changed in the last decade and a half or two. So the fact that half of the patients you have to pay for in every study receive placebo is ridiculous. The only rational justification for assigning exactly half the patients to a standard therapy or placebo would be if you are as ignorant of what happens with standard therapy as with the new drug, which is almost never true. Some smaller number ought to be assigned to the standard therapy, because we have prior information about it. Procedures have taken over, and we do these things without thinking about why. [We brought up the case of hypericin, an experimental antiviral just now beginning clinical trials. Apparently it was delayed for three years because financial resources were not available to meet the high FDA hurdles for initial human testing.] Dr. Sheiner: Asking a drug company capitalized at billions to invest another million dollars in some testing that makes someone feel a little more secure is no problem; they're going to spend 100 or 200 million dollars anyway. But take an academic institution, and 100 thousand dollars means something to you. The whole drug-development system is set up for people who have lots of money to spend. What we're doing is buying what I believe is a false sense of security, but none the less we've got many procedures in place that are quite costly. There are many [questionable] reasons for maintaining them because: (a) we did it before and it's unfair to do otherwise; (b) because somebody's going to complain that you haven't done enough toxicity studies if something goes wrong later; (c) you get raked over the coals in Congress if you didn't have the same standards; and on and on. It's mixed up with the political process, with the consumer. You just shouldn't be in the making-drugs business unless you've got millions of dollars in capital. Take hypericin. This is the sort of situation where somebody found a natural product [not created by rational drug design] and believes that it might work. But at the moment, we don't understand enough about that molecule and about the virus, etc., to say whether it ought to work or not to work. It's all based on empirical evidence. It's not like you designed this drug to interact with viral proteins, etc. I'm not even saying that would be the right way to go; the era of modern drug development, of designing drugs to interact with certain molecules, is very recent; it still doesn't account for the majority of useful drugs. The way that hypericin, or most drugs used today, came to attention has been the standard way for new drugs to come along; somebody notices that some natural compound does something, and you do a careful set of empirical experiments that leads step by step to the conclusion that this drug is useful. But in that case, it is hard to say what you ought to be doing other than that. You cannot jump over the process, know that a drug looks like another drug, and interacts with the same molecule, so you know that it will be active, and the only question is toxicity. Here, you have a long trail to go on. Unfortunately, it's a trail where the traditions have been developed in the context of an industry that has no problem spending ten million dollars on that phase. We suddenly have people [community-based AIDS research groups] wanting to enter the drug-development process in a legitimate way, but having to meet standards that developed when money was no object. I'm not sure that those standards make sense. What about the thousands of people who have taken (underground) drugs; does that experience mean nothing? [We suggested that, if safety is under control, then why not do a small trial first under close medical supervision -- quickly, before a drug goes into widespread "underground" use?] Dr. Sheiner: I have outlined where we really could change the way we do things in terms of asking drug companies to do some testing after marketing. Now you are talking about something that makes even more sense, which is that one size doesn't fit all. At every point, we have a balance of many factors: our past experience, what we know about whether a drug is dangerous or not, what we know about animals, the fact that people may have been eating it for ages as a natural product, the need for new treatment because it's a life-threatening disease. Why don't we sit down in each situation, thrash it out and think about it, and come up with what makes sense for that particular situation? Obviously that is the sensible way to behave. I despair that it will be done soon. [We asked about the usefulness of observational or epidemiological data, compared to data from randomized controlled trials.] People miss the difference between two situations. One is observational or epidemiological data which has been accurately gathered but on which we have not exercised control; such data are valuable, although a little bit of control adds a lot. But what is useless are data that are not accurate, because we did not even record them properly. The best can be the enemy of the good. Many clinical trials are so stringent that, for example, researches nurses must draw a blood sample exactly six hours after giving the dose. But often they can't draw it at exactly six hours; the patient is away from the bed, etc. But they write down six hours because they're afraid to write down the actual time. The methods of analysis that we use in classical trials are crude, and highly sensitive to violation of protocol, because they make no assumptions about what is going on, because they don't build into their model time variations, etc. So we make a very strict protocol; but then the actual protocol, what actually happens, generally does not look very much like the nominal protocol [which was supposed to happen]. So we fool ourselves, when we use these supposedly objective methods, because often what happened is not what we intended to happen. One reason for paying attention to more observational-type data is that you will get to find out what did happen. The nominal and the actual designs will match, although you need a more complicated model. We are so much worse off not knowing when people in studies use drugs that are not allowed in the protocol, than if we asked them to write down what they took and what dose. A basic rule in life is that you want to look at reality. These concerns are so mixed up with social and political issues that it's hard to just talk about what makes sense scientifically [aside from the social context]. In the public, and in Congress, we have to focus on the process of getting the right folks thinking about the problem, rather than on what actually happens. Or every time there's a mistake, you will have somebody like a (Congressman) Dingell making a fuss. The process itself has layers of assurance so that you avoid criticism, can engender a sense of security. You and I both know it's a false sense of security, and that we are paying this huge overhead for what is essentially a political and social phenomenon of everybody wanting to have their fingers in the pie and be able to second guess, trying to be sure of something you can't be sure about, trying to legislate away risk. We can and do spend a fortune trying to do it, but it's an ill- spent fortune. ***** AIDS TREATMENT NEWS Volume 2 Now Available AIDS TREATMENT NEWS issues 76 through 125, from April 1989 through April 1991, are now available in book form through bookstores or by mail. Volume 2 includes an extensive (53-page) subject index, as well as a separate name index, covering its two-year period. It is 627 pages in all -- longer than volume I (which covered three years, April 1986 through March 1989), because recent issues of the newsletter contain more material than the early ones did. In volume 2, dated announcements for clinical trials, public meetings, etc., were deleted; in volume 1, these had been included for historical purposes. Volume 1 is now mainly of historical interest, while volume 2 contains more recent treatment information, much of it still relevant. Volume 2 will be available in bookstores for $16.95. If your bookstore does not have it, it can order copies from the publisher, Celestial Arts in Berkeley, California, by calling toll-free 800/841-BOOK, or 510/845-8414. You can also receive volume 2 by mail from AIDS TREATMENT NEWS. But it is less expensive in bookstores; we add $5.05 postage and handling (total $22), because we send all U. S. mail by first class/priority mail. The complete set of back issues of AIDS TREATMENT NEWS -- including volume 1, volume 2, and all loose issues from #126 through the present -- can be ordered from AIDS TREATMENT NEWS for $75; this includes postage and handling to the U. S., Canada, and Mexico. Outside North America, there is additional postage cost. To order volume 2, volume 1, the complete set of back issues, or selected individual issues, call us at 800/TREAT-1-2 (U. S. and Canada) or at 415/255-0588. Or you can order by mail from AIDS TREATMENT NEWS, P. O. Box 411256, San Francisco, CA 94141. ***** AIDS TREATMENT NEWS Selected Index Compiled through 1991 by Denny Smith This index lists selected topics from past issues of the newsletter which still seem relevant -- and obviously the more recent the issue, the more current will be the information. Note that the entries listed here will be found in the text of an article in the issue(s) listed, but not necessarily in the table of contents. topic issue number(s) acupuncture 130 acyclovir (Zovirax) 83, 94, 108, 115, 132, 133 adrenal glands 140 aerosol pentamidine 88, 90, 114, 129 AGM-1470 135, 141 albendazole 129 alpha interferon 75, 87, 101, 119, 122, 133 amikacin 109 amphotericin B/liposomal AmB 41, 58, 117 Ampligen 67, 119 Antabuse (disulfiram) 29, 70, 132 anemia 82 angiomatosis 129 anti-angiogenesis 117, 122, 135, 141 anti-idiotype antibody therapy 93, 110 antisense 141 aphthous ulcers 133 Asacol 109 aspirin 109, 118 AzdU (azidouridine, CS-87) 72 azithromycin 75, 79, 108, 109, 111, 113, 124, 132, 133, 136, 139 AZT (zidovudine, Retrovir) 83, 86, 100, 107, 110, 113, 115, 121, 132, 137, 141 bacillary angiomatosis 129 bacteremia 129 bacterial infections 120 Bactrim (co-trimoxazole, TMP-SMX) 79, 108, 114, 123, 129 benefits 74, 76, 105 beta carotene 134 BHT 10, 71 biological response modifiers 120, 122 BI-RG-587 117, 125, 127 bleomycin 73, 122 blue-green algae (sulfolipids) 87, 99 cancer 93, 110, 112, 118, 122, 126, 135, 139 candidiasis (thrush) 37, 96, 133 capsaicin (Axsain, Zostrix) 121 CDA (chlorodeoxyadenosine) 93, 110 CD4-PE40 130 CD4 (recombinant soluble) 62 chemotherapy 73, 75, 93, 110, 122, 135 children/infants 90, 114, 120, 123, 124, 130 Chinese medicine 61, 68, 71, 75, 93, 107, 126 chiropractic 130 Chronic Fatigue Syndrome (CFIDS) 93, 132 cimetidine (Tagamet) 80, 122 clarithromycin 109, 113, 124, 129, 137, 139 clindamycin 79, 104, 108, 111, 129 clinical trials 116, 141 clofazimine (Lamprene) 79, 141 CMV 71, 76, 83, 89, 94, 96, 108, 110, 124, 129, 133, 138 cofactors 83, 108, 119, 124 coenzyme Q-10 (ubiquinone) 26, 119, 124 colitis 133 combination therapies 107, 115, 119 community research 65, 66, 83, 85, 105 compound Q (trichosanthin) 82, 88, 99, 104, 119 computerized information 83, 102, 114, 116, 124 cortisol 140 CPFs 108 cryotherapy (liquid nitrogen) 122 cryptococcal meningitis 41, 58, 96, 99, 117, 129 cryptosporidiosis 49, 58, 75, 80, 95, 107, 111, 113, 124, 129, 133, 139 cytarabine (ARA-C) 79, 93, 129 d4T 72 dapsone 79, 114, 125, 129 daunorubicin 117, 122 ddC 89, 103, 104, 112, 113, 115, 132, 141 ddI 83, 88, 99, 103, 110, 112, 125, 131, 137, 141 dementia 97, 101 dextran sulfate 50, 76, 89 dexamethasone (Decadron) 79, 88, 93 DHEA (EL 10) 48, 49, 84, 140 diagnosis accuracy 100, 111, 119 diarrhea 133, 141 diclazuril (Clinicox) 80, 95, 107, 111 DNCB 14, 116 doctor/patient relations 100, 111 doxorubicin (Adriamycin) 73, 122 doxycycline 95, 104, 108, 119, 124, 129 dronabinol (Marinol) 131, 133, 141 DTC (Imuthiol) 29, 70, 114, 131, 132 eflornithine (DFMO) 94, 95 encephalitis 79, 97 endocrine problems 140 enteritis 133 epidemiology 97, 99, 124 EPO (erythropoietin) 82 Epstein-Barr Virus (EBV) 93 erythromycin 129 esophagitis 133 etoposide (VP-16) 73, 122 FAACTS 119 Fansidar 42, 108, 114 FIAC 94 FIAU 129, 133 Flagyl (metronidazole) 129 5-fluoroucil/5-FU collagen matrix 122, 129 FLT (fluorothymidine) 72, 119 fluconazole (Diflucan) 41, 58, 80, 96, 103, 129, 133 flu shots 138 folic acid (folate) 134 foscarnet (Foscavir) 71, 83, 94, 108, 110, 129, 133, 136, 138 566C80 108, 109, 114, 123, 129, 133, 139 fumagillin 122, 135 funding/lobbying 97, 99, 111 fusidic acid (Fusidin) 42, 79 gall bladder 124, 133 ganciclovir (DHPG, Cytovene) 71, 89, 94, 96, 108, 124, 129, 133, 138 gastritis 133 gentamicin 109 germanium 90 glutathione 88, 92, 93, 119, 121 glycyrrhizin 17, 103, 115 G-CSF 122 GM-CSF 87, 93, 94, 105, 108, 110, 122 gp160 (vaccine) 130 gp120 (vaccine) 130 health care politics 99, 103, 111, 112, 120, 125, 126, 132, 135, 136, 137 hemophilia 89, 102, 103, 132, 137 heparin, substitutes 100, 122 hepatitis 126, 133 herpes/shingles 80, 83, 94, 100, 115, 133, 138 HGP-30 (vaccine) 130 histoplasmosis 41, 96 HPMPC 76, 96 Humatin (paromomycin) 107, 111, 129 hydrogen peroxide 49, 132, 134 hypericin 80, 86, 88, 91, 96, 117, 125, 138, 141 hyperimmune milk (colostrum) 49, 95, 107 hyperthermia 104, 122 ibuprofen (Advil) 109 idarubicin 122 immigration politics 89, 98, 114, 120, 125, 128, 129, 134 immune globulin (IVIG) 119, 120, 124, 129 immunomodulators 119 immunotoxins 140 Imuthiol (DTC) 29, 70, 114, 131, 132 indomethacin 109 insurance 74, 76, 120, 136 interferons 75, 87, 101, 108, 114, 119, 122, 132 interleukins 119, 122 Iscador (mistletoe compound) 92 isoprinosine 106 ITP 48 itraconazole (Sporanox) 80, 96 Kaposi's sarcoma (KS) 73, 75, 87, 99, 100, 117, 122, 129, 135 Kemron 97, 101, 114 labor unions 123 laser treatments 75, 96 lentinan 19, 73 letrazuril 133 leucovorin 49, 52, 79 levamisole 119, 122, 124 liposomes 109, 117, 122 liquid nitrogen (cryotherapy) 122 L661 & L229 139 L671,329 & L687,781 114 L697,639 & L697,661 118, 125 lithium 119 liver problems 103, 133 Lyme disease 132 lymphoma 93, 110, 136, 140 MAI/MAC 79, 109, 113, 124, 129, 132, 136, 137, 139, 141 marijuana 131, 133, 139, 141 Marinol 131, 133, 141 mebeciclol 95 Megace (megestrol acetate) 76, 77, 133 MEK 99 melanin 107, 139, 141 mexiletine 121 microsporidiosis 129, 133 mitoxantrone 93, 122 molluscum contagiosum 133 monoclonal antibodies 129 mycoplasma 95, 108, 124, 129 myopathy 119 NAC 88, 92, 93, 119, 121, 138, 141 naltrexone 16, 52, 119 nausea 131, 139, 141 neopterin 86, 100 neutropenia 94 neuropathy 121, 130 neuropsychiatric concerns 97, 101, 126 nonsteroidal anti-inflammatories 109 nutrition/malnutrition 73, 133, 134, 141 octreotide (Sandostatin) 58, 95, 127, 141 Oncolysin B 136 ozone 80 parallel track 82, 84, 85, 104 parasites 133 passive immunotherapy 67, 92 patient/doctor relations 100, 111 PCR 62 peliosis hepatis 129 pentamidine 114, 129 pentosan polysulfate 117, 122 pentoxifylline (Trental) 133 people of color 86, 99, 121 Peptide T 84, 119, 126 Persantine (dipyridamole) 79 pets (infection hazards) 79 PF4 (recombinant) 122 pharmacies 64, 86 physician interviews 47, 54, 56, 62, 100, 106, 119, 124, 126 piritrexim 122 PML 79, 88, 100, 115, 129 Pneumocystis 58, 83, 90, 106, 114, 115, 123, 129, 139 pneumonias, bacterial 119 pregnancy 90, 112 primaquine 113 prisons 106, 125, 126, 130 probenecid 86 prophylaxis/prevention 79, 90, 94, 100, 106, 108, 114, 119, 123, 129 propolis 37 Prosorba column (protein A) 75, 122 protease inhibitors 117 p24 antibody 100, 119 p24 antigen 100, 119 p24 (vaccine) 130 PWA coalitions 117 pyrimethamine (Daraprim) 79, 104, 108, 114, 129 radiation therapy 73, 93, 110 recreational drugs 119 R 82913 131 research priorities & policy 77, 78, 104, 105, 110, 112, 124, 126, 127, 136, 140 reverse transcriptase inhibitors 117 R-HEV test 85 ribavirin 141 ricin-A 140 rifabutin (Ansamycin) 53, 79, 109, 129 rifampin 79, 102 Ro 24-7429 141 roxithromycin 75, 81, 95 Salk vaccine (HIV) 98, 130 Sandostatin (octreotide) 58, 95, 127, 141 scabies 98 SCH 39304 99 Septra (co-trimoxazole, TMP-SMX) 79, 108, 114, 123, 129 shiitake 19 sparfloxacin 129, 132 spiramycin 49, 79, 95, 107 SP-PG 135, 141 steroids 114, 115, 133 sulfadiazine 79, 93, 104, 108, 129 sulfolipids (blue-green algae) 87, 99 sunlight. 58, 124 surrogate markers 119 symptoms 100, 119, 124 syphilis 124 tat inhibitors 127, 128, 132, 141 tests (blood values) 119 T4-helper (CD4) cells 119 thalidomide 133 3TC 140 thymopentin 123 TIBO derivatives 97, 131 TI-23 108, 129 TLC-G-65 109 toltrazuril (Baycox) 111 toxoplasmosis 79, 104, 108, 109, 113, 123, 124, 129, 139 TPN feedings 133 transfer factor 47, 119 treatment access 83, 84, 85, 115, 116, 118, 119 treatment strategy 83, 100, 111, 119, 124 tretinoin (Retin-A) 122 trifluridine (Viroptic) 115 trimethoprim/sulfamethoxazole 79, 108, 114 trimetrexate/leucovorin 49, 52, 108 tuberculosis 106 tumor necrosis factor 87, 88 vaccines 130 valley fever (coccidioidomycosis) 41, 96 Velban (vinblastine) 73, 122 vidarabine (Vira-A) 79, 94 vinblastine, vincristine 73, 122 vitamin A 134 vitamins B 134 vitamin C 111 vitamin D3 analogs 122 warts 112, 118 wasting/weight loss 76, 77, 88, 119, 134, 141 women 65, 90, 111, 112, 115, 118, 130 zinc 134 ***** 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 415/255-4659 fax Editor and Publisher: John S. James Medical Reporters: John S. James Michelle Roland Denny Smith Reader Services, Business, and Marketing: Thom Fontaine Keith Griffith Laura Thomas 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. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Canadians add 7% Goods and Services Tax. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U. S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1992 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display