THE TROUBLE WITH NEVIRAPINE
PaulKing
By Anthony Brink
April 2002
I could not stop something I knew was wrong and terrible.
I had an awful sense of powerlessness.
-- Andrei Sakharov
This article is divided into four parts: Part One relates the history and
licensing of nevirapine in the US and Europe, and outlines its
pharmacology and its toxicities; Part Two reveals the extraordinary
circumstances in which the drug was licensed in Canada; Part Three looks
at a South African clinical drug trial involving nevirapine and other
drugs, aborted by order of the Medicines Control Council in April 2001
after a spate of severe toxic reactions, several fatal; Part Four provides
a critique for non-expert readers of HIVNET 012, the Ugandan study of the
effect of administering nevirapine to HIV-positive pregnant women
conducted by Guay et al, on the basis of which the Treatment Action
Campaign won an order from the High Court on 15 December 2001 compelling
the South African government to supply the drug to such women and their
newborn children. Appended to this article are summary back-cover blurbs
from the author’s books, Debating AZT: Mbeki and the AIDS drug controversy
and Just say yes, Mr President: Mbeki and AIDS (in preparation for
imminent publication), reviews of the former, and an extract from the
preface to the latter concerning the professional South African AIDS-drug
lobby, the Treatment Action Campaign.
Part One
Take nothing on its looks; take everything on the evidence, Pip; there is
no better rule.
-- Charles ####, Jaggers the solicitor in Great Expectations
Nevirapine, the manufacturer tells us, is a "non-nucleoside analog reverse
transcriptase inhibitor." It prevents "viral replication" by binding
"directly to the HIV RT enzyme", thereby disrupting its ability to foster
the formation of viral DNA. In other words it clogs reverse transcriptase
a bit like spilt crude oil does penguins. But at a specific site. Like the
bird’s head only.
Or think of the enzyme being like a bricklayer laying DNA building blocks.
Nevirapine handcuffs his hands. Drugs in the AZT class, similarly
described, but without the "non-" prefix, are also said to inhibit reverse
transcriptase. But indirectly, like useless straw bricks slipping into the
place of clay ones, to prevent the wall going up. So the theories go.
Let’s close our eyes and pretend just for now that reverse transcriptase
has unambiguously been shown to exist as a distinct enzyme unique to
retroviruses and not also a component of uninfected human cells, and that
retroviruses exist outside textbooks, like Coffin’s, and children’s
imaginations, as in the Superman cartoon movie Cold Vengeance: "a Roscoe’s
retrovirus…100 per cent fatal", and that retroviruses can be malevolent
and have sufficient genetic complexity for the execution of their
nefarious intentions, and that HIV is one of them. Killing off our CD4
immune cells. No evidence for that? OK, not attacking them directly, but
hypnotising them into committing suicide. Even those they haven’t been
anywhere near. Like telepathically. They call it "programmed cell-death."
For ‘AIDS sufferers’ with sky-high CD4 cell counts, we’ll think up an
explanation another day. Likewise one for folks in peak health with cell
counts at rock bottom. Who should be gasping in hospices. Overcome by
opportunistic infections. Except that we’re talking about some US Olympic
athletes. HIV sits dormant in our cells, a lurking lentivirus, poised to
jump out and attack us after about a decade or so. No, no, we’ve dumped
that theory; the new one is that it replicates from the start, incredibly
rapidly but being neutralised by antibodies, although not quite
efficiently enough to avoid being eventually overrun. Actually that model
is now in the toilet too, so we ‘AIDS experts’ are not too sure what to
say anymore, but who wants to get bogged down by details when we’ve got to
get out there and save lives? I mean let’s keep our eye on the bigger
picture. Because like hey, people are dying.
Nevirapine was first mooted as a potential new hi-tech anti-HIV agent at
the start of the ‘90’s. In Impure Science: AIDS, Activism and the Politics
of Knowledge, sociology Professor Steven Epstein tells us that, "The
second generation of antiviral AIDS drugs – the non-nucleoside reverse
transcriptase inhibitors that had looked so promising in vitro – performed
poorly in clinical trials." This news was "nothing short of shattering" to
guys like Theo Smart of ACT UP New York, sister to our own Treatment
Action Campaign – massive expectations for it having been pumped up by
manufacturer Boehringer Ingelheim and its surrogates in AIDS activist
organisations across the country. Former history professor Elinor Burkett
picks up the trail in The Gravest Show on Earth: America in the Age of
AIDS: In February 1993, a first year medical student at Harvard, Yung-Kang
Chow, tooled around with the flop drug, mixing it with the older ones, AZT
and ddI. The test tube action he claimed to have seen was packaged in a
twelve-page press release by the Harvard Medical School as the next thing:
a likely cure for AIDS. The New York Times, the television stations, and
everybody else fell for it. Never mind that Chow was light on proof. The
nevirapine combo idea got its next big boost from a splash in Nature later
that month. With all the hype and hullabaloo, a large-scale clinical trial
of this novel drug combination approach was set up in the US over sixteen
centres. But after the 7th International AIDS Conference in Berlin was
over and English and American researchers got back to look at Chow’s
magical findings, and did a few experiments of their own, they couldn’t
replicate his results. So they started complaining. Chow’s supervisor, top
‘AIDS expert’ Martin Hirsch, took another look at Chow’s original
research. It was a ####-up, he announced. Chow had made a fundamental
blunder vitiating his conclusions. Dreadfully sorry, everyone. All the
newspapers that had written about nevirapine with such excitement in
February and March now rained tomatoes on it. Along with Nature, which
published a disavowal in July.
Now you might imagine that a formal concession that the root study on the
basis of which the drug went to clinical trials was invalid would be cause
to call off the trials. Because mirth had taken the place of the model for
the novel treatment approach. After all, humans were being treated with a
very poisonous chemical (we’ll see below) for which there was no in vitro
warrant, no evidence of any efficacy – no matter how ingeniously this
smart drug had been engineered. According to a design brief like all good
engineering projects. Assumed sound. One of its parameters being that
reverse transcriptase is that distinct stuff mentioned earlier – and part
of the tiny foe perpetrating the crimes, all likewise described. So it
would be a big mistake to think we’re just going to dump it after all that
time and trouble. After all that money invested in producing it, and all
those high hopes of making so much more. No way.
On completion of the clinical trials, this is what the investigators
reported: (i) Combined with AZT and ddI in patients who’d taken
antiretrovirals before, "nevirapine produced a sustained improvement in
CD4 count when compared with ZDV [AZT] plus ddI." (The fact that CD4 cell
counting as a surrogate marker for clinical health had been discredited
two years earlier in the biggest best longest AIDS drug trial yet
conducted, the Concorde trial in England, Ireland and France, didn’t
dampen the party.) (ii) The CD4 cell count boost was most pronounced among
folk who’d been on AIDS drugs previously, with cell counts of between 50
and 200 mm3. (iii) In the case of antiretroviral drug-naïve patients
(first-timers) with CD4 cell counts "between 200 and 600 cells/mm3,
nevirapine plus AZT and ddI resulted in a 140-cell absolute change from
baseline at 52 weeks, compared with a 26-cell increase with ZDV/ddI, and a
2-cell decrease with ZDV/nevirapine." Looking at the last figure, couldn’t
they see the futility of it all? You take AZT and nevirapine together and
your cell count actually goes down by the end of the trial. We note that
the trial overseers reported no effect on ‘viral load’, that is the
measure, according to ‘AIDS experts’, of HIV infection levels, and their
reduction by a given drug. (Subsequent investigations turned up reductions
in ‘viral load’, but transient only, returning to baseline levels within
weeks.)
On the basis of this crap, Boeringer Ingelheim duly made a pitch for FDA
approval. Obviously nevirapine wouldn’t have made it out of the starting
blocks in any ordinary drug evaluation process. But this was no ordinary
procedure. It was a quickie.
On 21 June 1996 after a fast-track review that lasted just 119 days,
nevirapine got its ticket. But it was a qualified one. It was not to be
used on its own. That’s because even on the worthless measure of efficacy
used by ‘AIDS experts’ (CD4 cell counting) it was ineffective solo. Get
that? It doesn’t work as an ‘anti-HIV’ drug on its own. Moreover, there
was no evidence to show that the drug afforded any clinical benefits: made
you feel better, and improved your health. In terms of the Accelerated
Approval Regulations, Boehringer Ingelheim was required to go home, do
some more studies on humans, and come back to describe and verify the
clinical benefit that it proposed the drug might have. Cool new system.
For drug companies. These times being pro-business ones.
A press release on the same day stated, "studies also showed that the
virus rapidly becomes resistant when nevirapine is used alone." Quite how,
no one has ever ventured to propose. Let alone suggest more frankly that
on a plainer interpretation of the data, the drug is simply ineffective.
It’s something like saying: ‘We lost Vietnam because all those frigging
gooks became resistant to napalm and saturation bombing and the systematic
selective assassination of their intellectuals by our special
operatives.’
"Therefore, nevirapine is only recommended for use in combination with at
least one other antiretroviral agent" in the nucleoside analogue class:
AZT, ddC, ddI and d4T. One that the patient hasn’t taken before. To
modulate the laboratory marker – CD4 cell counts – a bit better than AZT
and like drugs on their own. Not make the patient feel any better. The
fact that CD4 cell counts rise for a while in reaction to exposure to
metabolic poisons like AZT even among HIV-negative people (AIDS 1996;
10:1444-1445) evidently passed the FDA by. As did the fact that AZT and
nevirapine combined was no good according to the cell-count data.
What’s more, the effects of nevirapine on "surrogate endpoints" were only
noticeable among patients "with HIV infection who have experienced
clinical and/or immunological deterioration." Not for people appearing
well, and whose lab test results were considered normal, despite having a
virus ravaging their immune systems, according to their doctors.
That nevirapine is extremely poisonous was admitted on the drug’s label –
advising discontinuation "in patients who develop a severe rash or a rash
accompanied by fever, blistering, oral lesions, conjunctivitis, swelling,
muscle or joint aches, or general malaise." And make no mistake, when the
manufacturer talks of rash, it isn’t referring to a brush with stinging
nettles. It means a generalised symptom of drug intoxication so severe in
some cases that it shows up with thick layers of your skin dying off and
peeling in great chunks. An ad for the drug – featuring the endorsement of
"the dosing convenience of VIRAMUNE" by transatlantic sailor Mike Schmidt
– "WHEN THINGS GOT ROUGH VIRAMUNE DIDN’T GET IN MY WAY" – explains:
"Severe and life-threatening skin reactions have occurred in patients
treated with VIRAMUNE, including Stevens-Johnson syndrome and toxic
epidermal necrolysis. Fatal cases of toxic epidermal necrolysis have been
reported." The ad also warned of "severe…liver toxicity, including fatal
cases", apart from the bother of "fever, nausea, headache, and abnormal
liver function tests."
FULL REPORT AT: -
GMCarter
<aim...@aimultimedia.com> wrote:
>THE TROUBLE WITH NEVIRAPINE
>
>By Anthony Brink
>
>April 2002
snip...
> (The fact that CD4 cell
>counting as a surrogate marker for clinical health had been discredited
>two years earlier in the biggest best longest AIDS drug trial yet
>conducted, the Concorde trial in England, Ireland and France, didn’t
>dampen the party.)
LOL... most of this is the usual distorted, poor thinking. But here we
have truly dismal inaccuracy, about as bright as Bush.
Concorde showed nothing of the sort. What it showed was that AZT alone
sucks, especially early in disease. Indeed, a number of studies have
shown that "hit hard, hit early" is stupid. Other data have suggested
that waiting TOO long (e.g., CD4 < 50) can blunt the immunological
rebound from using ARV, but not necessarily impair the reduced risk of
AIDS-related infections. Best time to start is probably between
200-350 CD4 cells.
But as to CD4 count being a marker? Well, darling, it IS a marker. If
your CD4 count is high, chances are pretty good you'll stay healthy.
If it drops below 200...risks start rising...below 100, a variety of
infections become MUCH more likely.
Low-dose IL2 in virus-suppressed individuals can help some folks who
have been unable to break a 200 ceiling that some see with a nadir
count below 100--and they do better. Unfortunately, this isn't a
therapy that will like get to too many people in the world with AIDS.
As to nevirapine? It DOES have serious toxicities. It can really mess
up some people's livers. It should probably NOT be given to pregnant
women as part of a complete cocktail -- but to use one or two doses to
prevent mother-to-child transmission, it appears pretty safe.
George M. Carter
PaulKing
Tell that to the 10% of Olympic Games contenders who tested below 350. CD4
means very little if anything.
GMCarter
Citation. And relevance to the majority of people who are not Olympic
contenders?
George M. Carter
Robert S. Holzman
news:9idl909h7oolr35n0...@4ax.com:
Another non-issue. The only article I could find on CD4 and
olympic athletes is the one cited below, a study of 10 (count
'em) such atheletes. If 10% had low CD4s then 1 of the 10
did. The text is not available to me but the abstract doesn't
claim low cd4s for atheletes nor does it give the HIV status
of the atheletes. This study is no basis for the claim made
above (the 10 cyclists are hardly a random sample of olympic
athletes).
I swore I was not going to do this any more.
___________________________
Ferrandez, M. D., M. Maynar, et al. (1996). "Effects of a
long-term training program of increasing intensity on the
immune function of indoor Olympic cyclists." Int J Sports Med
17(8): 592-6.
We have studied, on blood samples, the level of
immunocompetence (concentration of immune cells, phagocytic
process of polymorphonuclear neutrophils, proliferative
response of lymphocytes to mitogens), the ascorbic acid
content of such immunocompetent cells and the "stress
hormone" status (cortisol, ACTH and beta-endorphin) of 10
cyclists, members of the Spanish Indoor Olympic Team and
participants in the Olympic Games of Barcelona '92. The study
was performed twice during their training for such an event:
during the third year of the program (February, 1991) and
immediately before the Games (June, 1992). As regards the
phagocytic process of neutrophils, we studied the different
steps of this process: adherence to endothelium, directed
mobility or chemotaxis, ingestion of latex beads and
superoxide anion production measured by the nitroblue
tetrazolium (NBT) reduction test. We observed a statistically
significant increase in chemotaxis and NBT reduction activity
just before the Games as compared to the third year of the
program, whereas variations were not found in the other
parameters. The values of the proliferative capacity of
lymphocytes were slightly higher in June '92 than in February
'91, but no statistically significant differences were found.
The ascorbic acid content decreased strikingly (especially in
lymphocytes) immediately before the Games. Regarding the
stress hormones and neuropeptides (cortisol, ACTH and beta-
endorphin), we observed an increase in serum ACTH and beta-
endorphin levels in the last determination (June '92) in
comparison to the first one (February '91). These results
suggest that, at the end of a long-term training program. no
immunosuppression occurs, although an important increase in
the concentration of stress hormones (ACTH and beta-endorphin)
is found. This is probably caused by the psychological stress
associated to the participation in such an important event as
the Olympic Games.
GMCarter
<robert....@med.nyu.edu> wrote:
snip..
>
>I swore I was not going to do this any more.
>
LOL. Me too...but what the hell. I've been learning more about ELISAs.
It is a useful method of learning; kinda reminds of buddhists when
they undergo debates about the meaning of scriptures (unlike other
religions that just demand subservient obedience to some psycho's
interpretation).
Here, again, tho, we show our resident psycho has once again perverted
out of all reason some data to press a point. Geez. Thanks for the
abstract....
George M. Carter
PaulKing
Only one study will be discussed in detail here, which was published in
1992 (Verde et al. 1992). In a controlled trial, ten athletes were asked
to over-train for three weeks. Blood samples were taken immediately before
starting, at the end of the three weeks, and again three weeks after
returning to normal. The researchers found steady declines in the
percentage of CD4+ T-cells, with the lowest amount occuring 3 weeks after
returning to a normal exercise schedule. The authors also found reductions
in the CD4/CD8 ratio, although these had normalized by the 3 week
endpoint. Finally, the authors also checked levels before and 5 minutes
after acute exercise, and again found reductions in CD4 percentages and in
CD4/CD8 ratios, although these normalized by 30 minutes post-exercise. It
is interesting that a stress as simple as overexercising for three weeks
could cause lowered CD4 counts, and that they did not correct for at least
three more weeks after returning to a normal exercise schedule.
Other studies have found increased infections in athletes, especially
during periods of heavy training or competition, which suggest the
presence of "clinically relevant immune suppression in well trained
athletes" (Mackinnon 1997).
Gary Stein
when the bellow mentioned athletes stop rigorous training there CD4 counts
return to normal, where in HIV those counts in untreated patients continue
to go down until either reaching 0 or the patient dies which ever comes
first. Sadly those are the only options for 90+% of those infected with HIV
who go untreated.
Gary Stein
"PaulKing" <aim...@aimultimedia.com> wrote in message
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