&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 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 # 164, December 4, 1992 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Atovaquone (Mepron; 566C80) Approved for Pneumocystis; Drug Development, Activism Success Therapeutic Vaccine Trials May Enter New Era Biggest Research Snafu: New Antivirals Neglected Polaris System: One Model for Government Success Fetal Tissue Research Background ***** Atovaquone (Mepron; 566C80) Approved for Pneumocystis; Drug Development, Activism Success by John S. James On November 25, the U. S. Food and Drug Administration approved atovaquone (brand name Mepron; formerly known as 566C80) for mild to moderate pneumocystis, as a second-line treatment for those patients who cannot tolerate the existing treatment, trimethoprim/sulfamethoxazole (TMP/SMX). The drug should be in pharmacies throughout the U. S. by early December. At the same time, Canada's Health Protection Branch also approved atovaquone -- the first time a drug has undergone a joint, integrated review by the two agencies. Atovaquone was approved for second-line not first-line treatment because a major comparative trial found that TMP/SMX worked better for those who could tolerate it; overall the two drugs had about the same "therapeutic success" (defined as sustained improvement over four weeks without having to discontinue the medication), but TMP/SMX had higher survival after eight weeks, 97 percent vs. 92 percent for atovaquone in that trial. However, 20 percent of those given TMP/SMX had to discontinue its use because of side effects; now atovaquone is available as second-line treatment for such patients. (Another trial found that atovaquone worked about as well as injected pentamidine, the existing second-line treatment, but had far fewer side effects serious enough to require drug discontinuation.) It is important to take atovaquone with meals, because in its current formulation at least, the drug is much better absorbed when taken with food. Burroughs-Wellcome, atovaquone's developer, announced a price to the wholesaler of $2.13 per 250 mg. tablet. The recommended dose is 2250 mg. per day (three tablets three times a day with meals) for 21 days, meaning that the wholesale price to treat one case of pneumocystis is about $402. (It is difficult to give a retail price, since markups by pharmacies can vary greatly.) Burroughs-Wellcome has announced a program to cap the annual cost for patients without third-party coverage who use more than 411 grams in a calendar year -- about $3500 wholesale. This cap may alleviate some cases of hardship, although presumably few will reach the limit. Burroughs-Wellcome also has other programs for providing drugs to patients with financial difficulties. Development History, Activist Involvement Atovaquone went from human trials to FDA approval in a remarkably short time. Yet during this time, Burroughs- Wellcome conducted the largest controlled trial yet of a pneumocystis treatment, at 37 sites in the U. S., Canada, and Europe. And while the trials were continuing, the company provided atovaquone without charge to over 900 patients who had no other treatment option, through a "treatment IND" approved by the FDA. Credit belongs to Burroughs-Wellcome, the FDA, and also to AIDS activists, especially in ACT UP/Boston, who have done much to expand access to this drug. The following is from a press statement released by David Peck of ACT UP/Boston after the approval of atovaquone: "Atovaquone's approval today represents a quantum leap in AIDS drug development -- cooperation between activists, government, and industry, large-scale access during early development (which should be the rule rather than the exception), and the sheer speed of the approval process... "ACT UP knocked on Wellcome's door 18 months ago, and asked for access to atovaquone during its development. Our agenda specified drug access guidelines, such as: the target patient population, 24-hour drug delivery, an 800 number, etc., and Wellcome implemented this expanded access program with FDA approval a year ago. Over 900 people got atovaquone free of charge during the program -- and ACT UP/Boston is proud of this accomplishment. "ACT UP/Boston applied constant pressure on the FDA to move this drug through the approval process. This included my testimony to the FDA antiviral drug advisory committee, which voted unanimously in September to recommend approval. As recently as last week, at our urging, the FDA changed the proposed labeling on atovaquone to make its use more inclusive... "Atovaquone proves that ACT UP and drug companies, despite our differences and our seemingly endless demands, can work together. For now, our role is key: we provide the power lines to carry community concerns to drug companies. If others in the industry are tired of our screaming, they can take lessons from the Wellcome of the 90s -- and put the pressing needs of the community at the top of their drug development agenda. Atovaquone's success proves how well this works." ***** Therapeutic Vaccine Trials May Enter New Era by Dave Gilden A special panel set up by National Institutes of Health director Bernadine Healy, M. D., is advocating an extensive test of therapeutic HIV vaccines. The panel's unanimous recommendation on November 23 follows pressure from AIDS treatment activists to provide community access to these vaccines, one of the few new treatment developments that could be available any time soon. Therapeutic vaccines seek to stimulate immune defenses in persons already infected with HIV, by periodically injecting synthetic HIV proteins. Preliminary trials have found that presenting these molecules in a format that differs from natural HIV infection prompts the immune system to increase the number of antibodies it produces against HIV. Other immune system responses may broaden as well. Therapeutic vaccines' clinical benefits remain a mystery at this point, however, and the best methods for properly evaluating these treatments are unknown. To settle the question, the panel is proposing a "large simple trial" that will test the vaccines efficiently and relatively rapidly by measuring clinical outcome in tens of thousands of persons. The NIH panel's original mission was to examine a unique $20 million appropriation in the US Army's AIDS research budget. Congress directed that the money be used specifically for a large phase III trial of gp 160, a therapeutic vaccine which is made by MicroGeneSys of Meriden, Connecticut. Researchers at the Walter Reed Army Institute of Research have been testing the vaccine since 1989. The MicroGeneSys product is the most extensively investigated of the current crop of 14 candidate therapeutic vaccines. It may not be the most effective, however. NIH director Healy reportedly was infuriated at the way MicroGeneSys used a high-pressure lobbying campaign to avoid the normal scientific review process. She was able to step in with her panel because the appropriation's language provided that the trial would not go forward should the director of the NIH, the commissioner of the FDA and Secretary of Defense jointly oppose it. The money would then go to other Defense Department AIDS research (which is centered on vaccines and diagnostic tests). Healy's panel opted for a choice that will require wide- scale community participation. The large simple trial will need up to 30,000 volunteers for a two to four year placebo- controlled comparison of three or more different vaccines. The proposed trial design has many features that make it attractive. People in all T-helper cell ranges would be included, although the majority would be in the above-500 group. Any interested physician or clinic would be able to enroll clients. Data reporting would be minimal: semiannual reports on adverse reactions and current health status are all that would be required for most volunteers. Finally, there would be no limitation on other medications taken along with the periodic vaccine. The large simple trial concept parallels most of the points raised in a consensus statement on the congressional appropriation signed by 15 AIDS groups around the country. Many researchers, in contrast, wanted the money to go to series of small preliminary trials. Despite the placebo received by some in the trial, those with minor to moderate immune impairment may have nothing to lose. There have been some concerns that added free HIV envelope protein is in one way or another immunosuppressive, but the experience at Walter Reed and elsewhere has consistently found no evidence of deleterious effects. For those with lower T-helper cell counts, the trial becomes more problematic. The one small test of a therapeutic vaccine in people below 400 helper T-cells (which used MicroGeneSys's product) found, not unexpectedly, that immune stimulation decreased as T-helper count went down. This one trial does not prove that people with advanced disease cannot benefit, and their inclusion is being justified on humanitarian grounds. Possibly, though, enrolling in the vaccine trial might make them ineligible for other trials of experimental HIV treatments should they arise. Another issue is how to incorporate future improved vaccine therapies into the large simple trial. Such additions will extend and complicate the study. An immediate question is whether the Army will agree to put the original $20 million into a community-based trial. Nothing in the legislation requires the Army to follow the NIH lead, and the kind of trial proposed by the expert panel is quite outside the Army's usual practice. ***** Biggest Research Snafu: New Antivirals Neglected by John S. James After six years of reporting on AIDS treatments and research, we believe that the biggest obstacle now to better treatments is in the early part of the drug-development pipeline -- getting promising antivirals through preclinical development and into their first test of biological activity in humans. As soon as a new drug shows evidence in people that it might work very well, then medical, political, commercial, and public opinion will mobilize to move it rapidly through the remaining tests required and to those who need it. But this mobilization will not happen if the drug remains untested and there is no data showing that it will work as an antiviral in humans. It will not happen if there is only laboratory data, or only a toxicity test in HIV-negative volunteers (which obviously cannot show if the drug is active against HIV in the body). In our last issue we outlined the problem of the empty pipeline of AIDS drug development ("Call to Activists: Focus Needed on Early Human Research," AIDS TREATMENT NEWS #163, November 20, 1992). Here we show that there is no lack of promising HIV treatment leads, by listing some of those which appeared in just one issue of one journal -- ANTIVIRAL RESEARCH, March 1992, which published the abstracts of the Fifth International Conference on Antiviral Research, held this year in Vancouver from March 8 to 13. We include this list to show that the lack of promising treatments for HIV infection reflects a management problem, more than the scientific difficulty of the task; very few of the existing leads are effectively followed up, because there is no one in a position to find the most promising potential new treatments, wherever they may be, and work together with industry or anyone else involved to make sure that they are handled appropriately and that unnecessary obstacles do not block progress. Drugs late in the development pipeline can easily develop a constituency, because researchers are paid to study them, data exists about them, and the public wants them. But each early drug is likely to have a constituency of at most a handful of people, and they do not have nearly the clout to get the drug into human development. (The decision to proceed seriously toward human testing is a very expensive one for a company -- and the rules usually require a huge investment before there is any information on how well the drug works in practice in people.) Sometimes there are underground efforts to get a new drug tried, but without mainstream support, these projects usually move slowly. The U. S. drug-development system is set up in such a way that only large companies can expect to operate it successfully (see "Clinical Trials: Asking the Right Questions -- Interview with Lewis Sheiner, M. D.," AIDS TREATMENT NEWS #142, January 3, 1992). We highlight these issues now because the incoming Clinton administration may signal that the nation is at last willing to take on the responsibility of addressing the AIDS epidemic effectively, instead of denying the problems and leaving them for someone else. As a result, there is now a chance that the real obstacles to more effective AIDS research and treatment development can be addressed. But the problems and proposed solutions must be on the table, discussed and analyzed by professionals and the public. Even activists have often failed to realize how many early leads are available; researchers could get the information, but their incentives have pushed them to emphasize drugs already marketed or close to marketing, and they could do little about the systemic misallocation of resources without public awareness and support. One approach to a solution would be using small teams of experts, with no conflict of interest, to pick perhaps ten to 20 of the most promising potential drugs, contract them out for the FDA-required animal studies, then contract them to medical centers for the first human tests on HIV-positive volunteers. If these tests were successful, a drug could easily get the attention necessary for rapid further development by pharmaceutical companies or by other institutions. (Such an approach has been used very effectively to develop certain key military technologies, by the Defense Advanced Research Projects Agency [DARPA], despite ideological resistance by the Bush administration, which objected to similar government involvement in civilian technology. The Clinton administration is likely to apply such approaches to support long-term U. S. economic competitiveness. Biomedical research would have the two-for- one advantage of developing the economy while saving lives through the same effort.) Examples: Potential Antivirals In each entry below, we give the title of the abstract, the first author, the institution(s) where the work was done, and the abstract number. For more information about these potential drugs, see the abstract (which is usually one paragraph in length) in the March 1992 ANTIVIRAL RESEARCH, Supplement I. This list omits studies of drugs which are generally familiar to the AIDS research community (such as ribavirin, hypericin, and the Roche tat inhibitor), as well as other studies which were more oriented to basic research or otherwise did not focus on new HIV treatment leads. Also, the conference had many presentations on other viruses which are relevant to AIDS treatment, including CMV and herpes simplex; we omitted those here, to focus on HIV. Some of the drugs listed below may already be getting all appropriate research attention. We do not intend to imply otherwise, only to give a sense of how many interesting leads are available, how much laboratory drug-development work is going on, and which institutions are most productive in developing leads for new antivirals. Many other new antivirals, not included here, are published elsewhere each year. In addition, there are many proposed "alternative" treatments which also are not included, as the collection below is mostly chemistry oriented, and weak on natural products. For these reasons, this list of potential AIDS treatments could be greatly expanded. * * * * New approaches for synthesizing antiviral nucleosides. Dennis C. Liotta. Emory University, Atlanta. Abstract 1. * Optically active isodideoxynucleosides: a new family of potential anti-HIV agents. V. Nair and others. University of Iowa, Iowa City. Abstract 3. * Potent and selective inhibition of HIV-1 and HIV-2 replication by a novel class of bicyclams targeted at viral uncoating. E. De Clercq and others. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium; Johnson Matthey Technology Centre, Reading, Great Britain; and Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania. Abstract 4. * HIV-1 specific phenylacetamide derivatives: A novel class of reverse transcriptase inhibitors with potent and selective antiviral activity in vitro. R. Pauwels and others. Rega Institute for Medical Research, Leuven, Belgium; and Janssen Research Foundation, Beerse, Belgium. Abstract 5. [Note: One drug of this class, code-named R89439, was covered in more detail in "Alpha-APA: New Anti-HIV Compound," AIDS TREATMENT NEWS #159, September 18, 1992.] * Cooperativity of a HIV-1 Protease Inhibitor (SKF 108922) with AZT in acute and chronic HIV-1 infections in vitro. D. M. Lambert and others. SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania. Abstract 8. * Synthesis and antiviral properties of Carbocyclic 3'-Oxa- 2',3'-dideoxyguanosine. S. W. Schneller and others. University of South Florida, Tampa; and Rega Institute for Medical Research, Belgium. Abstract 20. * Synthesis and structure-activity relationships in a novel class of polyamines that inhibit HIV-1 and HIV-2 replication. G. Bridger and others. Johnson Matthey Technology Center, Reading, Great Britain; Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania; and Rega Institute for Medical Research, Leuven, Belgium. Abstract 21. * Synthesis and in vitro anti-HIV activity of 2',3'-dideoxy- 2',3'-methanonucleosides and of 3'-deoxy-2',3'- (difluoromethano)thymidine. H. Maag and others. Syntex Research, Palo Alto, California. Abstract 22. * N-3 derivatives of azido- or fluoro-dideoxythymidine: synthesis and biological activities. D. Grierson and others. CNRS, Gif-sur-Yvette, France; Institut Curie, Paris; Rhone- Poulenc-Rorer Central Research, Vitry, France; Hopital Saint- Louis, Paris. Abstract 23. * Synthesis, anti-HIV activity and cytotoxicity of derivatives of 5-hydroxymethyldeoxyuridine. S. V. P. Kumar and others. University of Saskatchewan, Saskatoon, Canada; supported by MRC Canada. Abstract 24. * Antiviral activity of 9-{2-(phosphonomethoxy)- ethoxy}purines against HIV, FIV and visna virus. R. M. Perkins and others. SmithKline Beecham Pharmaceuticals, Gt. Burgh, UK, and Diagen GmbH, Dusseldorf, Germany. Abstract 29. * Differential inhibitory effects of the (S)- and (R)- Enantiomers of 9-(3-fluoro-2-phosphonylmethoxypropyl)purine derivatives on retrovirus replication in vitro and in vivo. J Balzarini and others. Katholieke Universiteit Leuven, Belgium; and Czechoslovak Academy of Sciences, Prague. Abstract 31. * Selenoorganic compounds useful as anti-HIV inhibitors. M Lemaitre and others, Rhone-Poulenc Rorer Central Research, Vitry, France. Abstract 32. * New potential anti-HIV prodrugs in the d4T series. M. Lematre and others, Rhone-Poulenc Rorer, Vitry, France, and Institut Pasteur de Lille, Lille, France. Abstract 33. * Combination studies with antiviral compounds to prevent reactivation of latent HIV-1 in OM-10.1 cells. P. M. Feorina and others. Emory University, Atlanta; Veterans Affairs Medical Center, Decatur; and Centers for Disease Control, Atlanta. Abstract 35. * Synthesis and anti-HIV activity of 2-substituted, 6- Benzyl- Pyrimidine Derivatives. P. La Colla and others, Universita di Cagliari, Italy; and Universita di Roma, Italy. Abstract 36. * Anti-HIV-1 activity of rev and gag phosphorothioate oligo- Deoxynucleotides in chronically and acutely infected cells. P. La Colla and others. Universita di Cagliari, Italy; and Universita di Napoli, Italy. Abstract 37. * Broad-spectrum antiviral activity of polyoxometalates against human immunodeficiency virus and other enveloped viruses. N. Yamamoto and others. Rega Institute for Medical Researach, Leuven, Belgium; Johnson Matthey Technology Centre, Reading, Great Britain; and Johnson Matthey Pharmaceutical Research, West Chester, Pennsylvania. Abstract 42. * Novel polyanionic albumin derivatives are potent and selective in vitro inhibitors of HIV, FIV, and SIV cell fusion and giant cell formtion. R. W. Jansen and others. University Center for Pharmacy, Groningen, Netherlands; and University of Leuven, Belgium. Abstract 43. * Metabolism of carbovir in CEM cells. W. B. Parker and others. Southern Research Institute, Birmingham, Alabama. Abstract 47. * Cell membranes, cell fusion and phospholipids: new targets and novel inhibitors of HIV-1. D. Kinchington and others. Medical College of St. Bartholomew's Hospital, London; University of Southampton, Southampton, UK. Abstract 49. * Anti-human immunodeficiency virus activity of a novel synthetic peptide, T22 ( [tyr5,12,Lys7]polyphemusin II ) -- a possible inhibitor for virus-cell fusion. H. Nakashima and others. Tokyo Medical and Dental University School of Medicine, Tokyo; Kyoto University, Kyoto; Seikagaku Corporation, Tokyo. Abstract 53. * Quinobene, a new synthetic sulfonated dye with potent anti- HIV activity. D. J. Clanton and others. National Cancer Institute, Bethesda, Maryland. Abstract 57. * Non-nucleoside inhibitors of an early stage of HIV reproduction [oxathiin carboxanilide, diaryl sulfone, and thiazolobenzimidazole]. J. P. Bader. National Cancer Institute, Bethesda, Maryland. Abstract 58. * Retroviral vectors expressing antisense and ribozyme RNA directed against HIV-1 tat can inhibit HIV-1 replication. K. M. S. Lo and others. Dana Farber Cancer Institute, Boston. Abstract 61. * Antiviral efficacy of 9-(2-phosphonylmethoxyethyl)-2,6- diaminopurine (PMEDAP) upon oral administration to moloney murine sarcoma virus (MSV)-infected mice. L. Naesens and others, Rega Institute for Medical Rsearch, Leuven, Belgium. Abstract 63. * Anti-HIV activity of 5-hydroxymethyldeoxyuridine in vitro and in vivo. V. S. Gupta and others. University of Saskatchewan, Saskatoon, Canada; CIBA-GEIGY Ltd, Basle, Switzeland; Rega Institute, Leuven, Belgium. Supported by MRC Canada. Abstract 64. * Didox and an analog are effective against retrovirus in a murine model (FeLV). D. L. Mills and othrs. Virginia Commonwealth University, Richmond, Virginia; Molecules for Health, Richmond, Virginia. Abstract 65. * Reversal of established FeLV-FAIDS infection after adoptive transfer of activated lymphocytes in combination with AZT and alpha interferon. NS Zeidner and others. Colorado State University, Fort Collins, Colorado. Abstract 82. * Experimental therapy of immunodeficiency-inducing feline retroviruses with phosphonylmethoxyethyl adenine (PMEA) E. A. Hoover and others. Colorado State University, Fort Collins, Colorado. Abstract 165. * * * Probably none of the potential new drugs listed above is ready for use today as an AIDS treatment. But a number of them should be candidates for emergency research and development. Instead, they are largely ignored. Very few of the AIDS clinical trials running today could possibly produce a major treatment advance. Researchers will sometimes admit that they are testing unlikely drugs or theories, saying that they have no better ones to try. Often they will say that the AIDS virus is very difficult to control, or imply that better treatments must wait for a better understanding of the disease process of AIDS (which may take years). The list above shows that many important leads are available. But they are almost always overlooked unless some pharmaceutical company makes the big decision to prepare for human testing. Individual researchers cannot carry out or sponsor the animal and other work required to get these drugs ready for the first human test. It is the responsibility of the Federal AIDS program to develop a coordinated response to this bottleneck, which no one person or company can overcome on their own. ***** Polaris System: One Model for Government Success by Keith Griffith Since the mid-80's activists have been calling for a "Manhattan Project" to accelerate research into finding treatments and a cure for AIDS, but only a few actually pursued the idea beyond the rhetoric. Now, with a new administration pledged to implement such a program, many are scrambling to see exactly what can be done to turn rhetoric into action. Government does have a successful track record at developing emergency programs when the country believes there is a genuine threat to national security. These successes, not surprisingly, usually involve the military. The Polaris System Development: Bureaucratic and Programmatic Success in Government, (published by Harvard University Press in 1972) by Harvey Sapolsky, a faculty member at MIT, provides detailed analysis of a successful undertaking of government that is still considered a model. Sapolsky conducted hundreds of interviews and examined reams of government documents to provide detailed insight into how Polaris overcame incredible bureaucratic and technological obstacles to become central to the American nuclear arsenal. Very early on, Polaris supporters identified the key obstacle to their success: government itself. It was felt that the competing agencies of government, many who did not share in their sense of urgency, would do everything possible to not upset the status quo. To avoid dependence on the rest of government, Polaris supporters secured their own organizational autonomy. Sapolsky identifies two key objectives that proved to be fundamental to the program success: (1) Developing widespread support of Polaris both within the military as well as in the business and civic communities at large. Gathering this support was essential because the technological breakthroughs necessary to achieve the program goals were quite formidable at the beginning, and would require a sizable commitment of resources over a sustained period of time. Sapolsky relates how the Special Projects Office deftly used propaganda to win over the nation. (2) Obtaining sufficient authority to manage the program independently from one central office, the Special Projects Office, which was created by the Navy specifically to develop this one missile program. The single best example of this success was budgeting. Early in the program, this one office was given authority to prepare and justify a consolidated budget that would include the financial needs of all programs involved in any way with development of Polaris. This gave one office, which was full of enthusiastic supporters of the program, significant power to determine the activities needed and to plan a truly integrated approach involving numerous parts of government. There is much to be learned from reading this book as AIDS activists seriously confront what a responsive government must do to bring about a cure and save millions of lives. For one thing, it will give us all some hope to see how government actually can work. While the Polaris program was for weapons of mass destruction, the explanations in this book can help us learn how to move government for saving lives. Additionally, the opportunity we now face will not happen again, nor should it need to happen again. We must seize this moment and provide the Clinton Administration with educated advice on how we can indeed develop a "Manhattan Project" and find effective treatments for AIDS. ***** Fetal Tissue Research Background by John S. James With the fetal tissue controversy in the news, it is important for the AIDS community to understand why there is interest in fetal tissue transplantation in AIDS. Since 1988, the U. S. government, over the objections of leading experts, has banned Federal funding of research involving transplantation to humans of tissue from aborted fetuses. Such transplants may be important for treating persons with Parkinson's disease, AIDS, or other conditions. Scientists had agreed on standards to prevent medical use of fetal tissue from causing any pressure on women to have an abortion; for example, by forbidding any payment for the tissue, and forbidding directed donation to a particular patient (who might be a friend of the donor, or have arranged for surreptitious payment). But antiabortionists argued that the fact that a stranger might benefit could possibly influence a woman's decision to have an abortion. As a result, the Bush administration overruled the expert panel set up to examine this issue, as well as an advisory committee to the director of the NIH. Congress attempted to overturn the ban through a provision in the recent NIH Reauthorization Act, but President Bush vetoed that bill. This funding ban is likely to be removed by the Clinton administration. Meanwhile the November 26, 1992 New England Journal of Medicine reported important progress in using fetal tissue in treatment of Parkinson's disease, in a series of three articles and accompanying editorials. Technically, the fetal-tissue ban only prevents Federal funding of research on transplanting fetal tissue into humans -- not other work with the tissue, such as laboratory studies. But the real impact has been greater than the wording of the policy would suggest, because the ban cast a stigma of Federal disfavor over the whole area of fetal- tissue research, causing scientists to avoid promising studies they would otherwise have conducted. (The ban is still in place, and AIDS TREATMENT NEWS found a reluctance among researchers interested in doing fetal- tissue studies to discuss the issue, apparently because they did not want to become involved in the politics surrounding it. Science is highly politicized because it is heavily dependent on Federal funding, permissions, and other decisions.) The Federal funding ban has not forbidden privately-funded research. But the National Institutes of Health would normally take the lead in areas such as tissue transplantation, which are difficult, expensive, and unlikely to interest a pharmaceutical- company sponsor. It is hard to fund transplantation research otherwise, except by charging patients to volunteer for an experimental procedure -- which has been done, although it raises ethical concerns. Tissue Transplantation in AIDS Treatment The AIDS interest in human fetal transplantation stems largely from a paper on thymic transplantation published in 1987 by researchers at the Yale University School of Medicine. Unfortunately this promising early lead was not been followed up. Revision of the Federal policy on fetal transplantation may facilitate new studies in this area. This paper(1) did not report on fetal tissue transplantation; instead, the tissue used came from young children who had to have part of their thymus removed during a heart operation. It was transplanted into 15 volunteers with advanced AIDS; the transplanted tissue survived, for several months at least, in eight of them. Remarkable clinical improvements occurred in some cases, although as expected the benefit appeared to be temporary. Neither antivirals nor pneumocystis prophylaxis was in use at that time (the paper was accepted for publication in July, 1986, so the work had to have been completed before then). Nine patients showed clinical improvement two months after the operation (including one in whom live transplanted cells were not found). The most dramatic case was one patient in which CMV retinitis appeared to resolve spontaneously with no other treatment: "A severe bilateral retinitis thought to be due to cytomegalovirus (three exudates with hemorrhage in each retina and a rise in cytomegalovirus titers in both blood and cerebrospinal fluid) cleared spontaneously, a development unique in our experience with patients with AIDS. "Tuberculosis control improved in two cases, "but the clearance of resistant Pneumocystis carinii pneumonia in case 12 and a cessation of the previously intractable diarrhea in case 13 may be more significant." T8 cells (a kind of T-cell, different from T-helper cells, which also may be important in controlling the AIDS virus) showed substantial increases in all eight of the patients in whom the transplant was successful, more than doubling in every case, and often increasing several fold. T-helper increases, however, were minor. All but one patient was anergic before the transplantation, and only two became able to produce a delayed- type hypersensitivity (DTH) response after the transplant. These results suggest that the AIDS virus (which was not being treated with AZT or any other antiviral) may have prevented improvement in the T-helper count and consequently in the DTH response, while having little effect on T8 improvement, since T8 cells are not infected by HIV. Thymic Transplantation: Comment Clearly these early results suggest that thymus tissue transplantation should be explored further. Several reasons may explain why it was not followed up years ago. While the operation itself is relatively minor (the tissue is implanted in an incision in the arm), thymic tissue must be carefully prepared so that foreign T-cells, which would attack the host, are removed. A much earlier paper(2) noted that, "Fetal thymus is not innocuous. After 14 weeks in utero, sufficient mature T cells have formed in the thymus tissue to cause fatal graft vs. host disease." The Yale team cultured and grew the tissue for 14 to 16 days before transplantation (partly to test each potential transplant for viability) under conditions in which the T-cells would leave. The potential implants were tested in other ways also. Clearly good laboratory skills are required, and infection control is critical. Also, the paper by Dwyer and others in some respects understates the results shown in the tables (a common problem which often is caused by conservative reviewers or editors, who cannot change the data but can change the interpretation). For example, we noticed that the T8 counts more than doubled in all eight cases of successful transplants; the text did not point this out. Readers who did not analyze the tables would not have found one of the most important results reported. Another potential reason for lack of follow-up is that in this early research, the improvements were temporary. Only three of the 15 patients were alive 18 months after the transplantation (perhaps better than expected with very advanced AIDS in 1986). Of these three, the average total T- cell count, which increased 2.6 times after the transplant (mostly due to the T8 cell increase), then lost 30 percent of its after-transplant value over the next year (our calculation from the published data). And the Federal policy on fetal tissue transplantation research also hurt. Fetal thymic tissue would be expected to work at least as well if not better than the tissue from children which was used. Even more important, as a result of the Federal policy the entire field has been largely neglected, as researchers sought less controversial areas to avoid the danger of their projects being blocked. Meanwhile, the procedure was too difficult for most physicians' offices or community clinics, and pharmaceutical companies were unlikely to be interested because the treatment was an operation transplanting human cells, not a conventional pharmaceutical product. And since there was no one in charge of the Federal effort against AIDS, no one had the mandate to recognize that an important opportunity was being lost, or the authority to get the problem addressed. Now with a new Federal administration, the AIDS community should make sure that thymic transplantation receives attention again. It should work even better now than six years ago, since antivirals are available, and immunological knowledge has greatly improved. Testing Drugs and Vaccines Faster: The SCID-hu Mouse Ending the Federal bias against fetal-tissue research could also encourage faster testing of AIDS drugs and vaccines through wider use of mice with a transplanted immune system. These mice are born with severe combined immune deficiency (SCID); then they are given a human immune system by transplantation of human fetal thymus and liver tissue. Scientists eager to pursue SCID-hu studies are looking forward to an end to the Federal discouragement of fetal tissue research. Originally it had been hoped that the SCID-hu mouse would permit large-scale screening of potential AIDS drugs, by allowing testing against HIV in animals, instead of cells in a laboratory dish. For reasons which are unclear, little such screening has been done. For those interested in technical background on the SCID-hu mouse, a review was published last year(3). References 1. Dwyer JM, Wood CC, McNamara J, and Kinder B. Transplantation of thymic tissue into patients with AIDS: An attempt to reconstitute the immune system. Archives of Internal Medicine, March 1987; volume 147, pages 513-517. 2. R. Hong. Present and future status of thymus transplantation. Annals of Clinical Research, 1981; volume 13, pages 350-357. 3. McCune J, Kaneshima H, Krowka J. and others. The SCID-hu mouse: A small animal model for HIV infection and pathogenesis. Annual Review of Immunology, 1991; volume 9, pages 399-429. Note: Nancy Solomon at AIDS TREATMENT NEWS contributed to the research for this article. ***** 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: Jason Heyman John S. James Nancy Solomon Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. 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