          ===============================
          Project Inform Briefing Paper
          Number 4
          February 1994
          ===============================

Copyright San Francisco Project Inform 1994

In this issue:
===============================
Future Directions In AIDS Research     1
Protease Inhibitors     4
Advisory Committee Reviews ddC     4
Update on Opportunistic Infections     6
Cell Therapy     7
Preventing PCP & Fungal Infections     7

===================================
Future Directions In AIDS Research
by Martin Delaney
===================================

In November of 1993, Project Inform co-sponsored the second meeting of 
Future Directions in AIDS Research (FDAR). The historic meeting 
concluded in Boston, where heads of national institutes, policy-makers, 
industry and regulatory representatives, researchers and a number of 
community activists met to discuss developing proposals aimed at 
accelerating the pace of AIDS research. These proposals, once fully 
developed, should compliment reforms to strengthen the Office of AIDS 
Research (OAR)1 at the National Institutes of Health (NIH). Clearly, 
AIDS research can be better managed, information flow can be enhanced 
and greater collaboration will lead to meaningful advances. While most 
areas of discussion received full consensus, others were more 
controversial. A few voices, some seeking greater detail, others overly 
invested in the status quo, were leery of a Second Front approach, 
which would pilot test a coordinated multidisciplinary team approach to 
managing AIDS research. What is certain, however, is that its time for 
a change and no amount of change will happen without first finding the 
will and courage to make it happen. Outlined below are the primary 
recommendations which have received intensified focus in FDAR working 
groups over the past several months.

1.     Create a Free-standing, Ad Hoc Task Force

AIDS research is afflicted by an incestuous assessment process which 
often lacks objectivity and is clouded by self-interest. The FDAR group 
endorsed the creation of an independent, multidisciplinary Task Force to 
oversee, assess and provide non-binding guidance to AIDS research. To 
assure the utmost degree of objectivity, it was suggested that the Task 
Force not be a part of, or convened by, the government.

2.     Encourage and Support the Inter-Company Collaboration (ICC) on 
AIDS Research

The ICC is a group of major pharmaceutical companies formed to increase 
industry collaboration in AIDS drug development, specifically 
combination approaches. The FDAR group recommended that the ICC be 
designated as the principal conduit for transmitting information and 
policy concerns into and out of the pharmaceutical industry. The ICC 
would be expected to supply periodic progress reports of its activities.

3.     Enhance the Use of Information Technology in AIDS

Surprisingly, in the age of computer technology and the dawning of the 
information super highway, there is no centralized communication network 
linking information on AIDS research, nor linking information on AIDS 
with research in other diseases. Information flow is haphazard, 
resulting in a large amount of duplicative effort and impeding the 
ability to apply discovery in other diseases to AIDS. The FDAR group 
called for funding advanced user-friendly communication technology in 
AIDS research. The working group proposed using the existing InterNet 
system and developing an AIDS-specific "gopher" system to provide 
immediate access to information. An AIDS-specific Unified Language 
System and a Unified "Metathesaurus" should be constructed. A "Meta-
thesaurus" would enable the linkage of general scientific concepts, 
providing easy access to related work in other diseases. The FDAR group 
recommended that the National Library of Medicine work with governmental 
and non-governmental groups in this endeavor, to best serve the large 
and diverse basic and clinical science constituencies.

4.     Create a National Specimen Repository

Thousands of blood, serum and tissue samples are stored from experiments 
conducted over the past 11 years. Much can be learned about HIV disease 
and the effects of various drugs from these existing specimens. 
Accessing samples and information is random and highly dependent on 
professional networking. Time and money could be saved by having a 
National Registry of existing specimens and a defined system for access. 
The FDAR group endorsed the creation and funding of a central NIH 
repository and a centralized, updated and available inventory of 
repositories. A Task Force should be established to monitor the process 
of accessing samples.

5.     Expand Training and Grant Programs

The objectives of the intended programs would include:

a.     Expanding college and training programs to nurture a multi-
disciplinary approach to AIDS, drawing together disciplines such as: 
cancer biology, molecular biology, immunology, et al in a common 
environment to foster the exchange of ideas and information.

b.     Funding sabbaticals, fellowships and other training programs in 
AIDS and non-AIDS-related fields to encourage participation in and 
contribution to AIDS research.

c.     Expanding the use of small interdisciplinary meetings to foster 
dialog on innovations in AIDS and other fields as they may be applied to 
AIDS pathogenesis or treatment.

d.     Encouraging (by small-money, fast-response grants) clinical 
scientists to conduct research on AIDS and novel therapeutics and 
similarly encourage basic scientists to apply laboratory discovery to 
the clinical setting.

6.     Set Up a Project to Test Methods for Accelerating AIDS Research Using 
Modern Management Methods

The present management structure of much of AIDS research does not fully 
exploit modern management methods of team work, goal orientation and 
process control. These methods are employed in some areas of AIDS 
research, the best example perhaps being the Biotech Industry. Many 
believe that the real advances in AIDS therapeutics will come from 
Biotech companies, whose hands are free from the cumbersome bureaucracy 
found in large industry and government, and whose economic survival is 
dependent on a successful product. Because AIDS discovery is not always 
defined by a  sellable product, many factors must be incorporated into 
the thinking of a coordinated research effort. Modern management 
technique can be employed to foster individual creativity and facilitate 
the process of discovery, however. How these principals will fare when 
applied to a large bureaucracy is less certain. Therefore, the FDAR 
group called for moving forward by defining a pilot project for an 
accelerated research initiative, in coordination with the Office of AIDS 
Research, focusing on a single but highly important aspect of AIDS 
research. The area of focus should be an area which might best benefit 
from increased attention and which could ultimately benefit AIDS 
research overall. An example of how such an approach might be used to 
accelrate discovery in immune pathogenesis, is described in the text 
below.

1.     For more information on the OAR Reforms, see the February 1993 PI 
Perspective.


<<<< PICTURE: Existing Model and Proposed model >>>

Existing Model, Research Management and Funding
===============================================

Description:
     OAR creates and maintains strategic plan, overseeing all areas of 
research for prioritization and minimizing duplication of effort.
     OAR lightly oversees drug development, basic science, vaccine 
development, population studies, clinical programs, and discretionary 
funds.
     OAR oversees budget and distribution of funds across NIH 
institutes,  academic grantees and contractors and private laboratories 
and institutes. 
     Because so many areas and responsibilities are involved in 
managing OAR, opportunity for intensified oversight in specific areas is 
slim.
     Cooperation and coordination among research sites is coincidental, 
rather than by design.
     Some number of the hundreds of grants may be loosely directed 
toward immune pathogenesis, but most of those who receive such grants 
are in no deliberate way coordinated with each other or working with 
each other toward achievement of anything but their own particular 
interests.



Accelerated Research Initiative
Proposed Model (Working Draft)
===================================

Characteristics:
     A central, critical issue is assigned to a team for concentrated 
discovery or accelerated development.
     Team members commit a minimum of 50% of their time to the project; 
management 100% of their time.
     Goals are chosen in collaboration with OAR; objectives and methods 
chosen by the team; team core may or may not include some lab 
facilities, depending on goals and resources.
     Project would have its own granting, contracting and hiring 
authority, with simplified requirements concentrating on achievement of 
goals rather than process compliance.
     Some research would be "investigator initiated," though always in 
concert with team goals, while other work would be assigned through 
specific grants; the balance would be decided by the team.
     All personnel would serve as part of a unified team, with regular 
"think-tank" style meetings; coordination and collaboration is by 
design; information would flow by design within the team and to the 
outside.
     Team would work in collaboration with an independent, 
multidisciplinary advisory board, including membership by the affected 
community and senior scientific advisors from outside the field.

==========================================
Protease: Crushing the Molecular Scissors
by Ben Cheng
==========================================

Protease inhibitors are an upcoming class of antiretroviral drugs that 
are now entering into large scale clinical trials. Some initial results 
have shown that these drugs have very few side effects and also show 
activity against HIV. There is a great deal of interest in this class of 
compounds from both the HIV community as well as from industry.

Nucleoside analogs like AZT, ddI, ddC, and d4T inhibit the HIV enzyme 
reverse transcriptase, which is at the beginning of the viral assembly 
line, after the virus has invaded a cell, but before it takes complete 
control. Protease inhibitors act at the intermediate stage of viral 
assembly, after the virus has incorporated into the cell and is ready to 
begin mass production. These viral proteins are like parts of a model 
airplane that must be cut from a plastic frame. Protease is like a 
chemical scissors that snips the parts from the frame, and other enzymes 
glue the parts together.

Like reverse transcriptase, protease is an enzyme required by the virus 
to reproduce. Enzymes are needed at each step of the assembly-line 
process to build viral particles. Protease is required for the newly-
assembled virus particles to be infectious. Virus assembled without 
protease is defective and cannot infect other immune system cells. 
Protease inhibitors target the virus when, or shortly after, a newly-
assembled virion buds out of a cell. In test tube experiments when 
protease was inhibited, HIV viral replication was completely blocked.

Early on, the development of protease inhibitors was complicated by a 
number of factors:
     The compounds were potent inhibitors of protease in test tubes, 
yet had poor antiviral activity in other experiments.
     The compounds did not absorb well into the system when taken 
orally and what was absorbed cleared the system very rapidly. This 
resulted in the necessity for intravenous administration of very large 
quantities of drug in order to achieve any measurable antiviral 
activity.
     Animal studies of these compounds demonstrated many harmful side 
effects.
     The compounds are very difficult to manufacture.
Some of these obstacles have been overcome and newer, more potent, oral 
drugs are now moving into clinical trials.

Several protease inhibitors are in clinical trials, including Hoffman-La 
Roches Ro 31-8959, which was the first of this class of drugs to be 
tried in humans. The Phase I safety studies were done in England, France 
and Italy. This is one of the original series of compounds which, while 
very potent against HIV, is not absorbed well when taken orally, though 
a little better when taken with food. Additionally, this compound is 
extremely difficult to manufacture. Results from the European studies 
show that the drug was well tolerated with very few side effects and the 
high dose (600 mg three times a day) showed some antiviral activity.

Study participants saw slight increases in CD4+ cell counts, a drop in 
viral load and a decrease in p24 antigen. Better antiviral activity was 
observed when this drug was combined with AZT. Currently R0 31-8959 is 
in Phase II studies (ACTG 229) in the US with larger phase III studies 
planned for the beginning of 1994. 

Abbott Laboratories, another company involved in protease research, 
found that their first compound A-77003, had good antiviral activity in 
animals but suffered from very poor oral absorption and had to be 
continuously dosed intravenously in humans. Abbott tried again with A-
80987, but the drug was found to cause serious side effects to the 
liver. Both A-77003 and A-80987 have been withdrawn from development 
despite some evidence of modest antiviral activity. Abbott has another 
protease inhibitor, A-84538, which in test tubes is about nine fold more 
potent against HIV than A-80987. This compound can be administered 
orally and is expected to go into Phase I safety studies in Amsterdam by 
the first quarter of 1994.

Merck, another company involved in this research, has an oral protease 
inhibitor L-735,524 that is now in Phase II clinical studies at Bellevue 
Hospital in New York, SUNY Stoneybrook, Pacific Oaks Medical Group in 
Los Angeles, University of Pennsylvania and the University of 
Pittsburgh. Initial data from Phase I studies have shown that this drug 
is well tolerated and has antiviral activity. The maximum tolerated dose 
found from the Phase I studies was 400 mg four times a day. Some 
encouraging news regarding L-735,524 is that thus far the virus does not 
appear to develop resistance to the drug, potentially allowing for long-
term antiviral benefit. Additionally, the antiviral activity of L-
735,524 appears to be enhanced when combined with AZT or ddI.

One other oral protease inhibitor is in Phase I dose escalating safety 
studies in Berlin, Germany. Searles SC-52151, in test tube studies, 
shows potent antiviral activity as well as good oral absorption. It is 
hoped that after the Phase I studies in Europe, SC-52151 will be studied 
in the US.

The rapid emergence of viral resistance to approved antivirals, AZT, ddI 
and ddC, has limited their long-term usefulness in the treatment of HIV. 
Emerging results suggest that HIV resistance to AZT is a marker for more 
rapid progression of disease. The development of resistance to AZT is 
related to: stage of disease; positive count for p24 antigen; high viral 
load, but not to the length of time on AZT therapy. It is hoped the 
development of resistance will be much slower and at a lower level for 
protease inhibitors. However, low level resistance has already been 
found in some protease inhibitors. Combining a protease inhibitor with a 
drug like AZT or ddI may delay the onset of resistance to both drugs. In 
addition, additive and synergistic anti-HIV activity was seen in test 
tubes when a protease inhibitor was combined with AZT, ddI, ddC, or 
alpha interferon. It is also hoped that the protease inhibitors will 
still have sufficient antiviral activity against HIV strains which have 
already developed resistance to the nucleoside analogs.

Protease inhibitors are likely to emerge as the next class of drugs for 
the treatment of HIV. Initial results from the current generation of 
protease inhibitors give reason for cautious optimism. Future 
generations of these drugs will hopefully be more potent against HIV and 
companies will overcome manufacturing obstacles. It is still unclear 
whether there will be any drug interactions with standardly used 
antivirals or commonly prescribed drugs for the prevention and treatment 
of opportunistic infections. Since most protease inhibitors are 
metabolized in the liver, chances are there will be some possible 
interactions with other common HIV/AIDS therapies that are also 
metabolized in the liver including: clarithromycin, TMP/SMX (Bactrim or 
Septra), rifabutin, rifampin and fluconazole. Further studies will be 
needed to better understand how these drugs should be used as therapies 
for HIV. 


==========================================
FDA Advisory Committee Reviews ddC
==========================================

On 20 September 1993, the FDA Antiviral Advisory Committee met to 
review data on ddC. Based on two studies, CPCRA 002 and ACTG 155, the 
Committee voted to recommend the full approval of ddC as a single 
agent therapy and to revoke the accelerated approval status of AZT+ddC 
combination therapy. Data from CPCRA 002, a study comparing ddI to ddC 
in people who had failed or were intolerant to AZT, demonstrated at 
best that ddI and ddC have different side effects. People taking ddI 
demonstrated a higher incidence of stomach pain, diarrhea and symptoms 
of pancreatitis, while people on ddC reported a higher incidence of 
mouth sores and peripheral neuropathy. While all of the study 
participants had very low CD4+ cell counts, the rate of progression to 
a new AIDS defining illness or death within one year was extremely 
high, nearly 66%. Recommending ddCs approval based on these very 
confusing data was quite a surprise. Equally shocking was the 
Committees recommendation to withdraw the accelerated approval status 
of ddC for use in combination with AZT. This was done on the basis of 
ACTG 155, a study comparing combination therapy to monotherapy in 
people with less than 300 CD4+ cells. People with greater than 100 
CD4+ cells appeared to benefit from combination, while people with 
less than 100 CD4+ cells appeared to fare worse, experiencing greater 
numbers of side effects and increased progression rates. Community 
activists are urging FDA to reconsider the wisdom of the Advisory 
Committee recommendations and not implement them. Pulling the approval 
for AZT+ddC combination therapy may affect access to this combination 
and studies demonstrate that some people benefit. A review of CPCRA 
OO2 can be found in the Feb. 1993 PI Perspective, and a review of ACTG 
155 is in the July 1993 Briefing Paper.  For back issues of these 
publications, call the Project Inform Hotline.

==========================================
Project Inform AIDS Treatment Update
==========================================

A new monthly audio report on current HIV/AIDS treatment options and 
public policy concerns is designed to keep you up-to-date and aware of 
the latest in treatment information. The report is available by 
satellite to NPR-affiliated stations around the country or through PI 
directly, by sending $10.00 for each tape.

Have you heard it on your local public radio station?  If you havent 
and want to, call the program director at your local radio station and 
tell them how important AIDS treatment information is to you. Suggest 
they "audition the tape off the latest satellite feed". Or call us and 
well give you the information to most effectively make your case.

If you want to help get Project Inform on the air in your community or 
if you would like to order monthly tapes for you or your organization, 
contact Ben Collins through our hotline at 800.822.7422 or directly at 
415.558.8669.

============================
Opportunistic Infections
by Ben Cheng
============================

Mycobacterium Avium Complex - MAC

A US Public Health Service Task Force has issued new recommendations and 
guidelines for the treatment and prevention of MAC (Mycobacterium Avium 
Complex). To prevent MAC, the Task Force recommends that people with 
less than 100 CD4+ cells take 300 mg of rifabutin daily. Although both 
azithromycin and clarithromycin are widely used in the community and are 
effective in treating MAC, the Task Force felt that there was 
insufficient data to recommend the use of either drug for prophylaxis. 

For the treatment of MAC, the Task Force recommends a combination of two 
or three drugs, with one of those drugs being either azithromycin or 
clarithromycin. Ethambutol is recommended as the second drug in the 
combination with the possible addition of rifabutin, rifampin, 
ciprofloxacin, clofazimine and, in certain cases, amikacin, if a third 
and fourth drug are needed.

Several MAC treatment studies, either open or about to begin enrollment, 
should determine which is the best treatment combination. These include 
a study of:
     Clarithromycin and ethambutol with different doses of rifabutin.
     Clarithromycin and clofazimine, with or without ethambutol.
     Ethambutol with either azithromycin or clarithromycin.
Of note are results from a drug interaction study between clarithromycin 
and rifabutin showing rifabutin reduced clarithromycin levels in blood 
by up to 50%. The clinical significance of this finding is still 
unknown. To further complicate matters, both clarithromycin and 
fluconazole can increase rifabutin levels by up to 80%. Additionally, it 
was recently discovered that people on the combination of clarithromycin 
(1000 mg twice a day) plus rifabutin (600 mg per day) and ethambutol (15 
mg/kg per day) were likely to develop uveitis, a painful inflammation in 
the eye. Most people who developed uveitis responded favorably to 
topical steroids. There were a few people who required continuous 
topical therapy for weeks.

Cytomegalovirus - CMV

Several CMV retinitis treatment studies are expected to begin shortly. 
One is a study involving HPMPC, which is administered intravenously and 
very potent against CMV in test tubes. Although this compound has good 
activity against CMV, it is also quite toxic, with kidney toxicity being 
the main concern. HPMPC is now being administered with probenecid, which 
may reduce some of the kidney toxicity. Probenecid is known to interact 
with other drugs including AZT, however. Interactions between HPMPC and 
other compounds are likely. One possible advantage of HPMPC may be the 
long half-life of the drug, which means less frequent dosing (once every 
two or three weeks) and no need for a permanet catheter. 

MSL-109 should also be entering into larger clinical studies early this 
year. This is a monoclonal antibody that will be administered 
intravenously every two weeks with either the standard daily dose of 
ganciclovir or foscarnet. Some of the data from the Phase I study have 
shown that the drug is generally well tolerated although the efficacy 
data are a little more controversial. 

A study of oral ganciclovir is expected to start later this year using 
higher doses than used in previous trials. There have been some 
anecdotal reports of better efficacy with higher doses (up to 6 grams 
per day) of the oral drug. Currently, there are three studies of oral 
versus IV ganciclovir for the maintenance of CMV retinitis ongoing. 
Results from these studies are expected by the middle of 1994. 
Additionally, two placebo controlled studies of oral ganciclovir for the 
prevention of CMV are ongoing. Interim results from one of these studies 
is expected by the middle of 1994.

Multiple OI Prophylaxis

There are some new PCP drugs in development including the echinocandin 
analogs that also have activity against some fungal infections. Merck 
and Lilly, two companies that have been developing this class of drugs, 
have compounds that are potent against fungi (candida and aspergillus 
but not active against cryptococcus) and PCP. Both of these compounds 
should be in safety studies by the end of 1994. If these drugs prove 
effective, they hold the possible advantage of preventing several OIs 
with only one therapy, decreasing the number of pills and possible drug 
interactions of other multiple prophylaxis approaches. 

Hoffman-La Roche also has a new PCP drug that has started human safety 
studies. Ro 11-8958 (Epiroprim) is a Dihydrofolate Reductase Inhibitor 
(DHFR) and in test tubes is quite potent against PCP as well as some 
bacteria. Other DHFR inhibitors include TMP/SMX, dapsone, and 
trimetrexate, commonly used PCP therapies. Epiroprim will most likely be 
used in combination with dapsone and has activity against toxoplasma, as 
well as other parasites. Unfortunately, Hoffman-La Roche, despite 
promising data, does not appear to be committed to moving this therapy 
into clinical trials.

================
Cell therapy
by Brenda Lein
================

Cell therapy is a broad field of research using immune system cells to 
augment the bodys ability to fight HIV, protect against opportunistic 
diseases and restore immunity lost due to HIV infection. AIDS is a 
disease of primary immune deficiency caused by a virus. Thus far 
therapies for HIV have targeted the virus. Cell therapy approaches begin 
to address immune deficiency and possible restorative techniques. While 
still in its infancy, cell therapy is receiving increased attention from 
the community and research establishment alike. Cell therapy can be 
broken down into three basic areas:
q     autologous cell therapy,
q     allogeneic cell transfer
q     and xenogeneic cell therapy.

Autologous Cell Therapy

Autologous refers to "self" and autologous cell therapy involves 
manipulating an individuals own cells, often outside the body, to 
enhance their function or their ability to resist infection by HIV. Thus 
far, research into autologous cell therapy has focused primarily on CD8+ 
(T8) cell expansion, but preliminary efforts into CD4+ (T4) expansion 
and cell manipulation are being initiated.

A number of CD8+ expansion studies have demonstrated that it is possible 
to grow cells outside the body, and toxicities associated with 
reinfusing the cells appear to be minimal. CD8+ expansion studies 
currently underway include a study being conducted at New England 
Medical Center in Boston, which expands HIV-specific cytotoxic cells, 
cells which are primed to specifically destroy other HIV-infected cells. 
A study sponsored by Applied Immune Sciences (AIS) and being conducted 
in Menlo Park, California, compares CD8+ expansion with two different 
doses of IL-2 (a chemical messenger which stimulates cell growth) to IL-
2 alone. A third multicenter study, also sponsored by AIS is looking at 
CD8+ expansion with IL-2 in people with KS. This study is being 
conducted in San Francisco at two locations, in Los Angeles at UCLA, and 
in Miami. Very early data from this study were presented in Berlin, at 
the International AIDS Conference last year, showing that a large number 
and repertoire of CD8+ cells could be successfully expanded. The major 
toxicity from this study appears to be associated with IL-2, which 
causes flu-like symptoms for several days.

Fearful of stimulating viral replication, and fearful of causing harm, 
studies of CD4+ expansion have thus far been confined to the laboratory. 
Using triple drug combinations of antivirals, researchers in Boston have 
been able to eliminate detectable virus from CD4+ cells of HIV+ people 
and successfully expand the cells of people with as low as 30 CD4+ 
cells. Additional experiments must be conducted to assure that triple-
drug resistant virus is not created in this process.

Last year three cell manipulation approaches were approved for human 
testing, allowing for two gene therapy and one ribozyme approach to 
enter clinical trials. Viagene, conducting research out of the Los 
Angeles area, is conducting a study through Shared Medical Research 
Group using a gene therapy approach to delivering a therapeutic vaccine. 
As we go to press, we have learned that while some study samples were 
destoryed in the LA earthquake, Shared Medical Trials will continue as 
scheduled. Another study, being conducted at the Howard Hughes Medical 
Institute in Ann Arbor, Michigan, involves inserting a gene into cells 
which will hopefully render them resistant to HIV-infection. A third 
study, still in development, will be conducted at the University of San 
Diego, in California. This study involves the use of ribozymes, which 
are like tiny molecular knives which disable the virus by chopping it 
into tiny pieces.

Allogeneic Cell Transfer

Allogeneic refers to "another" and allogeneic cell transfer involves 
taking cells from a person, usually a close relative who is HIV-, and 
transferring those cells to someone who is HIV+ in hopes of restoring 
immunity lost due to HIV-infection. Thus far, research in this area has 
focused on identical twins and siblings.

A number of cell transfer studies in identical twins have been reported 
on. The National Institutes of Health (NIH) is conducting a cell 
transfer study in identical twins, where one twin is HIV+ and the other 
is HIV-. Preliminary data from this study demonstrated 47% increases in 
CD4+ cell counts, sustained as long as 6 weeks. Side effects were 
minimal, limited to mild fevers. A very small study, conducted by Dr. 
Waites in San Francisco, demonstrated substantial rises in both CD4+ and 
CD8+ cells, as well as improvement in clinical status. Dr. Waites study 
differed from other studies in that the HIV- twin was pre-treated with a 
drug, G-CSF, to induce a large amount of important immune cells prior to 
drawing cells. A third identical twin study, which was conducted in Los 
Angeles by SEARCH ALLIANCE, demonstrated cell transfer to be safe but no 
dramatic effects were seen in clinical status or laboratory parameters.

Sibling cell transfer involves transferring cells from a family member 
who is not HIV-infected to someone who is HIV+, in hopes of 
reconstituting immunity. A pilot study of sibling cell transfer, 
conducted by the Center for Special Immunology (CSI), was reported on in 
the July 1993 Briefing Paper. The CSI study is expanding to sites in 
Miami, Chicago, Irvine and San Diego within the next few months. For 
more information, contact CSI sites in those areas. Interest in this 
approach stems from unpublished work conducted in Philadelphia in the 
mid-1980s in which 20 volunteers entering the study with a mean CD4+ 
cell count of 45 demonstrated a mean CD4+ cell count of 425 at end of 
study. Cell function tests rose from 12% to 75% of normal. While there 
were problems with this initial study, and measurements of cell function 
were not as reliable then as they are now, these data are compelling 
enough to warrant further investigation. A number of sibling cell 
transfer studies have been discussed, but currently the CSI study is the 
only study open. While initial data are appealing, there are potential 
risks and many unknowns in sibling cell transfer.

Xenogeneic Cell Therapy

Xenogeneic refers to "another species" and xenogeneic cell therapy 
involves taking cells from animals and transferring them to humans. Some 
animals, such as baboons, are naturally resistant to HIV-infection. Many 
of the issues in other cell transfer experiments, such as how to prevent 
expanded or transferred cells from becoming infected by HIV, may be 
addressed through xenogeneic cell transfer. While this technology might 
seem far from the clinic, it is important to remember that xenogeneic 
tissue transfer has already been done successfully. Senator Jesse Helms, 
for example, received heart valves from a pig after a serious heart 
condition led to surgery.

Finally, in contrast to traditional antiviral approaches, cellular and 
other immune-based therapy research demands a more holistic 
understanding of the immune system and how it interacts with the virus. 
The immune system communicates through a complex information network in 
a delicate balance of harmony. Manipulating immune responses holds the 
potential to either help restore this harmonic balance or further 
aggravate the immune dysfunction brought about by the virus. It is for 
this reason that cell therapy techniques should be approached with 
cautious optimism. For a more in-depth analysis of cell therapy, call 
the Project Inform Hotline and ask for the Cell Therapy Fact Sheet.


======================================
Preventing PCP and Fungal Infections
======================================

New data on the prevention of Pneumocystis Carinii Pneumonia (PCP) and 
fungal infections were recently presented at the AIDS Clinical Trials 
Group (ACTG) meeting. Data from two studies, ACTG 081 and ACTG 981 
will help to shape standard of care for preventing life-threatening 
diseases associated with immune system decline.

The first study, ACTG 081 compared TMP/SMX (Bactrim or Septra), 
dapsone and aerosolized pentamidine as first line prophylaxis for PCP. 
PCP is the leading cause of death in people with HIV and can be 
prevented. Study results show that TMP/SMX (Bactrim or Septra) appears 
to be more effective in preventing PCP than dapsone or aerosolized 
pentamidine, dapsone should be used for people who cannot tolerate 
TMP/SMX, and aerosolized pentamidine should be considered a third line 
approach. Important Note:  People who have experienced sulfa drug 
reactions should strongly consider desensitizing to sulfa drugs. 
Sulfa desensitization protocols are available through the Project 
Inform Hotline by asking for the PCP Prophylaxis Fact Sheet.
ACTG 981 compared fluconazole to clotrimazole troches in preventing 
fungal infections. People receiving clotrimazole troches reported a 
higher incidence of serious fungal infections than people who received 
fluconazole. Despite the fact that people receiving fluconazole had 
slightly lower CD4+ cell counts than those receiving clotrimazole, 
people on fluconazole still fared better.

==================
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Copyright San Francisco Project Inform, 1994

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