Subject: AIDS TREATMENT NEWS #196
From: "John S. James" <[email-masked]>
Date: 02 Apr 94 01:26 PST

AIDS TREATMENT NEWS Issue #196, April 2, 1994
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

National Task Force Meets April 14-15

More on LTR Inhibitors: No Drug Resistance to a Tat Inhibitor

New Nation-Wide Trial Tests Timing of Switch from AZT

Kaposi's Sarcoma, Genistein, and Soybeans

AIDS Hotlines: Selected List

***** National Task Force Meets April 14-15

The National Task Force on AIDS Drug Development will hold its first 
meeting on April 14 and 15, at the Sheraton National Hotel in 
Arlington, Virginia. The meeting is open to the public, and there will 
be time for public testimony. Those wishing to speak should notify 
the contact person (below) in advance, by April 7 if possible. Perhaps 
more importantly, information can also be submitted in writing.

The National Task Force "identifies any barriers and provides 
creative options for the rapid development and evaluation of 
treatments for HIV infections and its sequelae. It also advises on 
issues related to such barriers and provides options for the 
elimination of these barriers."

The contact person for this meeting is Jean H. McKay, Office of AIDS 
and Special Health Issues (HF-12), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, phone 301/443-0104, fax 
301/443-4555.

Comment

This task force, meeting occasionally for two days in an auditorium, 
cannot automatically fix the problems of AIDS research -- any more 
than the election of a sympathetic U.S. president could automatically 
do so. What the National Task Force can do is to enable those who are 
working in the laboratories and clinics to explain their practical 
problems and their suggestions -- and hopefully get results. But 
principal investigators, research nurses, lab assistants, etc. will need 
to approach the task force and tell what they know. Often this is 
difficult, because of the politics of funding, or of the workplace; 
perhaps we need an organization called Speak Up to encourage 
people to give the task force the depth of information it needs. You 
can write to the National Task Force on AIDS Drug Development, c/o 
Jean McKay at the address above, at any time, before or after the 
upcoming meeting, and your information will be forwarded to the 
members.

Incidentally, AIDS TREATMENT NEWS is always interested in such 
information; we read everything you send. You can write or call us at 
any time, anonymously if you want.

***** More on LTR Inhibitors: No Drug Resistance to 
      a Tat Inhibitor

by Charles Davidson

The rapid development of drug resistance by HIV continues to be a 
major obstacle in finding better treatments. Resistance to AZT and 
similar drugs is well known; resistance to protease inhibitors, a new 
class of experimental drugs, is now also being found. A number of 
different strategies may help to deal with the problem, however.

This article looks at what can be learned from one drug (Ro 24-7429, 
the Hoffmann-La Roche Tat inhibitor) to which HIV developed no 
resistance at all, in two years of laboratory studies which attempted 
to create such resistance.(1) We will also examine the class of drugs 
to which Ro 24-7429 belongs -- the LTR inhibitors. A look at how 
LTR inhibitors work suggests that they will need to be used in well-
designed combinations in order to work most effectively. 

[Editor's note: Ro 24-7429 was tested alone, and rejected by 
Hoffmann-La Roche for further development, after it failed to reduce 
the level of p24 antigen in people in a small clinical trial; this data 
was presented at the Ninth International Conference on AIDS, in 
Berlin, in June 1993. Since that time, laboratory tests have shown 
that the drug works many times better when combined with 
pentoxifylline, a readily available prescription drug. Unfortunately 
the company had been trying to kill the project for several years, for 
business reasons, and had only kept it alive because of pressure from 
scientists, who understood the importance of this unique drug; AIDS 
TREATMENT NEWS has covered these events over the years. The 
negative result presented in Berlin provided the necessary excuse to 
stop development; and as a result of this drug's political history, 
there is virtually no chance that the company will run combination 
tests, which it could have done long ago. Ro 24-7429 remains 
important, not only in itself, but also for the doors it opens for 
developing better treatments. These possibilities urgently need more 
attention. JSJ]

Note: This article is the second in a series, which began with "LTR 
Inhibitors, a New Kind of Potential AIDS Treatment: Interview with 
Arthur B. Pardee, Ph.D.," published in AIDS TREATMENT NEWS #192, 
February 4, 1994. Parts of this article are more technical than what 
usually appears in AIDS TREATMENT NEWS; for those who do not 
have a background in this area, we suggest reading the previous 
article first. If you do not already have a copy, you can obtain one by 
sending a self-addressed stamped envelope to: AIDS TREATMENT 
NEWS, P.O. Box 411256, San Francisco, CA 94141; be sure to mention 
"LTR" (or "issue #192") so that we will know which issue to send.

HIV and Drug Resistance

Nucleoside analog drugs (such as AZT or ddI) and protease inhibitors 
invite drug resistance because they are directed against viral 
proteins, which are highly prone to mutations (genetic changes) 
when HIV reproduces. Frequent mutations occur because reverse 
transcriptase (RT), the viral enzyme that produces copies of viral 
genes, is a thousand times more error-prone than the human enzyme 
that cells use when copying their own genes. Altered genes result in 
altered proteins. Therefore, while most essential human proteins are 
fairly accurately and consistently produced by human cells, viral 
proteins mutate at a rate hundreds of times faster. When mutations 
accumulate, the altered viral proteins are less able to bind to the 
drugs, so the drugs become less effective.

Background: The HIV Life Cycle

HIV is a retrovirus; and in retroviruses, the genetic information is in 
the form of RNA, not DNA as with most living things. After HIV 
infects a cell, the information in RNA is copied to DNA by reverse 
transcriptase (which is the enzyme inhibited by AZT). This DNA 
becomes incorporated into the DNA of the infected cell, whereupon it 
may either lie dormant or become active. If this "integrated" DNA is 
activated, more viral RNA is produced; some of it is "translated" into 
viral proteins, and some is encapsulated directly into new viral 
particles.

While some viral proteins are used in constructing the viral coat, 
others regulate the production and processing of viral RNA from its 
(integrated) DNA "template". The most important of these regulatory 
proteins is Tat. Tat activates high levels of viral RNA production -- 
the first step in viral replication in an HIV-infected cell.

About five percent of the viral DNA does not code for proteins at all, 
but instead acts as a binding site for a class of proteins known as 
activators. This portion of viral DNA is called the Long Terminal 
Repeat (or LTR); it functions as the "on" switch for the production of 
viral RNA. A number of proteins bind onto the LTR to activate it; the 
two most important are Tat (produced by HIV) and NF-kB (NF-kappa 
B, which is a normal and necessary human protein, but one which 
often becomes overactive in HIV disease and certain other chronic 
illnesses). Drugs which reduce activation of the virus by the LTR are 
called LTR inhibitors. Three potential treatments (topotecan, beta 
lapachone, and curcumin) have been found through a test to screen 
for LTR inhibitors (see AIDS TREATMENT NEWS issue #174, May 7, 
1993).

Antioxidants -- such as vitamins C and E, or curcumin (from the spice 
turmeric), or the amino acid N-acetyl cysteine.(2,3) (NAC), or the 
drug pentoxifylline -- are examples of one type of LTR inhibitor. 
These compounds work by preventing the binding of NF-kB to its 
DNA binding site, and those which have been tested have been 
observed in the laboratory to partially inhibit the production of HIV. 
Normal immune responses, inflammation, opportunistic infections 
and co-infection with other viruses all increase NF-kB binding and 
subsequent production of viral RNA. Individuals with HIV have 
impaired antioxidant defenses -- for example, they have abnormally 
low levels of cysteine. Conversely, a high cysteine level inside the 
cells (which provides for greater DNA-protective, antioxidant 
activity) is required for the DNA synthesis preceding T-cell 
division.(4) Therefore, not only does "oxidative stress" activate the 
LTR, it also inhibits the functioning of T-cells.(2) 

No Resistance with Tat Inhibitor Ro 24-7429 

 Unlike other activators, Tat binds onto recently formed RNA instead 
of onto DNA. Its binding site is a small region of the LTR known as 
TAR. There are only about 15 proteins coded for by the virus; 
therefore, HIV uses certain cellular (i.e., human) proteins to assist in 
its own replication. The Tat inhibitor, Ro 24-7429, however, prevents 
LTR activation by binding onto a cellular protein instead of onto Tat 
itself. Because this target is a human protein, not a viral one, 
resistance is unlikely to occur. Furthermore, when researchers 
flooded cells with the Tat protein in a 25-fold excess over that 
required for maximal activation, there was no decrease in the 
effectiveness of Ro 24-7429. This suggests that it does not bind to 
Tat, since if it did, the large excess of Tat would have overwhelmed 
the drug.(1)

Recent work by Alan Kingsman and colleagues at Oxford has now 
formally proven that Ro 24-7429 does not bind onto Tat at all, but 
rather to a cellular "loop binding protein." This protein, in turn, binds 
onto a small loop adjacent to the Tat binding site. Kingsman and 
colleagues suggest that the loop binding protein cooperates with Tat, 
and that Ro 24-7429 inhibits this interaction.(5) The hope from this 
research is that once the loop binding protein is physically isolated, 
its 3-dimensional structure will be determined. Knowing the 
structure could lead to the development of second-generation drugs 
with greater binding activity, smaller effective doses, and fewer side 
effects. 

In recently infected cell cultures exposed to very low doses of Ro 
24-7429 alone, viral production is suppressed for a while, then it 
returns to higher levels. The lower the dose, the less the inhibition 
and the shorter the interval before viral production rebounds to 
higher levels. Low-dose monotherapy may result in only a partial 
suppression. This effect is probably not due to HIV resistance, but to 
increasing numbers of infected cells and accumulating amounts of 
viral proteins. Infected cells respond to these proteins by secreting 
inflammatory substances that increase NF-kB activity, thereby 
driving viral production higher. This result also suggests the 
importance of combination therapy, to prevent viral activation by 
Tat, while also preventing excessive activation by NF-kB.

Synergy in LTR Activation and Inhibition

The interrelationship of NF-kB and Tat in LTR activation (and hence 
viral production) is far more than additive. A modified LTR, in which 
the Tat activation pathway has been disabled, is activated by NF-kB 
alone to 15-fold above unstimulated (or basal) levels. An LTR 
without NF-kB (but with an intact Tat activation pathway) can be 
activated by Tat alone to 80-fold above basal levels. But HIV LTR 
with both NF-kB and Tat pathways intact can be activated 388- to 
760-fold above basal levels by the combination of Tat and NF-kB 
(depending on the amount of Tat added).(6) And when both 
pathways are disabled, the virus cannot replicate at all. Such 
experiments indicate that NF-kB and Tat are required for replication 
and that they function synergistically. [Definition: "synergism" is 
defined by Steadman's Medical Dictionary as "coordinated or 
correlated action of two or more structures, agents, or physiologic 
processes so that the combined action is greater than that of each 
acting separately."]

It is exactly this type of synergism that Debajit K. Biswas and 
colleagues (at Harvard University's Dana-Farber Cancer Institute) 
built upon when they analyzed the effects of an NF-kB inhibitor 
(pentoxifylline) combined with a Tat-inhibitor (Ro 24-7429). They 
showed that when pentoxifylline and Ro 24-7429 were used 
together, instead of separately, only one-tenth as much of each 
compound was needed to produce the same LTR inhibition.(7)

These results are important for two reasons. First, the synergism of 
Ro 24-7429 with other LTR inhibitors would allow the use of lower 
doses, and might therefore eliminate the side effects of the drugs. 
Second, lower doses of pentoxifylline would lead to less marked 
inhibition of NF-kB and leave unhindered certain important immune 
functions still dependent on NF-kB.

More laboratory work is needed to determine the most effective and 
least toxic combination of LTR inhibitors. These would 
simultaneously reduce viral production and oxidative stress. Ro 24-
7429 should certainly be tested as a candidate for such a 
combination, as should the other recently developed Tat inhibitor 
from Allelix, Alx40-4C, which is presently in early clinical trials. LTR 
inhibitors with good toxicity profiles might sometimes show low 
efficacy as a monotherapy, but combinations would be expected to 
work much better. 

LTR combination therapy is definitely a here-and-now possibility 
that should go into clinical trials immediately. This new approach to 
treatment might become a valuable therapy in itself. And also, by 
reducing viral replication, it might help to delay the development of 
resistance to other classes of drugs, such as nucleoside analogs or 
protease inhibitors.

References

1. Hsu MC, Dhingra U, Earley JV, and others. Inhibition of type 1 
human immunodeficiency virus replication by a Tat antagonist to 
which the virus remains sensitive after prolonged exposure in vitro. 
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. July 
1993; volume 90, pages 6395-6399.

2. Roederer M, Staal FJT, Ela SW, Herzenberg LA, and Herzenberg LA. 
N-Acetylcysteine: Potential for AIDS Therapy. PHARMACOLOGY. 
1993; volume 46, pages 121-129.

3. Mihm S, Ennen J, Pessara U, Kurth R, and Droge W. Inhibition of 
HIV-1 replication and NF-kB activity by cysteine and cysteine 
derivatives. AIDS. 1991; volume 5, number 5, pages 497-503.

4. Gmnder H, Roth S, Eck H-P, Gallas H, Mihm S, Droge W. 
Interleukin-2 mRNA Expression, Lymphokine Production and DNA 
Synthesis in Glutathione-Depleted T Cells.  CELLULAR IMMUNOLOGY. 
1990; volume 24, pages 520-528. 

5. Braddock M, Cannon P, Muckenthaler M, Kingsman AJ, and 
Kingsman SM. Inhibition of human immunodeficiency virus type 1 
Tat-dependent activation of translation of Xenopus oocytes by the 
benzodiazepine Ro 24-7429 requires trans-activation response 
element loop sequences. JOURNAL OF VIROLOGY. January 1994; pages 
25-33.

6. Liu J, Perkins ND, Schmid RM, and Nabel GJ. Specific NF-kB 
subunits act in concert with Tat to stimulate human 
immunodeficiency virus type 1 transcription. JOURNAL OF VIROLOGY. 
June 1992; volume 66, number 6, pages 3883-3887.

7. Biswas DK, Ahlers CM, Dezube BJ, and Pardee AB. Cooperative 
inhibition of NF-kB and Tat-induced superactivation of human 
immunodeficiency virus type 1 long terminal repeat. PROCEEDINGS 
OF THE NATIONAL ACADEMY OF SCIENCES, USA. December 1993; 
volume 90, pages 11044-11048.

***** New Nation-Wide Trial Tests Timing of Switch from AZT

by John S. James

A new clinical trial -- the first conducted jointly by the Federally-
sponsored AIDS Clinical Trials Group and military institutions -- will 
study whether an advanced blood test can show the best time to 
switch from AZT alone to other treatments. This trial is seeking 300 
volunteers, 150 from civilian and 150 from military sites, and will 
last for up to four years. This is the first time an AIDS clinical trial 
has used a virological test to change the treatment regimen at the 
first sign of viral resistance to the original treatment.

All volunteers will begin this trial taking only AZT as the active drug. 
They will also take placebos for ddI, and for nevirapine, an 
experimental drug proposed for the "convergent combination" 
approach to triple-drug therapy.

As the trial proceeds, their blood will be tested for the presence of a 
particular mutation of HIV, at "codon 215" (position 215 in the viral 
gene which codes for reverse transcriptase, the enzyme which is 
targeted by AZT, and also by ddI and nevirapine). At least five 
different mutations are known to cause AZT resistance; however, the 
one at position 215 is the most serious.

When the mutation is detected (which can be at any time in the 
course of the trial, or never), the patient will be secretly assigned to 
one of three treatment groups: continuation of AZT, switch to AZT 
plus ddI, or switch to the triple combination of AZT plus ddI plus 
nevirapine. Neither the patient nor the research nurses, physicians, 
or study administrators will know if or when the switch occurs. 
Instead, one or more of the placebos will be changed to active drug, 
without their knowledge.

This will make the pill-taking somewhat complex. All patients, 
throughout the trial, will take AZT every eight hours, ddI placebo (or 
real ddI) every 12 hours, and nevirapine placebo (or real nevirapine) 
once per day. And when they take the nevirapine, they will always 
take one pill from each of two different bottles. The reason for this is 
the protocol calls for starting nevirapine at half dose for the first 
eight weeks it is administered; the half dose is given by changing 
only one of the bottles from placebo to real drug. Eight weeks later, 
the other bottle also will be switched from placebo to drug. Once the 
mutation has been detected and randomization has occurred, the 
assigned treatment will be maintained throughout the trial, unless 
side effects or other problems force it to be discontinued.

Note that this trial is designed to look for changes in blood 
measurements, not the development of clinical disease. It's main 
objective is "to validate that (the '215' mutation) precedes the 
increase in viral burden ... and decline in CD4 count which been 
observed in association with clinical failure" on AZT, and to see if 
adding the other drugs will prevent the increase in viral burden and 
decline in T-helper count. (The importance of the '215' mutation has 
been suggested by a small retrospective study of stored specimens. 
Seventeen patients with the mutation had a mean 50 percent 
decrease in T-helper count, during treatment of approximately three 
years; the other 21 patients had a mean increase of 11 percent. See 
Kozal MJ, Shafer RW, Winters MA, Katzenstein DA, and Merigan TC, 
Mutation in HIV Reverse Transcriptase and Decline in CD4 
Lymphocyte Numbers in Long Term Zidovudine Recipients, Journal of 
Infectious Diseases 1993; pages 526-532.)

The protocol chair for this study is Thomas C. Merigan, M.D., Stanford 
University Center for AIDS Research. The co-chair is Douglas L. 
Mayers, M.D., Walter Reed Army Institute of Research and Naval 
Medical Research Institute.

Switch to Non-Blinded Therapies

What about those who do poorly on the study, who may be randomly 
assigned to continue AZT after the resistance mutation has 
developed? The protocol calls for taking the volunteer off the study 
medication if (1) dose-limiting toxicity has developed, (2) an AIDS-
defining condition develops (using the 1977 definition, as amended 
for this study), or (3) the patient's T-helper count has declined by 
more than 50 percent, as shown by two consecutive measurements 
at least 72 hours apart. If any of these occur, the patient's physician 
can begin any other treatment; the patient may continue to be 
enrolled in the trial for followup. However, the study will not pay for 
AZT or ddI once the patient is off the study medication; whether 
nevirapine (which is not commercially available) can be provided is 
being negotiated as this article goes to press. Also, the blind will not 
be broken until the study is finished and the data analyzed, so the 
volunteer who is taken off study medication will not be told whether 
it was AZT alone or something else that did not work for them.

Eligibility, How to Enroll

To be eligible for the study, volunteers must be asymptomatic, with 
T-helper count between 300 and 600. They must have had AZT for at 
least one month, uninterrupted, before being screened for the study, 
but must not have had more than two years of AZT. They must be at 
least 13 years old (at least 18 for the military sites). They must not 
have a history of pancreatitis, and must not currently be alcohol or 
drug abusers. Women are encouraged to enroll in this trial, but they 
will be excluded if they are pregnant, or intend to breast feed during 
the study. During the screening, they will be tested for the '215' 
mutation, and be excluded if it has already developed. There are a 
number of other medical and laboratory entry criteria.

[One possible advantage of being screened for the study is finding 
out if one has the '215' mutation already; about half of those with T-
helper count between 300 and 600 who have been tested do have it, 
and therefore they are not eligible to enroll in the study. They might 
want to start treatment with something other than AZT, for example, 
with ddI; however, there is no professional consensus yet about the 
clinical meaning of this mutation, which is why the study is being 
run. Unfortunately for some volunteers, the T-helper count is tested 
first; both samples are drawn on the same day, to avoid an extra 
visit, but if the T-helper test shows that the volunteer is ineligible, 
the virology test for the '215' mutation is not run. As far as we know, 
this test is not commercially available; it could become available, 
however, well before the trial ends.]

The civilian trial sites are located in: Baltimore, Cleveland, Galveston, 
Los Angeles, Minneapolis, New York City, Philadelphia, Stanford (Palo 
Alto), Rochester, and Washington D.C. For the contact number to call 
for information at a site near you, call the AIDS Clinical Trials 
Information Service, 800/TRIALS-A. Ask for information about 
study ACTG 244.

The military study slots are open to those who have an ID card which 
shows that they are eligible to receive care at a Department of 
Defense medical treatment facility. They can be a veteran, on active 
duty, or a dependent (age 18 or older). The DoD will fly them to a 
participating center, which will usually be either Wilfert Hall USAF 
Medical Center, San Antonio, Texas, or Walter Reed Army Medical 
Center, Washington, D.C., or National Naval Medical Center, Bethesda, 
Maryland. (Those not on active duty can choose whether to enroll at 
a military or a civilian site.) To enroll at a military site, call Douglas L. 
Mayers, M.D., at Walter Reed Army Institute of Research, 301/217-
9410, or Kenneth Wagner, D.O., at National Naval Medical Center, HIV 
Research Unit, 301/897-3290; they will refer you to a protocol nurse.

Comment

This study is expected to take four to six years to affect the standard 
of care -- two to four years of treatment time (depending on how 
many of the volunteers develop the '215' mutation), and additional 
time for recruiting, getting all centers started, data analysis, and 
publication, dissemination, and use of the results. And then the 
results will apply directly only to AZT (and probably indirectly to 
other drugs in the same class, such as ddI -- although a different test 
would be used, as different mutations cause HIV to become resistant 
to ddI).

Our concern is not with this trial itself, but with the broader 
questions of research planning. Does a major study now to fine-tune 
the use of AZT several years down the road reflect a successful 
strategy for dealing with the epidemic? In treating bacterial 
infection, it has long been common to test for resistance, in order to 
avoid using antibiotics which will not work for a particular patient. 
HIV is different from bacteria, but a case could be made for using the 
'215' test now, at physicians' discretion, to switch from AZT to ddI or 
some other drug as soon as AZT resistance is indicated. Meanwhile, 
use clinical trials to test truly important leads, such as topotecan or 
conocurvone, which have been neglected because of the 
happenstance of politics.

The fundamental problem is that for over ten years, a research effort 
which could not possibly save most people's lives has been 
acceptable to the general consensus -- almost casually accepted as 
scientifically inevitable. Little serious effort has been made to think 
through the consequences and change direction. We wonder if this 
basic root of the failure of AIDS research can be changed today.

***** Kaposi's Sarcoma, Genistein, and Soybeans

by John S. James

A paper published a year ago, in the Proceedings of the National 
Academy of Sciences, USA, suggested that substances found in a 
plant-based diet, especially one high in soy products, such as the 
traditional Japanese diet, may help control abnormal angiogenesis 
(growth of blood vessels).(1) Angiogenesis is centrally important in 
Kaposi's sarcoma, and is  important in solid tumors (which cannot 
grow beyond a small size unless they can force the growth of new 
blood vessels to nourish the tumor), and in a number of other 
diseases.

The authors, at universities in Heidelberg, Geneva, and Helsinki, 
chemically fractionated the urine of volunteers who were eating a 
soy-rich vegetarian diet. They found one substance, genistein, which 
had a strong anti-angiogenesis effect in laboratory tests, and which is 
30 times more concentrated in the urine of those eating traditional 
Japanese diets vs. those eating typical Western diets. (Soy contains 
genistein precursors.) The higher urine concentrations were enough 
to affect angiogenesis in laboratory tests.

This paper did not mention KS, or anything AIDS related. Therefore it 
is not included on AIDS computer databases, and is largely unknown 
to the AIDS community. However, abnormal angiogenesis is central to 
KS. (Two reference on the AIDSLINE database do mention genistein; 
one of them noted that it suppressed KS cell growth.(2))

The urine of the volunteers was chemically fractionated into six 
fractions. Four of them had anti-angiogenesis activity. The two most 
active fractions were NOT analyzed in this study, however; genistein 
came from one of the less active fractions. (This suggests that plant-
based diets may supply other substances which may be better than 
genistein in anti-angiogenesis activity.)

The paper cited other published studies which suggested that the 
traditional Japanese diet may inhibit breast and prostate cancer. 
Incidentally -- though not cited in the paper -- there are popular 
"alternative" cancer treatments (for example, the Gerson diet) which 
emphasize large quantities of juices, etc.

Comment: The Next Step

"Macrobiotic" and other plant-based diets have long had advocates in 
the AIDS community. Unfortunately, these diets have often ignored 
the known nutritional needs of people with AIDS, as well as food-
safety requirements for avoiding infection. Diets not properly 
designed for persons with HIV disease can do much more harm than 
good.

We see little hope that enough money can be found for clinical trials 
to scientifically test diets, or nutritional products, for KS or other 
AIDS-related conditions. Mainstream research is unlikely to develop 
this area for years. Instead of waiting for trials that may never come, 
let's take what knowledge does exist and see if something useful can 
be done with it.

What is needed now is for a team, including an HIV-experienced 
dietitian, to prepare recommendations which meet the nutritional 
and food-safety needs of persons with AIDS, but also are formulated 
to have anti-angiogenesis effects, based on what is known at this 
time. Persons with KS might want to try such a diet to see if it 
seemed to help.

References

1. Fotsis T, Pepper M, Adlercreutz H, and others. Genistein, a dietary-
derived inhibitor of in vitro angiogenesis. PROCEEDINGS OF THE 
NATIONAL ACADEMY OF SCIENCES, USA. April 1993; volume 90, 
pages 2690-2694.

2. Amaral MC, Miles S, Kumar G, and Nel AE. Oncostatin-M stimulates 
tyrosine protein phosphorylation in parallel with the activation of 
p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is 
important in Kaposi cell growth. JOURNAL OF CLINICAL 
INVESTIGATION. August 1993; volume 92 (2), pages 848-857.

***** AIDS Hotlines: Selected List

The following listings are from AIDS TREATMENT NEWS Volume 3, 
which is now in press (publisher, Alyson Publications, Boston) and 
should be in the bookstores in late May or early June. We did not 
include all hotlines, but those we think will be most useful for our 
readers. You may want to keep this reference handy, for help with 
your own questions, or for referring other people.

General AIDS Hotlines

** National AIDS Hotline: 800/342-AIDS (800/342-2437), 24 hours; 
Spanish, 800/344-SIDA (800/344-7432), 8:00 a.m. - 2:00 a.m.; TDD 
for the deaf, 800/243-7889, 10:00 a.m. - 10:00 p.m.

This service, operated by the U.S. Centers for Disease Control, 
provides confidential information, referrals, and educational 
materials to callers in the United States, its territories, and Puerto 
Rico. Its information specialists use a database of over 10,000 service 
organizations to find appropriate local referrals, for example financial 
assistance, legal assistance, support groups, buddy programs, housing 
services, and medical referrals. They can also answer many kinds of 
general questions about AIDS. We have found that it is usually 
possible to reach an operator with little or no wait on the phone.

But the treatment information from government hotlines is limited at 
best. The reason is that there are many different ideas about AIDS 
treatment, and no official body to decide which ones are OK for a 
government agency to disseminate. For treatment information, you 
need to check with private organizations; some are listed in this 
directory, below.

 [Note: Any '800' telephone number can only offer confidentiality -- 
not true anonymity -- because the recipient is paying for the call, 
and therefore receives the telephone number of all callers with its 
phone bills. We think it is unlikely that this will be a problem for 
callers. But those who are especially concerned about confidentiality 
may want to call '800' numbers from a public phone.]

** PWA Coalition of New York Hotline: National, 800/828-3280; local, 
212/647-1420. Monday - Friday, 10:00 a.m. - 6:00 p.m. Eastern 
Time.

This toll-free hotline is staffed entirely by volunteers living with 
AIDS or HIV. Callers receive peer counseling, medical and treatment 
information, and referrals. Also available without charge is the 
monthly magazine, Newsline, and the Spanish language publication, 
SIDAhora. Mothers of people with AIDS or HIV volunteer on the 
hotline, Monday, Wednesday, and Friday, 2:00 p.m. - 6:00 p.m. 
Eastern Time.

** HIV Nightline, San Francisco: 415/668-AIDS; Northern California 
outside San Francisco, 800/273-AIDS. Monday - Friday, 9:00 p.m. - 
5:00 a.m. Saturdays and Sundays, 5:00 p.m. - 5:00 a.m. Pacific Time.

 Sponsored by the Suicide Prevention Project, the AIDS/HIV 
Nightline is the only service of its kind in the U.S. It receives calls 
from around the country, and is staffed by volunteers who are 
trained to speak compassionately and knowledgeably about a range 
of issues related to HIV infection and crisis intervention. Volunteers 
and donations for the Nightline are welcomed.

** AIDS Project Los Angeles AIDS Hotline: 213/876-2437; in 
Southern California, 800/922-2437; Spanish language in Southern 
California, 800/400-SIDA; TDD in Southern California, 800/553-2437; 
multilanguage communicator in Southern California, 800/922-2438. 
Monday - Friday, 9:00 a.m. - 9:00 p.m. Saturday, Sunday, and 
Holidays, 9:00 a.m. - 5:00 p.m. Pacific Time.

** AIDS Hotline of Gay Men's Health Crisis (GMHC): 212/807-6655; 
TDD/TTY, 212/645-7470. Monday - Friday, 10:00 a.m. - 9:00 p.m. 
Saturday, noon - 3:00 p.m. Eastern Time.

** San Francisco AIDS Foundation Hotline (English, Spanish, Filipino), 
415/863-2437; in Northern California 800/367-2437; Filipino-only 
in Northern California 800/345-2437. Monday - Friday, 9:00 a.m. - 
9:00 p.m. Saturday and Sunday, 11:00 a.m. - 5:00 p.m. Pacific Time.

AIDS Hotlines for Treatment Information

** Project Inform: 800/822-7422; 415/558-9051. Monday - Friday, 
10:00 a.m. - 4:00 p.m. Pacific Time.

Provides information on experimental treatments for AIDS or HIV -- 
including government and industry treatment trials, AIDS vaccines, 
standards of care, and treatment and prophylaxis of opportunistic 
infections.

** Seattle Treatment Education Project (STEP), Treatment 
Information Hotline: 800/869-7837. Monday - Friday, 1:00 p.m. - 
5:00 p.m. Pacific Time.

Provides information on experimental and alternative treatments for 
AIDS or HIV -- including nutrition, vitamins, herbs, etc.

** Critical Path AIDS Project: 215/545-2212, 24-hours.

This hotline offers in-depth and specific AIDS treatment information. 
It is not a general AIDS information hotline. Callers get individualized 
attention to treatment questions for conventional, alternative, and 
complimentary therapies. Additionally, literature searches from a 
CD-ROM AIDS library can be conducted while you wait.

** AIDS Clinical Trials Information Service: 1/800-TRIALS-A (1/800-
874-2572); TDD for the deaf, 800/243-7012. Monday - Friday, 9:00 
a.m. - 7:00 p.m. Eastern Time.

The AIDS Clinical Trial Information Service (ACTIS) provides current 
information about federally and privately sponsored clinical trials of 
experimental drugs and other therapies for adults and children who 
have AIDS or HIV infection. Both health professionals and the 
general public can call to learn about clinical trials which are open 
for volunteers in their area. Information usually includes a brief 
description of the study and of the investigational drug, entry and 
exclusion criteria for volunteers, sites where the study is being 
conducted, and whom to call at your local site for more information 
about the study, or to volunteer. ACTIS is jointly sponsored by the 
Centers for Disease Control, Food and Drug Administration, National 
Institute of Allergy and Infectious Disease, and the National Library 
of Medicine.

** Canadian HIV Trials Network: 604/631-5327; or fax requests to 
604/631-5210. Monday - Friday, 7:30 a.m. - 4:30 p.m. Pacific Time.

This registry for Canadian AIDS trials includes a brief description of 
each trial, centers running the trial, inclusion/exclusion criteria, and 
where to phone locally for more information. Information can be 
given over the phone, or mailed if requested, in English or French.

** HIV Telephone Consultation Service (for physicians, nurses, and 
other health-care providers only): 800/933-3413; or 415/476-7969. 
Every day, 7:30 a.m. - 5:00 p.m. Pacific Time; 24 hour voice mail. 

Sponsored by Health Resources and Services Administration's 
(HRSA), Community Provider AIDS Training Project at San Francisco 
General Hospital, and American Academy of Family Physicians.

Under the direction of Ronald Goldschmidt, M.D. in the University of 
California San Francisco Department of Family and Community 
Medicine, this is a telephone consultation service for health care 
providers who treat patients with HIV disease. Urgent questions are 
answered but it is not a substitute for emergency care or specialty 
consultation. The phone is answered by a clinical pharmacist, 
physician or nurse practitioner. Patient-specific information is 
requested (CD4 cell count, current medications, previous 
manifestations of HIV disease, sex, age, and transmission category) 
for case consultation, as well as demographic information about the 
caller (address, phone number, type of practice, number of HIV+ 
patients in the practice, field of medicine). Whenever possible, 
questions are answered immediately. Most calls are answered within 
2 hours, and almost all calls are answered within a day. Information 
available to primary health care providers includes case consultation, 
medications, infection control, clinical trials, and literature searches. 
Referrals to local clinical consultants and community resources are 
made through the national network of HRSA regional AIDS Education 
and Training Centers. This service is free, but restricted to health 
care providers.

** Information Line for AIDS Studies: 800/AIDS-NIH (800/243-
7644). Monday - Friday, 12:00 p.m. - 3:00 p.m. Eastern Time.

Provides information (English or Spanish) about AIDS trials being 
conducted at the National Institutes of Health Clinical Center.

Specialized Hotlines

** CDC National AIDS Clearinghouse: 800/458-5231; TDD for the deaf, 
800/243-7012. Monday - Friday, 9 a.m. - 7 p.m. Eastern Time.

This service works closely with the National AIDS Hotline, but it 
focuses on providing printed and audiovisual material used in AIDS 
education efforts, often to organizations -- while the National AIDS 
Hotline usually provides information and referral during the call. The 
National AIDS Clearinghouse has many kinds of specialized 
information, including funding opportunities for AIDS programs, and 
a database of national, state, and local HIV-related meetings, 
seminars, and workshops.

There is often a wait on the phone to reach an information specialist 
at this number.

** CDC Fax Information Service: 404/332-4565. 24 hours.

This automated service, which gives information by fax, includes a 
variety of AIDS information (statistics, transmission, 
education/prevention, anti-body testing, universal precautions, 
approved treatments, clinical trials, vaccines, etc.), health advice for 
international travelers (not AIDS specific), and other health topics. 
This service is a useful example of a "fax back" system, which 
organizations can use to provide detailed information by request to 
the public.

** CDC AIDS Statistical Information: 404/332-4570. 24 hours. 

This automated service, which gives information from the HIV/AIDS 
Quarterly Surveillance Report, either by voicemail or by fax, includes 
statistics for journalists and organizations.

** Indian AIDS Information Hotline: 800/283-2437. Monday - 
Friday, 8:30 a.m. - 12:00 noon. Pacific Time.

Operated by the National Native American AIDS Prevention Center to 
promote health in American Indians and Alaska Natives through 
empowerment and self-determination. This group serves as a 
resource to Native communities and to support community efforts by 
providing education and information services, thereby enhancing the 
physical, spiritual, and economic health of Native people.

 ** Consumer Nutrition Hotline: 800/366-1655. Monday - Friday, 
8:00 a.m. - 8:00 p.m. Central Time.

Sponsored by the American Dietetic Association, callers can speak 
with a registered dietitian about HIV/AIDS and nutrition, or ask for a 
referral to a registered dietitian.

** Body Positive Hotline: 212/721-1346. 10:00 a.m. - 6:00 p.m. 
Eastern Time.

This hotline offers information and referral, emotional and practical 
support, and treatment information for persons infected or affected 
by HIV. Hotline volunteers may be individuals with HIV who can 
provide peer support. If a person with HIV has not answered the 
phone, a caller may specifically request to speak with someone living 
with HIV and it can be facilitated (English, Spanish).

** National Hearing Impaired Hotline: 800/243-7889 (TDD).

** HANDI (Hemophilia and AIDS/HIV Network for the Dissemination 
of Information): 800/424-2634 (English, extension 3051; Spanish, 
extension 3054).

Sponsored by the National Hemophilia Foundation, this national 
hotline provides information about hemophilia and HIV/AIDS 
through a variety of publications, brochures, and articles. They also 
provide referrals to local service providers.

***** 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
   fax: 415/255-4659
   Internet: aidsnews.igc.apc.org
Editor and Publisher:
   John S. James
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. We 
interview physicians, scientists, other health 
professionals, and persons with AIDS or HIV; we also 
collect information from meetings and conferences, 
medical journals, and computer databases. Long-term 
survivors have usually tried many different treatments, 
and found combinations which work for them. AIDS 
Treatment News does not recommend particular 
therapies, but seeks to increase the options available.

Subscription Information: Call 800/TREAT-1-2
   Businesses, Institutions, Professionals: $230/year.
   Nonprofit organizations: $115/year.
   Individuals: $100/year, or $60 for six months.
   Special discount for persons with financial difficulties:
   $45/year, or $24 for six months. If you cannot afford 
   a subscription, please write or call.
   Outside North, Central, or South America, add air mail 
   postage: $20/year, $10 for six months.
   Back issues available.
   Fax subscriptions, bulk rates, and multiple subscriptions
   are available; contact our office for details.
   Please send U.S. funds: personal check or bank draft, 
   international postal money order, or travelers checks. 
   VISA, Mastercard, and purchase orders also accepted.

ISSN # 1052-4207 

Copyright 1994 by John S. James.  Permission granted for 
noncommercial reproduction, provided that our address 
and phone number are included if more than short 
quotations are used.