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Past Issues
Volume 15, number 5
May 2001
Contents
Questions About Industry
Influence
Has the AACTG lost sight of what's important?
Lose Weight Fast!
A first-hand account of wasting
Flipping Out
How to read a scientific paper (part 2)
NY: The State of HIV Research
CRIA's new guide is cause for comment
A TI Editorial
The AACTG Needs New Direction
Drifting Agenda for
Federal Treatment Research
By Bob Huff
Although U.S. government clinical trials for AIDS were once at
the forefront of HIV treatment research, during the past few years
pharmaceutical sponsors have taken over the job of conducting the
most important studies of new anti-HIV medications. The government,
which continues to play a central role in operating clinical trials
for vaccines, for treating the complications of HIV, and for treating
children, has fallen strangely out-of-step in its research of new
drugs and strategies for treating and managing HIV in adults. A
review of recent government clinical trials targeting HIV infection
suggests skewed priorities in the federal research agenda. In particular,
the unusual proportion of trials investigating two drugs, Agenerase
and Ziagen, both marketed by pharmaceutical manufacturer GlaxoSmithKline,
raises questions about the relevance of the government's vision
for HIV clinical research and concerns about industry influence.
Federally sponsored clinical trials for HIV/AIDS are conducted
under the broad umbrella of the National Institutes of Health (NIH).
Within the NIH are several Institutes that study HIV treatments
in people. The largest is the National Institute for Allergy and
Infectious Diseases (NIAID). Within NIAID, there are a number of
programs and trials networks conducting clinical research, such
as the HIV Vaccine Trials Network (HVTN), the Pediatric AIDS Clinical
Trials Group (PACTG) and others.
The oldest, largest, and best-funded NIAID research program is
the Adult AIDS Clinical Trials Group (AACTG), a network of research
sites around the country, usually affiliated with important medical
centers and universities. The AACTG was organized in 1986 to perform
high quality and rapid testing of emerging AIDS therapies. It was
created at a desperate time in the epidemic, with no treatment options
in sight and enormous pressure on government to speed up the glacial
pace of developing and approving new drugs. By late 1986, a Burroughs
Wellcome trial (BW 002) had delivered compelling evidence in record
time that AZT could slow disease progression and delay death from
AIDS. A few months later, on the basis of this trial, the U.S. Food
and Drug Administration (FDA) approved AZT for sale in the U.S.
Within the AACTG, Research Agenda Committees (RACs) direct clinical
investigations along three basic lines of inquiry: HIV-disease,
the complications of HIV disease, and the immunology of HIV/AIDS.
The AACTG has performed clinical trials to investigate new therapies
for HIV and its associated infections, to test various hypotheses
about the pathogenesis of the virus, and to explore strategies for
meeting evolving patterns of disease.
Since its inception, the AACTG has initiated nearly 300 clinical
trials, of which 118 have focused on HIV disease and its treatments.
Added to the overall number are more than 125 nested substudies
designed to investigate highly focused scientific questions using
trial subjects enrolled in one of the primary clinical trials. Substudies
may originate in one RAC to take advantage of a study population
assembled for another RAC's research. For example, immunology researchers
may nest a substudy of CD4 phenotype into an HIV trial comparing
the impact of two treatment regimens on viral load.
The AACTG: "The Amprenavir/Abacavir Clinical Trials Group"?
This report focuses solely on clinical trials of HIV treatments
and treatment strategies originating within the HIV RAC of the AACTG.
Ten clinical trials overseen by the HIV RAC are currently open to
enrollment and three more trials have closed but are still collecting
or evaluating data. In addition, more than a dozen substudies are
active.
Six of the ten open trials specify drugs in their protocols; four
trials prescribe no drugs. Five of the six trials that specify drugs
— half of all open trials — are testing two drugs marketed
by GlaxoSmithKline (Glaxo): the protease inhibitor Agenerase (amprenavir)
and the nucleoside analog Ziagen (abacavir). Of these five trials,
three include amprenavir, four include abacavir and two include
both. (Comparatively, one of the ten open trials prescribes efavirenz
and one other trial offers indinavir. Ritonavir is employed as a
metabolic modifier in several trials.) Each of the three trials
that have closed but are not yet completed also included amprenavir
or abacavir. Glaxo also manufactures AZT, 3TC, and Combivir, a popular
coformulation of AZT and 3TC into one pill. Combivir is the largest
selling HIV drug in the world.
Amprenavir is a drug molecule that was specifically designed as
a protease inhibitor for HIV therapy. The drug has a favorable side-effects
profile, achieves therapeutic concentrations in semen and the brain,
and is active against viral isolates with diminished susceptibility
to other protease inhibitors. Nevertheless, amprenavir is not without
drawbacks. Resistance does emerge and some studies have reported
a high rate of rash associated with the drug. These issues plus
a formulation that requires taking many uncomfortably large pills
twice daily have contributed to a lack of enthusiasm among clinicians
and a poor level of acceptance among people receiving HIV treatment.
Agenerase holds about 2% of the U.S. HIV drug market share (see
pie chart, below left).
Abacavir is a nucleoside analog reverse transcriptase inhibitor
with superior anti-HIV activity in the test tube. For some individuals,
twice daily dosing with a single tablet containing abacavir, 3TC
and AZT (a Glaxo product named Trizivir) can provide effective suppression
of viral load below levels of detection. This regimen is attractive
for those who wish to avoid protease inhibitors due to toxicity.
However, caution must be taken when initiating abacavir therapy.
A hypersensitivity reaction has been observed in about 3% of patients
who begin taking abacavir. Sometimes the symptoms of this drug reaction
can mimic those of the common flu. Serious adverse events may occur
if abacavir is reinitiated after discontinuation due to symptoms
of hypersensitivity reaction, whether recognized or not. Patients
have died after restarting abacavir. The potentially life-threatening
side effects and concerns about sub-optimal performance compared
to protease inhibitors are responsible for the drug's limited market
acceptance. Currently Ziagen holds about 5% of the U.S. market.
Initially, abacavir and amprenavir appeared to be attractive second-generation
therapies that addressed the need for simpler, less toxic and more
potent treatment regimens. One of the first AACTG trials of amprenavir
optimistically compared triple combination therapy to amprenavir
alone. Abacavir has been studied in a dual combination with amprenavir
and as an anchor drug in protease inhibitor-sparing regimens. Several
trials have employed the drugs as components of salvage therapy.
At least eight non-AACTG trials have studied abacavir at various
stages in its development and a similar number of non-AACTG trials
of amprenavir have been conducted. In the current round of AACTG
trials, amprenavir and abacavir are cast as intensifying agents
to forestall early virologic failure or as simple but potent first-line
treatments.
The Lineup of HIV Treatment Research at the AACTG
A) Five trials not using either amprenavir or abacavir.
Two of the ten open HIV RAC trials are investigating pharmacologic
or scientific questions. One trial, AACTG 317, which began in 1998
and is set to close soon, has been evaluating the effects of birth
control hormones on AZT metabolism. A recently opened trial, A5077,
is comparing changes in viral loads in the blood and other non-blood
compartments before and after initiating HAART.
Trial number AACTG A5076, which opened in late 2000, is a treatment
strategy trial comparing the selection of a second regimen after
virologic failure with and without guidance from phenotypic drug
susceptibility test results. A salvage strategy trial, A5086, is
designed for heavily pre-treated individuals experiencing virologic
failure. This study compares a strategy of immediately switching
to a regimen selected with the aid of resistance test results to
one of temporarily stopping all treatment for a period of time before
starting the new regimen. Another salvage therapy trial, A5055,
is investigating two dosing schedules of indinavir boosted with
ritonavir for individuals who have failed amprenavir, nelfinavir
or saquinavir.
B) Five trials using either amprenavir or abacavir
AACTG 371 is a trial of an intensive regimen of antiretroviral
therapy administered to recently infected individuals during primary
infection that will assess if viral load levels can remain suppressed
following a planned discontinuation of therapy. Each treatment arm
will receive amprenavir boosted with ritonavir and either abacavir
or abacavir placebo. One arm will receive amprenavir/ritonavir plus
abacavir with no other nucleosides. This trial opened in early 1998
and as of May 2001 had enrolled 32 of the targeted 120 subjects.
AACTG 371 has eight substudies attached to it.
A newly-opened salvage trial, A5061, is investigating the strategy
of treatment intensification for individuals starting to experience
virologic failure. Trial subjects will add either abacavir or amprenavir/ritonavir
to their current failing regimens. A similar trial, A5064, which
opened in 1999, is comparing intensifying the failing regimen with
abacavir or placebo. So far 15 patients have enrolled into this
80-person trial.
Another newly opened trial, A5095, expects to enroll over 1,100
previously untreated individuals into three treatment arms, each
containing abacavir or abacavir placebo. The abacavir is administered
as a component of Glaxo's triple combo, Trizivir. Participants will
also receive efavirenz or placebo. These individuals may also be
simultaneously enrolled into a separate Glaxo-sponsored study looking
for genetic markers associated with abacavir hypersensitivity.
One final HIV RAC trial currently enrolling is only accepting HIV-negative
individuals. This 90-person study, A5043, will investigate pharmacokinetic
interactions between amprenavir, efavirenz and other HIV drugs.
Subjects in this study are paid $1000 for their participation.
Past AACTG Studies of Amprenavir and Abacavir
As of May 1, 2001, three AACTG HIV trials involving amprenavir
or abacavir, AACTG 372, 384, and 400, are closed to enrollment but
have not yet been completed. AACTG 384 successfully enrolled nearly
1000 patients, but AACTG 400 was closed due to poor accrual after
only 21 of 300 expected subjects had enrolled during a three year
period.
Four additional HIV RAC trials, now completed, have also studied
the Glaxo drugs. One of these studies, AACTG 347, compared amprenavir
plus AZT/3TC to amprenavir alone. A subsequent study, AACTG 373,
compared amprenavir plus AZT/3TC with other treatment regimens for
people who had previously received amprenavir, primarily individuals
from AACTG 347. A salvage protocol, AACTG 398, added amprenavir
to other protease inhibitors or placebo in combination with abacavir,
efavirenz and adefovir. Finally, AACTG 368 investigated abacavir
combined with efavirenz and indinavir for individuals who had participated
in an earlier AACTG trial involving indinavir.
If at First You Don't Exceed...
Amprenavir and abacavir may be expected to continue playing significant
roles in the government's HIV treatment research agenda. Looking
ahead to HIV RAC protocols still in the planning stages, amprenavir
is proposed as part of a salvage trial comparing fixed-dose with
concentration-adjusted doses of protease inhibitors. Custom monitoring
and adjusting of doses to assure sufficient protease inhibitor blood
levels may have an important role to play in reducing virologic
breakthroughs due to individual metabolic variations. Kaletra, tenofovir
and DAPD are also slated to appear in several of these proposed
trials. Outside of the HIV RAC, Trizivir has been proposed as the
primary antiviral regimen in a trial of cyclosporin originating
with the Immunology RAC.
A water-soluble pro-drug of amprenavir, currently called GW-433908,
may allow improved amprenavir blood levels with a much smaller pill
burden by virtue of being metabolized to the active form in the
intestines. This new version of amprenavir has been selected as
the protease inhibitor in one arm of a proposed three-arm protocol
for salvage therapy and is also being considered for other protocols
in the conceptual stage. At least one protocol in development proposes
to investigate the safety and activity of abacavir administered
with mycophenolate mofetil, an immunosupressive anti-cancer agent
that may improve the competitive advantage of abacavir's active
metabolite within cells.
It's unclear if the current imbalance in AACTG treatment research
is due to outdated priorities that attained bureaucratic momentum,
an absence of critical thinking about these priorities, or lack
of vision within the leadership. At the very least, AACTG's leaders
have demonstrated a poor sense of propriety regarding apparent conflicts
of interest between government and industry.
Relative U.S. HIV Drug Sales — First
Quarter 2001
|
GSK U.S. HIV Drug Sales — First Quarter 2001
|
| AACTG Clinical Trials for HIV
Treatment — Currently Open (May 2001) |
|
AACTG
HIV Trials |
Description of Trial |
Currently
Enrolled |
Target
Enrollment |
Date
Opened |
| AACTG 317 |
The Effect of Birth Control Hormones on AZT Metabolism |
36 |
42 |
Jan-98 |
| *371 |
Intensive Antiretroviral Therapy with Amprenavir and Abacavir
During Primary Infection |
32 |
120 |
May-98 |
| *A5043 |
Pharmacokinetics of Amprenavir and Protease Inhibitors in
HIV-Negative Subjects |
6 |
90 |
Mar-01 |
| A5055 |
Indinivir Boosted with Ritonavir for Patients Failing Amprenavir,
Nelfinavir or Saquinavir |
28 |
50 |
Jan-00 |
| *A5061 |
Intensifying a Current Failing Regimen (with Amprenavir or
Abacavir) |
0 |
42 |
Dec-00 |
| *A5064 |
Intensifying a Failing Regimen with Abacavir |
15 |
80 |
Nov-99 |
| A5076 |
Switching Regimens with Phenotypic Susceptibility Results
or by Sequencing |
31 |
600 |
Nov-00 |
| A5077 |
Studying Viral Load in Blood and Non-Blood Compartments |
26 |
164 |
Nov-00 |
| A5086 |
Immediate versus Delayed Initiation of a New Salvage Regimen |
0 |
220 |
Feb-01 |
| *A5095 |
Comparing Protease Inhibitor-Sparing Regimens with Trizivir
and Efavirenz |
58 |
1125 |
Feb-01 |
| TOTALS |
232 |
2533 |
|
| *includes amprenavir or abacavir or both |
"What You Lookin' At?"
By Fred Gormley
Unlike Reinaldo Arenas, Cuban author of the AIDS memoir "Before
Night Falls", I'll never be on my deathbed writing about —
being on my deathbed. It's only after I've gotten to the safe side
of a tough situation that I can examine it. My recent experience
with HIV wasting is a case in point. It's over — for the time
being, thank God. Now I can milk it dry.
But first, meet me as a kid. A fat kid — 5 feet tall by 150
pounds wide — a tubby pouf sporting a pompadour and cowlick,
cockeyed horn-rims sprawled across my face, and black cotton X-PlodoPants¨
bursting at the seat. Let's face it, no junior queen wants to be
exiled to the fat kids' haberdashery, "husky" and "fashionable"
being oil-and-water terms. Intensifying the mix was my mother, a
woman concentrated on Maximum Presentability, social status be damned.
This is a lady who hauled out the spike heels, girdle and chignon
for K-Mart trips (Attention shoppers: talent scout in aisle 3!).
And it's not as if no one noticed; a plump sissy is an irresistible
target for bullies of all ages — other kids and adult men with
"issues" pounce with equal ferocity. Fortunately, by ninth grade
I had slimmed down, blended in, and haven't been overweight since.
But, O the scars run deep.
Leap forward a few decades and I'm a gay man in Manhattan, living
in a culture where presentation countsandcountsandcounts. I joined
a gym, cultivated pecs and washboards, and was able to say that
I was pretty damned pleased with myself (and, in spite of continuing
therapy, able to ignore that wretched chubby kid cowering deep in
my gut). As for buying into Gay New York's "looks are everything"
message, I was primed — clearly.
And so, the seasons danced by. If you're like me, as you grow older
— especially if you happen to mature at the same time —
it becomes natural for the workouts to grow less compulsive and
the need to keep on top of the edgiest trends, hottest labels, and
coolest stuff to ebb. Not that you've become immune to fashion —
it's still a priority, just not the priority.
Hear me well: I have nothing against looking good as I age —
but the Botox/lipo route just isn't for me. For one thing, I'm not
delusional. Martha Stewart herself can't hot-glue cotton balls to
a rat and call it a French poodle. For another, I'm old enough to
remember what happened to Totie Fields, a fellow diabetic. Since
I'd rather not be remembered as a dead, one-legged comedienne, elective
surgery isn't a good choice for me. I find simple merit in reaching
my half-century mark with something to show for it — a pulse,
for one thing; so many of my friends didn't make it this far. When
I go out, I'll be pleased to look like a really pulled-together
forty-nine year old — nothing spectacular; certainly nothing
flashy — absolutely nothing scary.
Boo!
I've been scary — twice. Which is to say that in the past
three years I've had two episodes where I've become so thin that
people stare. Now, I don't have a press agent to deny the obvious
("She's not too thin! She's a natural size zero!"), nor do I possess
the anorectic's trick of discerning something other than the mirror's
horrible truth. When I'm deathly skinny, I see it. Cheekbones spike
where I had none. I stare out through vacant eyes and crack a tight
rictus when an easy smile is called for. I read it on the scales
— no "well nourished" adult man of 5'8" weighs 120 pounds.
I feel my 29"-waisted pants slip past fashion's boundaries, and,
Jesus, even my hair looks burdensome and false, as if I'm balancing
a fresh batch of Dynel to sell in the village marketplace.
I also see other people seeing it. Folks who've known me for years
and remember what I'm supposed to look like fail to find the words
when we meet, horror trumping candor. I don't mind when they freeze
up or when they tiptoe around it. (I actually yearn for someone
to blurt out, "Yo, Calista! You servin' sauce with those ribs?"
so I can wittily crack wise.) But mostly, people cringe. That hurts,
and causes me to shun the day. My inner butterball wants to curl
up into a lump, pull down the shades and sleep for a week.
How does this happen, this wasting? Why has this happened twice?
I didn't catch on the first time, but I think I've finally figured
it out. Both times, my meds — or rather my uncanny ability
to tolerate large dosages and many pills —have gotten me into
trouble. Instead of discovering that my body is hurting soon after
beginning a new regimen, I can go for months, adding a bonus PI
or experimental nuke now and then, perking along just fine. And
then, imperceptibly at first, my body turns against me.
The pleasure of food begins to wane; nuance and subtlety going
first, until finally everything tastes like the box it came in.
Pounds slowly start to drip off like wax down a candle. The less
I eat, the less I'm able to keep down, and the spiral continues.
Nausea becomes a constant comment. Incontinence is the norm. Soon,
weight that has been slinking away suddenly starts flying off. Attempts
to add bulk with power-packed canned shakes achieve maintenance
at best. Elation gives way to frustration as the few pounds gained
during the day disappear overnight as if I'd spent eight hours jumping
rope instead of sleeping. Back where I started. Double Dutch bust.
In 1998, NBC Nightly News interviewed me at home on the eve of
that year's International AIDS Conference. The word had been dribbling
out that protease inhibitors, much touted, didn't work for everybody.
Resistance threatened to sink our ship of hope. As one of the "failures,"
they wanted to spend a few hours with me to see how's doing with
the terminally flunked. So a producer, a cameraman and a soundwoman
trooped into my apartment while I displayed my overflowing medicine
cabinet like a demented game show model (You've won a year's supply
of Imodium!). Ever the gracious host, I made a huge bowl of gazpacho
(which I had no appetite for, of course, but the crew devoured)
and expounded on my dismal prospects. As expected, two hours of
relative congeniality was pruned to a cranky 10-second sound bite.
But far more appalling was seeing my skinny self on TV for the first
time: old, tired and emaciated. It was truly an "Interview with
the Vampire" moment and I prayed that the folks back home weren't
tuned in.
Thankfully, the family didn't see me then, and there would be no
homecoming this go-round, either. A surprise appearance in my condition
would have been like a visit from a funhouse prop. Not that I was
anxious to sit still for a four-hour train trip — in my current
condition a subway ride across Manhattan was a vomit-inducing, diarrhea-restraining
ordeal.
Besides, I was stockpiling the Imodium for a real vacation —
a week in the desert near Palm Springs. My friend, Mike, has a place
on the edge of Joshua Tree and I was much looking forward to a serene,
meditative, high-desert experience. But at 5:00 a.m., two days before
the flight, my eyes popped open and I knew, right then, that there
was no way I could tolerate a five-hour plane trip, much less the
cab to the airport. I was defeated, and since I couldn't swallow
much of anything else, I swallowed the cost of my non-refundable
tickets. Then, on top of feeling sick and depressed, I became angry.
When I get angry, I get arbitrary. So I stopped my HIV drugs. All
of them. All at once. Need I tell you, taking six antivirals is
a lot of heavy-duty medicine (my doctor calls it "do-it-yourself-chemo").
I was on Agenerase, Kaletra (which includes ritonavir), Epivir,
Zerit and tenofovir, not to mention pills to counter the side effects
and more pills to prevent the opportunistic infections I'm susceptible
to, all topped off with daily insulin injections. Dropping the "big
guns" turned out to be an inspired move — within twelve hours,
I had regained my appetite, energy, taste, and even a little enthusiasm
for life. To careen from several months of 'round-the-clock feeling
lousy to abrupt normalcy gave me fresh insight into the word "gift".
My doctor, it turned out, supported my impromptu strategy. I'll
avoid the heavy-duty drugs for a while, then select a new regimen
(though I can't imagine what. After years of dosing, my virus was
no longer susceptible to any available treatment). I'll probably
choose something that doesn't make my toes tingle and lets my triglycerides
return from orbit. One recent bit of good news is that even staying
on drugs that have failed can help keep the virus in check. And,
this just in, according to the Phenosense report, I've developed
a sudden, inexplicable sensitivity to Rescriptor, of all things.
Life looks bright.
Now that I'm on the other side of this episode (I've gained 19
pounds in the past few weeks), I'm dealing with some lingering questions.
The fat little boy — the skeletal man — are they two versions
of the same creature? Do I have a set of inverted values working
here, where whether or not I look right is of more significance
than my underlying health? Possibly. After a point, living with
this disease — as much as it constantly reminds me of its presence
and even though I know it could finish me off — becomes a tad
dull. Why shouldn't health issues and the mundane, quotidian cares
of life, like "How do I look?" equalize over many years? Do I deceive
myself into feeling good, even as I'm rotting away internally, so
long as it doesn't impinge upon my comely form? Is my secret to
tolerating a quantity of drugs sufficient to stun a horse due to
good old-fashioned mind-body separation?
Frankly, I wouldn't be unique. I know many gay men, total knockouts,
whose glittering surfaces belie the deterioration within. It's the
old Dorian Grey thing — a confident faŤade concealing a decrepit
interior; Poe's House of Usher with vinyl siding. Or maybe (because
he has to share such cramped quarters with all of that virus in
there), it's The Revenge of the Fat Little Queen.
How to Read a Scientific
Paper
By Carlton Hogan, University of Minnesota, Coalition for Salvage
Therapy
(Second of a three-part series)
Part Two:
Filling in the Blanks
In Part One we looked at how a scientific paper is organized. Now
we can continue to the interesting stuff — the actual contents.
Of the thousands of papers published each year, some are far more
reliable and relevant than others. There are specific characteristics
to look for when deciding which papers to trust and base important
decisions on. Last month we learned that prospective trials are
more generalizable than retrospective studies and that some authors
carry more weight than others. This time we begin, naturally enough,
with endpoints.
Endpoints. What Do We Really Care About Here?
The term "endpoint" is an unfortunate choice, and confuses many
people. Endpoint sounds like it means the end of the trial, and
in a few cases, it might. A far better, but less memorable term
would be "key data item". That's all endpoints are. They are the
information that is most important to the purpose of the trial.
When a hypothesis, or the main question that drives a trial, is
set up, the endpoints are defined as the information necessary to
answer that question. Endpoints in HIV treatment trials may include
the occurrence of AIDS related conditions, death, serious toxicity,
or CD4 count and viral load thresholds. They are the essential measurements
that must be recorded, those that are critical for answering important
questions about a drug.
Endpoints are divided into primary (or main) endpoints and secondary
endpoints. Generally, but not always, a trial will have one primary
endpoint. It is the single most important piece of information to
be obtained, and trial design decisions should be made to best guarantee
getting accurate information on the primary endpoint. As you recall,
in our X-100 trial, viral load is the primary endpoint. All other
measures taken in our study are secondary to this main variable.
There should be no trial procedures or other design considerations
that interfere with getting the complete and accurate information
on viral load.
Generalizability and Eligibility
As we learned in Part One, a study is only useful to the "real
world" in proportion to its generalizability. This is the degree
to which a trial's findings can be applied to a wider population
outside of the trial participants. For any particular study, the
answers we get only refer to the people who were in that particular
trial at that time. Even if we redid the trial with all of the same
people at another time, the answer could be very different.
The extent to which we believe that our study findings can be helpfully
applied to other people who are similar to those in the trial is
perhaps the most important quality a study can have. If the results
can't be generalized, the trial is a sterile, abstract experiment
of no relevance. Once generalized, though, trial results can become
important factors not only in helping people make decisions about
care and treatment, but also by suggesting and helping to explain
additional research.
It may seem obvious that exactly who gets studied makes a big impact,
not only on the results themselves, but also on the later interpretation
of those results. The broader the eligibility criteria are, the
more diverse the group enrolled — the broader the population
to which the results can be extended.
Some studies call for a broad representation of possible patients
among the participants, whereas others study a very narrow range
of people. For example, if you wanted to know how useful our imaginary
anti-HIV drug, X-100, is for adults failing therapy with protease
inhibitors, you would have a problem if you only enrolled men. The
answers you received could not be applied to women with much confidence.
So for that particular question, you would have seriously failed.
But if you wanted to study X-100 in men alone (Who knows? Maybe
it had testicular toxicity in rats), then narrowing the eligibility
criteria makes sense.
Some eligibility restrictions are simply prudent. You'd never want
to enroll people who are highly likely to be harmed by a trial.
For this reason, persons with high liver function test results (also
called LFTs, transaminases, SGOT, SPGT, ALT or AST) are often excluded.
The intention is to avoid having persons who are likely to suffer
serious toxicity to be among the very first to try a new drug. But
sometimes there's a trade-off between protecting trial participants
and producing results that will be relevant. Many people with HIV
also have the hepatitis C virus (HCV), so persons with impaired
liver function will use the new treatment eventually. How will the
trial results apply to them? Fortunately, there is an increased
awareness of these issues, and most trials involving HIV+ people
have relaxed the eligibility rules about liver function, while still
barring those at imminent risk of suffering harm. The result is
research that benefits a broader range of people who are actually
likely to use X-100.
Human trials can be placed on a continuum from the highly restrictive
"lab rat" type studies, where intense efforts are made to control
every possible variable to "public health"-oriented trials that
intentionally seek diversity in order to mirror the populations
in which a drug will eventually be used. Both kinds of studies are
necessary and neither approach is "right". Each has unique benefits
and drawbacks, and they are used to answer very different kinds
of questions.
For example, if we wanted to know about the activity of X-100,
we would study its pure antiviral effect under conditions divorced
from "real world" issues such as adherence, interactions with other
drugs, the effects of gender, age, etc. We would try to control
all those variables as much as possible, to see what X-100 can do
under the most optimal conditions. This approach also excels at
studying other kinds of questions. If we wanted to know the "why"or
"how" of differences in a drug's activity between different groups,
such as women and men, being able to hold most variables steady
while changing one allows a precision we could never achieve with
a more diverse set of people and circumstances.
On the other hand, if what we care about is X-100's efficacy (the
degree to which it works under more "real world" circumstances),
we would try to create a study population that mirrors the range
of persons in which X-100 may eventually be used. If we overly restrict
enrollment, we may end up with results that have far less applicability
for public health. For example, if we arbitrarily said "no redheads!"
in the X-100 trials, I personally would be nervous about taking
X-100 if I had red hair. That is, of course, a frivolous example.
But restrictions on gender, liver function, previous treatment history,
or "substance abuse" may end up screening out those who most need
X-100.
Eligibility criteria are generally divided into two sections: "inclusion"
and "exclusion" criteria. The first tells who can get in, the second
describes who cannot. Sometimes it's not clear which category a
particular criterion belongs in. If our X-100 trial enrolls persons
with CD4 counts greater than 50, we can state "CD4 >50" as an inclusion
criterion, or we could use "CD4 <50" as an exclusion criterion.
As a general rule, though, inclusion criteria define the population
the trial intends to represent, while exclusion criteria define
the exceptions to that rule (for example, persons whose impaired
liver function puts them at high risk, even though they meet all
the other criteria).
The Lust for Power
A study's size is very important, for several reasons. As described
above, evaluating a drug for "real world" efficacy requires a diverse
study population — and the practical effect of achieving diversity
is that a lot people need to be enrolled. But far more important
than this practical problem, is a statistical concept called power.
Plainly put, the more persons you are able to observe, the higher
the power, and the more certain you can be that you will detect
an effect due to X-100, if one really exists. Increasing the power
also protects against mistakenly deciding that X-100 provides a
benefit when in fact none exists.
No matter how many people are enrolled in a trial or how long a
trial continues, you can never be absolutely certain you have found
the one and only "right" answer. But you can increase your confidence
that you have most likely obtained the right answer — or one
that is very, very close to the imaginary "true" answer. Large trial
sizes, and power, are a big part of achieving that.
Flip Out!
Let's leave X-100 aside for a minute, and talk about coin flips.
Pretend you are an alien, and know nothing about flipping coins.
Being a nerdy alien, you want to calculate the odds of getting a
"head" after any particular coin flip. Your friend, another alien,
decides you should do an experiment, a "trial", to learn how coin
flips actually work. He flips the coin one time, and gets heads.
If he was a statistically impaired alien, or one of our Congress
members that opposed sampling in the last census, he might just
let the issue die there, and say, "The odds are 1/1 (one out of
one). That's 100%! It is certain that I will get a head on the next
flip!"
But you are not so easily fooled. You, on the other hand, are a
rather more sophisticated alien, and you want to investigate a bit
deeper. So you flip again. Another head. Hmm. Well, maybe your easily
satisfied colleague was right. Or was he?
Most earthlings know that the odds of getting heads on the first
flip are 1/2 or 50%. Getting heads the next time is also 1/2, and
together there is a 1/4 chance of getting two heads in a row.
Well, you (the curious alien) say, "Hmm. Two heads is pretty convincing.
But I want to be sure," and flip again. Tails this time! Your colleague
says, "Oh, wait, I was wrong. The odds are 2/3 of getting a head."
Well, his reasoning is still wrong, but notice how his answer comes
closer to the "true" answer?
You keep flipping. You get HHTHTTTHTHHTHTTHTHHTHTTH. The fraction
(per flip) is getting closer to, and sticking closer to, 1/2 or
50% with every new flip. The more information you have, the more
certain you are of getting closer to the "right" answer.
Meanwhile, our alien colleague may not be so dumb after all, just
hasty. He sits back, watches the flips, and frantically scribbles
numbers. He gets the following sequence of fractions (see chart
at right):
Eventually, he gets the right answer. His initial problem was "confusing
the map with the territory" — that is, thinking that the answers
he got from his test coins said something with certainty about all
coins. But you, the curious alien, realized that although you cannot
predict how any particular coin toss will come out, you can still
make an excellent estimate as to what will result from an extended
sequence of coin flips.
If you look at this series of numbers, you may notice that they
oscillate above and below 50% with each toss, which emerges as the
center of the oscillations (see chart at right). As you accumulate
an increasing number of coin flips, the amount by which your result
differs from 50% gets smaller and smaller. Minor variations from
this pattern are to be expected. There's a little deviation from
that pattern after the seventh flip with three consecutive tails
in a row. Our gullible colleague, if he had only seen those three
flips, would be sure that all coins always come up tails —
exactly the opposite answer he got from seeing the first two flips!
Little wobbles like this happen in real life, so it's important
that clinical trials include enough people, and run for a long enough
time, so that temporary imbalances don't fool you. But even with
such minor variations, on average, as you flip more and more coins,
the results you come up with get closer and closer to 50%.
To put it even more simply, the more information you have, the
closer your estimate will come to the "truth" (our colleague never
realized he was measuring an estimate — he thought he was measuring
"the truth"). The fact is, you would need to keep flipping that
coin for infinity, past the end of the earth and the death of the
sun, in order to get near the "real" truth that the answer was 50%.
Most sensible beings, though, would hang it up after a couple of
hundred, or even a few dozen throws, when it becomes clear that
if the "true" answer isn't 50%, it's pretty darn close!
What does this have to do with science papers?
Exactly what does all this flipping coin flipping have to do with
AIDS research, you ask? By watching our aliens toss quarters, we
are now ready to understand most of the scary statistical concepts
that affect our confidence in the results of clinical trials, like
sample size, significance, p values, 95% confidence intervals, and
all kinds of other forbidding terms. As nasty and mathematical as
this stuff seems, understanding a few simple notions can really
help you judge the credibility and significance of the studies you
read. In every study, information is provided that, in essence,
describes how many times the coins were flipped and how far the
results wobbled around the true estimate. This information gives
crucial information about how trustworthy an answer is, or conversely,
how likely it is that the results are wrong.
Let's pretend that rather than wanting to know about coin flips,
our aliens want to know what the average CD4 count is for earthlings.
So they go on an abduction spree and start counting CD4 cells. They
choose a city and cruise through it, sampling the locals, collecting
more and more CD4 counts. Occasionally they get a PWA, and the average
drops; sometimes a person with lymph cell cancer has an abnormally
high reading which nudges the average up. But overall, the average
CD4 count swings back and forth in smaller and smaller increments
as more samples are collected. As it turns out, during their travels
they pass through an HIV clinic, and get a string of lower CD4 counts
— this is similar to getting three tails in a row. If the HIV
clinic had been their first stop, then in the beginning they would
have gotten a measurement that was far lower than the "true" average
CD4 count of everybody on earth. But later, after they had collected
measurements from a more diverse population, these early abnormalities
would even out. If the HIV clinic had been their last stop, though,
the low CD4 counts of the clinic patients would have had very little
effect on the overall average, just as the later coin flips caused
that average to deviate from 50% in smaller and smaller amounts.
To finish up and relate these concepts more clearly to clinical
trials, we will need to introduce a third alien with an incredible
"head-changing" ray gun. But I jump ahead.
In Part 3, we'll look at the effect treatment has on our results
and how we can tell if our trial results have statistical significance.
| First flip (heads): |
1/1 = |
100% |
| Second Flip (heads): |
2/2 = |
100% |
| Third (tails): |
2/3 = |
66.7% |
| Fourth (heads): |
3/4 = |
75% |
| Fifth (tails): |
3/5 = |
60% |
| Sixth (tails) |
3/6 = |
50% |
| Seventh (tails) |
3/7 = |
42% |
| Eight (heads): |
4/8 = |
50% |
| Ninth (tails): |
4/9 = |
44% |
| Tenth (heads): |
5/10 = |
50% |
| Eleventh (heads) |
6/11 = |
55% |
| Twelve (tails): |
6/12 = |
50% |
| Thirteenth (heads): |
7/13 = |
54% |
| Fourteenth (tails): |
7/14 = |
50% |
| Fifteenth (tails): |
7/15 = |
46% |
| Sixteenth (heads): |
8/16 = |
50% |
| Seventeenth (tails): |
8/17 = |
47% |
| Eighteenth (heads): |
9/18 = |
50% |
| Nineteenth (heads): |
10/19 = |
52% |
| Twentieth (tails): |
10/20 = |
50% |
| Twenty-first (heads): |
11/21 = |
52% |
| Twenty-second (tails): |
11/22 = |
50% |
| Twenty-third (tails): |
11/23 = |
48% |
| Twenty-fourth (heads): |
12/24 = |
50% |
|
24 Coin Flips
|
Video Killed the Radio Star
(but Klaus Nomi died of AIDS)
By Bob Huff
On phone kiosks and bus shelters around New York recently, last
year's ubiquitous Zerit and Sustiva ads have been replaced by close-up
photos of concerned faces, each overlaid with a Big Message: "You
need to know about MTV" or "Can you get MTV from Kissing?" These
ads for MTV are lifted from early AIDS information campaigns that
spoke to the general public's fear about a scary new disease. The
new ads tap into this nostalgic quality, camping on naive fear the
way 1950s A-Bomb and marijuana notions became objects of parody
in the seventies.
It's a clever spin. The acronyms rhyme, both HIV and MTV owe much
of their success to the lure of sex, both found a susceptible demographic
among youth, and both have spread across the globe like, well, viruses.
And each is marking its 20th anniversary this year. The parallels
are rich; someone should write an essay.
I wonder, though, how does this campaign play? Are these old AIDS
awareness nuggets freshened by MTV sensibility? Is there a prevention
message here? Or is it all a joke? MTV seems to presume that its
viewers know you can't get AIDS from kissing; that you can't tell
if someone has HIV. Aren't folks more sophisticated these days?
In the late eighties, MTV featured specials on AIDS and gay love.
I don't know how they're doing lately. Do they run condom ads? Are
these bus shelter ads too clever or not clever enough? I just can't
tell. I don't know if MTV will be around in twenty years, but, sadly,
I'm certain HIV will.
AIDS Clinical Research
for New Yorkers
The recent publication of HIV/AIDS Clinical Trials: A Directory
for New York State by the Community Research Initiative on AIDS
(CRIA) is something of a revelation. Measured by sheer quantity,
HIV research is thriving, with 126 clinical trials listed at sites
throughout New York, including trials accessible to New Yorkers
being conducted in Connecticut, New Jersey, Philadelphia, and at
the National Institutes of Health (NIH) campus in Bethesda, Maryland
(which pays airfare).
This comprehensive directory is designed for ease of use, with
one trial listed per page in a clear and consistent format. The
key drug or condition being studied is stated prominently at the
top of each page. Broad inclusion criteria are highlighted —
previous treatment experience, CD4 count and viral load — along
with a brief description of the trial's design and duration.
More complete entry criteria are detailed separately followed by
a list of study sites, contact names and phone numbers. The directory
is available without charge to people living with HIV and service
providers.
To obtain copies, contact:
Community Research Initiative on AIDS (CRIA)
230 West 38th Street, 17th Floor
New York, NY 10018
212/924-3934, ext. 123
www.criany.org
What is being studied?
This directory provides an interesting snapshot of the kinds of
HIV/AIDS research ongoing in this country. Here's a brief analysis
of what's being studied with a few highlights:
- Pediatric trials represent 25% of the listed trials. (In the
chart below right, pediatric trials are grouped together and include
anti-HIV treatments, immune therapies and treatments for associated
infections and conditions in children.)
- Of trials for anti-HIV treatments in adults, nearly half are
for approved drugs; with a third investigating nine new treatments
at various pre-approval stages. Overall, 10% of the 126 trials
are for new drug treatments.
- About a quarter of adult trials are studying treatment management
strategies such as treatment interruption and intensification.
- A surprising number of trials (see chart below left) are early
phase safety and efficacy studies of new agents for treating HIV
or its opportunistic infections.
What HIV CLinical Research is Available to New Yorkers?
What Kind of Studies Are Being Conducted?
istu |
What Kind of Treatments Are Being Studied?
|
A Treatment Issues
Editorial
It's Time for New Leadership at the AACTG
The U.S. government's premier clinical trials group for studying
HIV therapies is adrift. The HIV Research Agenda Committee (HIV
RAC) of the Adult AIDS Clinical Trials Group (AACTG) sees its mission
as performing small, scientifically challenging studies that quickly
respond to emerging questions about HIV pathogenesis and treatment.
In reality, its studies seem to respond to an entrenched leadership's
myopia, powerful drug company interests and an institutional need
to justify expensive technical resources.
AACTG protocols are slow to develop and often lag behind critical
questions when finally launched. Once open, many AACTG trials fail
to enroll patients due to therapeutic irrelevance, complex treatment
schemes or unrealistic entry criteria. Many of the trials currently
open to enrollment derive from concepts that entered development
in the late nineties — and several trials opening during that
period have languished from lack of interest.
Of the six AACTG HIV-disease trials currently offering drugs to
participants, five include the GlaxoSmithKline HIV products, Agenerase
or Ziagen. These approved medications have failed to catch on with
clinicians and patients due to an unpleasant pill burden or fears
about toxicity, and they rank near the bottom of U.S. HIV pharmaceutical
sales. Yet multiple studies of these two drugs, arguably more appropriately
sponsored by the manufacturer, seem to be a priority for the AACTG.
This should raise a question about the degree that Glaxo's interests
are represented at the AACTG. Dr. Robert (Chip) Schooley, Chair
of the AACTG's Executive Committee, participated as a non-AACTG
investigator on two early Glaxo-sponsored trials of Agenerase and
Ziagen — the two drugs dominating current AACTG treatment trials.
One could argue that Dr. Schooley's experience with these drugs
in the Glaxo trials convinced him of their potential importance.
Yet, despite increasing discussion in medical journals about the
problem of improper pharmaceutical industry influence over academic
research, AACTG leadership has clearly failed to appreciate the
appearance of a conflict of interest in this case.
The Chair of the HIV RAC at the time these AACTG trials were developed
was Dr. Daniel Kuritzkes, an associate faculty member at the University
of Colorado Health Sciences Center in the Division of Infectious
Diseases. Dr. Schooley is the head of this division. As Chair of
the AACTG's Executive Committee, Dr. Schooley, along with Dr. Constance
Benson, a full professor in Dr. Schooley's division, have exerted
a powerful influence over research priorities at the AACTG. This
concentration of power in one department at one university and the
possibility that a subordinate role on the faculty affected Dr.
Kuritzkes's independent direction of the HIV treatment research
agenda is troubling.
The problems with the AACTG may ultimately have more to do with
its structure than its leadership. Once every five years, the AACTG
applies for several hundred million dollars in government funding.
The Group's application undergoes a nominal review, but with no
other network in competition, it is invariably refunded. Then, for
the ensuing five years, the AACTG is left to manage itself, with
little specific peer-review of its scientific hypotheses, proposals
or progress. One could argue that this system creates an atmosphere
ripe for intellectual complacency, if not worse.
One idea for reforming the AACTG proposes that NIAID no longer
try to maintain a standing network, but instead ask individual institutions
to apply for grants in collaboration with other institutions to
answer specific clinical research questions. These resulting 'virtual
research networks' would be more adaptable, could be constituted
with specific expertise and resources to answer particular questions,
and be disassembled after a study was complete — a new network
arising to answer the next clinical dilemma.
Innovative research proposals remain scarce among AACTG concepts
in development. A publicly funded trials network unable to step
up to fundamental questions such as "How do immune responses differ
in women,"or "When should one start taking HIV drugs?" is avoiding
its duty. But when a key part of that program commits half its capacity
to seek incremental knowledge about a single manufacturer's products,
it is derelict and needs to be overhauled.
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