From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: ATN #164
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6632
Organization: unspecified
Date: Mon, 14 Dec 92 22:45:11 PST

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J O H N   J A M E S  writes  on  A I D S 
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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. 

***** 

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