AIDS TREATMENT NEWS Issue #354, November 3, 2000
phone 800-TREAT-1-2, or 415-255-0588

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CONTENTS

** Enteric-Coated ddI Approved: FDA Letter
A new form of ddI--named VIDEX EC--is easier to take.

** Retroviruses Conference: Registration Deadline for
Community Attendance is Nov. 17
AIDS advocates, activists, and "community press" must apply
by November 17 to attend the Retroviruses conference in
Chicago in February.

** Durban Conference Searchable Abstracts Now Available on
Web
Finally anyone can search and read the full text of the
abstracts of the XIII International Conference on AIDS.

** Bitter Publication Dispute on Remune Study: More Than
Meets the Eye?
Background on the high-profile dispute over the recent
publication of the large HIV immunogen study.

** Many People with HIV/AIDS Not Getting Proper Treatment
A study of four large states--Texas, Florida, California,
and New York--found that up to two thirds of persons who
need expensive HIV drugs are excluded by budgets, rules,
and other obstacles in the Medicaid and ADAP programs.

** Flu Shot Time: Vaccine Shortage in Many Areas
A nationwide shortage of influenza vaccine has limited
inoculations to person at high risk in many areas.

** Help Wanted: AIDS Writer for AmFAR in New York
The American Foundation for AIDS Research seeks a writer
for brochures, annual report, Web content, etc.

** AIDS TREATMENT NEWS Price Increase January 1; Act Now to
Renew at Current Rate
You can avoid the price increase by renewing before
December 31.

** HIV Treatment and Survival: Easy Language Version
"Low literacy" version of the longer article on AIDS
treatment and survival published last September in AIDS
TREATMENT NEWS #350.

** Has Anti-HIV Treatment Cut AIDS Deaths? (original for
copying)


***** Enteric Coated ddI Approved: FDA Letter

On October 31 the FDA approved a new once-daily formulation
of ddI which is easier and less complicated to take, avoids
certain drug interactions, and may reduce diarrhea or other
gastrointestinal side effects. But the overall safety and
efficacy of the drug remain about the same.

ddI (didanosine) is destroyed by acid in the stomach. So
the original drug had to be taken with a powerful antacid
to protect it--which had other disadvantages, including
causing diarrhea in some patients, and preventing
absorption of certain other drugs which require an acid
stomach to work properly. The new drug uses an enteric
coating--a substance which does not dissolve in the acid
environment of the stomach but does dissolve in the
alkaline environment of the small intestines, releasing the
drug there. We do not know why it took many years to
develop this improvement.

Here is a November 1 letter from the FDA describing the new
formulation:

Yesterday, October 31, 00, FDA approved a new formulation
of the nucleoside reverse transcriptase inhibitor, ddI,
called VIDEX EC.

VIDEX EC is an enteric coated, once daily formulation,
which, in combination with other antiretroviral agents, is
indicated for the treatment of HIV-1 infection in adults
whose management requires once-daily administration of
didanosine or an alternative didanosine formulation.

In VIDEX EC, the active ingredient, didanosine, is
protected against degradation by stomach acid by the use of
an enteric coating on the beadlets in the capsule. The
enteric coating dissolves when the beadlets empty into the
small intestine, the site of drug absorption.

In earlier, buffered formulations of didanosine,
administration with an antacid (buffer) provides protection
from degradation by stomach acid.

The peak plasma concentration (CMAX) of didanosine,
administered as VIDEX EC, is reduced approximately 40%
relative to didanosine buffered tablets.

The time to the peak concentration (TMAX) increases from
approximately 0.67 hours for didanosine buffered tablets to
2.0 hours for VIDEX EC.

The enteric coated capsule was approved because of
advantages related to not being buffered, since drug
interactions with ciprofloxacin, ketoconazole and
indinavir, that were caused by the buffer, are avoided.

Additionally, VIDEX EC can be swallowed without being
chewed or dispersed in water.

The previous formulation (which is buffered) was approved
last year for use in a once daily regimen.

The preferred didanosine regimen is twice daily with the
older buffered formulation because there is more efficacy
data with this regimen. There are limited data to date to
support the long-term durability of response with a once-
daily dosing regimen of didanosine.

The safety profile of the enteric coated and the buffered
products are the same.


***** Retroviruses Conference: Registration Deadline for
Community Attendance is November 17

Any "community" member who wants to attend the 8th
Conference on Retroviruses and Opportunistic Infections,
February 4-8, 2001, in Chicago, must act now. You cannot
get into this conference by paying at the door. If you
write for a well-known AIDS "community newsletter," you can
probably get in through the "community press" category, but
the registration deadline is Friday November 17. If you are
an AIDS advocate or activist not associated with a
publication, you may need to use the "scholarship" route
(even if you do not need the money); deadline for these
scholarship applications is also November 17. (AIDS
TREATMENT NEWS published Retroviruses conference deadlines
on September 22, but did not have the press and scholarship
deadlines at that time.)

Mainstream press have longer--until December 31 or until
the press slots are filled, whichever happens first.
Researchers and clinicians without papers accepted for
presentation the meeting can apply starting Friday,
December 1--and must apply as soon as possible at that
time. These doctors and scientists should remember to send
their faxes to reserve a place at this conference on World
AIDS Day (December 1).

Instructions for these and other application processes are
at http://www.retroconference.org


***** Durban Conference Searchable Abstracts Now Available
on Web

Finally the abstracts of the XIII International Conference
on AIDS (Durban, South Africa, July 9-14, 2000) are
available on the Web, through an easy-to-use site set up
by the U.S. National Library of Medicine at
http://www.iac2000.org

You can search for any topic of interest. For example, type
"vitamin" into the "Abstract Text" field and click the
"Search" button and you will see the titles of 22 abstracts
related to nutrition (they contain the word "vitamin"
somewhere in the text). Click on any of the titles to get
the whole abstract.

You can also select any group of the titles and display the
abstracts together, which is convenient for printing.

But be careful; "vitamins" (plural) only gets eight of the
22 "vitamin" abstracts. If a word has different endings
("malignancy" vs. "malignancies"), you can type just the
first part (malignanc", for example--13 abstracts). You can
type a phrase ("viral load", which finds 517 abstracts); to
see a smaller list of the abstracts likely to be most
important for your search, put "viral load" into the
Abstract Title field instead of into Abstract Text (76
abstracts have "viral load" in the title). And if you are
looking for authors, see the "Help" section on how to enter
their names. [Note: Do not type quote marks when doing the
searches.]

We did not find instructions for more complex searches
("viral load" *and* "HIV" for example), and could not get
them to work. But you can search for abstracts which have
one word or phrase in the title, and another word or phrase
in the text.

Also, we do not know if an Abstract Text search will also
find abstracts which have the word or phrase you are
looking for only in the title, but not in the text. If not,
you could miss some of the most important abstracts you are
seeking. After doing an Abstract Text search, it might help
to scan through an Abstract Title search as well, to spot
anything important which is missing.

Searchable, full-text abstracts on the Web are especially
important since the abstracts on the CDROM disks given out
at the Durban conference have a serious error. All the less
than ('<') and greater than ('>') signs are reversed
(except when they are part of less-than-or-equal or
greater-than-or-equal, which are not reversed). Corrected
disks, which also include the late-breaker abstracts, have
been prepared but may not have been widely distributed.

The new Durban conference Web search page can also be
reached through the home page of the National Library of
Medicine's Specialized Information Services
(http://sis.nlm.nih.gov/hiv.cfm), which provides
information on HIV/AIDS, toxicology, and some other topics.


***** Bitter Publication Dispute on Remune Study: More Than
Meets the Eye?

by John S. James

On November 1 the NEW YORK TIMES reported that the Immune
Response Corporation "tried to block the publication of a
scientific paper that showed its HIV vaccine was not
effective, and it has asked for damages of more than $7
million from the universities and researchers who published
the findings."(1) The disputed paper was published in the
same day's issue of JAMA (JOURNAL OF THE AMERICAN MEDICAL
ASSOCIATION,(2) along with several articles and editorials
on relationships with industry and conflict of interest in
medical research.(3,4,5,6) The NEW YORK TIMES story was
picked up or rewritten by many news outlets. Also see LOS
ANGELES TIMES, November 1.

Because we learned about this dispute shortly before press
time, we have not had time for our own investigation. But
in this case we see credible people on both sides--and
beyond the obvious issues, some difficult ones which did
not come out in the headlines. Of course it is wrong when
companies take legal action to pressure researchers and
universities to spin scientific results their way--that is
a no-brainer, and the community must support researchers'
right to report, especially when persons have volunteered
for participation medical research studies. This is part of
an enormous problem ["when an investigator has a financial
interest in or funding by a company with activities related
to his or her research, the research is lower in quality (2
references), more likely to favor the sponsor's product (5
references), less likely to be published (2 references),
and more likely to have delayed publication (1
reference)"(6)], and to that extent, the public was well
served by the press coverage.

But tougher questions about how best to serve the public
interest arise from the fact that today immune-based
therapy is an enormously important research area, and yet
there is no satisfactory way to test such treatments for
clinical efficacy in patients (see "FDA Meeting on
Approving Immune Therapies: Background and Comment," AIDS
TREATMENT NEWS #353, October 20, 2000). Immune Response
Corporation did what it had to do and ran a huge trial
originally designed to look for differences in survival
between those who did or did not receive Remune, the HIV
immunogen developed by the late Dr. Jonas Salk; both the
treatment and placebo arms had more than a thousand
patients each, who were allowed to use any antiretroviral
therapy they chose (including experimental treatments, or
including no antiretroviral therapy at all), in addition to
the immunogen or placebo, which was administered every
three months. But after the trial was designed, the
introduction of protease inhibitors reduced overall AIDS
deaths enough that the trial could not have detected that
the treatment improved survival even if it did--so the
trial was quickly changed to include AIDS-related illnesses
as well as deaths as end points.

But later, in May 1999, when the Data Safety Monitoring
Board (DSMB) secretly unblinded the data, it recommended
that the trial be stopped; "the basis for the
recommendation was the lack of evidence of a difference
between the HIV-1 Immunogen group and the control group
with respect to clinical progression and that continuation
of the study was unlikely to lead to a demonstrable
difference between the groups."(2) "Before the study began,
the predicted clinical endpoint event rate was 6%
progression per year, meaning that 6% of 2,500 patients
would progress to an AIDS defining condition or death each
year. However, when the study was stopped, only 0.73% per
year progressed using the original Centers for Disease
Control AIDS-defining conditions."(7) Due to the dispute
with the company, the study leadership was unable to obtain
the final data, and published from the data submitted to
the DSMB, with updates during the summer of 1999.

The treatment certainly did increase HIV-specific immunity
as shown by lymphocyte proliferation assay (p<.001),(2) but
this measure is not currently accepted as a surrogate
marker of drug efficacy, because there is no proof at this
time that increasing this response is clinically beneficial
to patients.

The company has long had a reputation of looking for
creative ways to interpret its data, which angers some
researchers and activists. A serious communication problem
with unconventional ways to look at data is that even if
they are valid, outside analysts have a hard time verifying
that--because they must ask, "If we were given unlimited
access to the raw data, and months to play with it (months
which we don't have), might we have found equally
convincing ways to come to very different conclusions?" Yet
when facing a serious situation where conventional ways of
analyzing studies of immune-based treatments do not work,
it might or might not serve the public interest to insist
on strict adherence to established data-interpretation
rules. Sometimes it is necessary to push ahead on faith in
what one is doing, break some rules and take some risks, or
nothing will happen.

The controversy over the publication of this study re-
emphasizes the importance of developing workable, well-
accepted standards for the relationship between researchers
and industry. But here again there are complications. For
example, telling sponsors to keep hands off of the
scientific publication clearly seems like a good idea. But
in this case the press, investors, and the public ended up
with a bottom line which is at least questionable, if not
wrong--that the "HIV vaccine was not effective" in general
and not just in this trial. Certainly this study did not
find a clinical benefit--but if no such finding were
possible because of unrelated improvements in HIV
treatment, the study did not find that the treatment was
not effective, either; rather, the result was inconclusive.
Can standards decree that a sponsor has no legitimate
interest in preventing such misunderstandings?

In this trial the treatment consisted of killed HIV plus an
adjuvant--a substance which makes vaccines work better. The
placebo consisted of the adjuvant alone. Has it been ruled
out that the adjuvant itself might have been beneficial,
without the killed virus--since the volunteers already had
their own HIV, including dead virus, on board? This seems
unlikely, given the lack of HIV-specific lymphocyte
proliferation in the "placebo" arm--but much is still
unknown, and if the adjuvant itself were effective, the
study result could have been negative even if the product
being tested were beneficial.

Other Important Findings

The paper included other information which should not be
overlooked because of the distraction due to the
controversy.

"This study provided the first information regarding
disease progression among a large group of well-treated
patients with CD4 cell counts between 300 and 549 x 10(6)/L
that was collected in the controlled setting of a
randomized trial. The progression rate of 1.8 per 100
person-years of observation was one third of what had been
reported in the literature prior to the widespread
introduction of protease inhibitors. This provides
additional evidence of the long-term benefits of highly
active antiretroviral therapies..."

The study also found a surprisingly high incidence of
lymphoma, "the second most common clinical progression
event" (the most common was oral candidiasis).

References

1. Hilts PJ. Company tried to bar report that H.I.V.
vaccine failed. THE NEW YORK TIMES. November 1, 2000, page
A20 (national edition).

2. Kahn JO, Cherng DW, Mayer K, Murray H, and Lagakos S.
Evaluation of HIV-1 immunogen, an immunologic modifier,
administered to patients infected with HIV having 300 to
549 x 10(6)/L CD4 cell counts: A randomized controlled
trial. JAMA. November 1, 2000; volume 284, number 17, pages
2193-2202.

3. Cho MK, Shohara R, Schissel A, and Rennie D. Policies on
faculty conflicts of interest at US universities. JAMA.
November 1, 2000; volume 284, number 17, pages 2203-2208.

4. Boyd EA and Bero LA. Assessing faculty financial
relationships with industry: A case study. JAMA. November
1, 2000; volume 284, number 17, pages 2209-2214.

5 Korn D. Conflicts of interest in biomedical research.
JAMA. November 1, 2000; volume 284, number 17.

6. DeAngelis CD. Conflict of interest and the public trust.
JAMA. November 1, 2000; volume 284, number 17.

7. Immune Response Corporation press release, October 31,
2000.


***** Many People with HIV/AIDS Not Getting Proper
Treatment

A report from the AIDS Research Institute of the University
of California San Francisco found that in the four large
states which were studied (Texas, Florida, California, and
New York), many patients are unable to obtain proper HIV
medications through both Medicaid and ADAP (the AIDS Drug
Assistance Program). In Texas, the worst of the four, about
half to two thirds of patients who rely on these public
programs are not getting proper treatment. The report was
scheduled for publication in March 2001, but was leaked to
the media in early November. An Associated Press story is
available at:
http://dailynews.yahoo.com/h/ap/20001103/hl/aids_treatment_1.html

Comment

This report puts numbers on a dirty little secret which has
been widely known but not much discussed--that even within
the U.S., whether you get lifesaving treatments for AIDS
depends greatly on where you live. Private insurance (not
studied in the research discussed here) also has great
geographic variations. Very few people can pay for
antiretrovirals entirely out of pocket, especially when
they earn less because of their illness.

Living in rural areas, and/or the South, have long appeared
to be significant risk factors for inadequate access to
expensive AIDS medication. But much of the variation seems
random.


***** Flu Shot Time: Vaccine Shortage in Many Areas

A nationwide shortage of this year's influenza vaccine has
temporarily closed the vaccination program of the San
Francisco Department of Public Health.

Because of the shortage, the Health Department's program
here is restricted to persons at highest risk of severe
complications from influenza: those "50 years of age or
older, chronically ill or immunocompromised, [or]
pregnant." Even this restricted program ran out of the
vaccine on the first day (Nov. 7) and had to close until
more can be obtained. Flu shots may still be available in
San Francisco through other public programs or through
private physicians. Or call the San Francisco Department of
Public Health Flu Telephone Referral Line, 415-554-2681,
for news on the Department's program.

Flu shots take about two weeks to become fully effective.

Persons with serious illness should check with their
physician or clinic to confirm that they should receive the
vaccine, and for information on where it is available.

Information about influenza in your area may be available
at http://www.fluwatch.com


***** Help Wanted: AIDS Writer, AmFAR in New York

On October 31 we received the following help-wanted
announcement from the New York office of the American
Foundation for AIDS Research:

"AmFAR seeks qualified individual to write/edit variety of
communications materials, including newsletter, brochures,
reports, web content, talking points, Annual Report, etc.
Emphasis on ability to translate science and policy issues
into clear language. Assist with in-house copy approval
process. Copy edit direct mail and event/conference
materials. Manage publications inventory. Excellent
writing, editing, and project management skills required.
Ability to work as part of team, multi-task, and meet
deadlines. B.A. plus 3-4 years related experience.
Fundraising background helpful. Knowledge of HIV/AIDS
preferred. Send cover letter, resume, and salary history to
Staff Writer, Dept HR-8, 120 Wall Street, 13th Floor, New
York, NY 10005. EOE"


***** AIDS TREATMENT NEWS Price Increase January 1; Act Now
to Renew at Current Rate

Effective January 1, 2000 we are raising all subscription
prices for AIDS TREATMENT NEWS except those for persons
with financial difficulties. The reason is the changing
demographics of the epidemic, which means we must provide
more free subscriptions, when we have less income because
fewer subscribers can afford to pay. Also, we want to avoid
becoming dependent on subscriptions from industry. (We have
never accepted grants, contracts, or contributions from
pharmaceutical companies or others whose products we
cover.)

Both renewals and new subscriptions are available at the
current rate if received by December 31; these rates are
listed on page 2 of this issue. You can pay by check, VISA,
Mastercard, American Express, purchase order, travelers
checks, or postal money order; see subscription
instructions on page 2. If you are renewing, please tell
us, so that we can make sure your payment is properly
credited.


***** HIV Treatment and Survival: Easy Language Version

A shorter, simplified version of Bruce Mirken's in-depth
article, "AIDS Treatment Improves Survival: Answering the
'AIDS Denialists'" (AIDS TREATMENT NEWS #350, September 8,
2000) appears on the last two pages of this newsletter. We
formatted it for easy copying so that service organizations
can make copies for their clients. (We prefer "easy
language" to the more common phrase "low literacy.")

OK to remove the footer line if you want to.

We also encourage service organizations to use this text in
their own brochures and other materials.


***** Has Anti-HIV Treatment Cut AIDS Deaths? (original for
copying)

See our Web site (http://www.aidsnews.org) for a PDF
version of AIDS TREATMENT NEWS #354. The fact sheet is on
pages 7 and 8 of this issue.

***** AIDS TREATMENT NEWS

Published twice monthly

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Editor and Publisher: John S. James
Associate Editor: Tadd T. Tobias
Reader Services: Tom Fontaine

Statement of Purpose:
AIDS TREATMENT NEWS reports on experimental and standard
treatments, especially those available now. We interview
physicians, scientists, other health professionals, and
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meetings and conferences, medical journals, and computer
databases. Long-term survivors have usually tried many
different treatments, and found combinations that work for
them. AIDS TREATMENT NEWS does not recommend particular
therapies, but seeks to increase the options available.

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