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Past Issues
Volume 17, number 3
March 2003
Contents
Long Path to Approval
A look back at the road to fuzeon
Fuzeon Data Review
A capsule review of T-20 efficacy data
FUZEON (Enfuvirtide,T-20)
Breaking Barriers or Breaking the Bank?
$15 Million for Infrastructure
but No AIDS Drugs for Jamaica
Richard Stern finds trouble in paradise
International Treatment
Preparedness Summit Opens
Zackie Achmat calls for scientific literacy in Cape Town
It's Time to Face the Zerit
Problem
Nelson Vergel asks for caution on Zerit
Long Path to Approval
A Look Back at the Road to Fuzeon
On March 13, 2003, the U.S. Food and Drug Administration granted
Trimeris, Inc. approval to sell T-20, brand name Fuzeon, generic
name enfuvirtide, the first of a new class of HIV drugs called fusion
inhibitors.
GMHC Treatment Issues has been tracking the development
of T-20 since 1996. Here's a look back at the path from laboratory
to pharmacy via some edited excerpts of reports that have appeared
in these pages. It's interesting to note how the core issues that
challenge us today with this drug were identified early on: it's
potential for salvage therapy, the problematic need for injection,
its difficulty of manufacture, and consistently, the expected high
price of T-20.
September 1996
Theo Smart — New Wave Antiretrovirals
Despite enthusiasm at the Eleventh International Conference on
AIDS in Vancouver over recent advances in anti-HIV therapy, it will
be a long time until there are manageable combinations of easy-to-tolerate
drugs that work for everyone. New agents are needed particularly
for the many individuals who already have failed on protease inhibitors.
There were a number of presentations on T-20, a compound made by
Trimeris, Inc. "T-20 is the most potent agent that we've ever
looked at [in a mouse model for HIV infection]," according
to Paul Black of the FDA. Since the drug is a protein, there is
a fear that it could provoke an antibody response that may inactivate
it. Another potential problem is that the compound cannot be taken
orally since it is broken down by acids and enzymes in the digestive
tract. In its current form, the drug would have to be given as an
injection two or three times a day. Trimeris is considering administering
the drug via "mini-osmotic pumps," small implanted devices
that secrete a constant level of drug over time. First, though,
Trimeris intends to determine whether the current form of T-20 has
activity in people. Dose-ranging studies are planned to begin by
the end of the year.
December 1997
Dave Gilden — Medical Merry-Go-Round
T-20 is one of the few novel (as opposed to merely "new")
drugs exhibiting efficacy in early human trials. Four volunteers
receiving 100mg every 12 hours for 14 days experienced a -1.5 log
drop in their viral loads. All achieved unquantifiable viral loads
(less than 500 copies). Since this dose-finding trial only lasted
two weeks, it is impossible to tell what T-20's ultimate effects
are, but clearly the principle works.
April 1998
Dave Gilden — Expect No Miracles
A portable pump ensures a constant level of T-20 in the body. Although
it is a very small removable device that delivers drug through a
thin tube inserted just under the skin, many persons with HIV question
its practicality. Also, a new pump needs to be purchased every five
years for about $4,500, and supplies add another $1,000 per year.
This expense would be on top of the anticipated high cost of T-20
itself. The drug presents a manufacturing challenge due to its lengthy,
specific amino acid sequence. However, T-20's non-oral administration
plus the lack of kidney or liver involvement in its metabolism means
that it avoids many of the major toxicities of current antiviral
drugs.
An article published in the Journal of Virology described the ease
with which HIV in cell cultures can develop resistance to T-20.
Resistance remains to be documented in the human body, but the cell
culture results are comparable to what has been seen with protease
inhibitor resistance.
Trimeris is concentrating on developing T-20 as salvage therapy,
where lack of treatment options would make its shortcomings acceptable.
Trimeris' two upcoming trials will test T-20 in 72 people who have
failed to have a stable response to indinavir, ritonavir or nelfinavir.
January 1999
Dave Gilden — Three New Drugs
The results of Trimeris' salvage protocol, TRI-003, were reported
at a late-breaker session concluding the 6th Retrovirus Conference.
At week 2, viral load drops in this heavily treatment-experienced
population averaged -0.3 logs to -1.6 logs, depending on dose. The
negative part is that by week four, viral loads in all the trial
arms had returned to within 60 percent of baseline. A genetic analysis
performed in a preliminary T-20 clinical trial found resistance
mutations previously identified in cell culture studies.
Nonetheless, one should not dismiss T-20's accomplishments. The
recent trial tested the compound in the population that is hardest
of all to treat. Another positive outcome of this trial was that
the simpler mode of administering T-20 via twice-daily subcutaneous
injections appeared as effective as a portable infusion pump. So
far, the major side effect has been rash and bumps at the injection
site.
The principal stumbling block at present is synthesizing this 36-amino
acid molecule at reasonable cost. Trimeris claims to be slowly expanding
production and attaining economies of scale, but the compound will
always cost substantially more than any of the anti-HIV agents now
in pharmacies.
September 1999
Gil Shepard & Theo Smart — New Drug Harvest
T-20, the first fusion inhibitor, is now being developed by Trimeris
in partnership with Hoffmann-La Roche. To the credit of Trimeris,
the company has made salvage therapy the focus of the drug's development;
but T-20 is costly to make and until the recent collaboration with
Roche, resources for the young company have been limited. Still,
Trimeris has been able to mount a few studies.
Results from the most recent of these were presented during a late-breaker
session at ICAAC. Subjects took 50mg of T-20 twice a day (bid) in
addition to an individualized oral regimen chosen on the basis of
each patient's history and genotypic results. At week 16, in an
as-treated analysis, 36 percent (20 of 55) were below 400 copies
and 20 percent were below 50 copies. But are these responses sufficient?
In the earlier dose-ranging studies of T-20, there was a clear
dose-response to the drug, which peaked at the highest dose tested,
100mg bid — twice the dose currently under evaluation. Why
did Trimeris not proceed with the 100mg bid dosage? [Note: Fuzeon
was approved at a dose of 90mg twice daily.]
For one, this is a costly agent to synthesize and will likely be
quite expensive when it is marketed. Aside from the issue of cost,
there is a limit to how many injections a person can tolerate. But
is there a danger that the doses being used are suboptimal? Even
100mg bid may be inadequate. Yet, there is no way of telling since
that was the highest dose ever tested. And if it is the cost of
therapy that is the dose-limiting factor, how much is cost-prohibitive?
Is $15,000 a year too expensive? $30,000? Just how expensive are
we talking? At present, neither company is anxious to say.
April 2001
Bob Huff — What's Taking T-20 So Long?
In the laboratory, bench-top machines can make very small quantities
of T-20 by adding one amino acid after another in sequence to create
a chain. But this process doesn't translate well into large-scale
production. To insure correct assembly of the chain and prevent
unwanted reactions that can't be easily controlled in the industrial
setting, the amino acid building blocks have to be processed in
a way that "protects" them until the chain is finished
being built.
This is where it gets complicated. The manufacturer purchases the
protected amino acids from third-party specialty chemical makers.
The unprecedented quantities of "building blocks" required
for the production of T-20 initially exceeded the capacity and experience
of these suppliers. So, not only has the pharmaceutical company
had to dramatically scale-up its factory capacity, so have the vendors.
To insure a redundant backup supply, the manufacturer has decided
that at least two suppliers should be capable of providing each
crucial component. The system depends on over 125 outside vendors
to provide 45,000 kilograms of protected amino acids and other chemicals
just to produce 1,000 kilograms of T-20.
After the T-20 precursor is assembled, the protecting molecules
have to be removed and the remaining product must be purified. Then
the purified T-20 is freeze-dried, inspected, tested for sterility,
labeled and packaged. It takes about ten weeks to assemble a batch
of T-20 and another 30 days to freeze-dry and package the drug.
The next milestone for the manufacturer will be to produce a registration
batch of T-20 for submission to the FDA.
Though it's impossible to predict how the drug will fare in its
continuing clinical trials, two years from now to approval may not
be unthinkable. Trimeris officials have pegged the expected profit
margin of T-20 to be in line with that for protease inhibitors.
The profit, of course, will be added to the cost of making T-20.
The price when and if T-20 is approved? Don't ask.
July 2001
Bob Huff — What does R&D Really Cost?
Trimeris, Inc. was founded in 1993 as a development-phase company
involved with the discovery and development of peptide-based fusion
inhibitors. Trimeris has a royalty-free patent from Duke University
for the underlying concept of fusion inhibition with peptides. From
inception to March 2001, Trimeris has spent about $130 million on
administration and R&D (research and development). The company
has never made a profit and does not anticipate any sales until
early 2003.
In July 1999, Trimeris announced an agreement with Roche to develop
and market T-20 worldwide. Since then Roche and Trimeris have shared
U.S. development expenses for T-20 equally. Under the agreement
the two companies will split revenues on sales within the U.S. and
Canada. In the rest of the world, Roche will bear all development
costs and pay Trimeris royalties on sales. The agreement with Roche
was made at a point when Trimeris had invested approximately $45
million in research. After the Roche agreement was signed, R&D
expenses increased rapidly as expensive Phase III trials were begun.
By the end of March 2001, cumulative R&D expenses had reached
$170 million.
During the first three months of 2001, Trimeris reported spending
almost $14 million on R&D. Since Roche matches this amount,
total R&D for the quarter ran $28 million. At this rate, with
no increases, over $360 million will have been invested in T-20
by the end of 2002. Expenses for international trials are Roche's
exclusively, which introduces some uncertainty in predicting the
ultimate investment required to launch T-20.
If opportunity cost, calculated at a rate of 10 percent compounded
quarterly is considered, the investment figure could rise to $460
million. That said, Trimeris has told investors to expect worldwide
sales of T-20 to reach $500 million per year.
March 2002
Bob Huff — Drugs in Development
The outlook for entry inhibitors is looking better. T-20 from Trimeris/
Roche is likely to be the first of this new class of drugs to be
approved, although that may be up to a year from now. Apparently
the generic name for T-20 has been settled; initially known as pentafuside,
T-20 will now be called enfuvirtide.
March 2002
Fred Gormley — T-20 Diary
Dear Diary, Today my doctor informed me that my first dose
of T-20 is just a week away! How I have yearned for this day! Scalding
tears of joy spilled copiously down my face onto my heaving, bountiful
pectorals, drenching my Donna Karan cashmere sweater. The precious
fusion inhibitor would soon be mine...
Well, of course not. One doesn't live in New York, wear all black,
and reach the age of 50 (14 years aware of my positive HIV-status)
to get exuberant about anything. What really happened was that,
after waiting since early December, my shipment was finally coming
in. As the result of a new safety study, I was the first of three
people in Howard Grossman's office to get T-20. It wasn't easy,
but the effort wasn't mine. The pharmaceutical companies (Trimeris
and Roche) set up a specific time when physicians around the country
had to phone in; availability was on a first-come, first-served
basis, and there was limited drug to be had. The volume of calls
overwhelmed the insufficient phone lines, and getting through was
hairy. Several weeks later, I found out I had made it, and that
the meds would come my way.
Friday
The instructional video! It answered all my innermost, private
questions! I ran to my Sony Wega and hugged its big flat screen.
There was nothing new here for me (except for the reconstitution
process — T-20 is a protein, and its powdered form must be
mixed with sterile water to be administered), so I concentrated
on the tape's production values. Professionally done. High-quality
video. San Francisco locale. And there's skin! The demonstration
subject doffs his shirt to give himself a shot in his well-tended
abs.
At the doctor's office, I did my first hit under Liza's direction.
No problems, but one potential annoyance, a possible future deal-breaker.
The reconstitution takes 15 to 20 minutes if you tap the bottom
of the vial and gently roll it around (no shaking!) and somewhat
longer if you just let it sit. For someone like myself who greets
the day with pills at 8:00 (no food!), pills at 9:00 (food!), protein
shake, two packets of testosterone gel drying on my belly as well
as the usual get-ready-to-go-out-the-door routine, another extended
multi-step procedure (repeated at night) could quickly lose its
charm and novelty. I'll bear with it, though.
Sunday
So, I've just given myself my fifth poke with no adverse reactions
evident so far. Some people have complained about swelling under
the skin at the injection site, but anything I've ever shot subcutaneously
has given that effect; mine goes away within an hour. There was
some itching with the in-office dose, and a vague feeling of momentary
heartburn, which may have been coincidental. It'll go as it goes.
It'll work or it won't, or the results will be ambiguous, as most
drugs are when you're on a heavy regimen. We'll see...
April 2002
Lei Chou and Anne Donnelly – ADAP Strapped
Pressure on state ADAPs (AIDS Drug Assistance Programs) is expected
to increase as new drugs such as T-20 become available next year.
Access to these newer products will probably require prior authorization.
Additional pressure will likely come from rising unemployment and
loss of insurance; a steady level of new HIV infections and a possible
rise in AIDS cases; the emergence of long-term drug side-effects;
and the tightening of state Medicaid programs.
July 2002
Bob Huff — T-20 Expanded Access Limps Forward
In a conference call with community members, Roche revealed their
plans for wider release of T-20 through an expanded access program.
Current plans (and there have been so many it wearies me to type
this) call for greater drug availability on October 1 when the company
expects about 600 slots to open up in the U.S. Although the hoops
that doctors must shimmy through have been minimized, a hitch may
come when providers learn they have to complete a full day's training
on proper T-20 administration technique. Because T-20 is a fragile
peptide that must be carefully reconstituted with sterile water
before using (swirled not shaken!!), this training isn't a bad idea.
Access won't be worth a hoot if patients fail to benefit from the
drug because they never learned how to prepare and inject it properly.
October 2002
Bob Huff – Onward T-20
The FDA announced they have given T-20 priority review status for
approval, which means they must say yea-or-nay by March 16, 2003.
T-20 sponsor Roche is happy about this, but a persisting problem
with drug production has them downplaying expectations about actually
being able to deliver the drug to everyone who'll need it. Roche
has scheduled a meeting with community members next month to discuss
this issue, its expanded access program, and rumors of "golf-ball-sized
nodules" at the site of injection.
December 2002
Bob Huff — Five New Drugs
Fuzeon (T-20) is the Godot of HIV therapy. The long awaited, much
delayed, first agent of a completely new method of suppressing HIV
infection is definitely at the top of the FDA's to-do list for the
New Year.
But a green light from the FDA won't be the end of the wait for
some. Because of manufacturing difficulties, Hoffmann-La Roche (Roche),
the drug's sponsor, has announced that availability of Fuzeon will
be limited during the first year following approval. Allocating
the drug fairly may be a challenge since there seems to be a gap
between those in greatest need and those who might expect the greatest
benefit from the drug. People who add Fuzeon to a suite of other
drugs active against their virus are likely to have a much better
response than those who take it on top of their worn-out regimens.
The catch here is that people with other options may not want to
go through the unpleasantries of twice-daily injection, while those
with no other options may not find Fuzeon the life preserver they
need.
January 2003
Lei Chou — Boulder Blues
On Valentine's Day, Roche invited state ADAP directors and community
activists to a meeting about T-20 pricing at its manufacturing plant
in Boulder, Colorado. Dani Bolognesi, the chairman of Trimeris,
kicked off the meeting with "The Fuzeon Story," the history
of the drug from discovery through development. Their excitement
about the pending FDA approval was palpable. They say they are also
continuing the development of pharmaceutical peptides by looking
at pegylation, pushing towards eventual once-a-week dosing.
It was revealed half way through his presentation that the price
has already been decided upon: "No, of course I can't tell
you what it is!" Roche's David Reddy said. At this point in
the meeting they assured us that pricing discussions will continue
and then herded us out of the meeting room and onto a tour of the
plant (in hard hat and goggles). They showed us giant tanks that
hold the raw materials and solvents used in production, different
machines that do the assembly of amino acids, and a myriad of dryers
and washers. The place smelled like a gas station, with water leaking
from ceilings, and a little room with two computers and two workers
overseeing the entire process.
After lunch, each ADAP director told those remaining about the
crisis facing their programs. Fuzeon will only come to those who
need it at a cost of reduced formularies and stricter financial
eligibility criteria. With a scary new Medicaid proposal coming
out of the White House, most states will wait until the dust settles
before committing to major initiatives. The price of Fuzeon will
be the first test of this new reality we live in. One hopes that
Roche will do the right thing. They've certainly been informed.
January 2003
Bob Huff — Informed Access
Community representatives met with T-20 makers Roche and Trimeris
in New York in January to get a briefing on plans to distribute
the injectable fusion inhibitor as soon as it is approved. Roche
will contract with a third-party pharmacy service corporation to
deliver drug kits (either by mail or to selected pharmacies), staff
a patient assistance hotline and handle prescriptions for patients
unable to pay.
The patient support component of this system will be critical if
patients are to have good outcomes when using T-20. It's becoming
increasingly clear that T-20 is not an easy drug to take and the
decision to begin enfuvirtide therapy should be made in consultation
with a physician who has been trained in the correct preparation
and administration techniques. Resistance to T-20 can develop fairly
quickly if full doses are not taken on a consistent basis, so an
individual's informed commitment to making the regimen work is a
must.
Although no price has been announced for Fuzeon, it is expected
to be a doozy. People with private insurance will be covered, as
eventually will Medicaid beneficiaries (hopefully). But this leaves
a large gap in the middle, especially if state ADAP programs decide
they cannot afford to add this budget buster to their formularies.
Roche has promised to make Fuzeon available to any who cannot afford
it through a patient assistance program administered by the third-party
distributor. Details of their plan to patch over access problems
remain to be seen.
And the U.S. price for a year of Fuzeon is...
$25,000
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Fuzeon Data Review
Fuzeon was approved in the U.S. primarily on the basis of 24-week
efficacy and safety data from two large clinical trials called TORO
1 and TORO 2 (T-20 versus Optimized Regimen Only, 1 and 2)
HIV-positive people with current viral load over 5000 copies and
experience with all three classes of antiretroviral drugs (ARV)
were recruited for the trials and evaluated for drug resistance
during a six-week screening period. On average, participants had
CD4 counts below 100, viral loads above 100,000 and had used 12
antiretroviral drugs in the past. An optimized regimen (OR) was
selected by the patient and doctor based on resistance results,
treatment history and tolerability experience. On average, the OR
contained 4 drugs (patients in TORO 1 were sensitive to fewer than
2 of their drugs, on average). Patients were then randomly assigned
to either start their OR along with twice-daily T-20 injections
or to start the OR alone. All in all, the participants in these
trials had fairly advanced HIV disease, were highly treatment-experienced
and had less than perfect susceptibility to the best available antiretroviral
regimens. Twenty-four week data are shown here but both trials were
continued and will eventually report 48-week data.
The primary measure of efficacy in these trials was the difference
at 24 weeks between viral load reductions in those taking the OR
plus T-20 and those on the OR alone.
In addition, the studies evaluated how many in each group had viral
load go below 50 copies and how many went below 400 copies. CD4
count changes were also reported.
TORO 1
TORO 1 was conducted in the U.S., Canada, Mexico and Brazil. A final
report of 24-week data was published in the New England Journal
of Medicine (NEJM), March 2003. This trial involved 491 people.
| Primary Result: (log10 copies) |
T-20 + OR |
OR (OR=Optimized Regimen) |
| Drop in viral load from baseline: |
-1.70 |
-0.76 |
Secondary Results: |
|
|
| Percent below 50 copies: |
20% |
7% |
| Percent below 400 copies: |
32% |
16% |
| Increase in CD4 count: |
+76 cells |
+32 cells |
TORO 2
TORO 2 was conducted in Europe and Australia. A preliminary report
of 24-week data was presented at the International AIDS Conference
in Barcelona, July 2002. Publication of final 24-week results is
expected soon. This trial involved 504 people.
| Primary Result: (log10 copies) |
T-20 + OR |
OR |
| Drop in viral load from baseline: |
-1.43 |
-0.65 |
Secondary Results: |
|
|
| Percent below 50 copies: |
12% |
5% |
| Percent below 400 copies: |
28% |
12% |
| Increase in CD4 count: |
+65 cells |
+38 cells |
Safety
Pooled safety data from both TORO 1 and TORO 2 were reported in
the NEJM article.
There was little difference between the frequency and severity
of the most common treatment-associated side effects in the T-20
group and the OR group and people taking T-20 actually had slightly
less nausea and diarrhea.
Local injection site reactions were the most frequent adverse events
associated with the use of T-20. In Phase III clinical studies,
98 percent of patients had at least one local injection site reaction.
Manifestations of injection site reactions may include pain and
discomfort, hardness, redness, nodules and cysts, itching, and bruising.
Hypersensitivity reactions have been associated with T-20 therapy
(less than 1 percent) and have recurred on rechallenge. Symptoms
of an allergic reaction may include rash, fever, nausea and vomiting,
chills, rigors, low blood pressure, and elevated serum transaminases.
In addition, an increased rate of bacterial pneumonia was observed
in patients treated with T-20 in the Phase III clinical trials compared
to the control arm. It is unclear if the increased incidence of
pneumonia is related to T-20 use.
FUZEON (Enfuvirtide,T-20)
Breaking Barriers or Breaking the Bank? Position
paper by Matt Sharp and Rob Camp
T-20 is the first drug of a new class of HIV inhibitors that perform
entry inhibition. More specifically, T-20 is one of a subset of
entry blockers called fusion inhibitors. It acts by preventing the
envelope of HIV from fusing to its target's cellular membrane. For
treatment-experienced individuals with multiple-drug resistant virus,
adding a drug from a new inhibitor class in combination with drugs
from previously used classes is thought to be the most effective
strategy for achieving durable viral suppression. As with all other
HIV therapies, T-20 must be used in a combination, preferably with
other new agents, in order to have the biggest punch.
Overview of Issues
Although therapeutically promising, unfortunately T-20 is not an
easy drug to use and may be difficult for some to access. Drawbacks
include:
Twice daily injection: Because it is a complex
protein peptide, T-20 has to be administered by subcutaneous (subQ)
injection twice daily, a substantial issue for most people. Adherence
to life-long oral HIV therapies is already inherently difficult
and we expect the technical demands of self-administering twice-daily
injections to be even more so. We find the Roche/Trimeris video
of people effortlessly incorporating T-20 into their daily lives
misleading. A specific educational program is needed to deal with
the complexity of drug reconstitution and self-injection. Patient
experience may be very helpful in elucidating some basic dos and
don'ts. Fuzeon also elicits concern from many former injection drug
users in recovery that the use of needles may act as a potential
trigger for relapse.
Reconstitution: The need to reconstitute T-20
is a significant drawback to ease of use. After mixing sterile water
with the drug powder, T-20 can take up 30 minutes or longer to dissolve
completely. It is unclear whether total reconstitution is necessary
for maximum efficacy. Often drug powder is drawn up into the syringe
before the drug has completely dissolved. Does injection of unreconstituted
substance contribute to PISRs?
Problematic Injection Site Reactions (PISRs):
The Achilles heal of T-20 may be the injection site reactions. T-20
injections cause a local, painful skin reaction, somewhat like a
wasp sting, and have happened to almost all (98%) people studied
thus far. Fifty percent of the reactions are reported as mild, while
the other 50 percent range between moderate and severe. Redness
at the site of injection (of more than 4") and pain have been
reported in 80 percent of people and hardness around the injection
site (2" or more) in 85 percent of people. Twenty percent of
the PISR nodules do not go away even after 7 days. For some, there
seems to be no improvement over time.
Supply: Producing enough T-20 for all the research,
the expanded access program and expected market demand has been
a major stumbling block in the development of this drug. Because
of the production difficulties, and the fact that a drug of this
complexity has never been produced before, there is no promise that
enough drug can be produced in a timely manner to reliably supply
all who need it.
Price: A price of over $21,000 has been announced
for the European market. Is this the drug that will break payers'
backs? Will providers be unable to justify or afford the high cost
and refuse to add T-20 to their formularies, despite patient need?
The Community Demands:
Commit to informed access
An aggressive commitment to patient and provider education will
be needed as the number of people using T-20 swells from 2,000 to
perhaps 15,000 by year's end. So far, the sponsor has not been ready,
willing, or able to do this. Education, for both the user and provider,
must be the top priority on the Roche/Trimeris agenda and the educational
programs must be scaled up and made accessible to all providers,
including those who primarily serve Medicaid beneficiaries.
Minimize barriers to adherence
Toxicity management issues need to be better studied. Health care
providers and patients need to understand the time commitment required
to use T-20 correctly and to obtain the best advantage from its
use. Treatment fatigue is common even with oral HIV treatments.
Simply skipping one dose per month may be risky with this drug's
resistance profile. Adherence issues and PISRs must be dealt with
aggressively by finding ways to make administering T-20 more user-friendly
and through additional programs to counsel people on the best and
safest methods of injection. The sponsor should create a patient/provider
advisory board to work on these issues. It is important that T-20
not join a person's list of quickly "used up" therapies.
Get to the bottom of PISRs
In an analysis of the pathology of (P)ISRs presented at the 10th
Annual Retrovirus Conference, one patient (out of seven studied)
who did not experience (P)ISRs "had insulin-dependent diabetes
and had self-injected insulin for many years using optimum injection
techniques." Are PISRs nothing more than bad injections? If
so, the sponsors' education plan has not worked. Some experienced
insulin injectors have suggested warming the syringe before injection.
If PISRs are caused by something else (allergy, etc.), then that
needs to be clarified. Does the incomplete dissolution of T-20 have
anything to do with the PISRs? Is there a point when, although not
completely dissolved, the drug is safe and efficacious to use?
Many users of T-20 are frustrated with the lack of importance
given to this issue by the sponsor. Because both the cause and the
resolution of the injection site reactions may be a key to success
with this drug, Roche/Trimeris needs to learn more about why PISRs
occur and they must look into other delivery mechanisms for the
compound.
Continue dosing research
Questions have been raised concerning the potency of the control
regimen and the small sample size used in the Phase II dose-finding
study T20-206. Trimeris never ascertained the maximum tolerated
dose for T-20 and based its dosing decision solely on the tolerability
of the number of injections. Roche/Trimeris should continue to look
for the maximum tolerated dose, which will mean more investigation
into delivery systems.
Help identify optimal background regimens
In multi-drug experienced people, therapy optimization should be
ascertained via genotyping and phenotyping. The recent news that
only 25 percent of practicing clinicians know how to use the results
of these resistance tests is very disconcerting. Providers who offer
T-20 must know they need to have a good understanding of resistance
test results in order to optimize the background therapy and maximize
response.
Availability for those who need it most
With only a 16 percent success rate for keeping viral load below
50 copies at 24 weeks in heavily pre-treated trial participants,
and with drug supply expected to be limited, T-20 may need to be
rationed to those most in need — people without other treatment
options. Use in other populations has not yet been studied, and
the risk-benefit ratio in a treatment-naive population has not been
determined. Finally, it should be noted that there are no study
results demonstrating the impact of T-20 on the clinical progression
of HIV disease.
Assure equitable access
Roche/Trimeris must assure that scaled-up production will be able
to meet demand with no further supply issues. Roche/Trimeris must
ensure that there is an adequate supply of the drug for continued
clinical trials, expanded access, and for sale throughout the world.
Roche should move to register the drug and assure access in all
countries that have participated in clinical trials for T-20. Sufficient
drug to conduct Phase IV studies of treatment options and side effects
should be assured.
Roche/Trimeris needs to come to reasonable terms over its price
with all payers, whether they be insurance companies, Medicaid or
ADAPs. Details of the sponsor's "Patient Assistance Plan"
(PAP) need to be defined (Roche has verbally promised one-third
of drug to those most medically needy). The entry criteria for the
PAP may well be determined by those who are unable to enter state
ADAP plans. Administration of PAP eligibility should be coordinated
with the ADAPs.
Tell the truth
The FDA needs to take its role as monitor of pharmaceutical advertising
very seriously and remember that the wording on the label and in
advertising for this drug should not be ambiguous or misleading
regarding target populations. The FDA should insist that those people
most likely to benefit from T-20 have first access.
$15 Million for Infrastructure
but No AIDS Drugs for Jamaica By Richard Stern
Seven minutes from Sangster International Airport in Montego Bay,
Jamaica, there is a somewhat run-down house perched on a hill with
a breathtaking view of the luxury beachfront hotels below and of
the cruise ships docked across the bay.
I spent Wednesday, January 22nd, 2003 in that house talking with
people who are living with HIV/AIDS (PLWHA) and with the small,
dedicated staff from a local NGO who support them. These people
are dying. Of about 25 who showed up on that Wednesday to see a
volunteer doctor who comes every two weeks, only one had access
to antiretroviral medications (ARVs). Several were so sick with
wasting syndrome and other opportunistic infections that they had
to be helped up and down the stairs to see the doctor.
Jamaica's response to its AIDS epidemic seems to have been too
little and quite late.
Max, a 44 year old, the only member of the group who could afford
antiretroviral medications, told me that when he was seen at the
local hospital a nurse refused to take his blood pressure after
she opened his medical file and saw his diagnosis. Max obtains his
medications from LASCO, a local importer of generic ARVs made by
CIPLA in India, and buys a cocktail of Duovir (AZT + 3TC) and nevirapine
for $120 per month, about four times what CIPLA charges for the
same cocktail if it is purchased in India.
Gladys, 28, told me how she had begged local hospital officials
and then private doctors to get medications for her five year old
daughter Emily who was becoming more and more ill every day. They
told her to first to get a CD4 test for the little girl, but she
did not have the necessary $100 for this test. CD4 testing in Jamaica
is only available at the University of the West Indies and viral
load testing remains unavailable. Emily died November 17th. It is
not clear why CD4 tests in Jamaica costs $100 when in many countries
in the region the cost of this test is under $30 per person. It
is also not clear why the doctors needed a CD4 test before starting
treatment for an obviously critically ill child. Presumably it is
because they had no pills to treat her with.
Joel, 26, who could not have weighed more than 90 pounds, is a
former taxi driver who alternately cried and slept while waiting
to see the doctor. He said he is lucky because his father cares
for him, while many others have been thrown out of their houses.
The Jamaican government does not provide antiretroviral medication
to any of the estimated 4,500 people with AIDS who need treatment
at this moment. Twenty-five thousand people in Jamaica are estimated
to be HIV-positive, and three people die each day of AIDS. Perhaps
150 out of the 4,500 who need treatment have access to ARVs because
they buy them privately or because they receive donated medications
or have contacts with relatives in the U.S.
Government officials told me the Health Ministry has no budget
for antiretroviral purchase. Ironically a $15 million loan from
the World Bank to Jamaica for AIDS-related activities might be inadvertently
delaying antiretroviral access in Jamaica. Dr. Yitades Gebre of
the Jamaican National AIDS Program told me that they are currently
focusing on how to utilize the World Bank money for prevention programs
as well as for capacity building and implementation of infrastructure
related to treatment access. The World Bank will not permit its
money to be used to purchase antiretrovirals.
But overwhelmed by its own incapacity to effectively absorb and
utilize these funds, the government of Jamaica did not even submit
an application last year for the second round of grants from the
UN's Global Fund for AIDS, TB and Malaria. So the government of
Jamaica is stuck with an excess of potential infrastructure, but
no funds for actual purchase of medications. The victims of this
unusual "embarrassment of riches" appear at this point
to be the people with HIV/AIDS who need medications now.
In a speech at the UN in 2001, Jamaican Health Minister John Junior
stated that, "We welcome the proposed establishment of a global
health and HIV/AIDS fund and hope that the allocation of resources
from the Fund will not be subject to bureaucratic impediments which
would limit timely and adequate disbursements to those worst affected."
We tried to reach Minister Junior to find out why Jamaica is one
of the very few developing countries which has not even submitted
a proposal to the now established Global Fund, but he was unavailable
for comment.
This reporter discussed with Dr. Gebre other issues related to
the situation of people living with HIV/AIDS in Jamaica who need
ARV treatment now. A single trained physician (Dr. Gebre acknowledged
that there are several physicians in the country with extensive
experience in utilizing antiretrovirals) can easily treat up to
100 people per month or possibly more, especially if CD4 testing
is available. The government will be using some of the World Bank
money to purchase a CD4 machine, thereby lowering the cost of the
test. Funds are now needed to purchase medications, but there is
currently no budget approved by the government for antiretroviral
purchase, except for prevention of mother-to-child transmission.
The World Bank loan will undoubtedly enable Jamaica to eventually
implement many excellent programs, but for those who need antiretrovirals
now it appears that there is no plan in place.
Antiretroviral access could also relieve the burden on the public
hospital system in Jamaica. AIDS patients who are treated rarely
receive medications for opportunistic infections and the overall
capacity of these hospitals to meet the need is minimal. When antiretroviral
access arrives, a high percentage of patients could likely by-pass
the public hospital system, since, if their treatment is successful,
the need for hospitalization should decline dramatically. People
on treatment could also return to the labor force, and their children
would not be orphaned, thus avoiding additional burdens on the government.
But Dr. Gebre gave no specific date as to when anyone with AIDS
in Jamaica would actually receive ARV therapy, although he indicated
that the government is hoping to begin treatment for several hundred
people this year. He said the government plans to eventually have
four AIDS clinics in place which will provide comprehensive services
for PLWHAs.
Jamaica may be able to apply for funds for a limited supply of
antiretroviral medications if the regional Caribbean proposal submitted
by "CARICOM" (Caribbean Community) to the Global Fund
is accepted. But, according to Dr. Gebre, CARICOM has only requested
enough funds to purchase ARVs for 4 to 5 thousand people, and that
must be divided between all of the CARICOM member states. As many
as 100,000 people currently need antiretrovirals in the entire region.
If the CARICOM proposal is accepted, Jamaica must then submit a
proposal to CARICOM to receive its share of funds, but because of
the regional need, it seems likely that this would only be enough
to buy medications for 200 to 300 Jamaicans during 2003.
A private pharmaceutical company called LASCO is importing generic
ARVs sold by CIPLA. This reporter obtained a copy of the price list
for LASCO products if purchased "wholesale." The combination
of Duovir (AZT +3TC) sells for $600 yearly and nevirapine sells
for $432, pricing a triple cocktail of AZT + 3TC + nevirapine at
$1,032 yearly per person. Yet CIPLA sells the same cocktail to LASCO
for about $360 per year.
Aside from the other problems with the public hospital system,
it also appears that stigma and discrimination are commonplace.
I was told that at Kingston General Hospital people with AIDS are
segregated into a back corner and routinely ignored by nursing staff.
If they have no family to visit them, they will live in appalling
conditions and are often discharged while still severely ill. Local
NGO's are summoned to the hospital on an emergency basis to try
to find space in hospices for those who are being asked to leave.
The stigma suffered by gays and lesbians also hurts efforts to
combat the epidemic. Gay sex is still illegal under "buggery"
laws enacted when Jamaica was a British Crown Colony. Prosecution
may occur for public as well as private acts and, when arrests are
made, names and addresses are routinely published in newspapers.
This situation reduces the opportunity to do prevention work in
the gay community, which remains largely underground. "Batty
Boys," as gay men are called, are subject to violent attacks
as well.
One of the fundamental arguments for providing antiretroviral access
is that it substantially reduces stigma and discrimination thereby
enhancing prevention efforts. By providing people with AIDS with
adequate medical treatment, the government would be giving a message
to the entire population that the lives of these individuals are
valuable and that their rights in society deserve to be protected.
Their visibility would increase and the subject of AIDS would no
longer be taboo.
Countries much poorer than Jamaica are providing ARVs with dramatically
positive results, but it appears that the best opportunity to make
ARV access a reality here soon has been mishandled. CARICOM's Global
Fund proposal may not have been well coordinated with other countries.
Technical advisors could have made it clear to all of the 29 member
countries that the amount of money requested is far below what is
needed to cover antiretroviral access in the region. Or perhaps
this was made clear, and Jamaica simply did not act.
Richard Stern is Director of Agua Buena Human Rights Association,
San José, Costa Rica www.aguabuena.org
International Treatment
Preparedness Summit Opens By Olayide Akanni
Cape Town, South Africa
A four-day International Treatment Preparedness Summit kicked off
here on Thursday, March 13, with over 120 treatment activists drawn
from 67 countries in attendance.
The meeting will identify ways to strengthen regional treatment
literacy and advocacy efforts in order to pave way for the realization
of the World Health Organization's (WHO) goal of providing drugs
to three million people by 2005.
Participants will also examine and map out strategies for expanding
access to HIV/AIDS treatment to the poorest communities in every
continent.
Addressing delegates at the opening ceremony, Gregg Gonsalves of
Gay Men's Health Crisis (GMHC), which is co-organizing the meeting,
noted that one of the objectives of the summit is to establish treatment
literacy initiatives in countries where there are none. The meeting
also aims to strengthen local and regional treatment advocacy and
education efforts where few exist.
Zackie Achmat, Coordinator of South Africa's Treatment Action Campaign
(TAC), however noted that in order to achieve these objectives,
all delegates present needed to focus on key issues. These issues
include bridging the economic, scientific and political divide between
the developed and developing countries, grassroots mobilization,
expansion of treatment literacy and the use of the law to advance
the principles of the right to health.
"In developing a global movement, our most important ally
is good faith and science. You don't need a degree to benefit from
science and we need to create scientific literacy about treatment
issues within our communities. Our governments have misused science
to deny people the right to medicines and the right to life, but
it is our duty to use the best that science and technology has to
offer to advance the cause of PLWHA" Achmat said.
He also noted that in mobilizing increased advocacy aimed at expanding
access to treatment, there was need to exercise caution. "We
have to be cautious of the tactics we use. Radical measures that
work to expand access to treatment in one country may not be applicable
in another country depending on the situation there. Each country
has to take stock of the areas where they are weak, and by building
upon that we can have a strong International Access to Treatment
Movement," he said.
Other key issues discussed in the course of deliberations include
ways of scaling up to provide treatment, and the state of treatment
preparedness in Eastern Europe, Africa, Asia, South and Latin America
as well as the Caribbean.
New E-mail Newsletter for Providers
in Limited-Resource Settings
"HIV & AIDS Treatment in Practice" is a new
e-mail newsletter for doctors, nurses, health care workers
and community treatment advocates. It will be published twice
every month by NAM, the UK-based HIV information charity behind
www.aidsmap.com.
The goal of HATIP is to consider how appropriate and effective
treatment, including but not limited to antiretroviral (ARV)
drugs, can become a practical reality in settings with few
resources. Each newsletter will contain specialist comment
from doctors with expertise in delivering ARVS and AIDS treatment
in resource-limited settings. Julian Meldrum, the editor,
says HATIP recognizes that "for medicines to be effective
in the real world, other things are important besides the
supply of drugs, including the relationships between treatment
providers and people with HIV as well as wider patterns of
support and care within families and communities."
Each edition will review one major topic in HIV & AIDS
treatment. The first issue features a review of the place
of co-trimoxazole prophylaxis (CTX) in expanding treatment
for people with HIV. It asks who could benefit from CTX prophylaxis
and sets out some issues for individuals and communities in
supporting CTX use. It looks at issues raised where CTX is
promoted in the absence of access to ARV and finally at how
it might be used to support the introduction of ARVs when
these become available. The article includes commentary from
Dr. Vijay Anthony Prabhu (India), Dr. Adama Ndir (Senegal),
Dr. Leon Regensberg, Dr. Douglas Wilson (South Africa), Molly
Tumusiime (Uganda) and Prof. Brian Gazzard (UK).
You can subscribe to the newsletter by visiting www.aidsmap.com
or by sending an email with your name, email address and the
country in which you work to: hatip@nam.org.uk with the words
"add HATIP list" in the subject line. |
It's Time to Face the Zerit
Problem By Nelson Vergel
When I give lectures on how to manage the side effects of HIV medications,
I am constantly reminded of how widespread the "sunken cheek"
look has become. Many if not most of the men and women sitting in
front of me show the severe facial wasting which has become HIV's
Scarlet Letter. Some, self conscious of their gaunt features, have
begun to isolate themselves at home lest their HIV status be "outed"
to a public that is increasingly aware of "that look"
and what it means. The City of San Francisco put up billboards featuring
repellant photographs of people with facial wasting and grotesque
lipodystrophic bellies. The ads were designed to scare HIV-negative
people away from engaging in unsafe sex. I hope they're effective,
but these campaigns certainly further stigmatize those who live
with body changes induced by HIV and its medications.
During my talks I review the existing data that tie lipoatrophy
(subcutaneous fat loss) to the class of HIV therapies called nucleoside
analogs (NRTIs) and I discuss the increasing body of evidence pointing
to one drug in particular: Zerit (d4T, stavudine). Although other
NRTI drugs have been implicated in facial wasting, it now seems
clear that, if it's going to happen, it will happen faster on Zerit.
Many people in my audiences have taken Zerit and they often wonder
why people newly starting HAART are rarely informed about the apparently
irreversible disfiguration that facial wasting brings, or about
thinning limbs and the psychological impact to a woman who develops
the "veiny" arms of a weightlifter. Some say that we are
complaining about superficialities, that we should be grateful the
drugs have kept us alive, but for a complication that may be preventable,
facial wasting has made far too many lives miserable.
Many people, now with undetectable levels of HIV in their blood,
desperately search for ways to repair their faces — to have
them "match their immune system," as several have told
me. The search for the perfect facial filler has become one of the
most asked about topics on Internet discussion groups and in treatment
seminars. None of the restorative medical options available —
products such as silicone injections, NewFill, Bio-Alcamid and Artecoll
— are FDA approved. Long-term effects are unknown. At over
$4,000 for a course of treatment, they are not cheap. Strong activism
is needed to get third-party payers to acknowledge this drug-related
side effect and pay for restorative therapy.
Research into reversing lipoatrophy has not been promising. A few
studies suggest that switching from Zerit to AZT or Ziagen may reverse
subcutaneous fat loss after 48 weeks. However most patients in those
studies reported little visible change in their appearance. And
unfortunately, therapies intended to improve body shape, such as
exercise, anabolic steroids, and growth hormone, actually seem to
worsen subcutaneous fat loss.
There is currently little research on ways to prevent lipoatrophy
in those who are just starting treatment with Zerit or the other
nucleoside analogs. Scientists have looked for the cause of lipoatrophy
in mitochondrial toxicity, impaired fatty acid oxidation, increased
TNF production, and the normal effects of aging. Some have proposed
that supplements like L-carnitine or B vitamins might have a protective
effect on mitochondria and may slow or prevent lipoatrophy. Many
questions remain.
Researching ways to maximize Zerit's benefits while minimizing
its side effects must become a priority for the drug's manufacturer,
Bristol-Myers Squibb. While that is ongoing, I believe this drug
should no longer be given to treatment-naive patients unless they
have been fully informed and agree to accept the risk of potentially
irreversible facial wasting. The FDA should examine the evidence
and, if warranted, add a specific caution to Zerit's label about
facial wasting. A federal HHS committee is set to issue an updated
version of their treatment guidelines. At the very least, that document
should reflect the growing consensus expressed by Martin Hirsch
at the recent Retrovirus Conference that "the combination of
ddI and d4T should not be used as part of an initial antiretroviral
regimen." Research studies involving previously untreated patients
should avoid the use of Zerit. Until we can predict who will have
an increased risk of developing lipoatrophy from Zerit, or until
there is an effective method of managing those complications, Zerit
should be dropped from the list of preferred drugs for use in treatment-naive
patients and only used for salvage situations in which the benefits
will outweigh the risks.
Nelson Vergel lectures frequently on lipodystrophy and HIV
treatment side-effect management from a consumer's point of view.
For more information, visit: www.facialwasting.org
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