Subject: AIDS Treatment News #101 Date: Apr 28 1990 (642 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1990 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue # 101, April 20, 1990 CONTENTS: [items are separated by "*****" for this display] Oral Interferon: Hope or Hype? Laboratory Test Suggests Possible Dementia, Neurological Treatment ACT UP Calls for NIH Demonstration May 21 AmFAR Community-Based Research Grant Letters Due May 8 ORAL INTERFERON: HOPE OR HYPE? by John S. James Startling claims, press reports, and rumors have turned a proposed AIDS treatment into the latest "miracle cure." Meanwhile, almost all AIDS experts who have looked into this matter are deeply skeptical, and often distressed, at how it has been handled. This article tells what is happening, and outlines some unanswered questions and reasons for skepticism. History and Background On February 7 of this year, researchers in Kenya reported success in treating AIDS with "Kemron," their name for a treatment consisting of very low doses of a kind of alpha interferon, held in the mouth but not swallowed. AIDS TREATMENT NEWS published a short article (issue #97, February 16); as far as know, no other news outlet in the United States mentioned the development for the next month and a half. The silence was broken this month, after Dr. Koech spoke in Japan, with articles in the newsletter Biotechnology Newswatch ("Oral IFN vs. AIDS Scores in Kenya; U. S. Trials Next," April 2); in The New York Times ("New AIDS Experiments Stir Hope Mixed with Wariness," April 4); in The Associated Press ("Medical Experts Skeptical of Interferon Results in AIDS Patients," April 5); and in the New York Native ("The Cure? " -- in two-inch-high letters on the cover -- with the subtitle, "Is Oral Alpha Interferon Too Good To Be True? " April 16). (In Kenya, a magazine called The Weekly Review published a cover article February 9, titled "KEMRON: A Miracle Drug Against AIDS -- At Last!") Interferons, produced by the body during viral infections, have been studied for about 30 years. Alpha interferon has been available as a prescription drug in the United States since 1986. In November of 1988 the U. S. Food and Drug Administration (FDA) also approved interferon as a treatment for Kaposi's sarcoma (KS); it had previously been used to treat hairy cell leukemia, and genital warts. The drug is normally given by injection, as it is believed that it would be digested in the stomach and destroyed if taken orally. Typical doses range from hundreds of thousands to millions of international units. Most interferon used in the United States is produced by genetically engineered microorganisms (the two brands available are 'Roferon-a' and 'Intron a'). In November 1989 the FDA also approved a "natural" interferon (produced by cultured human cells deliberately infected with a virus) to treat genital warts. This product ('Alferon N Injection') contains at least 14 variations of the interferon molecule, whereas each of the recombinant (genetically engineered) products contains only one. This natural interferon is the variety approved in the United States that is closest to the interferon used in Kenya; the latter is produced by Hayashibara Biochemical Laboratories in Japan by a different cell line and contains at least nine variations of the interferon molecule. (Although approved for prescription use, Alferon N Injection is not yet generally available because it is new and supplies are still limited. At this time it has been made available to physicians who treat genital warts, to familiarize them with the product. The Japanese product is not available in the United States, apparently not even for a formal clinical trial intended to replicate the Kenya studies.) Some experts doubt that it makes any difference whether interferon is "natural" or recombinant. This issue is an example of the broader fact that there is much confusion and disagreement among experts about interferons in general. The treatment tested in Kenya consisted of extremely small doses of alpha interferon, about 100 to 150 international units, thousands of times less than the doses routinely given by injection. The greatly diluted drug was held in the mouth but not swallowed. Possibly the drug could be absorbed in the mouth (some conventional drugs are given under the tongue), but no one knows how so small a dose would have any effect. (Somewhat larger doses were found to cause nausea, and the experimenters suspect that the dose must be within a critical range, with too much of the drug being less effective than the correct amount.) Because the dose is so small, the cost of the drug is only pennies per dose, even though interferon is very expensive in its normal use. Where did the idea come from to try using alpha interferon in such an unusual and seemingly implausible way -- less than a thousandth of the usual dose, and held in the mouth, not injected? The idea came from veterinary experiments. Interferon has been tried for treating viral diseases of agricultural animals and also for feline leukemia in cats. Some veterinarians have tried administering interferon by squirting it into the mouth. Dr. Joseph M. Cummins, a veterinarian and president of Amarillo Cell Culture Co., Inc. in Amarillo, TX, is working with the Kenyan researchers and suggested the low- dose, oral route of administration based on this animal experience. In Kenya, the leading spokesman for the treatment is Davy K. Koech, Ph.D., a well-respected medical researcher with dozens of published papers, mostly on tropical diseases such as malaria and schistosomiasis. The other principal investigator in Kenya is Arthur O. Obel, M. D. ; he also has published dozens of papers. Very few of these articles concern AIDS. The Claims Two claims have most caught the attention of the AIDS community: * Every U. S. press report we have been able to find has quoted the claim that 99 out of 101 (some say 99 out of 100, or 99 out of 99) AIDS patients treated with Kemron had all their AIDS symptoms disappear within several weeks. * Equally astounding is the claim that eight out of 40 patients "serodeconverted" -- changed from HIV-positive to HIV- negative -- during four to six weeks of treatment. T-helper count increases were also reported, especially in those who had low counts to begin with (contrary to conventional experience with alpha interferon, which usually works best for those with higher counts). Dr. Koech announced results of the 101 patients in late March at a conference in Okayama, Japan. A scientific paper about a more detailed study of the 40 patients mentioned above has been accepted for publication in June in Molecular Biotherapy, a journal published in the U. S. Some of the results of this 40- patient study appeared in The New York Native, April 16. According to Dr. Koech, the British journal Lancet rejected the paper because there was no control group (which in this case would probably have received a placebo). Questions and Doubts * No one, including its advocates, knows how the treatment could work. The dose is tiny compared to what is used in other interferon treatment. The drug might be absorbed under the tongue, or there might be interferon receptors in the mouth; some kind of cascade of effects must be produced. But so far these are only speculations, not supported by evidence. * The scientific study of 40 patients includes a table showing T- helper cell improvements. When we examined this table, we found that the initial T-helper counts, before treatment, had a median over 500; 33 of the 40 patients had T- helper counts over 270, with 18 being over 700. The mean T- helper count for these 18 patients -- almost half the total patients in the study -- was over 1000 before treatment began. Many if not most of the 40 patients would be expected to be asymptomatic. But patients were accepted for the study if they were HIV- positive and had certain symptoms which might be AIDS- related. The symptoms were: appetite loss or weight loss; fatigue or weakness; mouth sores or ulcers or candidiasis; fever; diarrhea; respiratory tract infection; night sweats; lymphadenopathy; and skin rash. (The average patient had 5.2 of these symptoms. Two in this study were were HIV-positive but asymptomatic; the others did have symptoms.) It is possible that some of these symptomatic patients in fact had no AIDS-related symptoms, but instead had ordinary, minor infections which caused the fever, diarrhea, appetite loss, rash, night sweats, etc. Being HIV-positive and having symptoms which can be AIDS-related, they were included in the study and started on oral interferon treatment. Then they recovered -- just as they would have if they had had no treatment at all -- and were counted as having all their AIDS symptoms go away after the treatment. We called Dr. Koech in Kenya and asked him about this possibility. He said that the molecular spectrum was not directly related to clinical symptoms, and that he was not trying to relate the U. S. and African diagnostic systems. He also noted that the disease itself and the results of testing are not directly comparable between Africa and the U. S. The scientific report of the 40 patients mentions that "Patients in Kenya were not staged by CDC or Walter Reed systems as might be expected in the USA. " But the concern we raised above -- that the symptoms observed in these patients may not have been AIDS related, and that in any case a group of patients selected only for being HIV- positive and having non-specific symptoms would, if followed for a few weeks, be expected to show many cases of recovery even without any treatment -- has not been answered. * A literature search conducted by AIDS TREATMENT NEWS found no evidence that anyone associated with the Kemron studies, in Kenya or elsewhere, had much experience with AIDS. Lack of solid AIDS experience might have allowed errors to remain uncorrected. We used Medline, a computer database maintained by the U. S. National Library of Medicine, to look for medical articles published during the last seven years (1983 through 1990) by any of the five authors of the scientific paper on the results of 40 patients in Kenya. Not all articles are included in the database, but it is usually complete enough to show the major fields in which a medical scientist has worked. Davy K. Koech, Ph.D., of the Kenya Medical Research Institute in Nairobi, was listed as author or co-author of 52 articles or other scientific publications. Most concerned tropical diseases such as malaria and schistosomiasis. We found only two which mentioned AIDS, immunodeficiency, or HIV in the title, descriptors, or abstract. These concerned false positives in HIV testing in Kenya (published in 1988), and AIDS in Nairobi prostitutes (1986). Arthur O. Obel, M. D., F. R. C. P., also of the Kenya Medical Research Institute, is the only other study author located in Kenya. He is author or co-author of 25 medical and scientific publications since 1983. But the only one we found on AIDS was a single case report published in 1984. Jun Minowada, M. D., D. M. S., of Hayashibara Biochemical Laboratories, Inc. in Okayama, Japan, was listed as author or co- author of 126 publications since 1983. We only found two concerning AIDS; both of them are highly technical studies of blood cells. Joseph M. Cummins, D. V. M., Ph.D., of Amarillo Cell Culture Company, Inc., Amarillo, Texas, was listed as author or co- author of 26 publications. Only one concerns AIDS, however: a 1987 letter on low-dose oral interferon in one patient. The other U. S. author of the 40-patient study, Val A. Hutchinson, M. D., of Amarillo Virology Research, was co-author with Cummins of the low-dose interferon letter in 1987. Our search found one other published article, not involving AIDS. The fact that AIDS was not a major field of anyone involved in the study does not mean that the results are wrong. But people are making decisions now on the basis of the Kenya results, which are completely different from what all other AIDS research would lead us to expect. The relative inexperience in AIDS of everybody involved might reasonably be considered in deciding how much practical weight to give these claims before they have been confirmed by at least one other research team. * There was no control group. In other contexts this writer has argued that good science is possible without placebos. But in this case a randomized controlled trial would be very important (for example, to answer our questions above, about whether these patients would have improved anyway without treatment). And a placebo study could be ethical, since many patients had high T-helper counts and would not be endangered by going without treatment for six to eight weeks (the time required to see all symptoms vanish in 99 of 101 patients). Not everyone would have to risk getting a placebo -- only a small number volunteers healthy enough to not face serious risk by remaining untreated for a few weeks. Most of the 40 patients had over 500 T-cells, and would not receive any AIDS-specific treatment anyway under standard medical care. * What about the completely unprecedented claim that eight of the 40 patients went from HIV-positive to negative after a few weeks of oral interferon? The two obvious possibilities are (1) that what Koech has called "serodeconversion" did in fact take place, or (2) that there were errors in the tests. Dr. Koech has published several papers on immunologic tests; his expertise in the area gives greater weight to the test results. ELISA tests were confirmed by Western blot. On the other hand, note that if any errors did occur -- either false positives letting uninfected patients into the study, or false negatives when they left -- all the errors would be cumulative, with no tendency to cancel each other out. Of the 80 tests (40 before treatment, and 40 after), a total of eight errors of either kind would be necessary to account for the reported result. It makes sense to wait for confirmation before accepting the unprecedented claim that this treatment can cause some patients to become seronegative. * A great increase in T-cell counts -- averaging over 500 for the 40 patients during six weeks of treatment -- was also reported. Again we would like to see confirmation by another study. T- cell counts vary greatly, for many reasons. All but two of the 40 patients were selected and entered into the study at a time when they were ill (showing non-specific AIDS symptoms). Perhaps the (non AIDS related? ) illness they had when they began the study temporarily depressed the counts, leading to a spontaneous rise as they recovered. Business Arrangements According to its April 2 issue of Biotechnology Newswatch, Dr. Joseph Cummins holds four U. S. use patents on alpha interferon, giving Amarillo Cell Culture exclusive worldwide rights to oral use. On April 4, 1990, Interferon Sciences (which makes Alferon N Injection) announced that it had licensed co-exclusive rights from Amarillo Cell Culture to human oral use of low doses of interferon. Interferon Sciences obtained worldwide rights except in Japan, where Hayashibara (which makes the drug used in Kenya) has exclusive rights. (According to the April 4 Interferon Sciences press release, Hayashibara owns 24 percent of the equity of Amarillo Cell Culture.) Under the new licencing agreement, Interferon Sciences aquired three percent of the equity of Amarillo Cell Culture. Interferon Sciences is an 82-percent-controlled subsidiary of National Patent Development Corp. Dr. Cummins is president of Amarillo Cell Culture. Dun & Bradstreet lists this company, incorporated in 1984, as having seven employees and a net worth of $309,351. Its current value would appear to depend heavily on how the world regards oral interferon. Plans for Trials In the U. S., a small study is planned at Mount Sinai Medical Center in New York. Joseph M. Hassett, M. D. heard Dr. Koech in Japan; he told Biotechnology Newswatch that, "If even one-half of what Koesch reports in his uncontrolled study is correct, it's important to repeat the studies. If he is generally correct, we will know in a matter of weeks." This study plans to use the U. S. "natural" interferon product (Alferon N Injection). It would be better to replicate the Kenya trial with the same medication used there, but apparently there was some problem in obtaining it for this study. The Mount Sinai trial still needs Institutional Review Board and FDA approvals. Another trial studied some patients in Amarillo and Lubbock, Texas, treated orally with Roferon, one of the recombinant interferons available in the United States. In a preliminary analysis, some blood improvements were seen. Now this study is being ended, and a new one will begin with a different dosing schedule and with the Alferon natural interferon, which was not previously available. An informal monitoring study is being organized in Ft. Lauderdale, Florida. For information call Lenny at the PWA Health Alliance, 305/763-7723. Internationally, a number of trials are being planned or at least discussed, some by the World Health Organization and some by Amarillo Cell Culture. On March 28, Tanzania announced that it was planning a trial, to prevent its citizens from going to Kenya in an attempt to obtain the drug. ***** LABORATORY TEST SUGGESTS POSSIBLE DEMENTIA TREATMENT by John S. James A study published in Science (April 20) showed that in a laboratory test, rat brain cells were injured by very small amounts of gp120, a protein made by the AIDS virus. The cells could be protected by small concentrations (100 nM) of nimodipine, a prescription drug used to reduce neurological damage in certain cases of bleeding in the brain. The concentrations effective in the laboratory test can be attained in patients. In the laboratory study, gp120 appeared to harm nerve cells by causing them to absorb too much calcium -- over 30 times the normal level. That is why nimodipine, a calcium channel blocker, was tried in this test-tube study. The authors suggested more research to see if this drug might be useful in treating or preventing AIDS-related dementia or other neurological damage. What Happens Next? Results from a laboratory study of rat brain cells cannot predict what will happen in patients. Even if the drug could work, no one knows the right dose. While nimodipine is fairly safe in its standard use (the most common side effect is decreased blood pressure), there is no information on its use by persons with AIDS, or on combining the drug with AZT or other treatments which would still be necessary, since nimodipine would have no effect on the HIV infection itself. AIDS TREATMENT NEWS called the senior researcher of this study, Stuart A. Lipton, M. D., a neurologist at Children's Hospital in Boston and at Harvard Medical School. He told us that he has a clinical trial ready to go; he is now talking with Miles Pharmaceutical, the company which owns the drug, seeking support for it. We mentioned that other funding might be found, but Dr. Lipton feels strongly that the company which owns the drug should pay for the study. We called Miles Pharmaceutical and reached a spokesman in the public relations office. He said that while Miles was ready to support pre-clinical and animal studies (he emphasized those words in our conversation), they wanted more information before trying it in patients -- for example, a test with another animal model. He mentioned that Miles had no experience with AIDS, but had been told that rats do not get the disease; scientific implications of that fact might be considered. Comment It became clear that here was another example of the kind of misunderstanding that repeatedly derails practical AIDS research, due to the lack of national leadership ready to move in an emergency. It is understandable that a pharmaceutical company unfamiliar with AIDS would want more than a study of rat cells in a laboratory dish before sponsoring a trial. And yet the drug is believed safe, and ultimately -- no matter how much animal work is done -- the only way to see if it works will be for patients to try it. Dr. Lipton wants a trial now so that people will not start using the drug on the basis of one laboratory study, in the absence of any human trial for its use in treating AIDS-related neurological damage. We sensed that the parties had been talking to each other for some time before the article was published; they seemed to have reached an impasse. Since no one knows if the drug will work at all for AIDS- related dementia or other neurological problems, no one knows if it would only be preventive, or if it could reverse symptoms already present. Fortunately AZT can often reverse dementia, showing that the damage is not irreparable. If nimodipine can clearly improve patients' condition, then a clinical trial would be relatively easy; it could be conducted by a community-based trials organization, or by an individual physician. But if the drug could only prevent the problem and had to be given in advance, a clinical trial would be difficult to administer, because it would require many patients and a long time to obtain the required evidence. If no trial happens soon -- we especially need the easy trial, for treatment as opposed to prevention -- it is inevitable that people will start trying the drug without waiting for a scientific study. ***** ACT UP CALLS FOR NIH DEMONSTRATION MAY 21 by John S. James A national demonstration for more effective AIDS research will take place May 21 at the headquarters of the National Institutes of Health (NIH), located in Bethesda, Maryland, near Washington, DC. NIH oversees most of the federal government's research into AIDS treatments through its AIDS Clinical Trials Group (ACTG). Other ACT UP chapters may hold simultaneous demonstrations at ACTG centers around the country. Research problems (the quotes below are from an April 16 press release from ACT UP/New York) include: * Lack of productivity. "After three years, not one single drug has been approved as a result of trials conducted by the ACTG. " * Poor priorities. "More than 80 percent of people in ACTG trials were given AZT," which was approved three years ago. AZT itself was developed outside the ACTG -- as was aerosol pentamidine, after NIH refused to fund the critical trial. * Conflict of interest issues. Almost all ACTG researchers have outside industrial consulting arrangements -- and many of them opposed recent proposals to require disclosure. Have these secret arrangements had undue influence on the closed meetings which set ACTG priorities and thereby influence the spending of hundreds of millions of dollars of public funds? * Lack of small, rapid phase I/II tests for new drugs. Note: One new and interesting demand of this demonstration is for tests of 30 or more new AIDS drugs each year in small phase I/II trials. Dozens if not hundreds of appropriate candidate drugs are ready. Almost none are being tested. We believe that the basic problem is that money, personnel, and other resources are being diverted to extra testing of existing drugs, because the latter have more commercial momentum. * Poorly designed trials, delays in releasing lifesaving information, too little research on treatment for children, lack of enrollment of women and people of color, and other problems. For more information about the demonstrations, call ACT UP/NY at 212/989-1114. Note: A Critique of the AIDS Clinical Trials Group, an in- depth background paper on what is wrong with the Federal program of AIDS clinical trials, will be published next week by ACT UP/New York. Authors are Mark Harrington, Jim Eigo, and Ken Fornataro, all of ACT UP's Treatment + Data Committee. For a copy, send a 9 by 12 or larger self-addressed envelope with $1.65 postage to: Mark Harrington, 611 E. 11th St., Apt. #7-A, New York, NY 10009. (A donation to ACT UP would be appreciated, but is not required.) For an introduction to the basics of what is wrong with the trials and what needs to be improved, see Mark Harrington's "Anatomy of a Disaster," Village Voice, March 13, 1990. Comment On November 11, 1988, a demonstration organized by ACT NOW, the national coordinating committee of ACT UP groups, brought at least 1,000 demonstrators to the headquarters of the U. S. Food and Drug Administration (FDA) and shut down the building for the entire day. Now activists are beginning to see problems associated with NIH as more serious impediments to effective AIDS treatment than problems at the FDA. But moving the target to NIH involves much more than just a different subway stop and another government agency. The NIH demonstration presents new challenges which must be handled well: * The public does not understand the NIH issues (by contrast to the FDA, which it can easily picture as the "heavy" keeping promising treatments away from patients). NIH issues center around scientific judgments and priorities; it is hard for the public to judge whether or not criticisms have merit. And FDA battles focus on known, existing treatments; it is harder to organize people around deaths caused by drugs which do not exist and perhaps never will, but should. It is our impression that awareness of research issues is not well developed even in the AIDS community, except in New York City, where ACT UP has taken a leading role in understanding what is happening in research, and informing others. * Productivity of AIDS research has been slow to emerge as an issue because activists fear that too many people would just as well abandon treatment development and let people die. For those fighting for AIDS research budgets, there is seldom or never a right time to air criticism of the program. But now the glaring lack of new drugs out of the ACTG, and lack of hopeful signs for the future, are forcing the issue. * Most NIH-related problems have nothing to do with the employees who work at NIH headquarters, who have long had a well-deserved reputation for dedication and usually could make more money in industry. Clinical trials at NIH itself ("intramural" trials) have long been models of humane, courteous patient care, and they have been medically and scientifically productive; ddI, for example, was first tested there by the National Cancer Institute. The problems have been with the "extramural" research contracted out to academic institutions through the ACTG. NIH employees do not decide who gets the money; that is done by outside experts in peer- review committees. In theory, the peer review system is excellent. In fact, it is highly vulnerable to manipulation and abuse by industrial interests, old-boy networks, and empire builders -- especially in AIDS, where outside scrutiny has been lacking due to the prevailing national unwillingness to deal with AIDS. * Tactically the demonstration must be organized with special care, because both inpatients and outpatients are being treated at NIH, and critical scientific experiments are being conducted; shutting down certain buildings, as was done at FDA, could endanger patients and be a public-relations disaster. ACT UP demonstrations often work through autonomous organizations and affinity groups. Organizers responsible for this demonstration must make sure that everyone involved -- demonstrators, employees, police, press, etc. -- knows exactly what is legitimate and part of the ACT UP demonstration, and what is not. Most of the problems associated with NIH do not really start at that agency. They arise instead from the national ambiguity about AIDS, and the resulting lack of high-level leadership and commitment. The ACTG program was set up several years ago, at a time when saving lives was not only unfashionable, but taboo even in the AIDS service community; virtually every organization assumed that its services would end only in death. This national lack of interest in practical saving of lives happened to mesh with the traditional value system of academic science, which most valued "pure" research, conducted without regard to the practical world. (Today's academic science is abandoning unworldliness in favor of money and deals -- not an improvement.) ACT UP's NIH demonstration conveys the message that glaring research deficiencies can no longer be kept out of sight. If it lets people know that medical research is not immune to national denial and lack of leadership, that these failures do kill, then the demonstration will have served its purpose. ***** AMFAR COMMUNITY-BASED RESEARCH GRANT LETTERS DUE MAY 8 The American Foundation for AIDS Research (AmFAR) has announced a new funding cycle for community-based trials. Applicants must be not-for-profit organizations of community- based physicians and other health care providers, usually within the United States, its territories, or Puerto Rico. Seed grants, operating grants, and project grants will be awarded to appropriate organizations; the maximum amount will be $100,000. A "letter of intent," due May 8 must contain a cover page as described by AmFAR, an abstract, a biographical sketch, and a list of participating physicians and information about them. It is not just a letter stating intent to apply. For more information, or a copy of the seven-page instructions for writing the letter, call Frank Nowicki at AmFAR, 212/719- 0033. ***** BACK ISSUES OF AIDS TREATMENT NEWS ARE AVAILABLE. FOR MORE INFORMATION, CALL 415/255-0588. 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 ARC. 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