AIDS TREATMENT NEWS Issue #360, February 23, 2001
phone 800-TREAT-1-2, or 215-546-3776

CONTENTS:

** Tenofovir DF Expanded Access
An important new drug is now available through a special
program for patients with advanced AIDS who have failed
approved therapies.

** New Immune-Based Treatment Approach: Trial Recruiting in
San Francisco
A clinical trial of a new kind of immune-based treatment --
using a drug widely available in Japan for other purposes -
- is now recruiting in San Francisco.

** Africa Access: Moving Fast, Outcome Uncertain
In many developing countries fewer than one in a thousand
persons with HIV receive modern treatment, mainly because
they cannot pay for the drugs, which are often sold at
rich-country prices although they cost little to
manufacture. Affordable treatments are clearly possible,
but have been held back for years due to pharmaceutical
companies' fears over patent protection. Now there is
intense interest in finding solutions, and several possible
approaches are on the table.

** South Africa Lawsuit: March 5 Worldwide Protest
Information
For three years some the world's largest pharmaceutical
companies have been suing South Africa to stop
implementation of its post-apartheid medicine reform law;
the case is scheduled to go to trial March 5. Solidarity
protests are planned for that date in Australia, Brazil,
Canada, France, Germany, Italy, Philippines, South Africa,
Thailand, United Kingdom, the United States, and probably
elsewhere as well.

** AIDS TREATMENT NEWS Publication Schedule, February-March
2001


***** Tenofovir DF Expanded Access

On February 1 Gilead Sciences announced a much-enlarged
expanded access program for tenofovir DF (tenofovir
disoproxil fumarate), a potentially important new drug
which is now in a phase III clinical trial with over 500
treatment-experienced patients (averaging more than five
years of HIV treatment before beginning this trial). The
new pre-approval program is limited to "patients who have
failed commercially available antiretroviral treatment
regimens, have limited treatment options and are at risk
for disease progression." It is now open in the U.S. and
France, and will soon begin in Germany, Italy, Spain, and
the United Kingdom. Gilead hopes to apply for marketing
approval for tenofovir DF in mid 2001 in both the U.S. and
Europe, and the drug has been designated for fast-track
evaluation by the U.S. FDA.

Criteria for U.S. Program

"The U.S. program will make tenofovir DF available to
patients at least 18 years of age with HIV infection who
have had a CD4 count less than or equal to 100 cells/mm(3)
and an HIV RNA level of greater than or equal to 10,000
copies/mL by PCR within the past two months. Patients must
also have failed treatment with at least two protease
inhibitors (PIs) or one PI and one non-nucleoside analog
reverse transcriptase inhibitor. Additionally, patients
with a CD4 cell count between 100 cells/mm(3) and 200
cells/mm(3) and an AIDS-defining opportunistic infection
within the last 90 days may also be eligible."

"Physicians will be required to evaluate patients at
baseline and after one month on therapy, then every two
months until drug discontinuation or study termination
following the protocol guidelines. Data collection is
limited to the report of serious adverse events, and no
specific laboratory testing is required except as indicated
for standard medical care."

The drug is taken as one pill per day -- and patients
should also be taking at least one other new
antiretroviral.

Phase III Results

On February 20 Gilead released 24-week results from the
ongoing phase III trial in treatment-experienced patients.
Those randomly assigned to tenofovir had a 0.6 log decrease
in viral load, compared to a negligible change in those
taking placebo. Both the tenofovir and placebo arms had the
same dropout rate, 6% -- indicating a good safety profile
at the 24-week time point. (This trial will run for 48
weeks.)

The drug is also being tested in a separate phase III trial
in treatment-naive patients.

For More Information

For more information about the tenofovir DF expanded access
program in the U.S., and for physicians to request
registration materials, call 1-800-GILEAD-5 (1-800-445-
3235) between 8 a.m. and 6 p.m. Monday through Friday
Eastern time. For the European program, call 33-1-44-90-34-
46.


***** New Immune-Based Treatment Approach: Trial Recruiting
in San Francisco

by John S. James

A new kind of potential treatment is about to begin its
first human trial in San Francisco.

A drug called Z-100 (also called Ancer 20) has been
approved for years in Japan and used by thousands of
patients there to stimulate growth of blood cells after
cancer therapy; doctors use it when filgrastim
(Neupogen(R)) would be used in the U.S. The drug, prepared
from the cell walls of the bacterium that causes
tuberculosis and injected in very small amounts, stimulates
the production of many cytokines in the process of causing
blood cell growth -- and has been found to increase the
production of MIP-1-alpha, which can help block many HIV
variants from entering cells, in laboratory tests with
cells from patients with HIV.(1) It appears to change the
immune response from Th2 toward Th1, which may be useful in
controlling this virus.

Laboratory tests with HIV found that Z-100 alone did not
reduce the growth of the virus -- but did reduce viral
growth when combined with a concentration of AZT which was
too low to be effective in itself.(2) These studies are
only suggestive, because patients usually respond
differently than cells in a laboratory culture.

The first study of Z-100 as a possible HIV treatment will
soon start at the University of California San Francisco
Medical Center. It will test Z-100 alone (without
antiretrovirals) in volunteers who are either
antiretroviral naive, or off antiretrovirals for at least
16 weeks, and whose CD4 count is between 300 and 800. Their
viral load must be between 2,000 and 50,000 copies, and
they must pass usual safety tests (liver enzymes, etc.).
Volunteers will be randomly assigned to take either 20
micrograms or 40 micrograms of Z-100, or placebo, for 8
weeks, followed by four weeks followup. There are no plans
currently for providing Z-100 after this trial.

Side effects of this drug are usually minor, mostly at the
injection site.

Comment

Volunteers should not expect personal benefit from this
trial, except from the laboratory testing that will be
provided. No one can predict whether this treatment will
work at all for HIV, or whether it will have any
antiretroviral activity if not combined with AZT or other
drugs. What is important is that this study is testing a
new approach to HIV treatment -- one which could readily be
applied if it is found to be helpful, since the drug
already exists and has been extensively used in patients.

For More Information

To find out more about this trial, patients or doctors can
call either Anna Smith, R.N. at 415-476-9296 ext 313, or
Brad Hare, M.D., at 415-514-0550 ext 360.

References

1. Suzuki F, Kobayashi M, Curry J, and others. The
induction of macrophage inflammatory protein (MIP)-alpha by
Z-100, a M. tuberculosis-derived arabinomannan, in cultures
of peripheral blood mononuclear cells (PBMC) from patients
with HIV infection. ABSTRACTS OF THE GENERAL MEETING OF THE
AMERICAN SOCIETY FOR MICROBIOLOGY, May 30 - June 3, 1999
[abstract V-30].

2. Sasaka H, Nomoto K, Pollard RB, and Suzuki F. M.
tuberculosis-derived arabinomannan (Z-100) enhances the
anti-HIV activity of zidovudine (AZT) in cultures of human
peripheral blood mononuclear cells. ANTIMICROBIAL AGENTS
AND CHEMOTHERAPY. 1998; September 24-27; 38:368 [abstract
I-18].


***** Africa Access: Moving Fast, Outcome Uncertain

Commentary by John S. James

Two years ago almost nothing was being done about access to
medical treatment in Africa and other developing countries;
today so much is happening that nobody could make a
complete list. Powerful people and institutions are looking
for a path forward. Clearly, workable solutions are within
reach -- and providing this treatment could be much less
costly than generally believed. But even though it is
feasible to distribute AIDS drugs in developing nations,
there is no guarantee it will happen.

The biggest problem now is lack of leadership on this issue
by governments and other major institutions. So the
immediate need is to find enough consensus among the
different stakeholders to induce governments to exercise
responsible leadership. But with most of the pharmaceutical
industry long opposed to any workable plan for widespread
access to treatment in developing countries, finding
consensus may be difficult. [For a fascinating and
appalling history of the global decisions not to provide
HIV/AIDS treatment to the poor, see Barton Gellman, "An
Unequal Calculus of Life or Death," WASHINGTON POST,
December 26, 2000, available at:
http://www.washingtonpost.com/wp-
dyn/world/issues/aidsinafrica/A51719-2000Dec26.html ]

Solutions Are Possible

The bottom line for any program on treatment access is
whether it actually makes treatment available. It is not
enough to generate press releases and heartwarming media
stories alone, as if to satisfy public demand until the
world's attention turns to something else. By this standard
there has been only one success so far: generic drug
manufacture and distribution, as in Brazil, and generic
competition to bring prices down. Pharmaceutical-company
discounts which still leave the drugs unaffordable, or
company "charitable" type programs which treat a select few
if they treat anybody at all, have not worked so far
(although these approaches cannot be ruled out for the
future).

But generic manufacture and competition will not solve the
problem by itself. Brazil can afford to treat its AIDS
patients at generic drug prices. But many African
countries, with much less money per person and a far higher
proportion of their population infected, cannot.

Jeffrey D. Sachs, a leading economist at the Harvard
University Center for International Development, recently
told the annual Retroviruses conference in Chicago, and
other forums as well, that government leadership is key,
and that without it, pharmaceutical-company programs could
not be expected to succeed on their own. He showed that the
resources required for assisting African and other poor
countries in controlling the epidemic (including access to
treatment, which is now recognized as a key element of HIV
prevention campaigns) would be a minor expense for the
world. He has outlined a solution in which pharmaceutical
companies follow through on their promises to drop prices
sufficiently in developing counties, governments respect
the companies' property rights, and rich countries together
contribute several billion dollars a year to buy the drugs
at the discounted prices. (You can hear Dr. Sachs' talk to
the Retroviruses conference at
http://www.retroconference.org -- select 'Hear the
Lectures', then select his address, "From Talk to Action in
Fighting AIDS in Developing Countries," and click the
button to start playback.)

There is no quick or total solution to making HIV or other
medical treatment available to everyone in the world. But
the AIDS community and others must urge governments and
other major institutions onto a path that will bring steady
improvement, by supporting doctors and others who are doing
the work, giving them the tools they need to be more
successful.

Why Treatment Will Cost Less Than It Seems

Until recently it was popular to estimate the cost of
providing HIV treatment to the 90% of people with AIDS now
denied it, by multiplying the price of the drugs (usually
$10,000 or $15,000 per year) by the number of persons
estimated to have HIV in developing countries -- resulting
in a figure of hundreds of billions of dollars per year in
drug cost, which of course could not be raised, thereby
ending discussion. This multiplication was never realistic,
for several reasons.

First, most people with HIV do not know they are infected,
and are not seeking medical care (and for many with
asymptomatic HIV, antiretroviral drugs would not be
recommended immediately even if cost were no obstacle).
There is no way around the fact that during the foreseeable
future, any treatment-access program contemplated for the
poorest countries will mostly treat those who are
symptomatic and come in for care. So already the cost of
providing treatment is reduced to a fraction of what had
been computed.

Even more important for limiting cost, the prices of the
drugs in poor countries can be reduced about 30 times or
more from current U.S. retail prices. On February 6, the
Indian generic manufacturer CIPLA offered to sell a triple-
combination HIV treatment (d4T, 3TC, and nevirapine) for
less than a dollar a day to MSF (Doctors Without Borders);
it offered a price of $600 per year to governments. So on
top of the reduced number of patients comes an
approximately 30-fold reduction in drug costs. The offer
itself has changed public awareness and generated much
discussion.

And the $350 price is available today. By the time much of
Africa is being treated there will have been huge scale-ups
in the manufacturing, resulting in further drug price
reductions.

In addition, researchers are now testing intermittent
schedules, such as one week on and one week off for certain
antiretroviral regimens, in the hope of reducing side
effects as well as drug cost; a team at the U.S. National
Institutes of Health reported early results at the recent
Retroviruses conference (Dybul M, Fauci AS, and others,
Short-Cycle Intermittent HAART: A Pilot Study, 8th
Conference on Retroviruses and Opportunistic Infections,
Chicago February 4-8, 2001, Abstract #354). Unfortunately
nevirapine probably could not be used in this way, because
it has a long half life in the body and would remain
present at low levels after the other drugs were
eliminated, creating conditions for HIV to develop
nevirapine resistance; a protease inhibitor might be used
instead.

Another huge cost reduction is less obvious and has been
largely overlooked. On February 23 the WALL STREET JOURNAL
reported that there was no great rush by governments to
take up the CIPLA offer of treatment at $600 per patient
per year ("Economy: Offer to Sell AIDS Drugs at a Discount
in Africa Is Met with Caution, Uncertainty.") That is not
really news; there was no reason to expect a rush. At
previous prices (around $10,000 per year per patient), the
issue was never on the table for African governments. And
providing AIDS treatment to a population which has not had
it is more than a matter of deciding to buy drugs;
professional and public education, training, management of
side effects, and many other infrastructure problems need
to be addressed. Until now there was no reason to develop
this infrastructure, since access was hopeless anyway due
to the prices of the drugs. Now planning can begin; but
doctors, officials, organizers, activists, and others need
to hear about the new availability and development
treatment and distribution plans to put on the table for
their governments, which then need to act. All this does
not happen in 17 days (the time between the CIPLA
announcement and the WALL STREET JOURNAL article).

So in addition to the other factors which greatly reduce
the cost of providing AIDS treatment to poor countries,
there is the slow scale-up -- which not only delays
expenses, but also eliminates some of them, since mistakes
and inefficiencies can be found and corrected while
programs are relatively small.

And finally, though it is hard to calculate, the remaining
costs of treatment must be offset against the costs of not
providing it. Opportunistic infections, hospitalization or
other care, faster spread of HIV, faster spread of
tuberculosis and other diseases, sick time, funeral leaves
for workers (sometimes for services many miles away), loss
of teachers, the need to replace trained workers, care of
orphans, the list goes on.

Who Will Negotiate?

How will the different stakeholders work together toward
serious government leadership on the AIDS epidemic? This is
the most difficult issue.

We have followed developing-country treatment access for
years, but it has been hard to find anyone in industry to
talk to about it. Pharmaceutical-company officials have
been either uninformed about the issue or unwilling to
address it, or fanatically committed to defending their
intellectual-property rights to the exclusion of everything
else (including the tens of millions of people being left
to die). The obvious group to address this issue, PhRMA
(the Pharmaceutical Research and Manufacturers of America),
has been even more fanatical than the companies it
represents -- still denying that intellectual property is
an issue, even while thousands of patients die for no other
reason except that fluconazole and other drugs are patented
and priced completely out of reach of their doctors, who
cannot buy affordable generics in India or elsewhere
because of patent laws. (PhRMA cites other problems, such
as infrastructure and corruption, which are also real --
though less able than intellectual property to stop
discussion cold and take everything off the table).

Reading African press reports on these struggles shows a
different world from that painted by pharmaceutical-company
statements released for rich country public consumption.
Even when patent and trade laws technically allow
exceptions, pharmaceutical companies and their money have
been active behind the scenes, in the superpower
government, the local governments, international agencies,
the business community, and elsewhere, to block solutions
they see as any possible symbolic threat to patent rights
in rich countries. (They care little about lost sales in
poor countries, since their markets there are negligible;
they do care about precedents, ideas, or information that
might erode patent rights or prices elsewhere.)

Also, who will speak for the AIDS community? Industry might
do what it has done in other areas -- create a hand-picked,
kept community of organizations which have names or
numbers, but have not been involved in international
treatment access, or are financially dependent on industry,
or which otherwise can be controlled. Today the kept
community is becoming a standard public-relations strategy,
and AIDS treatment activists are alert to prevent it from
happening here.

A result of industry rigidity on intellectual property vs.
treatment access in developing countries is that activists
have had little opportunity for industry dialog, and no way
to act except through opposition. It has long been clear
that industry would not cooperate meaningfully on treatment
access in poor countries (this might or might not change in
the future). The only possibility of success was the
development of a public insistence too strong to be
stopped.

We are mostly optimistic as the current confusion sorts
itself out. A key organization will be MSF (Doctors Without
Borders). It has credibility on this issue, and credibility
in the larger world as well -- although it could do better
in explaining this issue to the public. It might become the
cornerstone of a forum where the different interests come
together to discover what common ground could be found.

An Impossible Dream?

Recently a reporter mentioned the possibility that the
pharmaceutical industry could "get religion." As strange as
it seems, we cannot see any economic or other reason why it
would be impossible.

Under the current system, now being imposed around the
world by the WTO treaty, governments must give
pharmaceutical companies monopolies over life and death
treatments, so that the companies can charge high prices
for patented drugs in order to pay for research, and reward
investment. Society demands nothing from the industry
beyond quality control, and general obedience to the law.
So companies are free to use their money to corrupt medical
research, medical publishing, medical practice, patient
advocacy, governments at all levels, and international
institutions. They are not even expected to maintain
adequate supplies of life-critical medications in rich
countries, let alone research diseases that affect mostly
poor regions, or give any thought or plan for access to
life-critical medicines outside of lucrative markets. There
is also no control over "incestuous drugs," even in rich
countries -- the mis-design of clinical trials to promote a
manufacturer's products instead of testing the treatments
which are best for patients. In the last year this system
has changed little, but the public has become much more
aware of it, through in-depth reports in leading national
newspapers and medical journals. These issues are not going
away; and if the pharmaceutical industry will not change
voluntarily, it is likely to have changes imposed.

Pharmaceutical patents are different from most patents not
only because the product can be essential to life. They are
also different because human beings have risked their
health or their life in clinical trials to get these
products tested. (This should be remembered when the United
States threatens other nations with economic retaliation if
they use publicly available clinical-trial data to approve
drugs competing with those of U.S. companies, on the
grounds that registration data is proprietary, and its use
to approve drugs within those countries is an unfair trade
practice.)

Would it be possible to change public opinion and business
and legal practice, so that holding a patent on a life-
critical medical treatment would be regarded as a calling,
as well as a business? There is a precedent in the
traditional role of the physician, who until recently was
also well rewarded, but with the understanding that the
practice of medicine was not only a business, but involved
more than just making of a buck.

Could we ask that proprietary pharmaceutical companies be
the leaders in the public interest around the use of their
patented medicines -- be out in front of everybody else in
advocating their best use, not just maximum sales?

Such a social contract would be expressed partly in law, as
it has been with physicians. But widely shared, less formal
expectations can also be effective. A pharmaceutical
company cannot be successful without the cooperation of
many people -- including investors, doctors, scientists,
corporate partners, politicians, and regulatory officials.
If any social contract is serious, then how well or how
badly a company fulfills its obligations will be weighed by
many people in deciding whether or not to do business with
the company.

Public-interest leadership need not cost money. Last week
in New York, about 60 ACT UP New York and other activists
visited a Glaxo SmithKline meeting for investors, to
protest the company's role in the March 5 pharmaceutical-
industry lawsuit against South Africa to block its
medicines reform law; about 20 of them entered the room.
Later, financial analysts were asked about the issue, and
were quoted as saying that Glaxo could sell its drugs in
Africa at cost without losing money.

But sometimes profit motive and public interest would
conflict -- as when a marketing department wants to use a
questionable or unethical promotional campaign. How could
incentives be designed to handle this situation?

One possibility is that companies large enough to own FDA-
approved patented pharmaceuticals would be expected to have
a public-interest department reporting directly to top
management -- not to marketing. This department would focus
on creative ways of advancing the public interest, more
than on saying No to company projects. But sometimes it
would say No, and then the issue would go to management to
make the decision -- and be responsible for it.


***** South Africa Lawsuit: March 5 Worldwide Protest
Information

On March 5 many of the world's biggest pharmaceutical
companies go to court in South Africa, against the South
African government's post-Apartheid reform of its medicines
law. For three years this lawsuit has kept South Africa
from implementing its reforms. The March 5 protest,
organized on short notice after the trial date was
scheduled, now includes actions in Australia, Brazil,
Canada (Toronto and Vancouver), France, Germany, Italy,
Philippines, South Africa (Cape Town, Durban, Pretoria),
Thailand, United Kingdom (Birmingham, Crawley, Kent,
London, Manchester, and other cities, see
http://www.resist.org.uk), and the United States (Berkeley,
Boston, New York, Philadelphia, Washington).

The Treatment Action Campaign in South Africa maintains the
latest list on its Web site:
http://www.tac.org.za

The TAC site also has a background paper on the South
African law and the industry lawsuit.

Also see:

* WASHINGTON POST February 24 editorial, "Patent Wrongs,"
available at:
http://washingtonpost.com/wp-dyn/opinion/A49618-2001Feb24.html

* THE NEW YORK TIMES February 25 editorial, "Fighting AIDS
in Africa."

* THE PEOPLE (Kenya) February 26 editorial, "AIDS Generic:
Patent Laws Killing Kenyans."



***** AIDS TREATMENT NEWS Publication Schedule, February-
March 2001

AIDS TREATMENT NEWS is usually published on the first and
third Friday of each month. This year our February issues
have been delayed, due to our move from San Francisco.

To reduce confusion later, we are publishing two February
issues; these will be dated February 23 (the last Friday in
February), and February 28 (the last day in February).


***** AIDS TREATMENT NEWS

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