AIDS TREATMENT NEWS Issue #362, March 23, 2001
phone 800-TREAT-1-2, or 215-546-3776

CONTENTS

** Building Alliances for World Health Funding
This key moment in history offers the chance for a
breakthrough in world health for AIDS and many other
conditions, as political consensus demands that over 20
million people with HIV not be left to die without
treatment. We believe that instead of seeking earmarked HIV
funding, the AIDS community should work through broad
health alliances focusing on poor countries, to find
several billion dollars a year of new funding for projects
in HIV, tuberculosis, malaria, other infections, vaccines,
microbicides, behavioral prevention, research, training,
nutrition, clean water, and other cost-effective programs.

** FDA Gives Salvage Therapy Testing a Push Forward
Pharmaceutical companies like to test their drugs in
patients who are less seriously ill, so that the drugs will
look good. A recent FDA meeting focused attention on the
need for more trials in advanced patients, the importance
of long-term safety followup for all patients, and how the
necessary trials and monitoring could be conducted.

** AIDSWatch May 5-8: Visit Your Representatives in
Washington
The annual AIDSWatch, where hundreds of people travel to
Washington to meet their political representatives, takes
on special importance this year.

** AmFAR HIV/AIDS Treatment Directory Available
This 300-page directory explains almost all available
HIV/AIDS treatments, both approved and experimental, and
the major ongoing clinical trials. It also has practical
reference lists and tables, and articles on current
subjects.

** AIDS TREATMENT NEWS Publication Schedule


***** Building Alliances for World Health Funding

by John S. James

The last year has brought historic change in world
consensus -- from writing off and abandoning almost
everyone with HIV in African and other poor countries, to
serious discussion of how treatment could be provided to
many or most who need it. The key to this change was the
widespread realization that HIV treatment could be made
available for well under $500 per patient per year if
generic competition is allowed, instead of far higher
prices which, in practice, meant that widespread treatment
in poor countries was not going to happen. This change
became possible through the work of activists around the
world, over the opposition of some of the world's richest
corporations.

Today political leaders internationally are talking about
how to raise the several billion dollars a year that
worldwide access to antiretrovirals may cost even at the
new low prices (since $500 per year is still far beyond the
means of most individuals and governments in poor
countries). The money, "spare change" in the world economy,
is certainly possible; the real issue is building sustained
political commitment that will last beyond the current
flurry of attention.

What is the next step? We believe that now the AIDS
community should help broaden the discussion beyond
antiretrovirals alone, or treatment of people with HIV
only, through alliances and coalitions to fund world health
-- finding several billion new dollars a year for HIV,
tuberculosis, malaria, other illnesses, clean water,
nutrition, education, infrastructure, transparency, and
whatever else is needed, funding cost-effective health
projects which can differ greatly from place to place
according to local needs.

Practical and Political Advantages

A campaign for world health funding has important practical
advantages over a specific campaign for antiretroviral
funding:

(1) Persons with HIV need antibiotics, nutrition, safe
water, and many other kinds of care, as well as
antiretrovirals. Many medical professionals in poor
countries are asking for these other treatments first, to
save lives now. It wouldn't make sense to say, "No, here
are antiretrovirals only." Other health interventions must
be available for rational care.

(2) It would be wrong and a political nightmare to limit
treatment to persons with HIV -- to say to patients who
need an antibiotic to save their life, for example, that
they must be HIV-positive to get it.

(3) Politically the AIDS community alone is unlikely to
sustain enough of the current momentum to raise several
billion dollars a year for antiretrovirals. Historically
the world epidemic has been scandalously underfunded, for
prevention and otherwise, and we have been unable to change
that. But a larger campaign for health, focusing mainly but
not entirely on poor countries, could bring in many more
organizations, activists, and other supporters, and would
have a very good chance of finding this money.

(4) The donors and the recipient countries will control how
the money is spent through decisions made later, so the
campaign now to find the money will not have much control
over how it is ultimately spent. Politically this is
fortunate, since it means we can work together for health
funding, without fighting each other over where the money
will go. We *can* build consensus now on transparency and
accountability, to help assure that the funds will be well
spent.

(5) The AIDS community today has a window of opportunity to
use the recent world consensus and political momentum to
broaden the discussion beyond AIDS, toward a larger health
movement that can sustain victories and momentum into the
future. It's the right thing to do, and it can build a
solid base for future success.

* We would like to hear your comments, suggestions, ideas.
Send them to jjames@..., or mail them to AIDS
TREATMENT NEWS, Philadelphia FIGHT, 1233 Locust St., 5th
floor, Philadelphia, PA 19107.


***** FDA Gives Salvage Therapy Testing a Push Forward

by Emily Bass

The FDA is taking its most active role to date in
encouraging drug companies to address the needs of persons
with HIV who have exhausted all their treatment options.
Due to a long history of drug failures, these people
require innovative salvage therapies that are unaffected by
the drug resistance their HIV has built up.

In January, the FDA Antiviral Drugs Advisory Committee held
a meeting on salvage therapy trial design. The meeting
addressed thorny issues, including who to include in these
trials; how to design them; and how to put together a
successful New Drug Application (NDA) for a salvage therapy
agent. Many of the new recommendations will appear in a
"guidance document" on the use of HIV RNA measurements to
support accelerated and traditional approval for phase III
trials. Released for comment over a year ago, the finalized
version should be available by the end of 2001, said Jeff
Murray, an FDA antiviral medical officer.

These events are a major step forward, treatment advocates
respond. Michael Marco, of the Treatment Action Group
(TAG), commented after the FDA advisory committee meeting,
"Today is the day when industry can stop saying the FDA is
not sending a clear message."

Major Uncertainties on How to Test and Approve

Five years ago, protease inhibitors uncapped a revolution
for people living with HIV. Today, many of the people who
swallowed the first of these pills are facing a new
dilemma. Although the FDA has "routinely" asked for anti-
HIV drug developers to look at the effects of their drugs
in treatment-experienced populations, little such
information has been gathered, said Heidi Jolson, outgoing
head of the Antiviral Division, at the January meeting.

Although doctors and patients have no choice other than to
tackle difficult decisions about stopping or switching
therapies, drug developers have been able to sidestep the
issue by testing new drugs in treatment-naive individuals,
where the drugs have the most striking activity. Trial
results affect the drug's approval and marketing, and can
also have an immediate influence on the company's stock
price.

Any trial has to include a "background regimen" of active
drugs that support the company's experimental candidate in
attacking trial participants' HIV. Then there has to be an
agreed-on method to isolate and evaluate the benefit of the
particular drug in development. These requirements become
difficult to fulfill in salvage therapy trials. Persons
with long treatment histories and rebounding HIV likely
have many strains of drug-resistant virus, and constructing
an acceptably active supporting regimen may not be
feasible. The experimental drug may have only a partial or
transient effect as a result.

Persons eligible for salvage therapy trials also tend to
have more advanced disease and experience HIV-associated
opportunistic conditions. The symptoms and treatment of
such infections or malignancies may complicate use of
potentially toxic antiretrovirals.

Researchers considering salvage trials as well as many
patients have changed their treatment goals. An
undetectable viral load may be an unrealistic goal for
salvage therapy, while a 0.5 log (two-thirds) drop in viral
load is enough to discernibly improve health and boost CD4
counts. But will the prospect of a minimal, perhaps
temporary drop in viral load be enough to enroll sufficient
participants in a trial?

Companies have to address all these complexities while
simultaneously finding a trial design that makes their new
drug look good: effective, nontoxic and easy to take. The
updated FDA guidance documents will provide the clearest
road map yet for traversing this wild and woolly zone of
trial design in treatment-experienced patients. Among other
things, the new guidelines will urge drug developers to co-
sponsor trials, and depart from tried-and-true drug
approval packages consisting of several trials in
treatment-naive patients. Specific statements will be made
about how to use baseline resistance testing and other
diagnostics to identify the types of patients that are most
suitable for participation in particular salvage therapy
trials. The document will also advise on "superiority"
designs that use the maximum number of drugs likely to have
activity, whether experimental or approved, in an
"optimized background therapy" regimen.

Guidance documents are the foundation for negotiations
between trial sponsors and the FDA. In order to gain FDA
approval for a drug, a company or researcher submits a
package of data from a series of clinical trials. The
guidance documents give recommendations on how best to
design these trials to gain approval. Whether these
documents will be enough to spur pharmaceutical companies
into relatively unfamiliar territory remains to be seen.
The recommendations are only suggestions, not requirements.
"There's no teeth beyond encouraging [new trial designs],"
acknowledged Murray.

Some parts of the FDA's advice may be more appealing than
others. In particular, drug companies may be more willing
to assemble nontraditional NDAs. At the January meeting,
Jolson bestowed the FDA's blessing on NDAs made up of one
traditional trial that shows how well a drug works in
treatment-naive populations, paired with rational, well-
designed "supportive" trials that offer evidence that the
drug also works in treatment-experienced individuals. This
statement reflects the 1997 FDA Modernization Act, which
revised FDA drug approval requirements by stating, "data
from one adequate and well-controlled clinical
investigation and confirmatory evidence" may be sufficient
and constitute "substantial evidence" of a drug's merits.
Previously, at least two large comparison trials, with a
placebo or accepted treatment as a control arm, were
required to support an NDA.

Abbott Pharmaceuticals was one of the first companies to
use the new simpler package. The approval of its protease
inhibitor, Kaletra (lopinavir) was based, in part, on a 57-
person uncontrolled trial in protease-inhibitor-experienced
individuals. The trial, which correlated response to a
Kaletra-containing regimen with baseline tests of protease-
inhibitor resistance, provided valuable information about
the drug in treatment-experienced patients. Still, it was
not without its limitations. (See "Doctors Hesitate on
Kaletra," TREATMENT INSIDER, January 2001,
http://199.105.91.6/treatment/hiv+/january.pdf ). In order
to enroll, patients had to be NNRTI-naive. What the results
showed, therefore, is that treatment-experienced patients
responded well to a regimen containing Kaletra and another
drug, the NNRTI Sustiva (efavirenz). Abbott maintains that
the improvement in viral control was due to Kaletra, but it
can support this claim only with the indirect evidence
linking the extent of resistance to Kaletra with lack of
response.

Arranged Marriages

Drug companies may be less enthusiastic about a planned FDA
recommendation for co-sponsorship of experimental agents.
Rather than having each company compete separately, the FDA
will support drug companies testing two or more new agents
at once. This would provide information about how drugs
worked as part of a combination, rather than individually.
It could, theoretically, lead to approval of both drugs
with the requirement that they be used together. Jim Rooney
of Gilead Sciences testified at the FDA meeting as a
representative of the Inter-Company Collaboration (ICC), a
trade group that seeks to promote joint trials that combine
drugs from several companies. In an interview, he argued
that this type of cooperation could work for companies, "as
long as the indication could be modified later based on
data from additional studies in different patient
populations with different combinations, etc."

It may take more than a polite request from the FDA to get
companies to break the mold of competitive research. "I
can't say what kind of incentive could be provided [to
companies who collaborate] beyond saving on patient
resources," said the FDA's Jeff Murray. To date, there have
been no significant jointly sponsored trials of new agents,
even to determine how the drugs affect each other's
metabolic elimination. Gilead and Trimeris have taken steps
to include each other's experimental drugs, tenofovir and
T-20, respectively, in ongoing efficacy trials. Trial
participants are allowed to include the experimental drugs
in their background regimens. This could be important for
individuals deciding whether to take a single new agent or
wait until a better combination becomes available. But
having the option to take one experimental drug while in
trial for another will not provide valuable data about how
the two work as a strategy.

Activists and treatment advocates are ready to flex their
muscles to see relevant salvage therapy trials become a
reality. "If the FDA is enthusiastic, the community is
enthusiastic, and the researchers' only concern is that we
may not be able to persuade the drug companies [to
collaborate], I think we may have a chance," says Yvette
Delph, Antiviral Project Director of TAG. "I think the FDA
has far more persuasive power than it has been willing to
wield."

Futuristic Designs

Traditional trial designs work like simple addition
problems: experimental drug W is added to an approved
combination X+Y+Z. At the end of the trial, there is data
on whether X+Y+Z plus W works better than X+Y+Z alone. The
next, hotly debated generation of trials will be more akin
to multiplication. One model, which received considerable
support at the FDA meeting, was the "modified factorial
design." This type of trial is conceived in manner similar
to a multiplication table, with particular drugs rather
than numbers heading individual rows and columns. Each
multiple -- in this case a combination of drugs -- occupies
a different "cell," whose composition is determined by the
intersecting rows and columns.

The advantage of this design is that it allows several new
drugs to be tested in a single trial. Such a trial might
place all participants on optimized background therapy and
then randomly assign them to different cells, each of which
contains at least one, and possibly more experimental
drugs. The results from each of the cells could then be
compared to identify the most effective combinations.

There are drawbacks to this design. FDA advisory committee
member John Mellors (University of Pittsburgh) pointed out
that such trials will have to be quite large, to ensure
that there are enough people in each cell for meaningful
statistical comparisons. In addition, not all cells are
created equal. While each participant gets at least one new
drug, he or she may be deprived of the most promising
combinations. Modified factorial design could also lead to
a tangle of data on side effects, in which it might be
difficult to clearly assign blame.

These and other criticisms notwithstanding, the FDA used
the meeting to re-emphasize its support of modified
factorial trials as part of approval packages. Dr. Jolson
reminded attendees of a 1999 letter to industry indicating
support for this approach.

Fast Approval, Plus Long-Term Followup

For some patients with no treatment options, time is of the
essence. Although the FDA guidance document will not
include a clear statement about the appropriate length of
salvage therapy trials, Murray said that the FDA could
accept as little as 16 weeks of data on evaluating salvage
therapy safety and efficacy. At present, 24 weeks of data
is the standard minimum. Researchers support this slimmed-
down timeframe. "I'd vote for it one hundred percent," said
Dr. Michael Saag (University of Alabama at Birmingham), who
spoke at the FDA meeting. "Yes, it's taking a risk to
release a potentially toxic medication for which we don't
have a safety profile beforehand, but how does that
toxicity look to a patient who is going to die [without the
drug]."

In this scenario, drug approval will not hinge on 16-week
data alone. However, 24- and 48-week safety and efficacy
information might be gathered in a separate trial, perhaps
in a less pretreated population. "We often let companies
submit under earlier data and then update during the review
[process] anyway," said Murray. A TAG discussion paper
agrees that 16-week data could be used for "possible
submission for accelerated approval" but underscores that
"safety issues mandate the continuation of such studies up
to 48 weeks and beyond (after approval)."

The move to accept shorter trials comes as the consequences
from the first round of rapid approvals are becoming
painfully clear. All of today's antiretrovirals earned
approval with unprecedented speed, via the FDA's
"accelerated" approval process. Today, long-term
toxicities, such as lipodystrophy and bone disease, are
emerging. These toxicities were not apparent in the trials
conducted for approval of the drugs. Even one- to two-year
studies did not begin to show how common, or severe, these
problems would become.

To Saag and others, this long-term data is the crux of the
issue, not the eight weeks lopped off of a 24-week trial.
Here again, the FDA's power to change the industry is
limited. Its actual tactics are limited to the extreme step
of removing a drug from the market and the rather mild
threat of changing the wording of a drug's official package
insert. Accelerated approval is conditional, and can be
revoked if a company does not fulfill its post-approval
commitments to long-term follow-up and monitoring. Still,
many companies have altogether failed to make good on
promises of Phase IV post-marketing studies.

In the face of this patchy record of long-term HAART use,
there is a growing call for new data collection systems to
fill in the blanks. One possibility is to establish well-
coordinated databases that track adverse events and side
effects in all patients on approved therapies. "What may be
useful is to have more prospective cohorts that are
monitoring everyone [for toxic events]," said Yvette Delph.
As the list of long-term toxicities grows, it may be
increasingly difficult for the drug industry to sidestep
its obligations to help create such collection systems.

The salvage therapy arena has become an important one for
all parties concerned. Patients on failing therapy are
looking for rapid rescue. And drug companies are looking
for rapid testing and marketing of their products.
Meanwhile, the case for accelerated review of first-line
therapies is waning, now that the FDA has approved 14 anti-
HIV agents. The agency now is looking at how to meet the
unmet needs in HIV with all deliberate speed.

Salvage therapy is chief among such needs, and community,
industry and government have some convergence of interest
in demonstrating new drugs' efficacy in this setting.
Still, problems with determining individual agents'
contribution to combination regimens as well as the agents'
long-term effects may yet undermine the efforts at
cooperation evinced at the January meeting.

[This article was first published on the AmFAR Web site,
http://199.105.91.6/treatment/insider/salvage1.html
but has not previously appeared in print.]


***** AIDSWatch May 5-8: Visit Your Representatives in
Washington

This year is the 10th annual AIDSWatch, which brings
hundreds of people to Washington to help educate their
Senators and Representative on AIDS issues. AIDSWatch this
year will address funding for HIV prevention, AIDS
research, care and treatment (including ADAP and other Ryan
White programs), housing, substance abuse and mental
health, and international efforts. AIDSWatch is coordinated
by the National Association of People with AIDS, and
supported by over 175 national and regional AIDS
organizations.

AIDSWatch is particularly important at this time because
there is a new Administration, and many new members of
Congress who may not be familiar with AIDS programs and
their importance to constituents.

There is no fee to participate in AIDSWatch, but you need
to register by April 20, and pay your own travel and
expenses. On Saturday May 5 and Sunday May 6 training
sessions will familiarize participants with the issues, and
with how Congress works. On May 7 and 8 there will be a
rally at the Capitol, scheduled meetings with members of
Congress and their staffs, and an evening reception for
participants and members of Congress.

There are eight official AIDSWatch hotels, all near Dupont
Circle. They require early registration to get the
negotiated meeting rates.

For more information see
http://www.napwa.org/aidswatc.htm , or contact NAPWA
(National Association of People with AIDS), 1413 K St. NW,
7th floor, Washington D.C. 20005, 202-898-0414 ext. 124,
fax 202-898-0435.


***** AmFAR HIV/AIDS Treatment Directory Available

The 300-page HIV/AIDS TREATMENT DIRECTORY (volume 11,
number 1, winter 2001), is available without charge from
AmFAR (the American Foundation for AIDS Research) in New
York.

Major sections include:

* treatments for HIV infection (listed alphabetically
within each of three categories, FDA-approved drugs,
experimental agents, and immune-based therapies);

* treatments and treatment results for opportunistic
infections;

* articles on current issues: "Muscle, Fat, and HIV,"
"Nucleoside Analog Toxicity," and two articles on treatment
in Uganda, and in a separate section, "The Shifting Pattern
of Opportunistic Illness";

* actively recruiting clinical trials;

* the U.S. treatment guidelines for adults and adolescents,
pediatric guidelines, and guidelines on prevention of
opportunistic infections. [The adult guidelines were
recently changed, after this edition of the directory had
gone to press. So the adult guidelines, pages 91-103 of
volume 11 number 1, are not current and should not be used;
the current guidelines are available at
http://www.hivatis.org or by mail from HIV/AIDS Treatment
Information Service, P.O. Box 6303, Rockville, MD 20849-
6303. A new edition of the treatment directory with the
current guidelines should be published around June 2001.]

* information on understanding your lab results;

* a directory of state ADAP (AIDS Drug Assistance Program)
phone numbers;

* a directory of pharmaceutical company patient assistance
programs;

* an index to manufacturers, arranged alphabetically by
drug name;

* newsletters and other treatment information resources;
and

* the "HIV Experimental Vaccine Directory."

You can obtain a printed copy of the HIV/AIDS TREATMENT
DIRECTORY from American Foundation for AIDS Research, 120
Wall St., 13th Floor, New York, NY 10005, phone 212-806-
1600, or email txdir@.... An online version of the
directory is available at http://www.amfar.org/td


***** AIDS TREATMENT NEWS Publication Schedule

AIDS TREATMENT NEWS is usually published on the first and
third Friday of each month. This month we are behind, and
this issue, the first in March, actually went to the
printer on March 29.

To avoid confusion in the future, we want to maintain our
schedule of two issues each month. This month, to make the
publication dates more realistic, we are dating the issues
on the last two Fridays (March 23 and March 30), instead of
the first and third Fridays.

We expect to catch up in April, and resume our regular
publication schedule.


***** AIDS TREATMENT NEWS

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email: aidsnews@...
useful AIDS links: http://www.aidsnews.org

Editor and Publisher: John S. James
Associate Editor: Tadd T. Tobias

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 that work for
them. AIDS TREATMENT NEWS does not recommend particular
therapies, but seeks to increase the options available.

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ISSN # 1052-4207

Copyright 2001 by John S. James. Permission granted for
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