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Past Issues
Volume 15, number 11/12
November/December 2001
Contents
There's More to It Than Cheaper Drugs
Diagnostic tools are pricey, too
The Gift that Keeps on Kvetching
I left my brain to science
The Hepatitis B/Adefovir Match-up
Investigational drug may offer effective alternative treatment
ICACC in the Abstract
What's HIV-relevant at the conference this year
Once-a-Day Dosing
Is 'easier' always better?
Transparent Motives
A Treatment Issues editorial
Low Cost Diagnostics
By Bob Huff
There's still no reason to cheer, but in parts of the developing
world drug prices are coming down. Price reductions offered by the
major pharmaceutical manufacturers in response to competition from
generic drug makers are allowing a few small governmental and private
treatment programs to move forward. With easing of the drug supply,
questions about how to offer low-cost diagnostic and monitoring
tools for guiding HIV antiretroviral use in limited resource settings
are now starting to be addressed. While commodity priced diagnostic
tests may be coming on the distant horizon, in the near term, laboratory-dependent
assays in resource poor settings will be used sparingly — if
used at all — and may remain out of reach for day-to-day medical
management.
Unfortunately, the cost and availability of HIV diagnostic and
monitoring assays aren't likely to bend to the same market pressures
that are bringing drug prices down. In contrast to the ease of making
and distributing medications, most current HIV laboratory diagnostics
require blood samples to be collected, preserved and transported
to a central facility for processing by trained technicians using
expensive technology. The test results still need to be transmitted
back to a medical provider in the field who is qualified to interpret
the results and make an informed judgment about what should be done.
If weeks have passed and the patient is no longer in the area or
if there are no new drugs available to respond to a need for a change
in regimen, then the expensive test result has been wasted.
It is now accepted that triple combination therapy, when prescribed
and monitored by an expert provider, gives the best results in terms
of sustained suppression of HIV with minimal toxicity. Although
current generation treatments are not perfect and require a lot
of management and laboratory resources to get optimal results, even
the simplest 3-drug regimens given by rote are adequate to prevent
death for many in the near term. Still, even in the rich countries
of the world, optimal results are not universal. Poor adherence
and viral resistance frequently send patients back to their doctors
for more testing and a new lineup of drugs. Emerging toxicities
need to be identified and treated with a change in strategy or medication.
Although these problems can often be caught and corrected without
serious clinical consequences, the costs of increased utilization
of expert and technical resources are significant.
In rural Haiti, a small pilot project by Partners in Health has
been demonstrating that antiretroviral drugs, when given with directly
observed therapy (DOT), community support and guidance from a trained
healthcare provider, can be successfully offered with no special
lab monitoring at all. But what are the acceptable limits of unmonitored
antiretroviral therapy in less supportive settings? As Joep Lange
of The University of Amsterdam said at a recent meeting on affordable
diagnostics sponsored by GMHC in Bethesda, Maryland, "we may lose
2 out of 100 patients treated due to drug toxicity, but we will
lose 100 out of 100 patients who never receive treatment."
(Notes and slides from the meeting will be available at
www.gmhc.org.)
Spokespeople for the pharmaceutical industry have in the past defended
the refusal to lower drug prices by citing the absence of monitoring
infrastructure in developing regions. Now it is clear that the availability
of drugs is driving the formation of support resources, not the
other way around. As drug costs continue to drop, barriers to treatment
should continue to fall and treatment can be extended to an increasing
number of the 40 million people who need it most. But just as lack
of diagnostics should not be a reason to withhold treatment, the
increasing availability of drugs should not be a reason to stop
seeking better and cheaper assays and simpler clinical management
plans.
What do the Diagnostic Tools Diagnose?
Laboratory tests and assays are used by doctors to evaluate a patient's
general state of health, to warn of the need for prophylactic care,
to decide if antiretroviral treatment (ART) is warranted, to track
the recovery of health after treatment has begun, to monitor the
ongoing success of treatment, and to identify treatment toxicity
before serious symptoms arise. For the management of HIV disease,
two special laboratory tests are commonly ordered in addition to
standard blood chemistry tests. CD4 tests count the number of a
crucial immune cell circulating in the blood; low CD4 counts tend
to predict disease progression. Viral load tests report the number
of HIV particles floating freely in the blood. Viral load counts
tend to drop after antiretroviral therapy has begun; a rising viral
load result may indicate that a treatment is no longer working.
In most Western countries, CD4 counts are performed by flow cytometry,
a technology intensive process of marking blood cells with fluorescing
antibodies then passing them single file before a tuned laser beam
that illuminates each specifically marked cell as it is counted
by a computer. Flow cytometers begin at $30,000 and individual tests
may cost upwards of $50.
The standard HIV PCR test for measuring viral load involves extracting
the viral RNA in a known volume of blood, amplifying the RNA through
several cycles of a polymerase chain reaction (PCR) technique, then
separating and tagging the amplified genetic sequences for quantification.
Basic equipment to perform PCR ranges around $20,000 and individual
tests can cost about $100 apiece.
In the absence of laboratory tests, clinical evaluation and syndromic
management (as practiced in rural Haiti) can provide guidance for
administering and monitoring treatment. A CD4 count can be very
useful for evaluating if a new patient should begin treatment, but
the decision to treat can also be made based upon a positive HIV
antibody test and a finding of weight loss, fatigue and perhaps
some minor oral symptoms. While this may be acceptable for one person,
another HIV-positive individual may feel fine until she develops
symptoms of pneumonia, meaning that she has reached a dangerous
state of disease progression.
The value of viral load testing also needs further discussion.
Consider an individual on a simple daily regimen of pills prescribed
by a regional doctor and dispensed by a respected community member.
Because the response to antiretroviral drugs is fairly predictable,
if adherence is good and she reports feeling better, a viral load
test may not offer much extra useful information. A viral load test,
though, is the best way to get early warning that high level drug
resistance is developing — before future treatment options
are compromized. Yet without followup drug susceptibility testing,
the only strategic option may be to switch every drug in the regimen.
Individuals who only have a partial virologic response will probably
need several confirmatory viral load tests to establish a trend.
Often having one viral load result leads to the need for another,
a problem if resources allow for no more than one per year.
For limited resource settings, a question could be posed: If you
could only have one test per patient, which would you choose? Baseline
CD4 count? The CD4 count after several months of treatment? Viral
load after a few months of treatment to see if it's working? More
research needs to be done to find out when lab tests are crucial
and when they are luxuries.
Location counts
No country is likely to be without any laboratory support, although
distance and cost may render the resource impractical for routine
use in the clinic. For example, several countries in Africa host
facilities that can perform tests equal to those offered anywhere
in the world. Such national centers of excellence (COE) are usually
linked in a partnership with a Western university or as part of
research collaborations with international health organizations.
These high-tech centers have the potential to offer validation and
quality control for laboratories at regional and district hospitals
but they lack the capacity to provide routine diagnostic support
for more than a few elite patients.
Examples of the lower and mid-range of existing diagnostic technologies
are increasingly being installed at regional-level hospitals, with
funding coming from foundations and committed governments. To sustain
these facilities, personnel need to be trained, maintenance provided
and reagents and supplies purchased on an ongoing basis. Regional
centers may have the capacity to process tests for residents of
the immediate urban area as well for blood samples transported to
them from district centers. But cost (a single viral load test can
cost as much as several months worth of drugs) and the delay involved
in receiving samples from remote areas limit these facilities. At
best, regional level service may be able to provide only a single
key test (such as CD4) per year for patients within its reach.
Outside of the regional-level hospital, existing standard technologies
are impractical to implement beyond a few pilot projects. Current
technology depends on equipment that is costly to purchase and maintain
and must be located near clean water and a reliable electricity
supply. Furthermore, existing commercial diagnostics all require
skill and interpretation at the point of use. A few lower cost alternative
technologies appropriate for district-level hospitals are available
and are being used — yet all have problems.
One simple and practical approach to the problem is to design a
dedicated CD4 cell counter using commodity level technology (i.e.
lasers similar to those used in compact disk players). The advantages
to automated flow counters include high throughput with excellent
reproducibility. If equipment costs can be brought down sufficiently,
such technology might make cell counting available at district hospitals.
Innovations on this front will probably require one of the current
makers of cytometry equipment to commit to entering the market in
this unexplored niche. Once this commitment is made, however, progress
should be rapid since the underlying technology is well understood.
Dynabeads is a method of tagging CD4 cells with antibodies linked
to tiny magnetic beads. The tagged cells are separated from the
blood in a magnetic field and counted under a microscope. Dynabeads
brings down the cost of equipment for counting CD4 cells to under
$10,000 — but the technique is slow to perform and requires
a trained human eye for evaluation. Under ideal conditions, the
test can correlate well with results from flow cytometry, but in
multiple tests this has varied greatly depending on the laboratory.
Although the precision and reproducibility of the Dynabeads technique
remains uncertain, it is commercially available and is being used
in Senegal and elsewhere.
Another diagnostic short cut receiving a lot of attention is the
potential for total lymphocyte count (TLC) to stand in for CD4 counts.
TLC is much easier and cheaper to determine than CD4-specific T-cell
counts and some researchers have suggested that low TLC, especially
when combined with clinical staging, may be a good predictor of
survival and can be used to help decide when to start treatment.
However, while very low TLC correlates fairly well with low CD4
counts, higher TLC does not — even though absolute CD4 counts
may be dangerously low. TLC also fails to correlate with viral load
and short-term response to treatment. Other researchers are investigating
the value of hemoglobin levels when combined with symptoms as a
predictor of clinical progression.
On the virus counting front, a number of alternatives to PCR appear
promising although no single product stands out as ideal. It may
be possible to modify existing viral load technology to simply give
a readout within clinically relevant ranges instead of reporting
absolute quantification. For example, to tell if therapy is failing
it may be enough to have a reading fall into one of three bins:
say, under 5,000, 5,000 to 50,000, or over 50,000 copies/mL.
Per test cost improvements may be realizable with existing commercial
products such as real-time nucleic acid assays for HIV (NASBA).
Optimized p24 assays that don't rely on PCR are also in development
but these tests need continuing comparative studies with established
assays to standardize and validate their use.
As in developed nation settings, blood samples collected in rural
areas or primary care clinics have to be preserved and transported
to the nearest laboratory. A breakthrough in low cost point-of-use
diagnostics will undoubtedly find a market in healthcare facilities
in all parts of the world. Until then, researchers in regions without
access to dry ice and FedEx are experimenting with techniques such
as dried blood spots for preserving and shipping samples under adverse
conditions of heat, humidity and long delay.
For diagnostic monitoring performed at the district level to become
feasible, new assays will have to meet very demanding criteria for
accuracy, cost and ease of use. But if assays are to become useful
at the point of care, then radically different criteria need to
be imagined and met.
Cheap tests for cheap drugs
The cost of existing diagnostic technologies can be marginally
improved by finding alternative sources of antibodies and test reagents,
removing taxes and tariffs, and negotiating price breaks. But existing
systems are not amenable to the kind of price pressure that has
brought drug costs down. The only HIV diagnostic tool that has met
the criteria for a cheap, easy-to-use commodity for field use are
certain versions of the HIV antibody test, in particular those which
use simple dipsticks to give rapid results from urine or saliva.
Disposable dipstick tests are also a promising candidate to achieve
commodity status for use in HIV treatment management. Mass-produced
dipsticks could report one or possibly two test results at an affordable
though not negligible cost (several dollars per test). Unfortunately,
developing these products requires going through an extensive and
expensive multidisciplinary industrial process. Hopefully the projected
size of the market for easy-to-use technologies — in both the
developed and developing world — will attract sufficient investment
to realize this potential. Dedicated dipstick assays for HIV management
are not likely to appear within the next five years.
In the same way that the cell-phone has allowed many less-developed
regions to leapfrog to world-class communications without the investment
in costly land-based telephone infrastructure, the criteria for
universal, low-cost, easy-to-use testing may only be met after the
most technically advanced product candidates are fully developed.
Though still in its infancy, microarray chip assay technology might
ultimately offer a solution to the most difficult-to-meet criteria.
Imagine a small hand held device like a Palm Pilot. Place a drop
of blood onto a window and insert a blank card. The sample is mixed
with chemicals and distributed into hundreds of tiny wells where
various chemical reactions take place. Within a few moments, an
optical device scans the wells, the computer analyzes the output
into a readable form and the results are displayed or transmitted
to the user. A single HIV multitest chip might tell a patient's
CD4 range, viral load range, detect abnormal blood chemistry, report
liver enzyme levels, and even tell if he has a genetic predisposition
for having mitochondrial toxicity from one of the drugs he is taking.
A palmtop reader will cost a few hundred dollars, and because the
quantities used are so small, the reagents and chip itself will
cost only pennies per test. This technology is still on the horizon
but in fifteen years it may bring excellent standards of diagnostic
support to the even most remote rural areas.
The Field Heats Up
Two recent meetings examined the need for cheaper and more accessible
diagnostic assays for managing HIV therapy in less-developed regions
of the world.
In October, at its meeting in San Francisco, the Infectious Diseases
Society of America sponsored a Conference to Develop an HIV/AIDS
Therapeutic Research Agenda for Resource-poor Countries.
In November, a workshop sponsored by GMHC and Project Inform, Monitoring
and Diagnostic Tools for the Management of Antiretroviral Therapy
in Resource-poor Settings, met in Bethesda, Maryland.
Here's one viewpoint from the IDSA meeting:
Wendy Stevens (University Witwatersrand, Johannesburg):
Currently there is diagnostic anarchy. There are no standards for
pricing and no standard algorithms for how and when to test. We
need to evaluate the cost of testing versus the cost of not knowing.
In South Africa, there is a critical need to make an early diagnosis
of infection in babies — especially orphans, since they are
far less likely to be adopted if they stay in the system until they
are eighteen months old. For this we need an assay that is 98 percent
effective by six weeks after birth — something that is as good
as multiple PCR, the current gold standard, but much more accessible.
So far P24 has not been successful.
Manual assays like Dynabeads for CD4 counts are impractical in
high prevalence areas because the throughput is too low. It is also
difficult to centralize testing in areas with poor roads. We need
trial designs comparing low cost assays to the gold standards. The
commercial products do not serve us. We need to stop depending on
big companies and be creative about the problem; start a biotech
initiative if we must.
We also need to better understand when to test. What are the best
time points for testing — before or after breastfeeding? For
example, why order a CD4 count while a patient has active TB? It
will be misleading. Should CD4 counts only be measured when patients
are well or upon admission to the hospital when they are likely
to be sick? Treatment decisions are made based upon these results.
We need to understand their relevance.
We need to establish a range of CD4 normal values from around the
world and understand what affects these values. Complete blood counts
(CBC) are different in different countries and depend on nutritional
status, TB and malaria prevalence. We need natural history studies
to correlate CD4 counts with symptoms.
We need to find out if virologic failure is really a disaster or
if changing early is better than waiting. People who are essentially
well tend not to have treatment failure or side effects. Do the
surrogates we are measuring really track the disease? Like diabetes,
treating HIV produces immediate changes in lab values but clinical
effects may not be seen for years. In HIV, death is the outcome
we care about — and it happens even faster for kids.
A trial of clinical monitoring versus CD4 monitoring for managing
ART (The DART Study) is expected to begin soon in Uganda and Zimbabwe.
Working My Last Nerve
By Fred Gormley
They say a journey of a thousand miles begins with a single step.
Well, my feet and I have been on poor terms ever since 1964 when
I snagged a toenail under the door and destroyed any potential they
had for becoming high-fashion open-toed shoe models. The nail grew
back deformed and talonesque, for which I've never been forgiven.
In a fit of pique, my crestfallen arches instantly went hurache-flat
(the left in solidarity with the right), leaving me with a distinctive
lumbering gait. If I didn't compensate I'd galumph along all the
time — think Jan Brady in high dudgeon; Gabby Hayes, panic-stricken.1
A couple of years ago, however, my passive/aggressive peds started
to demand attention, at first with discontented mutterings (vague
numbness), then with the silent treatment (no sensation whatsoever).
Since I can't stand being ignored I decided to look for help. HIV
and diabetes — my constant companions — are each in their
own right good reasons to seek out someone who can really appreciate
feet (not a fetishist, a doctor. If the doctor is also a fetishist
and you find yourself laced into a tasty pair of dominatrix spikes
underneath the hospital gown, think of it as a bonus). But since
this problem is really about nerves, my primary care doc steered
me to a neurologist at Mount Sinai Medical Center in New York.
My journey took me through the hospital's labyrinthine corridors
to the neurology center where, like a rat, I was rewarded with an
hour's worth of basic psychological tests, mallet strikes, pin pricks
and tuning forks. The diagnosis: peripheral neuropathy. Actually,
I'd long taken it for granted that I was neuropathic (is that a
word?) and never sought out diagnosis since there isn't much in
the way of treatment. Between diabetes and my HIV meds, we decided
the latter was the most likely culprit (I'd only been diabetic five
years, insulin dependent for three). Evidently, this kind of nerve
damage is a common complement to the 'd' drugs: d4T, ddI, ddC, which
were all at one time or another components of my "cocktail." (As
with any old-timer at The AIDS Lounge, I've had one too many.) My
particular form of neuropathy is the "negative" type; I experience
numbness and tightness in my extremities, but rarely the stabbing
pains that define "positive" neuropathy. My most immediate worry
is that the range of numbness will start to spread beyond my feet.
Presently, I have no feeling in either foot up to about mid-calf,
and lately, no reflexes in my right leg. (When the rubber mallet
struck my right knee the only thing it triggered was a memory of
the time the same thing happened to Homer Simpson.2 Tickled
by this thought, I reflexively said, "D'oh!" The examiner, apparently
not a "Simpsons" fan, gave it another whack.)
If I tread on small objects when I go shoeless across my Cher-white
carpets, I only feel pressure — anything else, sharpness, wetness,
hardness, all feel alike. This is dangerous because if I don't realize
when I've stepped on something hazardous... anything from a tiny
glass shard to a carelessly displayed Emmy Award3...I
might cause a wound, which could become infected and fester, grow
gangrenous and, finally, require amputation. I learned I needed
to practice proper foot- and toe-care techniques. Especially important:
close, daily inspection of my dogs. Leprosy patients get the same
instruction, the neurologist told me. It isn't the disease that
causes the loss of body-parts; it's an overlooked injury cascading
into irreversible necrosis. Necrosis, I'm thinking. That's like
the Borg in "Star Trek". Who needs that? (As you have probably
guessed, I frequently make important decisions based on TV shows.
This is why I require constant supervision).
Just as I was about to shuffle out the door, the doc provocatively
slipped me an understated green brochure entitled: "The Brain Bank".
I thought he was making a snide comment a la "The Weakest Link":
Who's been writing checks they can't cash? But it was actually
an invitation to make a deposit: a donor opportunity for people
with HIV/AIDS. I just assumed that organ donation as a legacy gambit
evaporated with my 1988 diagnosis. Of course I was thinking in terms
of reusable parts, say if someone out there needed a set of buffed
abs or he'd just die. I'd never thought about leaving a little
something to science, and now I was delighted to think that my brain
might be just the thing. So I called to set up an assessment interview.
First Assessment
First there was the issue of what to wear. Hmm. Brain Bank. Dark
blue suit? Maybe too severe. Anyway, assessment determines a potential
donor's history and present status — physical, mental and emotional.
After passing the labyrinth exam by finding my way back to the neurology
department's front desk, I was told I needed to find the Brain Bank
coordinator. The receptionist wasn't much help: she hadn't even
heard of the Brain Bank. After a few circuitous phone calls, the
B-Bank coordinator finally appeared and escorted me to a small,
windowless room in a completely different part of the hospital.
Next time, I swore, I'd bring along a couple slices of Pepperidge
Farm. Breadcrumbs may be the only way out of here because...Pepperidge
Farm remembers!4
Looking over one of the forms I needed to sign I immediately had
a question: What's the difference between restricted and non-restricted
organ donation? The Brain Bank, I was told, is primarily interested
in central nervous system tissues and, if I want, I can limit what
is harvested to these delicacies. However, other specialists around
the country are studying AIDS and the impact on cardiac or renal
tissues and might be able to use those tissues as well. My assessor
was careful to explain that the autopsy (I would get a complete
one — FREE!) would leave my body looking virtually undamaged
when turned over to my family for disposal — even without cosmetic
attention. I doubt this: As I said, for me, TV is real life, and
I've watched HBO's "Six Feet Under" often enough to know it takes
cotton, spackle and two premium cat food cans to make a corpse sparkle
with vitality.5 However much Fancy Feast my folks need
to get them through their loss it is absolutely fine with me.
Now it was my turn to answer questions. Somewhat more grueling
than filling out one of those "new patient" forms at a doctor's
office, but maybe not so challenging as the final round of the Miss
America pageant ("I have four T-cells and I adore stuffed children
and little animals. Wait a minute, I don't think that's right...").
I was asked what medications I've ever been on, and for someone
who's imbibed, injected or absorbed practically every HIV medicine
there is, remembering them all is beyond my current capacities.
For occasions like this, I keep a "current drugs" list on my PC,
with dosages and times; whenever something changes I update the
list, print it out and hand it to whichever new provider I'm seeing.
This is less troublesome than writing it out longhand and it gives
the impression I'm the 'ideal patient', when in fact I'm just a
caduceus-chasing suck-up — with computer skills.
The assessment process requires two visits. The first installment
probes abstract thought abilities through a battery of psychological
and memory exams. My favorite? A steel and black matte version of
the "square peg/round hole" game (Oh, Dawson! I just don't fit
in!). They can make them as sleek as they like, it's still PlaySchool
to me. I also enjoyed a game that featured a set of secretly evolving
rules as it progressed. This was supposed to determine how my frontal
lobes are functioning and evaluate "executive reasoning" I, who
have never been an executive nor particularly reasonable, did very
well on this. I was told that it infuriates many people, however.
Apparently they don't think it's 'fair' or something.
There are flashcards, word play, connect-the-dots — total
regressive fun, until we got to the stuff with numbers, math being
my lifelong enemy. Anyway, after about two hours of this, I felt
I could have just faxed in my SATs...high verbal, sixth-grade mathematics...and
gotten the same results.
After some routine specimen taking (blood, urine) as I was getting
ready for my milk-and-cookie break, they dropped the big one: Would
you be interested in undergoing a lumbar puncture (spinal tap)?
If you're imagining my horror, you've got the wrong nutcase, because
I wanted an l.p. Despite all the bad stuff, having AIDS (and being
fortunate to have excellent insurance) has introduced me to a host
of top-ranked specialists who usually happen to be great people
as well. And, since in the course of my normal health maintenance
I've had to undergo many fascinating procedures, this would add
one more to the list (collect them all!). Besides, it was optional;
having a spinal tap or not wouldn't affect my participation in the
B-Bank. Hey, I had a bone marrow biopsy done last year; it was chock-full
of useful information and not at all painful. Since I'd never had
a l.p. before I was curious about the resultant health data. It
would be performed by a specialist not some earnest medical student,
and finally, ...they would pay me! So we scheduled the tap for two
weeks hence. I ate lunch, filled out some paperwork, received my
laminated organ donor card6, collected my cabfare and
was outta there. Halfway assessed. Two and a half hours, tops (if
you don't count the time spent perusing marriage material among
the choicer scrubs).
Second Assessment
Friday, 11:00 a.m. and my lucidity surprised me. Most days, perhaps
intentionally, I'm vague and dopey till about noon, but here I was,
at the hospital on time, negotiating the Mount Sinai maze like a
lab rat with a GPS implant, heading for my destiny: answer a whole
lotta questions then take a big needle in my spine. Behold the strong
and stately sugar maple, alone in the forest surrendering its sap
for the syrup of science (uh, where's my insulin?).
My chief questioner this time was a psychiatrist. As I settled
in he produced a cassette recorder, turned it on, and we began.
I soon learned two things about this man: he was dedicated to this
work and he didn't forget anything. Early in the interview
he asked, "When was the worst period of your life?" And I had to
think back to a bleak couple of years around 1979 when my partner
and I were splitting up, oh so sl-o-o-o-wly. At least an hour later,
he rephrased his question in the context of depression and that
wasn't hard to pin down...1992: lost job, best friend dying, bankruptcy.
But you said 1979. I stopped and thought and went with 1992,
but in my mind I appealed: Can't I claim both?
Two-thirds of the way through, I started to become embarrassed.
I was coming off like Goody Two-Shoes. I don't drink (prohibited
by my medications), don't smoke (I did at one time; 1979, of course),
am sexually interested but barely active, and I've got a chest full
of gold stars from faithfully sticking to my dosing schedules, doctors'
visits, regular workouts, and meditations. This guy must think I'm
a total fake. What could he dredge up to reveal me as the fallible
human being I am?
Did Someone Say 'Recreational Drugs'?
Aha! Now here's something I can dazzle him with. Granted, my druggy
period...again, wrapped around 1979...was, in the context of the
time, dilettantism. I dabbled in speed, coke, hallucinogens and
hash, but abruptly stopped partaking following a bad experience
sometime around 1982.7 I was bathed in memories as I
listened to him read off the names: 'ludes, black beauties, poppers?
He asked about my frequency of use and it all came down to, well,
browsing. Except for poppers. I don't think he understood how amyl
was used, because his eyes widened when I said, "Maybe ten a week."
I, of course, was talking about ten hits. Finally I had revealed,
to great satisfaction (his and mine), my dark side. Ooo.
After nearly two hours of talk, the surgeon became available. Now
for some action. I happened to know this doctor well enough to trust
her (she administered some of the neuropathy tests during my foot
visit and performed the physical exam at my first assessment). So
we adjourned from the psychiatric barrage and negotiated the hospital's
maze to arrive at a room in the neurology department. Standard accommodations
— iron bed, TV and Spartan bathroom — exactly as I pictured
it. The comfy flounce of Laura Ashley was completely absent, thank
you God.
I was invited to 'gown-up'...told I could keep my underwear on
(how they presume!). I assumed the fetal position, curling on my
right side, was wiped down with Betadine, primed with anesthetic
and within minutes, the plumbing began. Because I didn't feel so
much as a pinch, I hadn't a clue as to what was happening back there
(were they installing a spigot?8) Oh, I understood the
general mechanics. I knew that spinal fluid doesn't normally jet
out the way blood does into a test tube...it dribbles...and that
sufficient, properly administered anesthesia is essential. If I
had felt pain, it would have signaled I was not adequately doped,
but...nada. For about fifteen minutes, I hunched there like a comma
trying to remember if the umlaut goes over the 'n' or the 'i' in
"This is Spinal Tap". Afterwards I was bandaged then advised to
lie on my back for a half-hour. The two most serious side effects
of the procedure are headache, probably due to the brain missing
its full measure of cushiony soft liquid, and, if done under unsterile
circumstances, possible infection. Asking around in anticipation,
I had heard stories about headaches that ranged from, chop my
head off, I beg of you! to ehh!. As for me, two days later,
if my head pulsed, it was vague and very localized and, handily,
a couple of Tylenol did the trick.
With the tap finished, I was shown one of the vials containing
my fluid, clear as a mountain spring (why did I assume cerebrospinal
fluid would have a yellow tinge?). But judging by its clarity alone
would have been a layman's guess...it could have been Prell, for
all I knew. But the doctor seemed impressed, so I took that as a
sign that "I did good", and fantasized about a contest for 'Best
Spinal Fluid', the way municipalities compete for 'Best Tasting
Water.' That my crystalline sample probably teemed with microscopic
HIV quickly deflated my fantasy. Oh what a polluted creature. Can't
give blood, can't donate organs to the needy, can't have unbridled
70's sex...I'm suffocating! But just as quickly my innate optimism
took over as I recalled that there is at least one person on this
planet who has it worse than I do (thanks, Mariah!).
As I was drifting into my reverie, the psychiatrist breezed in.
Apparently we hadn't finished the full interview, and now, wordlessly,
he set up his recorder. I let my inner monolog spill out for, how
long? — fifteen minutes?— about —what? I wasn't sleepy,
wasn't spaced-out, just extremely relaxed. I could've stayed there
forever, it seemed, drifting in the moment. You know, they actually
lose people in hospitals sometimes.9 If no one came back for me,
it would suit me fine.
I guess this proves your feet can only take you so far before the
brain (pushy organ) has to horn in on the act. But I love an adventure
and I can't wait for my next visit in six months. Six months of
TV. Twenty new episodes of "e.r.".
Footnotes
- Jan Brady was the second daughter on "The Brady Bunch" and Gabby
Hayes was the perennial sidekick to Roy Rogers. Rumor has it that
both these characters were played by comedian Larry Storch.
- Father in "The Simpsons" but also a major character in Nathaniel
West's "The Day of the Locust" (1933), though never described
as having a bright yellow complexion.
- "Academy of Television Arts and Sciences (A.T.A.S). Never,
ever forget the phrase "Emmy Award" is a registered trademark.
- Catch-phrase from old commercial, when the P.F. guy was still
around and we all believed that there really was some place in
New England called "Pepperidge Farm". At least I did. Until I
tried to move there.
- Episode 5; the pornstar who got electrocuted when her kitty
pushed an appliance into her bathwater. Accident...or happenstance?
- "Judy Garland: Me and my Shadows" (TV Film 2001): One of the
women who witnessed my document signing reminded me of Judy Davis
doing Judy Garland. Attitude, look, everything. Worth a trip to
the hospital. Break a leg.
- "The Saint"; classic 60's British spy series starring Roger
Moore. In this context, though, The Saint was the disco where
I had my final acid trip (I started hallucinating that all the
dancers looked like Roger Moore, so there's the tie-in, okay?)
- "This Old House", episode 1520. Norm goes nuts from doing the
same plumbing show for the 65th time and strangles the homeowner
with a tape measure (upcoming show).
- "The Golden Girls", episode 130: Sophia gets misplaced in an
elevator at the medical center. You can tell the year this aired
—1990 — by
- 1) Blanche's earrings; 2) Dorothy's clothes; 3) Rose's hair.
Just the Facts, Ma'am The National NeuroAIDS Tissue
Consortium (NNTC, or "The Brain Bank") was suggested in 1996 by
Diane Rausch of The National Institute of Mental Health as a response
to the scarcity of high-quality central nervous system tissue from
HIV people. The program, with standardized protocols was initiated
in 1998. There are four centers (some with satellite sites) nationwide...New
York, Los Angeles, San Diego and Galveston...and participants are
drawn from diverse populations.
For further information,including phone numbers, visit www.nimh.nih.gov/oa/nntnhome.htm.
Low-Dose Adefovir for the Treatment
of Chronic Hepatitis B in HIV-Infected People
By Douglas G. Brust, MD, PhD
National Institute of Allergy and Infectious Diseases
Hepatitis, or inflammation of the liver, is a frequent problem
among HIV-infected people that can have serious health consequences.
The disease has many causes, but generally originates from either
a viral infection that attacks the liver, or a toxin/medication
that damages liver cells. Viral infections commonly associated with
hepatitis include the hepatitides (hepatitis A, B, C, D, and E viruses)
and the herpes viruses (cytomegalovirus [CMV] and Epstein-Barr Virus
[EBV]). Alcohol (ethanol) is the most prevalent toxin that causes
hepatitis, and a long list of medications are associated with the
disease, including many HIV antiretrovirals (such as ritonavir and
nevirapine) and cholesterol lowering drugs (such as atorvastatin
[Lipitor]). In the majority of cases, the liver inflammation gets
better (i.e. the hepatitis resolves) when the offending medication
is stopped, or the viral infection goes away on its own or after
specific treatment. However, some infections, most notably hepatitis
B virus (HBV) and hepatitis C virus (HCV), can become chronic, and
the resulting long-standing liver inflammation can lead to the development
of irreversible liver scarring (called cirrhosis). Cirrhosis is
linked to many grave medical complications, including a dangerous
form of liver cancer known as hepatocellular carcinoma.
Because HCV and HBV are acquired by the same routes of transmission
as HIV (i.e. through blood and/or body fluid exchange during sexual
contact, needle sharing, transfusion, or childbirth), HIV-infected
people are frequently co-infected with one, or sometimes both, of
these viruses. While much attention has been focused on the problem
of HCV infection, co-infection with HBV has been virtually ignored,
despite up to 10% of HIV-positive people in the USA having this
potentially life-threatening liver infection.1 Because
HBV is much easier to transmit sexually than HCV, the disease is
particularly prevalent among people who acquired HIV sexually, and
in particular, in the USA, is most frequently seen among men who
have sex with men [MSM]). Emerging medical evidence indicates that
HIV/HBV co-infected people are at a higher risk of developing advanced
liver disease (cirrhosis) and are at an increased risk of dying
when compared to people infected with HIV alone.2 Moreover,
co-infection with HBV can make treating HIV infection challenging,
because studies have suggested that chronic hepatitis B makes it
more difficult for people to tolerate their HIV medications because
they are more susceptible to some of the drugs' liver damaging side-effects.3
These potentially devastating consequences of HBV infection point
to the urgent need for more research to better understand the natural
history and treatment of HBV in HIV-positive people.
In the vast majority of HIV-negative people (approximately 95%),
infection with HBV causes temporary liver disease that goes away
on its own without any specific treatment. During the period of
liver inflammation, HBV infected people may develop clinical hepatitis,
an illness characterized by fever, malaise, fatigue, decreased appetite,
nausea, vomiting, abdominal pain, and white stools. A hallmark symptom
of hepatitis is jaundice (yellowing of the skin and mucus membranes),
a condition that is not necessarily seen in every infected person,
but is a result of the inability of the diseased liver to normally
process pigments being produced by the natural turnover of red blood
cells. In some people, however, including a higher proportion of
HIV-infected individuals, the acute hepatitis does not get better,
and the virus is not cleared from the liver. These people go on
to have chronic hepatitis B, a disease that is characterized by
on-going HBV reproduction (replication) that causes chronic liver
disease and may lead to early death from cirrhosis or cancer.
Unfortunately, because of the poverty of research conducted on
the therapy of HBV in HIV infection, the optimal way to treat chronic
hepatitis B in HIV-positive people is not known. Studies of alpha
interferon, one of the standard chronic hepatitis B therapies for
HIV-negative people, demonstrated that the drug was not effective
in the setting of HIV infection.4 The exact reason for
the medication's poor activity against HBV in HIV-infected people
is unclear, although one potential explanation is that the drug
acts as an immunomodulator and therefore may only be effective in
people with intact immune function (i.e. it may work better in people
who have preserved CD4+ T-cell counts). Because most alpha interferon
clinical trials for HIV/HBV co-infected people were conducted prior
to the introduction of effective HIV therapy, the drug may still
prove to have utility in treating chronic HBV in people who have
had their HIV infection successfully controlled with highly active
antiretroviral therapy (HAART), although the medication has not
been adequately studied in this setting. Nonetheless, even if future
studies demonstrate that it is effective, alpha interferon is frequently
poorly tolerated and associated with multiple toxic side effects.
Lamivudine (3TC [Epivir]), another standard HBV drug, works well
against both HIV and HBV, and in the overwhelming majority of cases,
was most likely prescribed to the HIV/HBV co-infected person for
the treatment of his/her HIV disease.5 However, similar
to the HIV lamivudine resistance seen with prolonged therapy, lamivudine-resistant
HBV inevitably emerges with long-term use. After using lamivudine
for four years, 90% of HIV/HBV co-infected people have HBV that
is resistant to the drug, a substantially higher rate of resistance
than that seen in HIV-negative people treated with lamivudine for
a similar period of time (67%).6 It is currently thought,
although not proven, that the lamivudine-resistant strain of HBV
can cause liver disease as serious as HBV strains that are lamivudine
sensitive (also called wild-type HBV). Because lamivudine and alpha
interferon are the only two FDA approved agents available for the
treatment of chronic hepatitis B in the USA, people who have developed
lamivudine resistant virus and are failing lamivudine therapy with
evidence of progressive liver disease have no medical alternatives
aside from experimental drugs. Most US clinical trials of investigational
hepatitis B medications exclude enrollment of HIV-positive people.
Moreover, liver transplant, a viable surgical option for HIV-negative
people with advanced HBV liver disease, is not available to most
HIV/HBV co-infected people because livers are rarely offered to
HIV-positive people at most transplant centers.
Adefovir dipivoxil, an investigational agent, may offer a medical
alternative to HIV/HBV co-infected people failing lamivudine therapy.
Adefovir dipivoxil is the oral prodrug form of adefovir, a nucleotide
reverse transcription inhibitor that works against HIV and HBV (both
the wild-type HBV and the lamivudine resistant form). The medicine
has a jaded history in the HIV-positive community because of kidney
damage seen after its use in some individuals who were receiving
high doses as part of clinical trials aimed at developing the drug
as an HIV antiretroviral. The manufacturer (Gilead Sciences) halted
development of the drug as an HIV medicine, and instead designed
trials questioning the potential of the agent at a lower dose (up
to 12 times less than people were receiving in the HIV clinical
trials) as a therapy for chronic hepatitis B infection. At this
substantially lower dose (10 mg daily, a dose that is not active
against HIV), preliminary results from a large on-going clinical
trial in HIV-negative people with HBV infection indicate that over
a 48 week period, the drug was not associated with any form of kidney
damage, was generally well-tolerated, and was effective in lowering
the amount of HBV in the blood and improving the health of the liver.
Importantly, a recent study suggests that these encouraging adefovir
results may be extended to the treatment of lamivudine-resistant
HBV in HIV-positive people.7
A French research group reported that adefovir is safe and effective
in suppressing HBV replication in a small group of HIV/HBV co-infected
people with lamivudine resistant HBV.7 Thirty-five HIV-positive
people who had HBV in their blood despite taking lamivudine and
had well-controlled HIV disease at enrollment in the study (receiving
antiretrovirals with an average HIV viral load = 759 copies/mL and
an average CD4+ T-cell count = 423 cells/mm3) were treated
with low-dose adefovir (10 mg daily by mouth) for a median period
of 48 weeks. In the 29 patients completing evaluation at Week 48,
HBV blood levels dropped approximately 10,000 times when compared
to starting values, a finding that indicates that adefovir potently
and durably stopped the HBV from reproducing. The study did not
address the impact of this impressive viral load reduction on the
health of the liver (as indicated by the pathology seen on liver
biopsy before and after therapy), a critically important indicator
of the overall utility of adefovir in treating hepatitis B liver
disease.
At this low dose, adefovir was well tolerated and, most significantly,
did not cause kidney damage. Two individuals had mild abnormalities
in their kidney function tests, but these were not thought to be
related to adefovir use because they improved with the discontinuation
of other medications known to affect the kidneys. As is frequently
seen with standard HBV therapy, approximately eight weeks after
the initiation of adefovir, fifteen people experienced increases
in their liver function tests (a hepatitis flare) that did not make
them ill (i.e. they did not have clinical hepatitis). This flare
period lasted approximately 12 weeks, after which liver function
tests declined and continued to improve until the end of the study.
Similar to prior studies on interferon and lamivudine, people on
the study who experienced a hepatitis flare had a greater reduction
in their HBV blood levels than subjects who did not experience a
treatment-induced hepatitis flare, indicating that hepatitis flare
might not be a bad side-effect of the drug, but a good indicator
of the medication's effectiveness.
These encouraging findings of the efficacy and safety of adefovir
for the treatment of lamivudine-resistant hepatitis B in HIV-infected
people give hope to HIV/HBV co-infected people with no HBV treatment
options. Ongoing clinical trials at the National Institutes of Health
(National Institute of Allergy and Infectious Diseases) are enrolling
HIV-infected people into adefovir studies for hepatitis B treatment.
For more information on participating in an adefovir clinical trial,
call 1-800-772-5464, ext. 49905.
Footnotes
1 Rustgi, V et al. Hepatitis B infection in the acquired immunodeficiency
syndrome. Ann Intern Med 1984;101:795.
2 Colin, J et al. Influence of human immunodeficiency virus infection
on chronic hepatitis B in homosexual men. Hepatology 1999;29:1306.
3 den Brinker, M et al. Hepatitis B and C virus co-infection and
the risk for hepatotoxicity of highly active antiretroviral therapy
in HIV-1 infection. AIDS 2000;14:2895.
4 Wong, D et al. Interferon alfa treatment of chronic hepatitis
B: randomized trial in a predominantly homosexual male population.
Gastroenterology 1995;108:165.
5 Benhamou, Y et al. Effects of lamivudine on replication of hepatitis
B virus in HIV-infected men. Ann Intern Med 1996;125:705.
6 Benhamou, Y et al. Long-term incidence of hepatitis B virus resistance
to lamivudine in human immunodeficiency virus-infected patients.
Hepatology 1999;30:1302.
7 Benhamou, Y et al. Safety and efficacy of adefovir dipivoxil
in patients co-infected with HIV-1 and lamivudine-resistant hepatitis
B virus: an open-label pilot study. Lancet 2001;358:718.
8 Miller, M et al. Adefovir and tenofovir susceptibilities of HIV-1
after 24 to 48 weeks of adefovir dipivoxil therapy: genotypic and
phenotypic analyses of study GS-96-408. JAIDS 2001;27:450.
Questions for Dr. Brust
Is there a risk of developing HIV resistance to adefovir or
other HIV antiretrovirals (such as tenofovir) when using low-dose
adefovir (10 mg/day) for the treatment of chronic hepatitis B?
The potential for the development of HIV resistance is always a
primary concern when adding a single agent to an antiretroviral
regimen. Under these circumstances, the risk of developing HIV resistance
to adefovir is presumably greatest in people who have detectable
HIV viremia (i.e. a viral load greater than the lower limit of detection
either because they are not taking antiretrovirals, or because their
medications are unable to effectively suppress HIV replication).
There are limited laboratory and clinical data to suggest that low-dose
adefovir therapy is not associated with the development of adefovir
resistant HIV. First, at the dose used to treat HBV (10 mg daily
compared to 120 mg daily that was used to treat HIV), adefovir apparently
has no activity against HIV, making it unlikely that the virus would
be under a significant selective pressure to develop resistance
mutations. Second, in the recent French trial (see article), none
of the 11 people evaluated, who all had HIV viral loads of at least
1,000 copies/mL at the time of genotyping, developed mutations associated
with adefovir resistance after using low-dose adefovir for 48 weeks.
Because adefovir is not FDA approved to treat HIV infection, a greater
concern is for the potential development of cross-resistance to
other antiretrovirals, most notably tenofovir, a recently approved
antiretroviral in the same class as adefovir. Although there are
no clinical data examining the development of tenofovir resistance
in people treated with low-dose adefovir, a recent study indicated
that use of adefovir for up to 48 weeks at 120 mg daily (the dose
used during the testing of adefovir for HIV infection) was not associated
with the development of decreased susceptibility to tenofovir8.
Ongoing studies at the NIH are aimed at examining this important
issue of the risk of developing HIV resistance to a variety of antiretrovirals
while taking low dose adefovir.
What studies are being done to investigate combinations of antiretrovirals
for treating HBV in HIV-infected people?
HBV, like HIV, has a reverse transcriptase enzyme and thus is susceptible
to drugs active at this stage of its lifecycle. Based on this similarity,
and our experience with treating HIV infection, combination therapy
for HBV infection would appear prudent, especially to avoid the
development of multi-drug resistant HBV caused by sequential monotherapy
treatments. However, because of the substantial differences between
HBV and HIV, the HIV paradigm of combination therapy may not be
valid for the treatment of chronic HBV, and a single potent HBV
agent may be sufficient to treat the infection. Only clinical trials
will help to determine the need for a single or multiple agents
to treat HBV. Current protocols are examining the combination use
of lamivudine and adefovir, in particular in people who have lamivudine-resistant
HBV.
What role might tenofovir play in treating HBV?
There are no clinical data available evaluating the efficacy of
tenofovir for treating chronic hepatitis B. The agent has activity
against HBV in the laboratory, but has not been tested in a clinical
trial. However, because tenofovir works against HBV in the laboratory,
clinicians should religiously screen people for evidence of chronic
HBV by serologies prior to initiating tenofovir (or lamivudine)
therapy. If chronic hepatitis B is detected, physicians should carefully
evaluate the indications, and necessity, to use an agent(s) that
treats both HIV and HBV.
Has HBV resistance to adefovir been detected?
To date, there have been no reports of HBV resistance to adefovir,
including analyses of studies in which HIV-negative people received
adefovir for over two years. These results are encouraging, especially
when compared to the rapid development of HBV resistance to lamivudine
seen in most protocols. Ongoing HBV clinical trials continue to
carefully monitor for any evidence of emerging HBV adefovir resistance.
House of Mirrors in the Virtual
ICAAC By Bob Huff
Every year the American Society for Microbiology sponsors the Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC), a large
conference linking the latest therapeutic advances from the laboratory
with clinical practice. This year's event, originally scheduled
for late September in Chicago, was postponed until mid-December
due to the attack on New York. Last month we offered a preview of
ICAAC presentations pertaining to the newly approved HIV drug, tenofovir
(Viread). This month we continue with a selection of other HIV-related
abstracts. Keep in mind that abstracts are submitted many months
in advance of the conference and often report preliminary or partial
data compared to the final poster presentation. For up-to-the-minute
reporting on the latest from ICAAC, visit www.natap.org
Drug Interactions
Interactions among HIV drugs are rife. Ritonavir, one of the nastier
AIDS therapeutics on the shelf in terms of its side-effects at full
dose, found new life due to its ability, at tolerable doses, to
plug up a drain that can flush other, less toxic protease inhibitors
(PI) from the body. Ritonavir "boosting" has since become a strategy
to beat drug resistance by keeping the blood levels of these other
PIs higher, longer. It's maker, Abbott Pharmaceuticals, rescued
both ritonavir and their new, not exceptionally potent PI, lopinavir,
by packaging the two together as Kaletra, a product that achieves
therapeutic drug levels without intolerable toxicity.
A-494 (Abstract titles and authors are listed at the end of
this article)
Push-me, pull-you drug interactions can be tricky. A poster originally
scheduled for presentation at ICAAC (but missing from the revised
program) by investigators from Agouron Pharmaceuticals reported
new details on pharmacokinetic interactions between ritonavir and
their company's non-nucleoside reverse transcriptase inhibitor (NNRTI),
delavirdine. It had previously been reported that delavirdine actually
increased blood levels of ritonavir, while remaining unaffected
in turn. In the new study, two groups of HIV-negative people (ten
per group, randomized) received either 100mg of ritonavir or 600mg
of delavirdine twice daily for 10 days. Following 14 days off drugs
as a washout period, all twenty individuals then received combined
doses of ritonavir and delavirdine twice daily for another 10 days.
Continuous blood level monitoring of drug concentrations was performed
on the last day of each 10-day dosing period.
The investigators reported that mean minimum inter-dose levels
of ritonavir were more than doubled by adding delavirdine; the maximum
ritonavir dose was increased by 50 percent; and the total exposure
to ritonavir (area under the curve) had increased by about 80 percent.
Headache and rash were most commonly reported as side effects. The
authors suggest that if delavirdine can boost ritonavir levels,
then, in a kind of chain reaction, therapeutic blood levels of other
concomitant PIs may also be improvable.
On a more practical note, these results suggest the need for care
when using delavirdine to avoid unexpected ritonavir toxicity. This
may be of particular concern when constructing regimens to treat
multiple-drug resistant HIV. Although to date, delavirdine has been
one of the least-prescribed HIV drugs, a quirk in how HIV resistance
develops may have opened a new niche for its use. Workers at Virologic,
Inc. after analyzing thousands of phenotypic drug resistance test
results, observed an anomaly described as delavirdine hyper-susceptibility.
They noted that some individuals who had formerly developed resistance
to virtually every nucleoside and non-nucleoside RT inhibitor, began
to show paradoxical renewed susceptibility to delavirdine. For people
with few options, this is a slender thread of good news provided
they are willing to bear the initial rash and itching that usually
accompanies starting delavirdine. If this strategy is employed,
however, the report on PK interactions with delavirdine should reinforce
the importance of closely monitoring complex regimens containing
multiple drug classes or multiple protease inhibitors, especially
ritonavir.
Pass, Fail or Incomplete?
There has been much discussion about when to start antiretroviral
therapy, but evidence about what happens after treatment has begun
can be contradictory. HAART was quickly recognized as a miraculous
gift for many people with very low CD4 counts and AIDS symptoms
when they were pulled back from the brink of death. But not everyone
had such a dramatic experience.
The hoped-for result of starting HIV treatment is for the virus
to disappear and the immune system to come bouncing back. But there
are other scenarios. The virus can go away but the CD4 count may
languish. If the immune system is in the basement to start with,
then the risk of getting sick remains even after actively replicating
HIV is out of the picture. Much has been written about treatment
failure as defined by renewed viral replication and subsequent decline
in CD4 count. Another situation, though less common, is when virus
levels come back and hover around a middling level while the CD4
count remains stable.
I-1906
An NIH study looked at the rate of viral decay in 38 previously
untreated patients who started HAART. At baseline, most had uncontrolled
viral loads above 10,000 copies/mL, however their CD4 counts varied
widely, ranging from 6 to 784 cells/mm3. HIV RNA was
quantified daily during the first week on treatment and then at
fixed time points thereafter. Initial viral decay rates ranged from
.15 to .35 log copies per day, which correlated with viral load
results observed at weeks 4, 8 and 12. There was no association
between the rate of viral decay and baseline viral load, CD4 count
or CD8 count. The authors concluded that the initial clearance of
plasma virus is due to drug therapy with no assistance from immune
control. This means, they say, that ARV should work as well for
those with advanced disease as for those with healthier immune systems.
But reducing viral load is not the whole story: to avoid AIDS symptoms
and time in the hospital, CD4 counts need to go up as well. Researchers
from the Ramon y Cajal Hospital in Madrid, Spain offered two studies
that examined the clinical outcomes for previously untreated individuals
who failed to have CD4 counts rise despite excellent viral control
after initiating therapy.
I-1911
This observational cohort study looked at 288 patients who started
HAART after March 1996 and subsequently maintained viral suppression
for at least 24 months. The median CD4 count in this group was 186
cells/mm3. After one year of viral suppression below
50 copies/mL, 40 individuals (14%) had CD4 counts that declined
or did not rise by more than 50 cells/mm3 despite successful
control of virus. After two years of viral suppression, 25 individuals
(10%) remained discordant, with CD4 counts failing to rise by more
than 50 cells/mm3. During this period, 52 clinical events
were recorded, primarily among patients who failed to have absolute
CD4 counts rise above 200 cells/mm3. Non-significant
associations were found between discordance and pretreatment viral
load and age. The authors caution that complete viral suppression
may not guarantee adequate immune recovery for a significant proportion
of newly treated individuals with low baseline CD4 counts who remain
at risk for disease and death.
I-1912
These investigators also reported on a two-year follow up study
of 187 previously untreated patients from the hospital cohort who
initiated HAART with CD4 counts below 200 cells/mm3.
The main endpoint of this study was defined as the persistence of
severe immunosupression (PSI), or CD4 counts remaining under 200
cells/mm3 despite control of HIV RNA below 200 copies/mL.
The median baseline CD4 count was 87 cells/mm3 (ranging
from 2-200).
Remarkably, 83% of the individuals achieved successful control
of plasma HIV RNA after one year. The proportion of individuals
with PSI dropped to 45% at 12 months; 21% at 24 months; and to 8%
at 36 months. Having PSI was associated with lower baseline CD4
counts and male gender. The rates of hospital admissions, clinical
events and death were not statistically significant between the
PSI and non-PSI groups. However, the number of admissions per patient,
the number of out-patient visits, and the time to the first hospital
admission were significantly greater for those with PSI. These data
support concerns about slower recovery for those who begin ART with
advanced immune suppression. The authors also find that, although
clinical outcomes were not greatly different during the study period,
resource utilization was higher for PSI patients.
If the greater utilization among PSI patients is responsible for
the lack of increase in death, this reinforces the continuing importance
of attentive clinical management of AIDS-associated disease. Worldwide,
an increasing number of individuals receiving treatment for the
first time may be encountered in this danger zone of very low CD4
cell counts. While HAART may work its miraculous benefits on most
people at this advanced stage of disease, these reports anticipate
a need to support potentially large numbers of patients with complex
clinical management during a long, slow recovery to functional immune
competence.
The decision to offer antiretroviral treatment in low-resource
settings may of necessity be governed by syndromic management if
access to expensive assays is limited. Too-early initiation of treatment
will also be discouraged to minimize toxicity and expense. The development
and widespread deployment of a low-cost CD4 assay may become critical
if timely treatment decisions are to be made before immune suppression
is signaled by symptoms.
Finally, it seems that increased resource utilization is masking
the appearance of clinical events that would occur otherwise. Can
these measures serve as a stand-in for disease and death in clinical
trials? The potential of resource utilization as a surrogate marker
of clinical disease should continue to be investigated to determine
its usefulness as an endpoint in long-term effectiveness studies
of treatment interventions and strategies.
These papers looked at people who failed to have CD4 cell counts
rise despite admirable control of viremia. Another study from the
very large Eurosida cohort examined people on stable HAART regimens
who have not completely controlled their virus yet haven't suffered
dramatic declines in CD4 counts either.
I-1915
The investigators selected 471 patients from the Eurosida cohort
who had been on HAART for more than six months; had been on the
same regimen for at least 3 months; and who had a confirmatory viral
load between 1000 and 10,000 copies at the baseline visit. Those
selected were followed-up for one year or while they remained on
their baseline drug regimen (median duration, 8 months). The median
change in viral load during the year was +0.2 log copies/mL. The
median change in CD4 count during the year was +13 cells/ . The
authors commented that whereas the increase in viral load is consistent
with natural history observations, the stability of CD4 counts during
this period is notable.
These findings awaken interest in theories about the possibility
of achieving equilibrium between therapeutic control and immune
control of an evolved virus with impaired drug susceptibility but
also impaired replication fitness. The authors suggest that genotypic
analysis of these patients' isolates is a next step.
Abstracts cited:
- I-1494
J.Q. Tran, Delavirdine (DLV) Significantly Increases Exposure
of Low Dose Ritonavir in Healthy Volunteers
- I-1906
M. Polis, Plasma HIV-1 Decay Rate Constant during Initial Therapy
Is Independent of Baseline CD4+ and CD8+ Lymphocyte Counts and
Baseline Viral Load
- I-1911
F. Dronda, Long-Term Outcome of Naive HIV-Infected Patients (pts)
with Small Increases in CD4+ Cells after Successful Virological
Suppression: a Study of Discordant Responses with HAART
- I-1912
A. Moreno, Clinical and Immunological Outcomes in Severely Immunosuppressed
Naive Patients on Effective Protease Inhibitor-Based HAART
- I-1915
J.D. Lundgren, The Stability of the Viral Load in Subjects with
Virological Failure who Remain on the Same HAART Regimen: The
EuroSIDA Study
ICAAC: Then and Now
Before the relief brought by HAART, when the emergent therapeutic
battles in AIDS focused on treating opportunistic infections, the
annual ICAAC conference was the place one went to cull through hundreds
of posters and abstracts looking for promising new antifungal or
antiparasitic drugs and glimmers of hope. ICAAC is still the major
conference for showing new research on how to use coming and currently
available antimicrobial agents of all kinds with over 1500 data
presentations on display.
This year, HIV-specific antiretroviral research comprises about
10 percent of ICAAC's content with two slide sessions scheduled
to present 16 papers before a live audience and another 169 papers
to be presented as posters. In addition to a number of symposiums
on current care strategies, one of the keynote sessions opening
the conference is dedicated to AIDS in Africa and another to the
state of our knowledge about HIV's initial entry into cells.
The poster sessions in the HIV category are organized into six
topical groups including hepatic and metabolic complications, prevention
and epidemiology, adherence and pharmacokinetics, resistance, pathogenesis
and diagnostics, and two sessions devoted to antiretroviral therapies.
Each session presents about 25 posters.
A surprising note is that over half of the HIV category posters
are from foreign research groups, with a particularly large number
originating in Spain and Italy. Overall, pharmaceutical companies
have sponsored about 20 percent of the HIV posters — research
primarily involving antiretroviral therapies, adherence and resistance.
Yet reports about opportunistic infections associated with HIV
disease haven't disappeared from ICAAC. Presentations on leishmanaisis,
salmonella, histoplasmosis, herpes simplex, and hepatitis viruses
A through G, to name but a few, are abundant.
What a Difference a Day Makes
By Bob Huff
At the 8th European Conference on Clinical Aspects and Treatment
of HIV Infection in Athens this Fall, results were reported from
a 48-week randomized trial comparing the standard twice-daily form
of d4T (stavudine, Zerit) with a new once-daily extended release
form of d4T.
One hundred fifty treatment naive patients were enrolled into the
double-blinded study and received efavirenz, 3TC plus d4T in either
the once-a-day or standard twice-a-day doses. Patients assigned
to receive once-daily d4T also took a twice-daily placebo, while
those randomized to receive the standard form also took a once-daily
placebo.
While the mean viral loads for each group were similar (around
45,000 copies/mL), the mean CD4 count for the once-daily group was
higher than that for the twice-daily group (354 vs. 261 cell/mm3).
All but one of the 75 patients assigned to receive the extended
release d4T began treatment while 4 of the 80 assigned to the standard
form dropped out without receiving the drugs. Of the individuals
who started treatment, 91% of those on once-daily d4T completed
the 48-week study compared to 82% of those on twice-daily d4T. Non-adherence
and adverse events were responsible for most discontinuations before
the end of the trial. The incidence of peripheral neuropathy was
higher in the standard d4T group while those on extended release
d4T reported more headaches.
The primary endpoint of the trial was the proportion of patients
achieving viral load below 400 copies/mL by the end of 48 weeks.
Among all patients who started the trial (including those who dropped
out), 78% of those on extended release d4T compared to 67% on twice-daily
dosing successfully suppressed viral load below 400 copies. But
if the bar was raised to suppression below 50 copies/mL, the proportion
of those who were successful dropped to about 49%, with no difference
between the groups.
The Bristol Myers press release on these data was content to claim
that the new extended release form of d4T is safe and effective.
This was wrapped by a larger context suggesting that once-daily
d4T can be part of simpler HAART drug regimens for treating HIV.
In presenting this data at the conference, the investigator stressed
the association between ease of adherence to one's treatment regimen
and the likelihood of that regimen successfully suppressing viral
load. The implication (and hope) is that once-daily pills are going
to be easier to remember to take and will make life easier for the
person taking them without letting up pressure on the virus.
It should be noted that this trial was not designed to uncover
the benefits of simpler dosing, only to establish equivalent safety
and efficacy with the existing twice-daily formulation. As a blinded
study, all patients took pills (either placebo or the real thing)
twice a day — even more pills than normally taken for the standard
dose. Therefore ease of adherence should not have been a factor
in the results from this trial. Yet the company presents, without
comment, data that shows apparent improvements in efficacy between
the two forms of d4T. If there is equivalency between the two formulations,
then what explains the differences in response and frequency of
toxicity in the results?
To understand this we need to see results from pharmacokinetic
studies that track the levels of drug in the blood over time. In
particular we would like to compare the difference in peak concentrations
and in the area under the curve (AUC) which charts the available
blood concentration of the drug during an entire day.
Another open question about once-daily dosing is the impact a skipped
dose will have upon blood levels. With a twice-a-day regimen the
catch-up dose enters the blood twelve hours late; with daily dosing
a full day will pass before drug levels are brought to recommended
concentrations. Longer term studies of daily regimens are needed
to determine if there is a greater risk of drug resistance developing
when doses of these less burdensome regimens are missed.
A Treatment Issues Editorial
Seeking Disclosure The annual Meeting
of the Infectious Diseases Society of America was held in San Francisco
during late October of 2001. Eight of 65 total conference sessions
specifically addressed HIV issues. These included a plenary talk,
a symposium, three early morning "Meet the Professor" sessions,
an interactive session and a walking tour of HIV posters. All of
these sessions offered continuing education credits and were conducted
by experts in the field. A single slide session offered six oral
presentations of recent HIV research selected from among poster
submissions. One hundred and forty-four HIV-specific posters were
presented in five categories.
As the academic sponsor of the continuing medical education (CME)
program, Johns Hopkins Medical School requires faculty members to
disclose any significant financial relationships with the manufacturers
of products discussed during their educational presentations. Faculty
self-reported their financial relationships. Poster and slide session
presenters were not asked to make this disclosure.
Of 219 faculty members presenting at the conference, 20 addressed
HIV-specific topics (two faculty members presented twice resulting
in 18 individual experts presenting on HIV issues). Of the eighteen
individual HIV experts, six (33%) did not provide disclosure of
financial relationships. This compares to 24 (12%) of 199 non-HIV
faculty who did not disclose.
Of faculty who responded to the request for disclosure, 36% of
non-HIV versus 58% of HIV faculty listed companies with which they
had financial ties. The 63 non-HIV faculty who disclosed having
financial relationships reported ties to an average of 4.4 different
companies; HIV faculty reported relationships with an average of
8.0 companies.
Because of the small number of HIV faculty members relative to
the overall faculty and because a large proportion of the HIV faculty
did not participate in the disclosure process, conclusions must
be general. Four of the six HIV faculty members who failed to disclose
were presenters in a single session, which may indicate administrative
error.
Conclusions:
- HIV faculty members at this conference were less likely to provide
disclosure of financial relationships than were non-HIV faculty
members.
- Of faculty members who did provide disclosure, HIV experts were
more likely to have financial relationships with companies discussed
during their presentations than non-HIV faculty.
- Of faculty members reporting financial relationships, HIV experts
reported involvement with nearly twice as many companies as did
non-HIV faculty.
Recent studies have identified the subtle and pervasive influence
that funding sources can have upon the design, conduct and presentation
of medical research with commercial ramifications. Disclosure by
expert faculty of financial relationships with companies discussed
during their presentations has unfortunately become necessary to
fully evaluate the content and context of scientific presentations.
Conference organizers should routinely attempt to collect and present
this information in both print and electronic versions of published
abstracts. Faculty members should attempt full and timely compliance
with disclosure guidelines.
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