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Past Issues
Volume 17, number 12
December 2003
The Work Begins
New issues driving activism
SAVE ADAP Campaign
New actions announced
Open Letter To Abbot:
"Roll back the Norvir price hike!"
T-1249 Trial Suspended
Formulation woes blamed
Gene Therapy
The ultimate fusion blocker?
Advocacy Essentials
Ask for what you need
Eastern Exposure
AIDS advocacy in Russia
Out of the Lab
A new target and a new agent from Gilead
We've Got the Power
But what's the point?
Groundswell
Gary Karch reports from the wilderness
Advocacy in America
By Bob Huff
2003 was a year of abundance — as far as new HIV drug approvals go.
Five new drugs entered the marketplace — making a total of 21 approved
antiretrovirals in the U.S. — and a consensus is forming about which
among the bewildering number of potential combinations are safe and reliable
— and which should be avoided. Yet despite the best of care with all
of our medicines and strategies, people continued to fall to AIDS last year
— including several good friends of this publication. Meanwhile,
around the world, the first fledgling steps were taken to place just a few
of these drugs into the hands of millions of people with HIV who do not know
abundance. The magnitude of this effort will transform whole societies,
hopefully including our own here in the States. Although there is no cure
and still no vaccine, our increasing knowledge about the virus and our
bodies justifies hope: that, as long as the will to vanquish AIDS remains
strong, living with HIV will one day be easier than it is today.
But is that will durable?
Perhaps it's inevitable that after a year of abundance some bad news
would turn up. At the end of 2003 two events sent signals that there
might be stumbling blocks on the road to a new era of trouble-free
treatments. First, in early December, Abbott Laboratories, the makers
of Kaletra, announced that they were dramatically raising the price of
their other HIV drug, Norvir. Then Roche and Trimeris announced that
further development of T-1249, the successor to their fusion inhibitor,
Fuzeon, was being curtailed. These events come in the context of
continued shortfalls in government support for AIDS services and treatment
programs, ever rising drug costs and insurance premiums, and a faltering
political will to pay for just and equitable health care. In response to
fears of a coming era of scarcity — of services, care and research
— a slumbering AIDS activist movement has awakened and begun to
lobby Congress and the drug companies from the frontlines of the fight
against HIV. Enabled by the Internet, local groups from around the
country are increasingly speaking out on a national level to provide
ideas, energy and leadership in an unprecedented groundswell of activity.
Norvir More
Norvir had never been very successful on its own as a therapy, and most
people who took it as a liquid in the early days still remember its foul
taste. But Norvir (ritonavir) had an interesting side effect that gave
it a new life: it was unsurpassed at increasing the blood levels of
certain other drugs, and only a tiny amount was necessary to do the job.
In fact Abbott's follow-up to Norvir, the protease inhibitor lopinavir,
depends on ritonavir to give it a boost in the bloodstream — the
combination of the two is called Kaletra. But Norvir could boost drugs
from other manufacturers as well, including two of 2003's new protease
inhibitors (PIs), Reyataz, from Bristol-Myers Squibb and Lexiva, from
GlaxoSmithKline, and it has given new life to some drugs from the first
wave of PIs, such as saquinavir and indinavir.
Someone at Abbott no doubt looked at this situation and noted that
they were selling a drug for pennies a day that enabled all of these
competitors to make gains in the marketplace at their expense. Particularly
threatening to Abbott must have been the arrival of Reyataz, a drug
that, when boosted, is as potent as Kaletra, without any of the
tendency to raise blood lipids to worrisome levels. So Norvir got
its own boost: from $4.28 a day to $21.44 for a typical add-on dose,
priced, in the words of the company, "to reflect its value."
This 400 percent increase sent a shock wave through the HIV treatment
community and almost immediately stimulated a surge of activism at local,
national and international levels. Activists first confronted Abbott
community reps at the NATAF conference of treatment advocates in Phoenix.
In the days that followed, doctors in England (not even affected by the
price change) started calling for a boycott of Abbott products and speaking
fees. Doctors in the U.S. pledged to turn away Abbott salespeople. The
Desert AIDS Project in Palm Springs was the first local AIDS organization
to issue a statement denouncing the move. The increasingly vocal HIV
professional organizations, HIV Medical Association (HIVMA) and American
Academy of HIV Medicine (AAHIVM), each issued strong letters of criticism.
The national AIDS Treatment Activists Coalition (ATAC) began circulating
press releases and building media interest. Reports in the Wall St. Journal,
Washington Post and Seattle Times followed. As the new year begins the
groundswell of anti-Abbott activity does not seem to be abating.
ADAP Action
While the price increase may pose no immediate threat to already cash-strapped
state AIDS Drug Assistance (ADAP) programs or to Medicaid, which have locked-in
prices for Norvir that should hold until 2005, ADAP program directors and
watchdogs are concerned that a 400 percent price increase by one company will
signal open season on pricing for the rest of the industry. With government
AIDS funding falling far short of current, not to mention anticipated needs,
the carefully constructed safety net systems for vulnerable people who need
HIV therapy is in danger of failing. The past year has seen a resurgence of
grassroots activism working on these issues, both on the state and national
levels, with the SAVE ADAP Committee of ATAC leading the way. In an election
year, this effort is set to scale up to a new level of intensity, with
individuals from states that have already put people on wait lists for
treatment heading to Congress to tell their stories. Some of the first
groups to sign on to the lobby effort have been the AIDS Alliance of Northwest
Georgia, the Eastern Triad HIV Consortium of North Carolina and Tennessee AIDS
Support Services. In response to these challenges, it is encouraging that the
grassroots seem to be coming alive, putting a much needed renaissance of AIDS
activism into motion.
Abbott Bashes Back
Abbott's reaction to the protest has been as clumsy as the price hike. Thomas
Gegeny, executive director of Houston-based The Center for AIDS, which had
publicly criticized Abbott, reported to an email discussion list that an HIV
community representative from the company contacted him and suggested they
needed to "discuss" their relationship, implying that future financial support
from Abbott for the Center's educational projects was in jeopardy. Unrestricted
educational grants from pharmaceutical companies are commonly given to local
AIDS organizations to fund treatment education and adherence counseling. They
are called unrestricted because the companies have no direct control over
the content or the materials used in the programs. Gegeny said he later received
a visit from another Abbott representative who told him "the only people who
seem to have a problem with the price increase were 'gay, white, long-time
survivors' and the doctors who treat them — not the minority-based
groups."
AIDS activist Jen Curry recognized this as a crude form of damage control:
"This is a classic divide and conquer tactic. The comment manages to insult
everyone — somehow placing elitism and classism at the feet of people
with AIDS, rather than on Abbott itself. It renders invisible all the women
and people of color who are furious at Abbott."
The Center for AIDS has issued an open letter stating it "will not accept
funding from Abbott for any of our community educational forums, publications,
etc., on account of the irresponsible and unwarranted increase in the price
of Norvir."
Retreat on Research?
The Abbott price hike also sends a chilling message to the sponsors of
experimental drugs in the pipeline. For example, tipranavir, from Boehringer
Ingelheim, is a protease inhibitor that will depend on Norvir to achieve
proper blood levels. Thousands of people are in need of tipranavir's ability
to suppress HIV that has become resistant to the approved PIs. The new Norvir
price threatens to put the price of a tipranavir regimen in a range to rival
the most expensive AIDS drug yet, Fuzeon, from Roche/Trimeris, which also
entered the market last year at a price of over $20,000 a year. Abbott's
move also came just before the FDA approved an application by Roche for
ritonavir-boosted Invirase. A new 500mg formulation of Invirase soon to
be released promised to resurrect this overlooked first generation PI. Now,
with the Norvir price hike, the price of this interesting combination will
effectively double.
There is much concern that new, needed drugs that can combat resistant
virus or that are safer than Kaletra, will be abandoned, due to their
dependence on Norvir. Why take a risk of entering the market when Abbott
can destroy your product with a new price jump?
Some have drawn a parallel between this situation and the case of
anti-competitive behavior that was brought against Microsoft over its
bundling of a web browser within its Windows product. Already letters
have been sent to several states' attorneys general asking them to look
into Abbott's behavior. Indeed, Abbott is currently the subject of
lawsuits by the federal and several state governments involving price
fixing. Attorney General Ben Chandler of Kentucky is pursuing an action
claiming that Abbott manipulated the Average Wholesale Price (AWP) to
squeeze higher prices out of Medicaid and Medicare by "knowingly,
willfully and intentionally (providing) false and inflated AWP and
other pricing information" for their drugs. According to Associated
Press, "Chandler said his prosecutors believe pharmaceutical companies
have been setting the price 'just wherever they want to set it.' He
said consumers feel the effect through the loss of tax dollars and,
in the case of Medicare recipients, through excessive prescription
co-payments."
Detour for Trimeris
The price of Fuzeon was a shock when it was announced last year despite
explanations that it was the first of a new class of HIV drugs called
entry inhibitors, and a drug that was extraordinarily difficult to
manufacture. Amid much acclaim, Fuzeon received its approval in the
spring of 2003, but acceptance by doctors and patients since then has
been disappointing and sales have lagged. As the first example of a
new technology, Fuzeon was never expected to be perfect, and the HIV
treatment community was looking forward to the arrival of a
next-in-line drug from Trimeris, code-named T-1249 (Fuzeon had been
T-20). T-1249 promised a few improvements over its older sibling,
mainly once-a-day injection instead of twice daily, and a resistance
profile that could rescue people who with virus that had become
resistant to Fuzeon.
There was sadness but no real surprise when Roche/Trimeris
announced just after the new year that the one ongoing clinical
trial of T-1249 was being halted due to emerging uncertainties
over its formulation and manufacturing profile. Trimeris and Roche
say that they are not abandoning AIDS but rather retreating to look
for better ways to administer peptide-based fusion inhibitors. If
they can come up with a drug that only requires one shot a week, no
mixing and no refrigeration — all at a reasonable price, most
observers think the outlook for these drugs would brighten
considerably. But any such step forward is still years away.
Looking Ahead
If all this seems gloomy, it might be worth imagining what treatment might
be like in the year 2010. There are oral entry inhibitors now in early
clinical trials that, if and when they achieve approval, might bring big
improvements in tolerability and strength. Since entry inhibitors work
on the outside of cells, they are not expected to cause the sort of
toxicities that the current generation of drugs do. Also, since they keep
cells from becoming infected there may be immunological benefits to increasing
the pool of uninfected cells. Protease inhibitors, while effective at
reducing viral load, only work on cells that have already been infected.
Also, there are reports of some experimental drugs with such long half-lives
that they may only need to be taken once a week. Short of a cure, an ideal
regimen might keep HIV completely suppressed, preserve uninfected T-cells,
be easy to take, have no long-term side effects, and cost little more than
cable TV. This is all speculation, of course, but one can hope — and
work to make it a reality.
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Join Us For The ADAP Emergency
Supplemental Campaign!
The SAVE ADAP Committee of the AIDS Treatment Activists Coalition thanks
everyone who worked hard this past year advocating for adequate funding
for the AIDS Drug Assistance Program. While we have fallen far short
of getting the money needed, we have succeeded in educating Congress about the
importance of this lifesaving program. Your calls, letters, emails, and meetings
with your elected officials have played a major role in this success.
Below is an update on the current status of ADAP appropriations and
information about our upcoming advocacy campaign aimed at getting an emergency
supplemental to help relieve the current ADAP crisis. We hope that you will
continue to join us in this fight and that you will encourage
others to do the same. This is an election year, which means that many
legislators are more accessible to their constituents. We must take advantage
of this by making 2004 a year of massive grassroots advocacy focused on
demanding the funds needed to ensure access to treatment for everyone who
needs it.
Thank you again for all your hard work. Please look for Alerts in the coming
weeks with more details on how you can get involved. To make sure you receive
these Alerts, send an email to
saveadap@hotmail.com
with "subscribe" in the subject field.
Update on Fiscal Year 2004 Appropriations:
Congress has yet to complete work on the Fiscal Year 2004 appropriations bill.
Because the fiscal year began on October 1, 2003, Congress has passed a series
of "continuing resolutions" to keep programs funded until it can pass a final
bill.
It does not look like ADAP will get an adequate increase in the FY '04
appropriations bill, however. The joint House/Senate conference committee
approved a $35 million increase, far short of the $215 million identified
as needed to alleviate the ADAP crisis. The full House of Representatives
approved this recommendation by the conference committee, and the Senate
is expected to vote shortly.
Because ADAP is likely to receive such an inadequate increase, SAVE ADAP
is focusing immediately on a campaign to ask for an emergency
supplemental appropriation of $180 million. This means that we are
asking the Bush Administration and Congress to pass a bill authorizing the
immediate spending of an additional $180 million for ADAP for the current
fiscal year. This could happen as a separate bill, or more likely as an
amendment to another emergency supplemental bill.
The Emergency Supplemental Campaign:
The SAVE ADAP emergency supplemental campaign has begun and there are several
ways you can get involved. Below are some of the activities.
Week of January 12: "ADAP Emergency Visibility Week." Members of Congress
were called this week to demand an emergency supplemental for ADAP. Congress
needs to hear from us that its lack of leadership is resulting in waiting
lists and other restrictions to treatment access. We also started circulating
an organizational sign-on letter urging the Bush Administration and Congress
to provide an emergency supplemental.
Our goal is to obtain 1,000 organizational signatures
on this letter by urging local ASO, clinics, etc. to add their
names. Contact your local AIDS organization and urge them
to sign.
Week of January 19: "Pill Bottle campaign."
SAVE ADAP will mail an empty pill bottle to each Member of
Congress with a message inside demanding an emergency supplemental.
Everyone is encouraged to participate in this campaign by
sending their own empty bottles with a personal message inside
once a month to their elected officials.
Look for more details in upcoming Alerts.
February 23–25: SAVE ADAP Lobby Day.
Members and supporters of SAVE ADAP and other advocates will
go to Washington, D.C., to meet with Representatives
and Senators to identify champions for an ADAP emergency supplemental.
Scholarships for this event are available, with priority going
to ADAP clients, people on ADAP waiting lists, women, people
of color, PWA/HIVs, and frontline service providers living
in one of the following ADAP crisis states (Alabama,
Alaska, Arkansas, Colorado, Idaho, Indiana, Kentucky, Montana,
Nebraska, New Hampshire, New Mexico, North Carolina, Oklahoma,
Oregon, South Dakota, Texas, Washington, West Virginia, Wyoming).
To receive a scholarship application, contact Lei Chou at
theaccessproject@aol.com.
These are just a few of the activities that you can participate in
to make 2004 the year that Congress decides to show leadership and
fund ADAP at an adequate level. Please take a few minutes
to read over our Alerts in the coming weeks and help us make a difference!
The SAVE ADAP Committee is a Working Group of the AIDS
Treatment Activists Coalition (ATAC), a national coalition
of AIDS treatment activists and policy advocates. Working
in conjunction with ADAP clients and service providers on
the grassroots level, Save ADAP aims to ensure adequate funding
for the AIDS Drug Assistance Program. For more information,
go to www.atac-usa.org/adap.html,
or email Ryan Clary at rclary@projectinform.org
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Open Letter from ATAC
to Abbott's CEO, Miles White
Dear Mr. White:
A recent action by your company has shaken the HIV/AIDS community to its
very core, threatening to transform and erode a productive relationship that
has evolved between us in combatting this epidemic. The AIDS Treatment Activists
Coalition (ATAC) is a national coalition of AIDS activists, many living with
HIV/AIDS, working together to end the AIDS epidemic by advancing research on
HIV/AIDS. We recently became aware of a price increase of greater than 400%
for Abbott's protease inhibitor ritonavir (Norvir). This price increase may
well have been the result of overly eager marketing and sales personnel seeing
and seizing an opportunity without considering the absolutely appalling
effects this move would have on public perception and community/consumer
relations.
As you know, Norvir was granted accelerated approval by the U.S. Food
and Drug Administration, based on its encouraging performance in clinical
trials evaluating its effects on both surrogate and clinical markers. When
used at the approved therapeutic dose (600 mg BID), it is associated with
significant toxicities and side effects that render it intolerable for many
HIV-positive individuals. However, the drug has enjoyed continued and growing
use, albeit at smaller doses, as a pharmacokinetic (PK) booster for other,
more tolerable protease inhibitors by inhibiting the CYP3A4 hepatic enzymes,
which metabolize other drugs. In fact, Norvir-boosted protease inhibitor
therapy has created a novel therapeutic approach for achieving more potent
antiretroviral efficacy, especially in patients with fewer treatment options,
such as "salvage" therapy patients who harbor resistance to several or many
HIV drugs. Consider the example of an investigational protease inhibitor,
tipranavir, being developed by Boehringer Ingelheim, which has activity
against resistant virus but which will also require boosting with up to
400 mg.of Norvir.
Surprisingly, the price of another Abbott drug, Kaletra (itself a
Norvir-boosted protease inhibitor) has stayed the same, providing an
unquestionable economic advantage to choosing Kaletra over other boosted
protease inhibitor regimens (such as the recently approved drugs Reyataz
and Lexiva), which may now as much as double in price. The price of boosted
tipranavir, if approved, could now be around the price of Fuzeon, the most
expensive antiretroviral drug ever developed (around $20,000/year). Does
this seem like a rational direction for protease inhibitor-based therapy?
Instead of being grateful that Norvir still has therapeutic application
and will enjoy continued sales, Abbott has apparently made an ultimatum
that salvage patients who need new therapeutic options, or even those who
just need more potent therapy (arguably any patient with HIV), will pay,
and pay dearly. Unless, of course, doctors and patients choose Kaletra,
which, as mentioned above, has not increased in price and will be cheaper
than other boosted options.
Unfortunately, one drug regimen does not fit all, and many patients
can benefit virologically or metabolically from drugs other than Kaletra.
We appreciate the need to remain profitable, especially in uncertain
economic times, but this price increase goes far beyond what is reasonable
or necessary. No amount of research and development justifies this type
of increase for this type of drug, especially when research to improve
Norvir will also extend its patent life. We understand Abbott's preemptive
move to ease restrictions on its Patient Assistance Program for Norvir.
We know that prices for AIDS Drug Assistance Programs (ADAP) will not be
affected until renegotiation in 2005. However, we cannot accept this
unprecedented opportunism in the face of dwindling resources and growing
numbers of HIV infections.
What Abbott has done will negatively affect healthcare resource
allocations (public and private), drug research and development, and
patient care and well-being for decades to come.
Abbott has just changed the landscape of HIV/AIDS for the worse. Is
this what it wants to be known for? ATAC urges Abbott to reconsider its
recent actions and to rejoin the battle against HIV/AIDS by advancing
research and therapeutics until this scourge against humanity is conquered.
Further, we challenge you to roll back the price of Norvir. Abbott has
obviously regained its development costs many times over with this drug,
which received full approval on the basis of a minimal development
package and without an Expanded Access Program.
We believe that it is in the overall best interest of your company to
reconsider this shameful and destructive path. We look forward to learning
that you have reversed this inhumane decision as soon as possible.
Very truly yours,
Lynda Dee & Matt Sharp, Co-Chairs
Drug Development Committee
AIDS Treatment Activists Coalition (ATAC)
Call Miles White and tell him what you think: (847) 937-6100
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T-1249 Development Suspended
By Bob Huff
As the New Year began, Roche and Trimeris announced that they had decided
to halt further development of their experimental entry inhibitor, T-1249. The
drug was a follow-on to T-20 (enfuvirtide, Fuzeon), the first-of-its-kind fusion
inhibitor that received FDA marketing approval in March of 2003. Since then,
and despite high expectations, sales of T-20 have been disappointing due to
its steep price and difficulty of administration. The $20,000-a-year drug
must be injected under the skin two times a day. Some patients begin taking
Fuzeon, then stop after a month or two due to fatigue with preparing and
administering the drug. Yet many others adapt to the routine without difficulty
and enjoy sustained results; there seems to be no argument about the ability
of Fuzeon to suppress HIV for those willing to stick with it.
T-1249 was the subject of high expectations because it was said to only
require one shot per day and because it retained activity against virus that
had become resistant to T-20. Trimeris now says that T-1249 has problems
with its formulation that make once daily dosing unlikely.
Another factor that may have contributed to the decision is the progress
being shown by several orally available entry inhibitors now in early clinical
trials. Both Schering and Bristol-Myers Squibb have drug candidates in this
class that could reach the market before 2008.
Just three years ago, T-1249 was said to be only about two years behind
T-20 in the development pipeline. As the push to approve T-20 heated up,
this timeline was extended. Now, after six months of lackluster Fuzeon sales
it appears that T-1249, at least in its current form, is finished.
Trimeris says it has decided to address the drug's administration handicap
before moving on. One line of research will try to find ways to extend the
life of T-1249 and other peptide-based entry inhibitors within the body,
possibly by protecting the peptide with molecules that withstand metabolism,
such as polyethylene glycol or albumen. The companies have also signaled
their intention to develop new drugs in the class. News of the cancelled
T-1249 program was coupled with an announcement of a research agreement
to "discover, develop and commercialize the next generation of HIV fusion
inhibitors."
The companies have pledged in a press release that the 40 or so patients
currently receiving T-1249 in a clinical trial will be assured continued
access to the drug. It is not yet clear, however, how long this supply will
be guaranteed after the date when the cancelled trial was scheduled to end.
Out of luck will be those patients who are currently taking T-20 and may
be developing resistance; they can no longer look forward to T-1249 for
salvage.
Both T-20 and T-1249 are chains of amino acids called peptides. The
peptides are matched to complementary parts of the HIV protein responsible
for pulling the virus into contact with a target cell. The viral protein,
called gp41, is attached to another protein called gp120, which becomes
embedded into the surface of its target. As gp41 folds back upon itself,
the lipid membranes of the virus and cell are brought into proximity where
they begin to mix. When enough of the two surfaces are in contact, a pore
opens between the virus and the cell and widens until they become one, a
process called fusion. Both T-20 and T-1249 jam gp41's folding mechanism,
which effectively blocks fusion.
While T-20 and T-1249 bind to certain overlapping regions of gp41,
T-1249 also binds to parts of the protein beyond the reach of T-20. It
has been shown in clinical trials that HIV that has become resistant to
T-20 will retain susceptibility to T-1249.
The approval of T-20 was one of the bright spots in HIV therapeutics
last year. It was the first drug of a novel class and promised a respite
to the growing number of people who have run out of treatment options
among the conventional classes of drugs. Its discovery and development
over the past 10 years has been an inspirational story of a small company
pressing forward with a novel ideal against formidable obstacles. The news
that further development of T-1249 has been curtailed is disappointing.
Gene Genie
Can Gene Therapy Deliver a Better Fusion Blocker?
By Bob Huff
If the daily grind of subcutaneous injection of T-20 (Fuzeon) has got you
down, why not let your T-cells make their own — with gene therapy?
Dorothee von Laer and Marc Egelhofer from Georg-Speyer-Haus in Germany and
colleagues recently reported on progress in constructing a vehicle for an
artificial gene called C36 that produces a peptide with the same fusion-blocking
sequence of T-20 (Fuzeon). The idea is to inject the gene, deliver it to blood
cells, and let the cells manufacture a new protective weapon against HIV to
place on their outer envelopes.
So far, the field of gene therapy has been beset by false starts and a few
tragic incidents, which have left scientists understandably wary about inserting
foreign genetic material into people. After all, HIV itself is nothing more
than a collection of alien genes that hijack normal cellular activity in order
to propagate and multiply; immunological havoc is the result. But von Laer's
group has engineered an elegant bit of genetic trickery that not only blocks
HIV before it can get its foot in the door, but is carefully designed to
minimize unwanted side effects.
Other projects are investigating gene therapies to treat HIV by blocking
the expression of viral proteins such as tat. But these approaches would only
be able to minimize viral activity after a cell had already become infected.
Mathematical models suggest that such downstream gene therapy strategies
would cause the proportion of HIV infected cells in the body to steadily
increase. Lead author Egelhofer cautions that, as the number of cells harboring
integrated HIV provirus grows, the burden of controlling viral expression would
become overwhelming. But a fusion-blocking gene therapy that worked upstream
of infection would preserve uninfected cells, thereby increasing their
proportion.
The idea is to attach the 36 amino acid peptide to a hinged transmembrane
protein that would allow it to reside on the surface of a target cell. If an
HIV virion attaches to the cell and begins the process of bringing its lipid
envelope into contact with the cell's membrane, the C36 peptide would jam the
gp41 mechanism that mediates fusion — exactly as T-20 does. The advantage
is that, rather than injecting the peptide into the body in sufficient
concentrations to achieve a high rate of blocked infections, the peptides will
be assembled inside target cells then exported to the cells' surface, precisely
where they are needed.
The genes that code for the production of C36, the hinge and other
supporting members, are cleverly delivered to the cell by a retroviral
vector that gains entry by attaching to cells bearing the CD34 cell surface
protein. Once inside, the vector deposits its genetic cargo, which is then
shipped to a protein processing factory in the cytoplasm. The finished gene
product is delivered back to the cell surface and implanted in the membrane,
where it is free to move about and interact with any encroaching gp41s.
After an initial demonstration of the concept with a construct that
inhibited infection in a limited set of cell types, van Laer and colleagues
have now created an optimized version of the therapy that works in a broader
range of primary cells and HIV isolates. The design improvements are also
intended to minimize the potential for unwanted immunogenicity. Animal
toxicity studies of the vector, called M87oRRE, have been successfully
conducted and plans for first human testing are now being made.
As with any HIV therapy, the emergence of resistance is a concern,
especially since resistance to the C36 peptide of T-20 is known to occur
clinically. But the scientists found that by extending the length of the
peptide with 10 additional amino acids, the resulting C46 peptide was
active against C36-resistant isolates, and may be inherently less prone
to developing resistance, since the elongation covers a highly conserved
region of the gp41 fusion protein missed by C36.
Although still in very early stages, and yet to be tested in humans,
this simple and elegant approach to gene therapy to prevent HIV entry
into uninfected cells holds exciting prospects.
This report was an update of a poster presented at the 10th Annual
Retrovirus Conference (CROI) in 2003. Hopefully new progress will be
reported at the upcoming conference in San Francisco.
Egelhofer M, Brandenburg G, Martinius H, et al. Inhibition of
Human Immunodeficiency Virus Type 1 entry in cells expressing gp41-derived
peptides. Journal of Virology, Jan. 2004, p 568-575.
vanLunzen J, Brandenburg G, Baum C, et al. A comprehensive
approach to gene therapy of HIV infection. Abstract 230. 10th Conference
on Retroviruses and Opportunistic Infections, Boston, 2003.
Learning to Ask for What You Need
By Gregg Gonsalves
"If there is no struggle there is no progress," said the great American
abolitionist leader Frederick Douglass. "Those who profess to favor
freedom and yet depreciate agitation, are men whoÉwant the ocean without
the awful roar of its many waters." The history of the AIDS epidemic
underscores Douglass' contention: People living with HIV/AIDS have never
gotten anything without asking for it. Most of the programs that serve
the needs of communities affected by HIV/AIDS and ensure their human
rights were the result of community mobilization and agitation. Whether
we are gay men and drug users in the United States, heterosexual men and
women in South Africa, or sex workers in India, most of the advances in
our lives have come from going to our leaders and demanding change.
The HIV epidemic in Central and Eastern Europe and the former Soviet
Union (CEE/fSU) is the fastest growing epidemic in the world. People
with HIV — most particularly the injection drug users who make up
more than 80 percent of all reported HIV cases in the region — face
rampant and severe stigma. Harm reduction services are usually not supported
by local or national government. Treatment advocacy efforts are virtually
unknown in many countries in the region.
Changes in the lives of drug users and people with HIV in CEE/fSU will
not come without concerted local advocacy efforts. Yet the kind of activism
that has worked to shift AIDS policies elsewhere in the world is largely
lacking in the region.
In response to this dearth of activism, in 2002, the International Harm
Reduction Development (IHRD) Program of the Open Society Institute and Gay
Men's Health Crisis (GMHC) established a fellowship at GMHC in New York City
for people from CEE/fSU. The program is supported by IHRD and the John M.
Lloyd Foundation.
The program's goal is to ensure that fellows learn the skills they need
to change the policies of governments and private institutions, such as
pharmaceutical companies and employers, so that they best serve people living
with HIV. The program also brings increased visibility in the United States
and elsewhere to the epidemic in CEE/fSU.
The six-week program in civic engagement is based in GMHC's public policy
and advocacy department and exposes fellows to GMHC departments that provide
direct services to people with HIV, such as substance abuse counseling. The
program involves regular interaction with the staff of IHRD and meetings with
global networks of advocates for people with HIV so that fellows can continue
to enhance their advocacy skills once they return home.
The fellows are introduced to the history, culture, and values of
community-based AIDS organizing and treatment and prevention advocacy. They
conduct site visits at other organizations serving and advocating for people
with HIV/AIDS and those at risk in NYC and around the world, including the
Harm Reduction Coalition, the Chemical Dependency Institute at Beth Israel
Medical Center, Médecins Sans Frontières, and African Services Committee.
Fellows meet U.S.-based experts on harm reduction, media advocacy, AIDS
research, and clinical care, and participate in major community conferences
such as the North American AIDS Treatment Action Forum (NATAF) and attend
policy meetings in Washington, D.C. with other AIDS organizations and U.S.
officials.
In the fall of 2002, the first fellows arrived in New York City: Olena
Semenova from All-Ukrainian Network of People Living with HIV/AIDS and
Bogdan Glodeanu from ALIAT, the first needle exchange program in Romania.
In the spring of 2003, Vitaly Zhumagaliev from the Open Health Institute
and Roman Dudnik from AIDS Foundation East West, both in Moscow, arrived
at GMHC. And November 2003, the latest recruits, Anastasia Kamlyk of
Positive Movement in Belarus and David Ananiashvili from the Georgian
Plus Group began a six-week stay in New York.
Gregg Gonsalves is the director of treatment and prevention advocacy
at Gay Men's Health
Crisis in New York.
Reprinted from Harm Reduction News: www.soros.org/harm-reduction
Seeking a Definition of Advocacy
By Vitaly Zhumagaliev
Advocacy is a strange thing in Russia. There is no equivalent term in Russian
— and there seems to be no equivalent concept. People have always hoped
to solve their problems on a personal level: "The Czar/Party Secretary/Boss/President
is fair, he just doesn't know about my trouble. If I can make it clear to him, he
will do something, for sure." Yeah, right.
HIV advocacy is even less familiar. Although Russia has one of the world's
fastest growing HIV infection rates, HIV is still terra incognita for most Russians.
It took President Putin four years to declare that HIV/AIDS is a national problem.
One-on-one lobbying doesn't work. To get things moving, organizations and
individuals involved in HIV/AIDS must join forces to strengthen their efforts. This
is advocacy. But when there is no history of advocacy or culture in your own country
to draw on, you have to look elsewhere for guidance. The success of AIDS activism in
the United States is well known. The advocacy fellowship designed by the International
Harm Reduction Development (IHRD) Program of the Open Society Institute and Gay Men's
Health Crisis (GMHC), enables people from Central and Eastern Europe and the former
Soviet Union to learn from the U.S. experience and develop ways of changing AIDS
policies at home.
The fellows' program, based at GMHC, was intense. We had meetings every day with
new people in different organizations. We visited the Harlem Hospital and talked to
the staff of the Callen-Lourde Gay and Lesbian Community Health Center. We went to
the Bedford Hills Correctional Facility, and met with pharmaceutical companies. Since
the HIV epidemic in the region is largely driven by injection drug use, we had to
understand how HIV activism could work with the harm reduction movement. We met harm
reduction specialists at the Positive Health Project and the Harm Reduction Coalition,
and spoke with experts such as Robert Newman, M.D., and Jay Dobkin, M.D. The heart of
advocacy is networking and coalition building, even if sometimes HIV/AIDS activists
have to lead the way.
The fellowship helped change my thinking about what needs to be done. I hope the
knowledge and skills I gained are not wasted. As the policy program officer at the
Open Health Institute (OHI) in Moscow, my goal is to more actively engage HIV
advocacy in Russia. I was on the organizing committee of the Russian HIV/AIDS NGO
Forum whose inaugural meeting in September 2003 brought together for the first time
more than 60 nongovernmental organizations working in HIV/AIDS from all over Russia.
At the AIDS conference of the Ministry of Health of Russia in October, OHI and
its Russian and international partners made a strong case for access to treatment
for all PLWHAs. Currently, OHI is completing a survey on the needs of Russian harm
reduction projects, which will be used for developing a strategy tailored to the
needs of our clients.
More than one million, mostly young Russians now live with HIV. They have
virtually no access to HIV treatment and limited access to primary health care.
Experts believe that 50,000 Russians will need HIV treatment in two years, but
the total budget for the 2004 national HIV/AIDS program is $4 million, which is
supposed to cover prevention, treatment, testing, monitoring, and anything else.
We don't have time for warming-up. We need to push our government to change its
HIV policies and save those in the younger generation who still can be saved.
Vitaly Zhumagaliev is a program officer at the Open Health Institute in Moscow.
Reprinted from Harm Reduction News: www.soros.org/harm-reduction
News From the Bench
By Bob Huff
This space reviews early laboratory findings from the Journal of
Virology that shows scientists at work uncovering new ways to think about
— and ultimately beat the virus.
Betting on Betulinic Acid
In the January issue of the Journal of Virology, Jing Zhou, of Vanderbilt University
in Nashville, reported on a betulinic acid derivative called DSP that had been observed
to inhibit HIV replication in vitro. Although previous studies had concluded that DSP
was acting at a late stage of virus production to inhibit the release of new virions,
Zhou and colleagues have now resolved the activity of the substance to a fine degree,
finding that DSP acts to slow processing at a final stage of viral maturation.
Apparently, DSP binds to a segment of the gag precursor protein that eventually is
cleaved to form the capsid protein (CA) and a small assembly protein called p2. DSP
attaches on or near this crucial CA-p2 junction and effectively stops protease (PR)
from making the cut. Yet the drug does not otherwise affect PR, and even HIV with
resistance to protease inhibitors are blocked by DSP.
The team identified the precise point where DSP acts by growing HIV in the presence
of increasing concentrations of the drug until a DSP-resistant mutation was generated
and broke free from drug pressure. Finding the site of this mutation allowed them to
pinpoint exactly where in the protein chain DSP was acting. Importantly, they learned
that, although DSP-resistant mutants were difficult to produce, when they did occur,
it appeared that they were less replication-competent than wild-type virus. Furthermore,
viruses with the resistance mutation remained sensitive to protease inhibitors.
When DSP is present, new virions may still be produced, but they do not efficiently
form stable central cores and are much less infectious than control virus which did
not receive DSP treatment. Surprisingly, the virions with incomplete processing of
Ca-p2 were still able to fuse to and enter uninfected cells. The impact of the defect,
Zhou demonstrated, did not appear until after entry, during reverse transcription. So,
although DSP acts at the point when protease is processing a newly formed virus, its
inhibitory effect is not realized until the new virus enters a new cell and tries to
replicate itself.
They also found that DSP does not inhibit CA-p2 cleavage completely but merely
delays maturation; given enough time, mature virions can still be produced despite
the presence of the drug, although these never seem to become as infectious as
untreated virions. Because the betulinic acid derivative acts on such a specific
and highly conserved cleavage point, and because resistance, when it occurs, results
in impaired viral fitness, the authors conclude that DSP may be an attractive lead
compound for the development of a new class of anti-HIV drugs.
Zhou J, Yuan X, Dismuke D, et al. Small-molecule inhibiton of Human
Immunodeficiency Virus Type 1 replication by specific targeting of the final step
of virion maturation. Journal of Virology, Jan 2004, p. 922–9, Vol. 78, No. 2.
|
Gilead Files IND for New Protease Inhibitor, GS 9005
Gilead Sciences, makers of Viread (tenofovir) and Emtriva (FTC) have filed
an application with the FDA to begin clinical trials with a new protease
inhibitor (PI) called GS 9005. The agent was developed by Gilead using a
proprietary prodrug technology. Prodrugs are typically metabolized into their
active form after entering the body. Based on preclinical studies in animals
and in the laboratory, Gilead hopes the drug can be dosed once daily. They
also say the drug may have "a resistance profile that is distinct from
commercially-available drugs in the PI class."
The next steps will go slowly as Gilead investigates the first use of
the drug in humans. The plan is to conduct bioavailability, pharmacokinetic
and safety studies of GS 9005 first in non-HIV volunteers, then in HIV-positive
persons.
Gilead says their prodrug technology allows a drug to specifically target
the white blood cells that are the primary targets of HIV. The technology has
already been clinically tested in studies of a prodrug of Tenofovir, called
GS 7340. If validated in larger studies, this approach could result in a
generation of much more tolerable HIV drugs. Stay tuned.
|
Dodging Bullets
The Problem with PowerPoint
By Bob Huff
PowerPoint presentations are the central spectacle at any scientific conference.
In cool, darkened rooms, slide after slide marches from background to methods
to results with inexorable logic. But PowerPoint has come under criticism lately
for a tendency of the form to abbreviate truth, gloss over details, create an
impression of analysis where there is none, and facilitate spin. The leading
critic of Microsoft's ubiquitous presentation software, Edward Tufte, author
of several books on representing complex quantitative data, points to the role
of PowerPoint misdirection in the catastrophic failure of the Columbia space
shuttle. During a critical post-launch meeting the potential for serious wing
damage at takeoff was masked by a bland slide title disguising the alarming
reality nested within dumbed-down bullet points below. PowerPoint, Tufte says,
has come to signify authority, and audiences numbed to an endless succession
of slides are rarely given an opportunity to critically evaluate what is being
presented.
In February 2004, at the Moscone Center in San Francisco, thousands of
PowerPoint slides will flash before the eyeballs of the most important workers
in HIV research, as the annual four-day Conference on Retroviruses and Opportunistic
Infections (CROI) unfolds. A quirk of scientific conferences is that the papers
deemed most important are presented as oral slide talks, while the rest are
relegated to the poster hall where the data is hung on row after row of poster
boards. The paradox is that important data from the slide shows, which can sometimes
have an immediate impact on clinical practice, may never appear on paper;
they are ephemeral and often difficult to reference. Meanwhile, the lesser,
paper-based presentations usually contain much more detail; they can be
studied at length and their authors examined in the gauntlet of the poster
hall. It's as if the reward for scientific excellence is to receive less
scrutiny and accountability.
The data from a featured oral slide presentation may eventually appear
in a peer-reviewed journal article or, if a drug company has an interest
in the data, it will be repackaged into ever-slicker slide shows and shown
again and again at seminars and sponsored educational forums.
But until the study appears in print, the only source for the data is
the conference abstract, which may have been written many months before
the conference. Often, data presented in the slides can be substantially
different from that in the abstract. This leaves third-party reports by
online sources such as Medscape, NATAP or TheBody.com as the only way
for people who missed the conference to find out what was presented.
Since CROI is a top-notch conference, the PowerPoint presentations
on display will typically be well organized and checked for errors.
Often, where data has been produced with pharmaceutical company investment,
the slides will be carefully crafted by contract or in-house medical
communications experts, who are very sophisticated in seeing that the
correct nuance is given to each bit of data displayed. An amateurish
slide show may have the narrative force of Rocky II, but this won't be
as effective as a display in which the hand of the communications expert
has been carefully effaced and the data appears to glow on it own. For
a product in the pharma pipeline, a slide talk at an important conference
becomes a key plot point in a larger tale of home run inevitability that
culminates in FDA approval. Fortunately, there are always sharp scientists
in the seats who will pop up to the microphone to skewer any egregious
spin — or put in a plug for their own company's interpretation.
Good scientists instinctively look between the slides for what is not
shown. They know that, while the process of viral entry can be boiled down
to three bullets, in reality the shifts of energy and matter that move
these molecules into their crucial alignments are contingent on forces
near and far in space and time. Such evidence-based, complex mental maps
do not lend themselves to frame-width sentence fragments.
PowerPoint, like industrial agriculture, is not going to go away soon.
But maybe one conference session could be reserved for presenters who
prefer to use a chalkboard.
Groundswell
By Gary Karch
Michigan Positive Action Coalition (MI-POZ)
The country's first major winter snowstorm left air traffic centers
from LaGuardia to O'Hare temporarily paralyzed the first weekend in
December 2003. Despite the deep freeze, approximately two dozen HIV/AIDS
advocates from across the country battled long lines at airport terminals,
waited all night for rescheduled flights, went on wild bus rides and
tromped through snow drifts on New York City streets to reach the offices
of Gay Men's Health Crisis to attend the first-ever strategy planning
meeting of the AIDS Treatment Activists Coalition (ATAC).
Initiated as a conference call among 20 participants in 2001 and
having grown now to an email list with over 100 members, ATAC has mainly
been a "virtual" organization. Many of the group's most active participants
had only known each other by the sound of their voices during conference
calls or by email address in online discussions. Meeting for the first
time in person brought an opportunity for in-depth discussion of a number
of key issues and for strategizing on long-term objectives while also
building camaraderie.
So far, ATAC has assembled a pool of talent, passion and conviction
in an association of activists from the Pacific Northwest and Texas, to
the Midwest and various points in between, all united in a sense of
urgency based on frustration with years of federal funding shortfalls
for HIV care and prevention. We share a common realization that if we
are to succeed in presenting our views in a manner that sticks with
legislators and the public alike, we must utilize our resources intelligently
and effectively.
To this end ATAC's SAVE ADAP Committee is planning a Washington, DC
event in February 2004 to highlight the emerging crisis of waiting lists
for ADAP access and the inadequate funding at the federal level responsible
for this situation. Its Drug Development Committee has met with the FDA and
several major drug companies to lobby for community concerns. A new Prison
Working Group was formed at the summit that hopes to facilitate cooperation
between regional activists.
With many of the first wave of AIDS activists now dead or retired from
the movement — exhausted from the never-ending fight — a vacuum
has been left. Attracting a new generation of HIV/AIDS activists is recognized
as a priority of utmost importance, in order to "replenish shrinking ranks of
AIDS activists" operating at a national level, said ADAP maven Lei Chou. Part
of ATAC's mission is to identify how best to attract new people into the movement
who are willing to do the necessary work. Instituting an effective mentoring
program, supporting local skills building, and providing periodic teach-ins on
various topics will be important factors in achieving these goals.
As one who has often felt like a lone wolf crying in the wilderness of Michigan,
the NYC summit allowed people like me to take comfort in the recognition that no
matter how distanced one may sometimes feel from the national scene, our experiences
on the home front are universal and can pull us together in our common cause.
Realizing that our personal experiences aren't merely localized phenomena but in
fact are symptoms of chronic ills permeating the country, whether urban centers or
rural outposts, reawakens the feeling of being a part of a greater community.
Members from around the nation report an increasing groundswell of "screaming"
by community-based organizations that are feeling the pain of budget cuts, and
a growing demand for effective advocacy training that helps them get results.
The emergence of ATAC is a major step in that direction.
As we've been saying in Michigan lately: "We're taking command of our disease
one T-cell at a time." As more and more individuals and organizations come to
recognize that significant change only occurs by standing in allied strength with
fellow advocates, it appears that a coalition with the potential of ATAC may be
the best vehicle we have for reaching that goal. Now we need to harness those
individual T-cells and put them to work fighting for health and justice in the
body politic.
© 2003 Gay Men's Health Crisis |
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