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Past Issues
Volume 16, number 3
March 2002
Contents
New (Sort of)! Improved (Somewhat!)
How much better will the next generation of antiretrovirals actually
be?
Moving Targets
Cutting off HIV's replication in new places presents fresh complications
Dope Opera
My T-20 diary
Keeping Up Appearances
Life as an HIV 'success' is really a lot of work
Nevirapine Squabble
Misplaced concern over resistance from one-dose NVP?
Canarypox Gets the Bird
A Treatment Issues editorial
HAART Version 2.0
By Bob Huff
What will a true second-generation antiretroviral drug be like?
It's a common marketing claim and there have been several pretenders,
but so far, failing to step cleanly away from the shortfalls of
its forerunners has compromised every new bid for the title. Atazanavir
is a fledgling protease inhibitor that may be just the ticket for
knocking down virus levels in therapeutic newbies without incurring
lipid problems — so long as its few toxic quirks remain benign.
But what about folks whose ship of susceptability has long since
sailed? Which criteria have to be satisfied for antiretroviral therapy
to become truly effective, easy to live with, resilient, flexible
and safe in the long run? And what are drug developers doing to
try to get there?
Potency is at the top of everyone's wish list for a new antiretroviral.
Reduction of viral load by at least 1.5 log copies within a few
weeks is nearly an accepted standard for first line protease inhibitors
(PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI).
The standard for nucleoside RT inhibitors (NRTI) tends to be a little
less stringent, with 1.0 log drops in viral copy numbers often deemed
very good. But it's clear from the gap in the proportion of trial
subjects with viral load results below 200 copies and those below
50 copies that a lot of people on the fringes of suppression are
barely getting by. A breakthrough in potency should be able to push
viral replication down so far that virtually everyone who goes below
400 also goes below 50. That kind of potency would effectively arrest
HIV activity whenever and wherever it kicks up and will be what
it takes to hold out against the inexorable pressure of drug resistant
viral mutants.
There are other benefits to potency. A drug able to stop HIV in
the test tube at very low concentrations may also be likely to work
at doses far below the point where toxicity kicks in. Such a drug
might also give the advantage of being far more tolerable in day-to-day
use. And it's been demonstrated that tolerability is a big factor
in keeping adherent to any particular regimen. This is the second
big criterion where there's ample room for improvement: offer consumers
an effective drug that they won't dread taking because of queasiness,
loose bowels or nightmares, and they will vote with their feet.
Good tolerability makes the bitter pill of lifetime HAART much easier
to swallow.
The current Holy Grail of convenience is to achieve once-daily
dosing with a coformulated product — all your pills in one,
tiny tablet in the morning. (Did someone mention The Patch?) Dosing
intervals depend on the rate a drug is cleared from the body by
metabolism. Most protease inhibitors have had a tendency to activate
the very mechanisms responsible for flushing drugs out of the body.
The big exception is ritonavir, which has the opposite effect. So
powerful is ritonavir at slowing down the metabolism of PIs that
its main use has turned out to be as an inhibitor of liver enzymes
rather than an inhibitor of HIV. Unfortunately, PIs that rely on
ritonavir for longevity have made a deal with the devil. Ritonavir
brings with it tolerability problems as well as unpredictable interactions
with other medications and uncertain but worrisome associations
with long-term toxicity. Any drug that depends on ritonavir boosting
to stay in the race is living in the past.
Which brings up another vexing quality: long-term safety. As the
giddy flush of success during the first years of HAART tempered
after lipodystrophy, lipoatrophy and cardiac risk factors began
to show up, physicians and community members began questioning the
underlying assumptions of the Hit Hard, Hit Early treatment dogma.
They started looking for a middle path that treads a little more
lightly without letting HIV get the upper hand. One problem is that
the only way to uncover long-term side effects is to put people
on drugs then wait and see; long-term effects are the most difficult
aspects of drug therapy to pin down. But the consequences are finally
being appreciated; if the mounting fears over cardiac risk have
had a silver lining, it's that researchers are now more willing
to use powerful research tools such as randomized trials in order
to detect signs of toxicity before they begin cropping up everywhere
at once. Nonetheless, consumer voices will need to grow louder before
significant post-marketing and surveillance studies become routine
responsibilities of bringing a new drug to market.
The other great long-term failing of most current generation drugs
is the ease with which drug resistant mutations can erode their
activity. In part, drug resistance stems from inadequacies in all
of the previously mentioned criteria. A drug that inherently lacks
potency will let HIV replicate in its presence, leading quickly
to loss of susceptibility. Skipped doses mean inadequate drug concentrations,
which can also drive resistance. And poorly tolerated drugs are
more likely to be skipped than pills with benign side effects. Metabolic
and genetic variations among individuals also come into play; drugs
that never quite achieve maximum blood levels may dip below effective
concentrations during the normal course of a day for some and not
others. It remains to be seen if this variability becomes more problematic
as dosage intervals are stretched to ever longer — and more
convenient — periods. Interactions between agents affecting
liver metabolism can play havoc with other drug levels. Finally,
even people who have had excellent success on their regimens for
many years may eventually take drug holidays due to fear about what
is happening or might happen to the shape and constitution of their
bodies. Unsupervised or ill-considered stopping and starting of
therapy is another probable source of viral replication and resistance.
A truly next generation antiretroviral will not only need to have
activity against the canonical HIV of yore — fast becoming
a museum piece — but should also strike in a way that the multitude
of variants resistant to existing drugs are also stopped cold. This
dream drug would act against viruses from multiple worldwide subtypes
and recombinations of subtypes, both from drug naive and drug exposed
persons. Even so, having flexibility against existing mutant strains
isn't enough; the new drug will need to remain resilient against
end runs by HIV genes freshly mutated against its particular shape
and function. The ideal drug would block HIV at such a crucial step
in its life cycle that no mutation could get by. Even if replication
continued in sanctuary sites receiving sub-therapeutic concentrations,
the drug should be able to stand up to low level sniping and hold
fast.
Taken all together, it's easy to understand why coming up with
a breakaway second generation drug is such a tall order. But that
doesn't stop the pharmaceutical companies from trying — or
from practicing wishful thinking. Several manufacturers have made
or are making the claim for new drugs in their pipelines, but which
ones have a shot at the title and which ones fall short?
Pipeline
While agents directed against new targets are exciting and a few
candidates are on their way to the pharmacy, there's still a lot
of room for improving inhibitors of the old standby HIV targets,
reverse transcriptase (RT) and protease. (See New
Targets Bring New Challenges below for a look at future classes
of ARV.)
Atazanavir is a protease inhibitor with efficacy comparable to
current PIs in a treatment-naive trial population. As a welcome
step away from the ranks of existing PIs, atazanavir seems to have
a minimal impact on cholesterol and triglyceride levels. In trials,
asymptomatic, elevated, bilirubin levels occurred in a third to
a half of trial participants and jaundice was observed in a few
others. A genetic predisposition to these side effects has been
proposed, suggesting that susceptible individuals may one day be
identified before putting themselves at risk. Moderate diarrhea
was the main tolerability complaint. A recent bit of uncertainty
over abnormal cardiac rhythmic patterns has brought out the caution
flag for a very-large pre-approval access program that should have
started by now. Otherwise, the drug seems to retain good activity
against HIV with early-stage resistance to other PIs — although
strains with multiple PI-resistance mutations probably become increasingly
less susceptible to atazanavir. The good news is that viral strains
developing resistance to atazanavir may still be susceptible to
the existing lineup of PIs. Once-a-day dosing, low lipid toxicity
and the ability to rescue emerging resistance with earlier protease
inhibitors all contribute to the case for using atazanavir as a
first-line agent. Its usefulness for PI failure and salvage situations
is not as clear, however. Barring setbacks, Bristol Myers Squibb
indicates the large expanded access program should begin shortly.
Tipranavir is a compound designed with a twist on the chemical
structure that defined most earlier protease inhibitors. Although
it has been tested in far fewer patients than atazanavir, tipranavir's
most notable characteristic seems to be an ability to suppress multiply-PI
resistant and wild-type virus with about equal efficacy. Primary
resistance to tipranavir itself seems to be slow to develop. On
the down side, tipranavir may share lipid-raising problems similar
to earlier PIs. Furthermore, achieving sufficient blood levels to
combat resistant strains and allow convenient dosing may require
combining tipranavir with low-dose ritonavir, a strategy which brings
the familiar set of cautions about tolerability, drug interactions
and uncertain long term toxicities. In trials to date tolerability
issues included gastrointestinal, neurologic and psychiatric effects.
Due to those limitations, tipranavir can't really be considered
a second-generation product and it would probably never enjoy significant
market acceptance if it is approved. But the drug deserves special
attention because of its unique potential to patch over problems
created by resistance to the first wave of PIs. It represents a
solution that is urgently needed today: a lifesaver for people who've
run out of treatment options. Tipranavir's conventional course of
development has been limping along. Maybe the best plan for this
drug is to fast track examining the dosage and safety issues, then
to start making it available through compassionate use on a case-by-case
basis before opening up an expanded access program for people unable
to construct any other viable treatment regimen. This could conceivably
start happening later this year. If sponsor Boeringer-Ingleheim
is unable to consider taking extraordinary steps to move tipranvir
forward, then perhaps an orphan drug development company could step
in. This one is too important to treat as business-as-usual.
There are quite a few non-nucleoside reverse transcriptase inhibitors
in the pipeline. The biggest failing of current generation NNRTIs
is the ease with which resistant mutations develop that can also
wipe out susceptibility to other drugs in the class. Coming up with
a unique resistance profile is the principal goal of these newcomers.
DPC-083 is an NNRTI from Bristol Myers Squibb currently in Phase
II studies in drug naive patients. The agent is chemically similar
to efavirenz with similar potency against wild-type HIV but has
also shown activity against virus with efavirenz-resistant mutations.
On the tolerability front, early trials have reported more episodes
of rash but fewer problems with dizziness compared to efavirenz.
DPC-083 is also a potent inducer of a liver metabolic pathway, which
could mean drug interaction issues down the line. This drug doesn't
seem to be running away from the pack, but as a transitional compound,
maybe valuable lessons can be learned to help guide the development
of future NNRTI candidates.
Two NNRTI drugs from Belgian biotech Tibotec have also appeared
on the horizon. TMC125 is in very early development but has shown
activity in brief studies with both drug-naive as well as efavirenz-resistant
individuals. Less is known about TMC120, another NNRTI, although
short periods of dosing in people with HIV demonstrated activity.
As for new nucleoside analogs, two candidates from Triangle Pharmaceuticals
merit watching. FTC (emtricitabine) is furthest along in development
and may be offered to the FDA for review by the end of this year.
FTC is chemically similar to 3TC and has similar potency against
wild-type HIV. A longer half-life in the blood makes FTC a good
candidate for once-a-day regimens. Unfortunately, overlapping resistance
with 3TC means that people already resistant to its cousin won't
benefit from FTC's convenience.
Further back in the pipeline is DAPD (amdoxovir), which may have
excellent activity against AZT- and 3TC-resistant viral strains.
Although resistance to DAPD itself can occur, it's still not certain
how common or problematic that will be. It's thought that HIV with
certain mutations conferring resistance to NNRTIs may actually become
more susceptible to DAPD. On the whole, the drug remains attractive,
especially for rescuing individuals with NRTI resistance, but its
development has been slow. Triangle recently dropped one of its
drug development projects and is moving FTC towards completion,
so maybe DAPD is up for some long overdue attention from its sponsor.
Walk Don't Run
Last year, new enrollments to trials of capravirine, a NNRTI being
developed by Agouron/Pfizer, were put on hold because of vascular
inflammation observed in animal studies. No such toxicities have
been seen in people who have received capravirine in clinical trials
and people already on studies have continued to receive the drug.
This agent is attractive because it promises to rescue individuals
who have developed resistance to efavirenz (although not nevirapine).
Early studies described gastrointestinal side effects, but significantly,
did not report problems with rash.
Wipe Out
A number of drugs early and not so early in development bit the
dust recently. Emivirine, an NNRTI from Triangle Pharmaceuticals
was canned after data from large and expensive Phase III trials
told the company that their drug was not potent enough to stand
up in the marketplace. Triangle also pulled the plug on DMP-450
(mozenavir), a protease inhibitor that promised little more than
existing PIs offer.
Several compounds in the Dupont stable acquired by BMS after their
merger last year have been left on the moving van. Two promising
protease inhibitors, DPC-681 and DPC-684 were dropped due to toxicity
as has an NRTI candidate, DPC-817. One NNRTI candidate, DPC-961
was tabled after an unusual number of patients reported suicidal
ideation. At a major conference two and a half years ago, Dupont
billed two of their new NNRTI hopefuls, DPC-081 and DPC-083, as
second generation breakthroughs; these too have now been quietly
scrapped. Hopefully these stillborn progeny are part of the price
to be paid before a stronger and gentler generation of HIV therapy
finally appears.
| Second Generation
Scorecard — Still Waiting |
|
| Drug |
Improved potency |
Easy to take and tolerate |
Works against class-resistant
HIV |
Holds off new resistance |
Long-term safety |
atazanavir
tipranavir |
~
~ |
+
~ |
+
++ |
~
++ |
+?
? |
FTC
DAPD |
+
+ |
~
~ |
~
++ |
+
~? |
?
? |
TMC 125
DPC 083 |
~?
~ |
~
~ |
+
+ |
+?
+ |
?
? |
~ similar to current generation
+ some
improvement
++ big improvement
? too soon to say |
New Targets Bring New Challenges
By Bob Huff
A new drug to block HIV at a new point in its lifecycle will be
a welcome development. But approving a new drug from a new chemical
class will also bring great uncertainties. It's not enough to simply
be active against HIV, the new drug will also have to leave host
functions alone and meet all of the other criteria for a medicine
that is tolerable, easy to take, safe, and affordable. That's a
lot to ask for a first time at bat. Advanced lead screening techniques
and early use of better toxicity assays will hopefully accelerate
the pace of developing the next generation of drugs. Still, the
first wave of new-target drugs may go through a few false starts
before they become useful medicines used in seamless combination
with the older, more refined PI and RT inhibitors. Here's hoping
one of these can knock the ball out of the park.
Information on new antiretroviral (ARV) drugs entering human trials
was somewhat thin at this year's 9th Annual Retrovirus Conference
in Seattle, but a few items stand out. Maybe the most encouraging
news is that drug development is alive and chugging away on new
products. Despite doomsday warnings by pharmaceutical executives
about having to pull out of HIV research if political pressure for
affordable access to medicine threatens industry profits, there
was evidence of commitments to develop new drugs for new HIV targets
from Bristol Myers Squibb (BMS), Glaxo-SmithKline (GSK), Schering
and Merck.
Researchers from Shionogi & Co., a Japanese pharmaceutical firm,
presented a new inhibitor of integrase, an HIV protein that performs
an essential step in the viral lifecycle. Integrase is one of the
unique-to-HIV targets that have yet to be attacked with an effective
drug. The big news in this presentation was the "GSK" logo that
appeared in the corner of the slide. This means that HIV pharmaceutical
leader Glaxo has joined the hunt for a novel integrase inhibitor...
and if anyone has the capacity and know how to get an AIDS drug
developed and moved through the pipeline, it's Glaxo. The drug is
currently called S-1360. It is a diketo acid compound that
has shown in vitro synergy with approved ARV drugs from every class.
Merck also has a diketo acid integrase inhibitor that has previously
been reported susceptible to site mutations in the enzyme; additional
resistance mutations were also reported at this conference. Has
the Shionogi compound gotten around this? S-1360 is proceeding with
first human trials in a small number of HIV-infected individuals.
History shows that a new drug might enjoy glowing reports at one
year's conference then never be heard from again; it's wise to reserve
enthusiasm for agents that have at least entered full Phase II clinical
development. In an example of the subtle scientific sniping that
goes on at these conferences, a Merck researcher stood up after
the Shionogi presentation and inquired about plasma protein binding
for S-1360. Drug molecules can become gummed-up with proteins in
the blood such as albumin. Protein-bound drugs aren't able to cross
into the cells where they need to be and are ultimately eliminated
from the bloodstream; too much susceptibility to protein binding
in the body can eclipse a drug that shines in the test tube. Yes,
S-1360 is highly protein bound, the Shionogi scientist admitted.
Dare we hope that Merck has a new integrase inhibitor in the works
that overcomes these problems?
The outlook for entry inhibitors is also looking better. T-20 from
Trimeris/Roche is likely to be the first of this new class of drugs
to be approved, although that may be up to a year from now. T-20
works by blocking HIV as it tries to insert itself into new cells.
While a few posters filled out the clinical picture of what to expect
from T-20, one detail incidentally slipped out in an unrelated talk
by a BMS executive about their new entry inhibitor. Apparently the
generic name for T-20 has been settled; initially known as pentafuside,
T-20 will now be called enfuvirtide. (See A
T-20 Diary below.)
The new BMS entry inhibitor was another welcome surprise. Currently
called BMS-806, the drug was discovered by screening a library of
several hundred thousand variations on a chemical theme to detect
potent anti-HIV activity. Eventually a few promising leads were
narrowed down to number 806 which showed viral inhibition at concentrations
that were not toxic to cells. The molecule is said to be highly
specific for binding to the gp120 HIV envelope protein and probably
interferes with attachment to cellular CD4. A green light so far,
but experience with antibodies against the highly changeable gp120
protein tells us that the evolution of resistance may quickly become
a problem. And in case you were wondering, BMS-806 is not highly
bound by plasma proteins.
The other prominent entry inhibitors discussed at Retrovirus take
a different approach to blocking viral attachment. Instead of sticking
to the virus, they bind to receptors on a cell's surface that HIV
uses to gain entry. Schering's SCH-C is in human trials and moving
through a series of doses to find the best balance between activity
and toxicity. Work is proceeding carefully because of abnormalities
in a cardiac rhythmic parameter called QTc observed after volunteers
received a single 600mg dose. A ten-day study of 25mg twice daily
in 12 HIV-positive persons has been completed and a 50mg study is
underway. At this point it seems that a slight prolongation of the
QTc interval predictably occurs with increasing drug exposure, but
it is too soon to say if this effect will doom the drug. After 10
days of SCH-C monotherapy at the 25mg twice-daily dose, mean viral
load for the 12 patients had dropped by over 0.5 log.
SCH-C stops HIV from using the R5 receptor to infect new cells.
A more virulent strain of HIV employs the X4 receptor, and is not
inhibited by SCH-C. One fear is that using the drug could favor
the evolution of X4-using mutants and actually accelerate disease
progression. So far there is no evidence from test tube or animal
studies that this occurs, but experience in human trials is the
test that matters.
AMD 3100 is an entry inhibitor that acts on the X4 cellular receptor
— the one that SCH-C doesn't attack. Although anti-HIV activity
was noted in early clinical trials of the drug, studies were stopped
a year ago after failing to meet targets for reducing viral load.
A look back at the data from those trials and a new analysis of
the volunteers' viral genotypes suggest that some patients may have
turned in a poor performance on AMD-3100 because they harbored a
mixed population of X4 and R5 viral strains. The single individual
infected solely with the X4 strain experienced respectable viral
suppression. One question: If AMD-3100 acts on the viral phenotype
that SCH-C does not, could one drug rescue the other in a synergistic
fashion? In another AMD-3100 study presented at Retrovirus, increased
heart rates combined with a lack of significant activity at the
highest doses caused researchers to take pause. A new oral formulation
will hopefully address toxicity problems seen with earlier infused
versions of the drug. AMD-3100 may not be dead yet but its tiny
biotech developer will surely have to partner with one of the big
companies if this drug is to move forward.
For in-depth reports and more background, visit:
www.natap.org
www.aidsmap.com
Abstracts, posters and video from the 9th Annual Retrovirus Conference
are available online at www.retroconference.org
T. Yoshinaga, et al. Persistence of Transmitted Drug Resistance
among Subjects with Primary HIV Infection not Receiving Antiretroviral
Therapy. 9th Retrovirus Conference, Seattle, 2002. Abstract 8.
M. Witvrouw, et al. Novel Mutations in HIV-1 Integrase Associated
with Resistance to Diketo Acids. 9th Retrovirus Conference, Seattle,
2002. Abstract 573.
P-F Lin, et al. Identification and Characterization of a Novel
Inhibitor of HIV-1 Entry - II: Mechanism of Action. 9th Retrovirus
Conference, Seattle, 2002. Abstract 10.
J. Reynes, et al. SCH C: Safety and Antiviral Effects of a CCR5
Receptor Antagonist in HIV-1- Infected Subjects. 9th Retrovirus
Conference, Seattle, 2002. Abstract 1.
D. Schols, et al. AMD-3100, a CXCR4 Antagonist, Reduced HIV
Viral Load and X4 Virus Levels in Humans. 9th Retrovirus Conference,
Seattle, 2002. Abstract 2.
C. Hendrix, et al. AMD-3100 CXCR4 Receptor Blocker Fails to
Reduce HIV Viral Load by > 1 Log following 10-Day Continuous Infusion.
9th Retrovirus Conference, Seattle, 2002. Abstract 391.
A T-20 Diary
By Fred Gormley
Friday, March 1
Dear Diary,
Today my doctor informed me that my first dose of T-20 is just
a week away! How I have yearned for this day! Scalding tears of
joy spilled copiously down my face, onto my heaving, bountiful pectorals,
drenching my grey Donna Karan cashmere sweater. What cared I: "Let
the damage be done!" I exulted, whirling around my physician's office,
gleefully tossing several other patients' files in the air. The
precious fusion inhibitor would soon be mine and I would have closure
to end all closures...
Well, of course not. One doesn't live in New York, wear all black,
and reach the age of fifty (fourteen years aware of my positive
HIV-status) to get exuberant about anything. What really happened
was that, after waiting since...early December?...my shipment was
coming in. As the result of a new study, I was the first of three
people in Howard Grossman's office to get T-20. It wasn't easy,
but the effort wasn't mine. From the time the protocol was announced,
a Phase III open-label exploration of T-20's safety for people who
have failed all other regimens, there were hurdles, the most aggravating
of which was "call-in day". The pharmaceutical companies (Trimeris
and Roche) set up a specific time when physicians around the country
had to phone; availability was on a first-come, first-served basis,
and there was limited drug to be had (see Treatment
Issues Volume 15, Number 4 detailing T-20's unique production
difficulties). The volume of calls overwhelmed the insufficient
phone lines, and getting through was hairy. And this was only to
submit names! Each candidate was then reviewed as to appropriateness
for the program. Several weeks later, I found out I had made it,
and that the meds would come my way in February.
Don't think me overly blasé, but while I was gratefully
anticipating this new tool against my AIDS, the intervening two
months brought me distractions — or horrors — enough.
I was receiving twice-weekly infusions of amphoteracin-B to fight
a stubborn strain of candidiasis while recovering from a Christmastime
bout of wasting, the most severe yet. And then, in the very beginning
of January, my Mom died. At this writing, the weight's back, I'm
still hooked up to the ampho, and the grief plays out its process.
T-20 was something to look forward to, but eagerness for anything
had been stomped right out of me.
Monday, March 4
The 'informed consent' has been signed! I kissed the precious
document and clasped it to my chest as if each page were illuminated
in lapis and gold...
Back in the doctor's office for the intake. Liza, the nurse-practitioner
who administers all studies and trials in Dr. Grossman's office
had given me an informed consent package the previous Friday and
I'd read it during the weekend. It was one of the heftiest consent
documents I'd ever put my hands on, though it was written in plain
English rather than standard medico-legalese (example: "Can I be
kicked out of the study?") And I don't know where I got the idea
that this drug had fewer side effects than others, but with a brief
pause over stroke... and I'd be willing to gamble on that...
the downside passed my muster, which is to say that no one has reported
growing antlers or such. The intake exam included an ECG, blood-drawing,
a dipstick urinalysis and lots of questions. Liza handed me a videotape
to view between then and when I picked up the meds.
Friday, March 8
The video! It answered all my innermost, private questions! I
wanted to run to my Sony Wega and hug its big flat screen. So I
did.
Whenever anyone assigns me something to read or view, I
avoid it until the last minute, or never, if it's a high school
book report. So the videotape waited until Friday morning, at which
time I cozied-up with the procedures of self-injection.
There was nothing new here for me (except for the reconstitution
process. T-20 is a protein, and its powdered form must be mixed
with sterile water to be administered), so I concentrated on the
tape's production values. Professionally done. High-quality video.
San Francisco locale (every scene shot in open white rooms with
crisp available light). And there's skin! The demonstration subject
doffs his shirt to give himself a shot in his well-tended abs. The
only treacly touch was the instructor, a young woman who's a little
too upbeat for my jaded tastes at that hour and frankly could use
her own dose of something to bring it down a notch. Minor distractions,
but if I weren't already a long-time needle user (insulin, Serostim,
Epogen, Procrit, testosterone) I would have missed the point entirely.
How very "me".
At the doctor's office, I did my first hit under Liza's direction.
No problems, but one potential annoyance, a possible future deal-breaker.
The reconstitution takes 15 to 20 minutes if you tap the bottom
of the vial and gently roll it around (no shaking!) and somewhat
longer if you just let it sit. For someone like myself who greets
the day with pills at 8 (no food!) pills at 9 (food!) protein shake,
two packets of testosterone gel drying on my belly as well as the
usual get-ready-to-go-out-the-door routine, another extended multi-step
procedure (repeated at night) could quickly lose its charm and novelty.
I'll bear with it, though.
Liza hauled out the accompanying supplies. YOU GET: One box safety
syringes for mixing; one box safety syringes for injecting; a decent-sized
sharps container; vials of sterile water; alcohol pads; the medication
itself. BUT WAIT! THERE'S MORE: a small insulated bag for transporting
chilled T-20 (must be refrigerated); instructions; an offer to participate
in a marketing survey seventy-five days after your first injection
($50!) and a huge canvas tote bag to carry it all home in (by the
way, nothing has a logo on it. They've finally learned!)
Sunday, March 10
So I've just given myself my fifth poke; no adverse reactions evident
so far. Some people have complained about swelling under the skin
at the injection site, but anything I've ever shot subcutaneously
has given that effect; mine goes away within an hour. There was
some itching with the in-office dose, and a vague feeling of momentary
heartburn, which may have been coincidental. It'll go as it goes.
It'll work or it won't or the results will be ambiguous, as most
drugs are when you're on a heavy regimen. We'll see...
Que sera, sera...and yay!
Life on HAART
By Michael Carter
Reprinted from AIDS Treatment Update, March 2002
For subscription information: atu@nam.org.uk
or visit www.aidsmap.com
For the past four years I have been taking antiretroviral therapy.
I've seen my CD4 count quadruple and my viral load fall from the
high hundred thousands to below 50. It would therefore be easy to
conclude that for me treatments have been a success. Not least because
it is now well over ten years since I was diagnosed with HIV, and
nine years since my first AIDS-defining illness. Quite simply, without
my anti-HIV drugs I expect I would be dead by now, or in the last
stages of advanced HIV disease.
However, even though my treatments have proved, according to my
blood tests at least, a success, I am still very much aware of how
serious a condition HIV is and the extent to which it impacts on
my life and is likely to do so for the foreseeable future. I am
still very medicalised. For a start, there are visits to the clinic
every eight weeks for blood tests to monitor the success of my treatments,
and their impact on my metabolism. This means that I'm seeing my
consultant at least as often as I did in the days before I started
taking my combination. What's more, my visits to the clinic last
at least as long as they used to. But on top of that, treatments,
combined with the length of time I have had HIV, mean that there
are other medical issues which require me to visit the hospital.
In one week in late January this year, even though my CD4 count
was over 600 and my viral load undetectable, I had to attend three
separate outpatient clinics, none of them specifically HIV focused,
to see specialists for the monitoring or treatment of conditions
which have developed either as a consequence of my treatments, or
as a consequence of having a potentially life-threatening illness
for well over a decade.
Living with HIV has started to impact on my mental health; just
as my lab results started to indicate that its damage to my immune
system was being controlled, my mental health declined. I have had
two major depressions since I started treatments, each of them as
debilitating as any physical illness which HIV has caused. My consultant
and the specialist HIV psychiatrist who he referred me to, have
assured me that I am far from alone in experiencing mental health
problems since starting treatments. For some people these problems
have been the direct side-effect of their medication — depression,
psychosis and vivid dreams are all recognized side-effects of efavirenz.
For me the causation has been more indirect. I've been corroded
by living with HIV for all these years. I've grown pessimistic,
and the renewed hope of a future which treatments have provided
me with has been compromised by the side-effects and uncertainty
which accompanies them.
Fortunately, I've been spared any of the disfiguring body changes
(lipodystrophy) which are caused by treatments, even though I've
many of the factors which seem to be associated with it, particularly
chronic infection with HIV and many years of antiretroviral therapy.
A friend, however has not been so lucky, and as he put it: "It's
the ultimate irony, you're spared dying of AIDS only to look like
you are". Not surprisingly, another friend, who recently started
his first combination, has been anxiously monitoring his body shape,
fatalistically attributing changes in weight, or post-Christmas
thickening of his gut, to early signs of lipodystrophy.
I've had my fair share of side-effects too, including the diarrhea
which accompanied my first year on nelfinavir and felt like a tap
being turned on in my bowel. Then there was the peripheral neuropathy
in my feet and lower legs — the worst pain I've ever been in,
and which still hasn't resolved three years after stopping the drug
which caused it. And most recently I've been required to see a cardiologist
after developing an irregular heart beat. As I neither smoke nor
drink, eat a low fat, high fiber diet, rarely take drugs, have taken
regular vigorous exercise since my teens, and currently run at least
five times a week, this would seem to be without obvious cause.
That's if I wasn't taking antiretroviral medication which has been
shown to raise levels of fats in the blood (a risk factor for heart
disease), particularly in people like me, with a family history
of cardiovascular illness. So far the signs look good — I may
well have bradycardia, a benign condition seen in people with low
resting heart rates (particularly runners), but it's required numerous
visits to the hospital and a heart rate-raising degree of worrying
uncertainty just to get to this potentially hopeful diagnosis.
It is the uncertainty such as this which has become such an unsettling
feature of my life on treatments. I am uncertain how long my current
drug regimen will continue to work for. Indefinitely I hoped, until
last week, when I was told that after years of being undetectable,
my viral load was 125. Admittedly modest, but does it mean that
I'm becoming resistant to my current combination? It may well only
be a 'blip,' but only more visits to the clinic and more tests will
determine this.
Even though my treatments have caused problems, I have found a
way of living with them. They're easy to take; twice daily with
food (which I've realized can be something as easy to eat as a chocolate
bar), and no longer cause any nausea or bowel problems. I don't
relish the prospect of having to change to a new regimen. I can
well remember the bewildering array of choices between different
drugs and combinations which my doctor presented to me in the Spring
of 1998 when I started my first regimen. Similarly fresh is the
memory of the fretful decision I was asked to make a year later
when it was clear that the d4T-related peripheral neuropathy was
becoming unbearable, and I'd have to stop the drug despite having
good lab results, and choose between AZT and abacavir. Neither of
them appeared particularly attractive, well aware as I was of their
respective side-effect profiles. In the end I went for abacavir,
half expecting to experience the potentially life-threatening (though
rare) allergic reaction.
Then there is uncertainty about how long the body can tolerate
a chronic viral infection and potent drugs necessary to control
it. Rates of cancer in people with HIV are being carefully monitored
after some research suggested that non-AIDS-related tumors were
more commonly seen in people with long-term HIV infection. As my
consultant said to me: "It's another set of worries for you. First
of all there was opportunistic infections. Then there was treatment
choices, then side-effects, and now the possibility of other fatal
illnesses."
Coupled with the medical uncertainty is a lack of security, particularly
as regards employment and money. I've been in and out of work for
the past decade, meaning that my CV has many gaping holes. My experiences
with work have taught me that for me at least, having HIV does pose
very real limitations on my employment opportunities. I have been
severely ill, with both physical illnesses and depression, meaning
that I have been forced to leave jobs. And even sustained periods
of employment and good health have involved regular visits to the
clinic, accommodated as far as possible outside the working day,
but often at times of the day and with a frequency which even a
sympathetic employer found hard to accommodate. Now in my mid-30s,
I'm facing the possibility of a future of financial insecurity as
life with a chronic and demanding illness leaves me ill-suited to
a fast moving and competitive jobs market. With the safety net of
benefits which accompanied the chronic illness of HIV disease long
since removed, this could mean that chronic poverty may well become
another unwelcome side-effect of my life on treatments.
It's also necessary to inject a bit of perspective here. The terrorists
attacks in New York and Washington last year made many people feel
less secure and worry about their employment prospects. In addition,
it's become easy to blame HIV and treatment side-effects for just
about every medical condition which raises its head. For example,
I'd noticed some lines developing down my cheeks recently, and my
instinct was to attribute it to treatment-associated fat loss, rather
than look for a less sinister explanation, like aging — which
is in fact the case.
With treatments has also come a redefinition of the way I perceive
myself, and I think, the way others look at me. Although I have
just written at length about some of the issues I have faced, there
is no denying that I am likely to live for many more years, possibly
as many as my HIV-negative peers. I'm to expect things from life,
not least enjoyment and fulfillment and a determination to make
the most of the years of life which treatments are hopefully offering
me. I'm no longer prepared to accept the poor quality of life issues
which accompany the day to day drudge of living with HIV. On the
whole I've become a lot more open about my health. When asked in
polite dinner-party chit-chat how I managed to get a housing association
flat in central London I didn't try and dodge the question, or hedge
the answer, but said simply "I've got AIDS." It killed further envious
questioning. Similarly, I've become much more explicit about taking
my medication in public, and now either honestly respond to inquiring
glances about the handful of pills I'm downing, or simply ignore
them, rather than apologetically lying about "vitamins" or scurrying
off to the bathroom to take my medication in secret.
There are still limitations to my openness and honesty, not least
that I've never told my parents I have HIV, maintaining elaborate
fictions for their (or is it my own?) benefit about crucial aspects
of my life. This is not because I fear that they'll reject me —
I'm fortunate in knowing that they love me unconditionally —
but because in some way I'm ashamed of having HIV. Luckily I've
never had a bad reaction from a person who I've either told I'm
positive or has guessed. But, the popular prejudice about the disease
has, despite my best efforts at rational thought, penetrated deep
into my consciousness. And this popular prejudice isn't only found
amongst uninformed Daily Mail readers. Some recent correspondence
to the British gay weekly Boyz showed that there's an unhealthy
amount of prejudice directed towards people with HIV within the
group most affected by HIV in the UK, gay men.
Having said that, because of treatments, and their success for
me, I no longer feel I have the right to the sympathy and the allowances
which people made before. I'm very aware of how hard it was for
many of my friends and particularly my partner of ten years, to
support me through what looked like it was going to be a terminal
illness. To an extent, the problems I now face aren't as serious,
and are more generic — lots of people live with serious illness
which can be controlled with medication which causes nasty side-effects.
I want to make the most of the fact that treatments mean that very
possibly I am alive when I expected to be dead. But to do this,
I need to be honest. I've found living with antiretrovirals hard,
often harder than life before treatments. But, like HIV, they're
something which has become part of my life. I hope that at least
some readers will identify with what I've written as they too, find
a way of coping with, and making the most of, what life with treatments
means.
Let Nevirapine Do What It Does
Best
By Bob Huff
S.J. Little, et al. Persistence of Transmitted Drug Resistance
among Subjects with Primary HIV Infection not Receiving Antiretroviral
Therapy. 9th Retrovirus Conference, Seattle, 2002. Abstract 95.
A single-dose of the AIDS drug nevirapine when taken at the onset
of labor is a proven method for dramatically reducing rates of mother
to child transmission (MTCT) of HIV. So why does Dr. Joep Lange,
President of the International AIDS Society and vocal advocate for
expanding the worldwide access to antiretroviral (ARV) drugs, take
every opportunity to warn that resistance to nevirapine (NVP) can
arise after single-dose use? His purpose is to raise this question:
if single-dose NVP brings resistance, then should the drug be reserved
exclusively for chronic treatment regimens and never used as a single-dose
for preventing MTCT? Such talk causes shivers of alarm to dance
through the networks of doctors and advocates working to extend
ARV medicines to all corners of the world. But what is the basis
for his nervousness?
Dr. Lange is correct that NVP resistance can appear after only
one dose, but his conclusion about how to use this valuable drug
is exactly wrong. NVP is very well suited for preventing MTCT. It
acts quickly to lower viral load in the mother and the effect lasts
for more than a day —enough time to protect a baby during labor
and delivery. A single-dose given to the newborn continues the protection
for up to a week. The drug crosses the placenta and appears in breast
milk during the first critical days when the newborn receives its
antibody-rich colostrum. No serious toxicity has ever been reported
for single-use nevirapine, although longer-term follow up for children
exposed to nevirapine at birth still needs to be performed. Though
not as sure as an extended course of AZT or triple therapy to prevent
transmission, in settings with limited prenatal care and little
money to spend on medicines, single-dose NVP is cheap and effective.
Compare the profile of single-dose nevirapine to that of nevirapine
used for chronic HIV infection. Severe rash has occurred in as many
as 8% of people who start nevirapine therapy and some cases of liver
toxicity have been fatal. These life-threatening side effects may
not show up for several weeks or months after starting the drug.
While close liver enzyme monitoring and careful medical management
may be able to catch most incidents of toxicity before they become
serious, this is precisely the kind of care likely to be scarce
in resource-poor countries. Furthermore, there is some evidence
that women on full-time NVP may suffer liver complications and serious
rash at a higher rate than men. The toxicity problems are possibly
due to the long half-life of nevirapine in the blood. The slow rate
of clearance that makes nevirapine ideal for single-dose use during
labor may cause trouble over time if blood concentrations accumulate
to toxic levels during daily chronic dosing.
Dr. Lange's concern stems from the ease with which resistance can
develop to nevirapine. As little as a single DNA mutation is sufficient
to allow HIV to evade suppression by not only nevirapine, but also
by efavirenz and delavirdine, the two other currently approved members
of the non-nucleoside reverse transcriptase (NNRTI) inhibitor class
of antiretroviral drugs. In one study, resistant mutations were
observed in 30% of women eight weeks after single-dose nevirapine
exposure. Dr. Lange is worried that women with the K103N mutation
will never be able to use nevirapine, efavirenz or delavirdine as
part of a chronic ARV regimen — should one become available
to them in the future. Yet it's likely that having had resistance
previously may not be a problem for women who only use NVP to avoid
infecting their newborns. After the single dose has cleared the
blood, the body's ecology no longer favors the nevirapine mutant.
After a period of weeks to a few months, the wild-type nevirapine-susceptible
virus should again overtake the woman's viral population. If she
uses nevirapine during her next delivery, the fast acting drug should
quickly suppress the dominant viral population and lower her viral
load to help insure a safe delivery. Since the nevirapine-resistant
virus is now archived in latently infected cells, she may experience
a bloom of the resistant strain, but not until the baby has been
safely delivered. No reports of a second labor and delivery treated
by nevirapine have yet been published, but real-world data should
soon become available as several nevirapine MTCT pilot programs
enter their third year.
In a study presented at the 9th Retrovirus Conference by Susan
Little of the University of California, San Diego, the K103N mutation
associated with NNRTI resistance persisted for up to a year in women
who had been infected with drug resistant strains of virus. Dr.
Lange, a convener of the panel that heard Dr. Little's presentation,
was quick to ask if her findings should provoke a "rethinking" of
single-dose nevirapine. Dr. Little agreed that the data was "extremely
concerning."
Dr. Little found persistent NVP resistance in four of her six study
participants. However, there is a crucial distinction that limits
applying her observations to women who develop nevirapine resistance
from drug exposure. Dr. Little's subjects were infected by sexual
contact with partners who had been exposed to nevirapine and then
transmitted a resistant strain. This means that her study patients
carried a drug resistant clone and lacked an archived copy of a
wild-type drug susceptible virus. For the drug resistance phenotype
to disappear, a spontaneous N103K mutation had to occur then grow
out as the dominant strain. This chain of events is far more dependent
on the play of chance and environmental factors than is the process
of an archived wild-type strain re-establishing itself after a few
days of drug suppression. If anything, the spontaneous loss of N103
in this small group suggests that NVP resistant virus is less fit
to replicate than the wild-type and argues for a quick rebound of
drug-susceptible virus in most women exposed to single-dose therapy.
Since nevirapine resistance is so quick to develop, perhaps the
real concern should be with the impact that widespread NNRTI resistance
might have on successful efforts to prevent MTCT. Nevirapine resistance
can be expected to rapidly arise in populations that adopt it as
part of triple-drug ARV regimens. Even if adherence is near 100%,
normal variations in absorption, metabolism and viral dynamics may
allow virus replicating in the presence of nevirapine to quickly
generate drug-resistant mutants. In resource-poor settings, viral
load monitoring is likely to be minimal or non-existent. Therefore
individuals failing nevirapine may be more likely continue on their
failing regimens, perhaps infecting new individuals with NNRTI resistant
strains — including women who could benefit from single-dose
nevirapine when delivering their children. This would be the true
tragedy, dimming one of the few therapeutic bright spots in the
world AIDS crisis.
It is unquestionable that the best solution for stabilizing a family
invaded by HIV is to not only give treatment to prevent MTCT, but
also to provide continuing treatment to suppress virus in the mother
and in other members of her family, including her children and husband.
Indeed a new study of continuing ARV for mothers, called MTCT-Plus,
is springing from the foundation of successful mother and infant
research programs. These MTCT programs have moved forward because
they have had the support and funding to successfully demonstrate
results. Sadly, the lack of enthusiasm among drug companies, governments,
foundations and the Global Fund for paying for chronic treatment
means that the slow pace of bringing therapy to the vast majority
of people who need it will continue to drag.
The unique suitability of nevirapine to prevent MTCT may be overshadowed
in many minds by another of its attributes, its low cost. Nevirapine,
whether supplied by Boeringer-Ingleheim or by a generic manufacturer,
is by far the cheapest choice for the potent leg of a three-drug
combo — and cost often looms larger than other issues when
access to treatment is discussed. But proponents of universal therapy
need to critically ask, is the cheapest drug really the best drug
for the job? Despite the low cost of nevirapine itself, the expense
for chronic dosing added to a nucleoside backbone, plus viral load
and toxicity monitoring, will keep this regimen from being widely
deployed for years to come. Meanwhile, the MTCT programs are reaching
people, educating them, testing them and increasingly, treating
them. Although confirmatory data about single-dose NVP used in subsequent
pregnancies are eagerly awaited, it does a disservice to the most
successful current efforts to expand HIV treatment in the developing
world by promoting entirely theoretical objections.
A Treatment Issues Editorial
Canarypox in the Coal Mine
There's been a shakeup in the government's efforts to test a vaccine
for HIV. First, the National Institutes of Health (NIH) cancelled
plans by its HIV Vaccine Trials Network (HVTN) to launch a large,
international study of an HIV vaccine next year. The reason? Disappointing
smaller studies with a canarypox-based vaccine combination gave
little reason to think it would do any better in an 11,000 person,
eighty million dollar trial. This leaves the HVTN all dressed up
with no date, its painstakingly built network of global partners
standing idle.
Then came news the White House had heeded the advice of Secretary
of the Army and recent Enron vice chairman, Thomas E. White, to
shift responsibility for another large trial of a similar canarypox
vaccine away from the U.S. Army and over to the NIH. This study,
planned in cooperation with the Royal Thai Army, is slated to start
in that country later this year. So the NIH is back in the canarypox
business again — with little more chance of success than before.
What is the rationale for moving ahead with large, expensive trials
before the underlying science to make an effective HIV vaccine has
been solved? One answer: infrastructure. Beatrice Hahn, a widely-respected
HIV scientist, explained the problem to Nature magazine: "They have
made such an investment in training, infrastructure, technology
transfer, assays and equipment that at this point it's impossible
to pull the plug. This is more than just a vaccine trial" she said.
Indeed, it has the potential to be a disaster. The only thing worse
than a minimally active vaccine bombing out in a ballyhooed trial
is if it were actually believed to have had a benefit when it didn't.
The Thai trial is designed to see if the canarypox combo can cut
HIV infection rates in half. Proving that would be terrific —
though highly implausible — but the problems start if some
smaller, ambiguous, degree of protection is reported. In theory,
even a modestly protective vaccine could have a significant impact
on the pace of the epidemic over many years and large populations.
But what would this news do to ongoing or planned trials for more
sophisticated vaccine candidates? An ethical quandary over the "best
proven treatment" means the landscape for testing vaccines would
change altogether.
With a "proven" though marginally effective vaccine having set
a standard, it's no longer ethical to conduct trials using placebo.
You have to go up against what you already know works. To make an
ethical comparison, all study participants would get the standard
vaccine, and then only half of them would get the new, hopefully
more effective vaccine. A trial's complexity is increased, its size
and cost go up, and the time needed to get an answer now stretches
out longer and longer. John McNeil, an architect of the surviving
canarypox study, estimated that the planned 16,000-person Thai trial
could balloon to require 100,000 people if there were a standard
vaccine in the picture.
Meanwhile, the HVTN still lacks a mission for its global partners.
Although many smaller studies are starting up, the most promising
new vaccine candidates are several years from needing large scale
testing. What can the vaccine networks do to justify their budgetary
existence and keep their infrastructures intact? Must they wait
for an AIDS vaccine? Or could they put their assays and equipment
to work testing vaccines and preventive measures to combat other
global heath disasters just as well?
The U.S./Thai collaboration on HIV vaccine research dates back
a decade and is part of a longstanding partnership that has also
tackled malaria and dengue virus. An effective vaccine for tuberculosis,
malaria or pneumococcal infections would have dramatic health benefits
for millions of people — with and without HIV. Vaccine candidates
are languishing in under funded programs at the NIH, the Army and
the CDC, as well as at laboratories throughout the world. The emerging
capacity and infrastructure to conduct global vaccine trials is
too important to let stagnate, but science and good sense demand
spending that capital on a candidate with a chance to do some good
in the broadest possible view. The time for a large HIV vaccine
trial will come, but for now the networks should be thinking outside
of the pox.
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