Subject: AIDS Treatment News #119 Date: Jan 17 1991 (1047 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1991 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #119, January 18, 1991 phone 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Treatment Strategies: Interview with Paula Sparti, M. D. Major FDA Meeting on Drug Approval Standards, February 13 and 14 Peptide T: New Access Obstacles FLT: Correction and Update Announcements: Seventh International Conference Early Deadlines; FAACTS: Alternative Treatment Information Available ***** Treatment Strategies: Interview with Paula Sparti by Denny Smith For a practical look at AIDS treatment advances, we interviewed Paula Sparti, M. D., who has a large HIV and family practice in Miami, Florida. Dr. Sparti also participates in the recently reconvened immune-based therapies group at the National Institutes of Health (NIH). Traditionally, most AIDS/HIV treatments have been divided into antivirals, treatment or prophylaxis for opportunistic infections, and immunomodulators. New developments in these areas include combinations of antivirals (for example AZT with ddC, or with interferon, or with compound Q), and multiple opportunistic infection prophylaxis (using drug combinations to prevent most or all of the common OIs, not only pneumocystis). Immunomodulators (agents which might fight HIV by affecting the body's various natural immune mechanisms rather than by acting on the virus directly) may account for the most numerous and least understood approaches. Since immune responses involve elaborate "cascades" of precise, sequential events in the body, attempts to alter a certain immune activity can prove even more complicated than the prospect of developing treatments which act against HIV directly. We hope to cover specific immunomodulators in upcoming issues of AIDS TREATMENT NEWS. DS: I want to pose some questions to you which we at AIDS TREATMENT NEWS are often asked to answer, such as when to start anti-HIV drugs; what combinations of drugs look feasible; when to start prophylactic measures; is there such a thing as planning for infections, or planning access to various drugs? The notion of immunomodulation is gaining momentum now, but the spectrum of potential agents and rationales is overwhelming. Also, and perhaps most urgently, many people are facing the prospect of AZT resistance, with unanswered questions about the prospective antivirals -- ddI, ddC, and compound Q. PS: In deciding when to begin antiretrovirals, I monitor bloodwork every three months, because I have seen a number of people who have had precipitous T-helper cell drops in a six month period of time. I have also been following some patients for nine or ten years who have had very stable counts. So I look for a sustained decline in helper cells and the T-cell ratio, more than just an absolute count that drops below 500 once or twice. I have two or three people who have had absolute T-helper cell counts below 500 since 1981, and who have been completely stable without an antiretroviral; without a doubt they would have been damaged a long time ago had I started them on nucleoside analogs. I try much more to follow how stable people are, their percentage of T-helper cells, and their helper/suppressor ratio, rather than an absolute cell count. If you follow the absolute count over a long period of time, you can see that it goes up and down, and it is very dependant on an individual's total white count and lymphocyte count on a given day. I haven't found that beta 2 microglobulin is very helpful. Sometimes I will see an increase in the beta 2 and the neopterin before a decline in immune competence. I'm finding that the p24 antibody [not to be confused with p24 antigen] is probably much more sensitive; I am just now getting fairly consistent results on quantitative p24 antibodies. You can follow them, and if they begin to fall, it may herald a fall in T-helper cells as well. When I do start people on antiretrovirals, I start them on AZT alone. For years I have been starting people on 400 to 600 mg daily, for a typical 150 lb. person. There is community access to other drugs, and I know a number of my patients who are choosing to add ddC to their AZT. I think there is a lot more myopathy [muscle disorder] associated with AZT than other people seem to be reporting. I have had some patients on AZT for up to four years, and they may not have obvious myositis [muscle discomfort]; they don't necessarily show significant increases in their CPKs, but they experience progressive wasting and muscle loss. There were a number of sessions at the last ACTG meeting elaborating the effect of AZT on mitochondria of muscle, and of ddI and ddC on nerve mitochondria. So although early intervention is very, very important, I think we still have to remember how toxic nucleoside analogs are. DS: Would such myopathy be distinct from anything HIV alone might cause? PS: It is distinct. HIV myopathy is inflammatory, for the most part. We can do a muscle biopsy here at the University of Miami and distinguish inflammatory myositis from a necrotic kind of cell death caused by AZT. And the difference is important to know, too, because if it is inflammatory and not due to AZT, you can treat it with non-steroidal anti-inflammatories, and if it's really bad you can treat it with short term steroids. You could stop the AZT to see if the myopathy or weight loss stops. But the problem is that it takes a long time to develop the myopathy and a long time to reverse it. It's not wise to have people off of an antiretroviral for the time it would take to decipher the problem, unless you have an effective substitute. A biopsy can help you know what you're dealing with. DS: Is there any immediate way to mitigate the AZT- related myopathy? PS: One of the things that comes to mind, considering the mitochondrial defect related to myopathy, is coenzyme Q- 10 [not to be confused with compound Q], which supposedly helps the function of the mitochondria. This isn't strictly scientific, but I know that in Japan, coenzyme Q-10 is given to decrease the cardiac damage resulting as a side effect of adriamycin. It's available here by prescription. DS: You know it's also available without a prescription at local buyers' clubs. PS: Yes, and at health food stores, but I was thinking that for people who have insurance, a prescription may help to pay for it. Another solution to myopathy, and side effects generally, will be combinations of low-dose AZT with low-dose ddI or ddC, which are less likely to cause myopathy, or the neuropathy seen with higher doses of the single drugs. DS: Regarding nucleoside combinations, do you think it's better to use them together in low doses, or to alternate them? PS: I think that using them together is better; the likelihood of postponing resistance could be better in a simultaneous combination than in an alternating regimen. But that's the kind of thing we don't know for sure yet. I'll be happier when we have more to combine than two nucleoside analogs! DS: Are there non-nucleoside candidates you feel strongly about? PS: Well, I'm interested again in Ampligen, as an adjunct, as something used in combination with other drugs. It's now planned for phase I and phase II studies combining it with AZT. Ampligen may make AZT more active. DS: Ampligen seems to have been hard to categorize as either an antiviral or an immunomodulator. PS: Right, it may have activity of both. It's mismatched double-stranded RNA. DS: Are you optimistic about compound Q? PS: Well, I know Martin Delaney and Drs. Alan Levin and Larry Waites are very much behind it. I'm not negative about Q, I just haven't seen the same results they've reported. I also haven't had as much experience as they've had. I have followed maybe 30 or 40 people who have used Q, while they have seen hundreds. I would probably need more exposure to see the results they're seeing. I have noticed that a few people who were on AZT or ddI with slowly declining bloodwork seem to have been stabilized with the addition of compound Q. So, although I don't have a lot of experience, I think with some people I'm seeing a stabilization benefit from Q, and perhaps a modest increase in T-helper cells. DS: Have you seen any serious toxicities from Q? PS: Nothing life-threatening, but quite a few allergic reactions; fortunately the Q doesn't stay in the body very long, so we just stop the infusion and give IV Benadryl, and epinephrine if we need it. In subsequent treatments we premedicate those people with Hismanal, and Decadron too, if warranted, for several days before their infusion and also the day after. This way we've been able to reinfuse people who have had reactions. DS: Other antivirals or experimental agents you're interested in? PS: I am anxious to see what happens with the non- nucleoside RT inhibitors. Merck and Upjohn have several possibilities. The sooner we get results the sooner we get expanded options. I have also been eager to see trials of hyperimmune HIV globulin, or passive immunotherapy, get started. Medicorp has not had the funding to sponsor a major protocol, but Abbott Laboratories, which is much larger, may be able to back one. DS: What about some popular community treatments, like oral interferon, NAC, and hypericin? PS: NAC is more popular than hypericin, in which interest seems to have faded for lack of controlled clinical trial results. With NAC, a number of people report increased energy and appetite. I think there is a good rationale behind NAC, since it purportedly increases glutathione levels, which are deficient in virally infected cells. But the real benefits and dosage are uncertain, so again, we need clinical trials for quantitative results. I have seen absolutely nothing with oral alpha interferon. I have heard of people who claimed increases in T-helper cell counts, but I have not been able to find anyone in my practice or our local community who has been able to show a sustained increase from oral interferon. DS: That's pretty much what I have heard from other physicians. However, another antiviral I wanted to ask you about was the injectable alpha interferon, approved by the FDA to treat Kaposi's sarcoma. Anthony Fauci seems to talk a lot about it in terms of a potential HIV agent. PS: I think the limitation there is that you have to use it early in HIV disease. If you use it later, you risk further compromise of the immune system. People with higher T- helper cells can tolerate interferon, and if you combine it with low- dose AZT you can obtain significant increases in T-helper cells as well as diminish their KS lesions. One of the factors is that late in HIV disease, endogenous [naturally occurring] levels of interferon are high, anyway. Simply adding more is not going to be helpful in that case. I think interleukin [IL] is more interesting. The interleukins 2, 4, and 7 have a lot to do with T-cell proliferation and maturation. Of course IL-2 can be very toxic, but apparently you can use less of it if you combine it with IL- 4. I think this is the beginning of being innovative with immunomodulation. When you have been treating HIV for several years, you have a lot of patients with less than fifty T-helper cells, but who are not ill yet. We're desperately trying to find ways to increase the T-helper cells. DS: I have spoken to a couple of people who have tried lithium as a way to boost their helper count, but I understand that it only produces a broad, non-specific increase in white cells. PS: A few of my patients wanted to take lithium, but you're right -- if you're not increasing the number of mature T-helper cells, then it's not going to be really helpful. You may get a sort of artificial sense that T-cells have increased, because you've elevated the total white count, but not necessarily the percent of functioning, mature T-helper cells. DS: Any thoughts on isoprinosine or Imuthiol (DTC)? PS: Those two, and levamisole as well, have been receiving a lot of interest out here. Several recent reports show that levamisole increases cell-mediated immunity. Imuthiol has been studied much more in Europe than in the U. S., and it now is available in New Zealand. People here have tried an industrial grade DTC, or antabuse as a DTC substitute. We just need more results of controlled clinical trials to know for sure. Isoprinosine is something which more of my patients used back in 1984 and '85, not so much lately. People should give more consideration to transfer factor. It may be a crude lymphocyte extract, with an indeterminate mixture of lymphokines, but I have definitely seen people whose energy and well-being improved on transfer factor. Perhaps it suppresses some of the herpesviruses. I had two patients in the past couple of years with CMV retinitis who chose not to go on ganciclovir, yet both of their infections were stabilized while on transfer factor. The people at the NIH are not prone to pursue transfer factor -- their position would be that this is just a concoction of various biological products, and it would be difficult to attribute a response to any one of its constituents. So verifying its worth may be a job for a community-based research group. I have been trying quite a bit of intravenous immune globulin (IVIG) in some of my patients with very low T- helper cells. It's clear to me that their ability to produce antibodies to specific antigens is severely damaged. [IVIG supplies antibodies.] The results are anecdotal, but I have seen benefits in people with chronic sinusitis and chronic bronchitis after several months on IVIG. DS: If you had a proven immunomodulator right now, when would you give it to patients? Would it be helpful to asymptomatics, including those with healthy blood markers? PS: Well, we know so little about immunomodulation, it's difficult to say for sure. But agents that cause T-cell proliferation, the interleukins, for example, would probably work better when the T-cells are higher, when stem cells are in better shape. If your bone marrow is wiped out, there's not much for the interleukin to work with. If we had something that would help cell-mediated immunity, then using it early might avoid some of the down-spiraling which results from immune-complex disease and inflammation. DS: It sounds like you're saying that immunomodulation should have specific targets. PS: The more I learn, the more I realize how incredibly intricate the immune cascade is. You can't just throw an interleukin into somebody's body and obtain a known effect. You have to know how to use it and when to use it, in what dose and in what frequency. I'm excited that the immune-based therapy group is back together at the NIH. DS: Regarding opportunistic infections, and prophylactic measures to thwart them, I spoke to Dr. Larry Bruni, who practices in Washington, DC, who suggests that not only does HIV infection allow other pathogens to cause infections, but those secondary infections might transactivate HIV, or enhance HIV progression, as well. So both things may be happening in tandem. What do you think about that, and the role of prophylaxis for the various AIDS-associated infections? PS: I definitely believe that when people get sick, whatever that "sick" is, it affects viral replication and it affects their T-helper cell count. I have been using more and more multiple opportunistic infection prophylaxis. A lot depends on the toxicity of the drugs in question. Some of the studies being designed to address prophylaxis, other than for pneumocystis, are a little disturbing in that they use an inflexible, uniform T-helper cell cut-off of 200, even though infections do not appear uniformly at 200 helper cells. Most infections other than pneumocystis don't appear above 100, or even 50, T-helper cells. Given that, I tell those patients that, although there is no proof that a certain drug will prevent an infection, my recommendation is for a prophylaxis. I offer fluconazole, 100 mg a day, to prevent cryptococcal meningitis in people who already need an antifungal for candidiasis. I see who can tolerate pyrimethamine, 25 mg a day, to try to prevent toxoplasmosis. In people with symptoms of herpesvirus infections, including leukoplakia, I use acyclovir liberally. And I think multiple prophylaxing works. I now have many more people who are three or four years past their first OI. That is different from what was happening a while ago, when people would die within the first year or two of an initial opportunistic infection. DS: Is it useful first to check people for past exposure to a certain infections? PS: Oh yes, we always do that. We always test for toxoplasmosis, which is common in Florida, as well as CMV, Epstein-Barr, herpes simplex. If people are negative, you can avoid the drugs and their possible side effects. DS: Do you see many identifiable mycoplasma infections? PS: I keep mycoplasma in mind, and if I see someone with interstitial pneumonitis, or pulmonary problems that I can't really explain, or they're just not getting better, I liberally use doxycycline. You can give it intravenously if necessary, or orally if they are not that ill. DS: Have you seen results from doxycycline? PS: You cannot always know what you're treating, and you see some strange things. I have seen thrombocytopenia resolve temporarily on doxycycline, for no apparent reason. Recently there was a relevant article in the Tropic, which is the Sunday magazine of the Miami Herald. It asked if the people at the NIH are missing the boat by having just one paradigm, the antiviral paradigm, and not looking at the importance of cofactors, and the autoimmune part of this disease. But if you ask me whether Mycoplasma incognitus is more important than syphilis, or CMV, or HIV, I really doubt it. Of all the possible cofactors, so many are present, including some we may have not even identified yet. Mycoplasma is only the newest kid on the block. DS: Do you see patients who use recreational drugs, and are some of those drugs a risk for aggravating HIV progression? PS: Well, opiates are known to cause immune suppression. Interestingly, some of my patients are still using naltrexone, which is an opiate antagonist. One of them, anecdotally, has been using it for five years now, and he has had totally stable T-helper cells. I think that the use of opiates is immunosuppressive, as are cocaine and alcohol. Narcotics are compromising also because they chip away some of the will to live, the will to fight. Some of my drug abusers want to feel better, but they don't want to do the work required to feel better. For them it's "too much trouble to eat, too much trouble to take a deep breath," or to get to appointments. The will to live is part of being a long- term survivor. I think antidepressants are probably helpful. Depression itself can deplete T-helper cells. There is a fair amount of evidence that antidepressants used to treat chronic fatigue syndrome can achieve some beneficial immunomodulation -- increased natural killer cell activity, sometimes increased T- helper cells. DS: Do you think there are particular AIDS diagnoses that frequently get overlooked? PS: Nothing stands out, although I think sometimes people do not get treated at all because their complaints are simply chalked up to AIDS. I hope that's unusual. I push to make a diagnosis if at all possible. If someone has got a fever, I don't wait for something horrible to happen; I begin a comprehensive workup. It is important to treat something before it gets out of hand. If someone has a fever, part of a fever workup should be sending them to an ophthalmologist to have them checked for CMV retinitis that may not yet be causing visual disturbance. You may have to check for cryptococcal antigen even though they might not have a headache. It requires a sixth sense. Some practitioners who do not have a daily familiarity with AIDS don't know to diagnose and treat aggressively, and when their patients are finally seen by AIDS experts, they are really sick, and more difficult to treat. DS: What would you like to see added to the current treatment picture? PS: I'm anxious to see a lot more things evaluated. I would like to see more results on photopheresis. There are some interesting discussions of low-dose total body irradiation as a method of decreasing suppressor cells, with a consequent increase in helper cells. There are so many potential therapies out there to be evaluated, and I'm frustrated because I want them all to be evaluated as soon as possible. Now that I am working within the NIH, I see that there's a handful of people who make most of the decisions. Maybe we will be able to get them to really look at more substances, and new procedural ways of doing things, and not to be so immediately negative. You would think that under the circumstances they would give anything and everything the benefit of the doubt. It will be interesting to see what happens in the next year or so. ***** Major FDA Meeting on Drug Approval Standards, February 13 and 14 Crucial issues on how to prove efficacy for new-drug approval will be considered at a meeting of the FDA's Antiviral Drug Products Advisory Committee on February 13 and 14, near Washington, DC. The meeting is open to the public. The Wednesday, February 13, session concerns endpoints in AIDS trials, and the role of CD4 and other laboratory markers as indicators of clinical benefit. While this meeting is not scheduled to consider ddC and ddI, those drugs clearly provide its immediate context and rationale. On Thursday, February 14, the Committee plans to focus on AZT, especially followup on the trials which supported expanded indications for treatment (T-helper counts to 500). While there has been little public attention to this meeting, there has been much activity behind the scenes, especially preparations by scientists. Since AIDS treatment activists from around the country will be in Washington on those days, there may also be activist meetings before and after the antiviral committee meets. The Antiviral Drug Products Advisory Committee is scheduled to meet at the Holiday Inn Crown Plaza, Rockville, MD, at 8:30 a.m. on both days. Comment Here is a scenario which we find useful for organizing our thoughts for this meeting. Suppose that in the near future an AIDS or HIV treatment is found which works very well -- either a single drug, or more likely, a combination. Suppose that almost everyone who uses the treatment becomes healthy again (except for any irreparable damage which might have been caused by severe illness): weight and energy return, all blood work becomes normal, and there are no opportunistic infections or new malignancies, as long as patients keep taking the treatment. Assume that the toxicities are small or manageable. The question is, "What would happen then" -- and what should happen? The present system Under the current system it does seems clear what would happen. First, if the treatment were a combination of new drugs, it would not be tested at all, because the FDA almost never allows a trial of more than one unapproved drug at the same time. All but one of the drugs would have to go through the entire approval process separately, proving itself alone compared to AZT. Then, years later, the combination could be tried. Suppose the new treatment were a single drug, so that the above problem was not an issue. The first bottleneck- -organizing corporate commitment and funding -- would already have occurred. Waiting for the patent office could have delayed the project for a year or more. Then, if luck were bad, additional years could have been spent in litigation. We have not investigated the detailed requirements for animal testing. But we have heard from persons familiar with this area that they are often grossly excessive and irrational. Next comes the process of getting approval for phase I (dosage and toxicity) human trials. Here the biggest problem is juggling busy peoples' schedules to get the required people and papers into the same room at the same time. Perhaps the IRB or other required body does not finish its other business in time, so the drug is postponed for weeks or months until the next meeting. Then some of the people cannot attend, and the trial is postponed again. Finally the phase I trials actually start. They often take more than a year, because one group must take the drug for an extended time at a very low dose, before the next group starts at the next dose, etc. for a number of different doses. Traditionally, these phase I trials were planned to run until toxicity was found, even if it became clear that the drug showed efficacy at a non-toxic dose. The higher doses that would never be used still had to be tested. (ddI was substantially delayed for this reason.) Next comes the design of phase II comparative efficacy trials. Traditionally this is done by research physicians, with no input from the "front line" physicians experienced in treating patients. Therefore the resulting trials can be difficult to administer, and often have trouble recruiting patients. The early steps in drug development, before phase II, are outside the scope of the Antiviral Drug Products Advisory Committee. Now we come to the later steps in development, where the public pays attention, creating pressure for reform, and therefore meetings like the one in February. (The earlier steps do not generate such pressure, because they are usually secret until human trials begin. The public does not see the inefficiency, and until recently, was simply told that good science takes time, and that the only issue was whether or not to weaken the scientific process.) Today there is much confusion about what standards to use to judge efficacy of AIDS drugs. The traditional ones, which still prevail, are illustrated by the large ongoing trials of ddI and ddC. The original idea was that each new drug would be compared with a placebo -- and the trial would have to prove superiority of the drug, by accumulating a statistically significant number of deaths or major opportunistic infections in the placebo group. When it became unethical to use a placebo in a trial designed to end in death or major illness, AZT was simply substituted for placebo, and the goal of drug equivalence was more or less substituted for superiority. No one thought through the effects of these changes on the trial design. With or without these complications, it was necessary to wait for deaths or OIs in the volunteers not receiving the treatment being tested. Therefore, even if the new treatment cured everybody instantly, it would still take many months or years to meet the efficacy standards set for these trials. Because deaths in the AZT group occur slowly, these studies need to be very large and/or run for a long time (for example, 18 or 24 months) to expect to attain statistical significance. Hundreds of volunteers are required. Each trial needs to run identically at a number of major medical centers in order to find enough qualifying volunteers, creating major delays for administration as well as for recruitment. (For example, the IRB for each site must meet to approve the study -- and each IRB meets on its own schedule. Each IRB must either accept or reject the study exactly as given -- it cannot change any of the science, or the data will not be compatible. Since IRBs do not like to serve as rubber stamps, they exercise themselves by making insignificant changes in the informed consent form which the volunteers will sign -- the only changes they are allowed to make. The study then has a separate consent form for each site -- a minor, almost humorous problem, compared to the others.) When the trial finally begins, a group of experts called a Data Safety Monitoring Board meets periodically during the trial and secretly unblinds the data, to stop the study for ethical reasons if extreme differences between the groups are found. But in practice, the standards for stopping the trial early are extremely severe. Therefore the Data Safety Monitoring Board serves more as a public-relations cover than as a real protection for patients; but because its deliberations are secret, the public does not realize this fact. An additional problem now is the lack of clarity about what will be considered evidence of drug efficacy. Proof that a new drug is superior to AZT, in preventing death and major disease progression, is the most conservative possible standard. The problem with this standard is that for reasons cited above it will take a very long time to meet this level of proof, even if the drug is in fact better. In addition, a drug which is only equally effective as AZT -- or even less effective -- could save many lives, if it has different toxicities, is effective in different patients, or has unique value in combination with AZT or other drugs. What is happening today, however, is that companies are confused about what standards the FDA will use; therefore they are reluctant to submit their data, and the FDA does not see it. These operational problems explain why, years after AZT approval, no new AIDS antiviral has been properly tested and approved, although attractive candidate drugs have long been available. The problems continue because no one is in charge of the national response to the epidemic, so no one has the authority to correct them. What Should Be Done? The hope is that the February 13 meeting will reduce the confusion by recommending a viable efficacy standard. What might such a standard be? There is considerable movement toward a consensus of accepting improvement in T-helper cell count (or percent), together with at least some measurement of clinical improvement, such as regained lost body weight, as proof of efficacy for an antiviral (unless, of course, there is some good reason to reject the evidence; we are not suggesting that approval would be automatic). Part of the rationale is that there seems to be no group of persons with HIV whose average T-helper counts will increase over time without treatment; the direction is always down. If a drug increases T-helper count by means of its antiviral effect -- a result which can be seen within eight to 12 weeks, about a tenth the time required by a trial which looks for death or major disease progression -- and there is no reason to believe that the drug would increase T-helper cells by any mechanism other than inhibiting the virus which causes AIDS -- then it is hard to believe that the drug is not having an effect on the disease. Requiring some measure of direct patient benefit is an additional precaution; it should cause little objection, as few physicians or patients would want to use a drug if there was no direct evidence that patients using it got better. If a drug (or combination of drugs) can pass this test, then it should be considered to have met the efficacy standard for approval -- at least in the current emergency. Otherwise, the practical consequence of maintaining the current system is that all new AIDS antivirals will be delayed for years, the new generation of drugs such as protease inhibitors will not be developed expeditiously, and tens of thousands of deaths will be guaranteed. We have heard little opposition to changing the efficacy standard for AIDS antivirals along the lines of the developing consensus described above. The issue is not whether there should be a change, or even what the change should be -- although academic arguments will likely be raised concerning any particular proposal. The real issue is whether anything will get done, given the lack of coordination and high-level leadership on Federal AIDS policy. ***** Peptide T: New Access Obstacles by John S. James For several months there have been increasing reports of difficulty in obtaining peptide T, an experimental treatment which is generally agreed to be safe and is in clinical trials. (AIDS TREATMENT NEWS last covered peptide T in issue #84, July 28, 1989.) Recently the situation came to a head when two buyers' groups had their supplies cut off, due to Federal action against two different suppliers; in one of these cases, Ron Woodruff of the Dallas Buyers' Club sued the FDA, and lost in Federal court in San Francisco. We started investigating, but soon learned that Treatment Issues, the treatment newsletter published by Gay Men's Health Crisis in New York, was already working on this problem. "Peptide T Access Blocked," by Wayne Kawadler, was published last week in Treatment Issues, volume 5, number 1, January 10, 1990. [Note: To obtain a copy, send a note asking for the peptide T issue to: GMHC, attn: Medical Information, 129 West 20th St., New York, NY 10011, or call Wayne Kawadler at 212/337-1950. Also note: Treatment Issues is published ten times a year by Gay Men's Health Crisis. There is no charge for a subscription, but a $20 per year contribution ($40 international) is suggested if possible. A $10 contribution is suggested for all back issues, for the last three years. To request a subscription, write or call to the number above. Note that that number is only for Treatment Issues; for other AIDS information, call the GMHC hotline at 212/807-6655.] We will not restate Mr. Kawadler's article, but it included the following points: * FDA agents recently visited Peninsula Laboratories, in Belmont, California, and told them that some of their peptide T, sold for animal research, "was actually being used by people and that the commerce must stop." [Note: Peptide T, like most experimental drugs, can be sold as a chemical for research or industrial purposes without advance approval; but if intended for human use, it can only be sold to someone with an IND (Investigational New Drug approval), i.e., permission from the FDA to conduct human trials.] This FDA action against Peninsula Laboratories led to the unsuccessful lawsuit by Ron Woodruff. Peninsula Laboratories had previously provided peptide T used in clinical trials. * Carlbiotech, a pharmaceutical company in Denmark, recently received a contract to provide peptide T for a clinical trial at the University of Southern California. At about the same time, the FDA wrote to Carlbiotech and told them not to sell peptide T to anyone without an IND. * The FDA has a well-known policy of allowing importation for personal use of limited amounts of drugs approved elsewhere but not in the U. S., under certain conditions. Apparently peptide T does not meet the guidelines for this policy, however, since it is not approved as a drug in any country. * One clinical trial of peptide T now recruiting -- a five- year study at Yale for intravenous drug users -- will enroll 24 volunteers per year. The protocol for the study at the University of Southern California is not yet final; current plans are for a six-month placebo study to enroll 150 volunteers. [We called the U. S. AIDS Clinical Trials Information Service, 800/TRIALS-A, and it had no information on peptide T trials now recruiting.] Comment Peptide T has been a hidden but appalling scandal for years. AIDS TREATMENT NEWS first covered this drug four years ago, on January 16, 1987 (issue #22). At that time we reported that the drug had been given to four terminally ill patients in Sweden, and their condition had improved. We concluded that January 1987 article with an unfortunately prophetic paragraph: "The public, through its AIDS, medical, and other public- service organizations, must continue to watch the development of peptide T, as well as other treatment research. In the past, too many promising AIDS treatment leads have been strangled in red tape or left on the shelf to collect dust instead of being tested promptly. Only continuing public vigilance can make sure it doesn't happen again." Later, we heard a credible (but not confirmed) report that the Swedish research had been stopped by U. S. pressure. It would take a book to trace the convoluted history of peptide T and investigate the many allegations of wrongdoing in its history. What happened to this drug is a grotesque microcosm of problems with drug development in this country. We do recommend such a study for a serious researcher; many hundreds, if not thousands, of pages of documentation are available. (For starters, see "Peptide T" in Treatment Issues, volume 3, number 1, February 6, 1989, published by Gay Men's Health Crisis, New York; also see "Peptide T and the AIDS Establishment," Boston magazine, June 1990.) Does the drug work? Our understanding is that it was originally intended to be an antiviral, and did show such activity in laboratory tests; the mechanism of action was believed to be similar to that of soluble CD4, i.e., preventing the virus from binding to and entering uninfected cells. But human tests which looked for antiviral activity were disappointing, and as a result, some researchers lost interest. Clinical trials have, however, repeatedly found neurological or other symptom improvements. [See, for example, reports on human trials at the Sixth International Conference on AIDS, San Francisco, June 20-24, 1990 -- abstracts number S. B. 459, S. B. 501, S. B. 505, and 2183.] And personal reports we have received do suggest that the drug is helping -- even if the mechanism is not known. For example, one of the people whose supply was recently cut off told us that he had been trying AIDS treatments for years, and had been through the "placebo effect" many times, enough to tell that his improvement with peptide T was not just a psychological effect from trying a new treatment. We do not know how difficult it will be to get peptide T in the future. Unfortunately, the drug is rather expensive. It is usually administered by injection; it can also be prepared for nasal use, although that route is less efficient. One big unanswered question is why would the FDA move against peptide T now? Everyone agrees the drug is safe. Furthermore, as far as we know, it is not being and has not been promoted. Instead, a few people learned that the drug was especially helpful for them -- sometimes by volunteering for FDA-approved trials and then having their drug cut off when the trial ended -- and quietly found ways to obtain a supply, either from U. S. or international sources. This system has continued for many months, if not for years, and as far as we know there have been no problems, no complaints. When there are many real problems to worry about, why would the FDA move now on a non- problem, when doing so will not do anyone any good, and may cause some people serious harm? Until now the AIDS community has had only a sporadic interest in peptide T, because other issues are more important -- for example, the early evaluation of ddC and ddI -- and beyond that, the development of workable efficacy standards for an epidemic emergency. The new generations of drugs now beginning human trials -- from Merck, Boehringer Ingelheim, Hoffmann-La Roche, and a number of other major pharmaceutical companies -- must have a rational development path, so that they do not waste the two years or more that the current system requires. Our main focus must naturally be on the most critical issues. But access issues will not go away. For no matter what happens in FDA and drug-development reform, for years to come there will be many people who face death or irreparable injury because of lack of approval of treatment they need, when they are in fact right about their need for the drug, and the FDA and its experts are in fact wrong (or, more commonly, have not yet evaluated the drug, or even seen or tried to see the data). The FDA-suggested alternative of an individual compassionate IND is seldom available for AIDS. No community can abandon its people when they are sacrificed for bureaucratic convenience. One of the problems we will face is bad court decisions left over from the decade-old battle against laetrile, a dubious cancer remedy. Under decisions of the U. S. Supreme Court (and also of the California Supreme Court), patients and their physicians have no right to treatment access; instead, the FDA makes that decision (but only when pharmaceutical companies, for their own reasons, ask it to). If the system is corrupt or ineffectual, or if the experts are incompetent, mistaken, or (most commonly) just too busy, then the patient has no recourse except to die or obtain treatment underground. It is important to realize that this monstrous outcome occurred because the courts were asked to decide the wrong question. Laetrile advocates proposed that persons terminally ill should have the right to try anything, since the alternative was death. This position hardly seems unreasonable. But the problem is that the courts saw that they were being asked to put the terminally ill outside of the regulatory process entirely, in effect declaring open season for any hustler ready to take advantage of their desperation. This the courts were unwilling to do. What the courts should have been asked instead was to give the ultimate access decision, in extreme cases, to the patient and physician -- but to clearly distinguish this right of access from the marketing or promotion of unproven drugs. Currently, the laws control both drug access, and drug marketing (forbidding unsupported claims); but the mainstay of unapproved-drug regulation is in fact the control of claims (at least in California, which has some of the strictest health-fraud regulation in the nation). In one case, for example, a California physician was arrested after treating a patient with a drug the physician had invented. We heard later that State authorities said they did not object if the patient continued to receive the treatment, by getting a pharmacist to formulate the drug; their objection was to statements made by the physician to patients, apparently heard by an undercover agent. We do not propose this case as a model; it does, however, illustrate the difference between control of access and control of claims. We suspect that if the courts had been asked to respect the autonomy of the terminally ill, but without at the same time removing them from regulatory protection, the decisions might have been different. Unfortunately, it takes a long time for court rulings to change. One resource we should mention for those who have to fight the access issue now is the book Catastrophic Rights (subtitled Experimental Drugs and AIDS), by John Dixon, president of the British Columbia Civil Liberties Association (published by New Star Books, Vancouver, 1990). The phrase "catastrophic rights" refers to expanded rights of treatment access by persons who are catastrophically ill; the book develops this concept through discussion and analysis of relevant legal, medical, and scientific issues. Above all, we believe that the best single strategy for the AIDS or other patient communities in fighting for treatment access is the development of medical consensus. When mainstream, respected experts who are familiar with a treatment have a well- supported belief that the treatment is valuable, then courts are reluctant to stand in their way. But we must also remember that while medical consensus will defeat most philosophical obstacles to treatment access, it will often not defeat the commercial and practical ones -- as illustrated by drugs like fluconazole and EPO, which were not readily available until long after physicians realized they needed them. Nothing will replace continued hard work by activist and medical organizations to discover the real source of the obstacles, and ways to eliminate or circumvent them. ***** FLT: Correction and Update by John S. James On December 21, 1990, AIDS TREATMENT NEWS mentioned FLT, an antiviral that we had listed two years ago as an important potential AIDS/HIV treatment. We said that we had found no published articles about FLT in a recent computer search, and assumed that the drug was not being developed. In fact, FLT is being developed by Lederle Laboratories (a division of American Cyanamid Company), and has already begun human trials. A number of articles have been published; we missed them because we did not know that several different spellings of the drug's chemical name are in use. (The best single name to use for a computer search is "fluorothymidine".) Stanley A. Lang, Ph.D., project director at Lederle Laboratories, called to give us the correct information. He explained that a very early phase I trial, a single dose human study, has been finished; such studies are used to test pharmacokinetics, meaning how well the drug is absorbed, how long it stays in the body, etc. The drug was found to be very well absorbed orally, and it remains in the blood long enough that it would be used only twice daily. Now Lederle is about to start a phase I/II trial with 50 volunteers at three sites: Sloan Kettering in New York, Johns Hopkins in Baltimore, and the University of North Carolina in Chapel Hill. This trial will use five different doses, with each tested for four months. In laboratory tests the drug has worked well against strains of HIV taken from patients. (Many earlier drug-development efforts went astray when they used the more convenient laboratory cultures of HIV in such tests; these viruses, which have been cultured for years in laboratories, are different from those found in patients.) FLT also (like most new antivirals being tested) is effective against virus strains which are resistant to AZT -- despite the fact that FLT is chemically similar to AZT. Unfortunately, FLT also shows toxicity in animal tests, especially bone-marrow toxicity like AZT. AIDS drug expert Raymond F. Schinazi, Ph.D., was quoted in the December 13, 1990, Medical Tribune as saying that FLT "is one of the most potent compounds around. A promising drug, but it has to be used with a lot of caution." ***** Announcements *** Seventh International Conference: Early Deadlines January 28 The 1991 International Conference on AIDS is in Florence, Italy on June 16-21. The earliest deadlines occur next week, January 28: * Deadline for hotel reservation and deposit; * Deadline for lower-cost advance registration fee (Lit. 500,000 general, 150,000 student), or for cancellation of earlier registration at no cost; * Deadline for receipt of abstracts, and for presenting authors of abstracts to register. The number of participants will be limited to 8,000, so persons are advised to register early to be sure of admission. The contact for the Conference is: 7th International Conference on AIDS, General Secretariat, Laboratory of Virology, Istituto Superiore di Sani, Viale Regina Elena 299, 00161 Rome, Italy. Telephone (396) 4457888; (396) 4462331; fax (396) 4453369. *** FAACTS: Alternative Treatment Information Available by John S. James A new volunteer group, assisted by specialists in computerized searching of medical and scientific literature, is providing information from journal articles and abstracts to AIDS libraries, activist organizations, clinics, and others interested in treatment alternatives. FAACTS (Facts on Alternate AIDS Compounds & Treatments) has currently assembled a total of 750 pages of information, on 16 topics. The treatments currently covered are: astragalus, Carrisyn, DHEA, DNCB, glycyrrhizin, DTC (Imuthiol), IL-2, isoprinosine, levamisole, NAC, passive immunotherapy, peptide T, AL 721 and blue-green algae (both treatments covered in one packet together), THA, and transfer factor. Each of the 15 packets contains 25 to 45 pages of information, including five or more selected journal articles, plus additional abstracts. For information on how to obtain the individual packets, or the complete set (in two binders) plus updates as available, call FAACTS, 415/548-9654, or write to 5337 College Avenue, Suite 517, Oakland, CA 94618. Comment We joined the advisory board of FAACTS because we consider the organization a much needed effort to help provide in-depth treatment information. While the same material is available in medical libraries, most people do not have access to a medical library; even if they did have access and knew how to use the library, there would still be the problem of selecting relevant information. The frustration was well expressed recently by one AIDS treatment activist, who went to a buyers' club for information about DHEA, and found "one page of nothing." This project began when two information specialists offered to do computer literature searches for a friend with AIDS. They wanted to make the service available to more people, and FAACTS was formed to do so. FAACTS is being coordinated by Peter Moreland, who can be reached through the phone number or address above. ***** Statement of Purpose AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists, physicians, and other health practitioners, and persons with AIDS or HIV. 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. We also examine the ethical and public-policy issues around AIDS treatment research and treatment access. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display