AidsMyth News Daily Rethinker ePaper

Nevirapine
flesh-eater
halted SA Aids Trials
AidsMyth.com Investigation
BY
Fintan Dunne, Editor.

31st October 2000
Tragic underestimation of flesh-sloughing side-effects and failures in patient monitoring -led to the deaths which forced halting of South African Nevirapine trials. **

This is not Aids **
This is the high cost of 'cheap' Nevirapine.
A ghastly side-effect called Stephens- Johnson syndrome:
a 'rash' that kills in a flesh-eating flare-up.

"JULIE was 10 months old. Her mouth was filled with blisters... Her face was unrecognizable. She looked like she had been deep fried. Her lungs collapsed... [She] lost all sight in her right eye"- Jean

Tragic, gross underestimation of Nevirapine risk -in patients using antiretrovirals for the first time, led to 5 deaths which halted a South African drug trial earlier this year.

Official data available before the clinical trial commenced showed that 'cheap' Nevirapine was five times more likely to cause the deadly, drug-induced, Stevens-Johnson syndrome than was more expensive AZT.

But, our investigation has also found vital data buried in prior clinical trial results, which indicates the risk of Stevens-Johnson syndrome, gastrointestinal disorders and other serious side-effects in first-time users of antiretroviral drugs who take Nevirapine -are at least doubled again. Yet we could find no highlighting of this serious concern in drug information from manufacturer Boehringer-Ingelheim. Furthermore, medicating with Nevirapine in an African setting could quadruple the impact from Stevens-Johnson syndrome because of poor infrastructure.

These photos show Stevens-Johnson syndrome, which killed three the five women who died in now-halted South African trials of Nevirapine. Appearing within weeks of commencing Nevirapine -at first as a rash, all the skin can be sloughed off; mouth and trachea blister; lungs and intestines can shed layers inside the body. Despite emergency 'burns unit' intervention, Nevirapine can cause serious lifetime disability, or death. SA opposition leader, Tony Leon has recently lionized Nevirapine for HIV treatment.

Prevention of this side-effect of Nevirapine requires careful patient monitoring. By far the most common complication is described as 'rash' when mild, or as SJS when severe. Immediate withdrawal of the drug is mandated in all but mild reactions.

Nevirapine was approved unanimously by a Federal Drug Administration committee in the USA, despite evidence that in treatment-naive individuals, the incidence of 'rash' and other side-effects was considerably higher than in patients who had already been medicated with other antiretroviral drugs.

Rash of complaints

On Thursday April 6th, SA PAC chief whip Patricia de Lille said that she had uncovered a “nest of abuse and exploitation” in clinical trials for US-based Triangle Pharmaceuticals. The trials are on HIV/Aids patients under
Dr. M.E. Botes at the Kalafong Hospital in Pretoria.

Trial participants told De Lille of severe side effects of the drugs and irregularities in the way patients were asked to sign consent forms they did not understand. The trials are investigating the drug Emtricitabine (FTC) -using a combination of three drugs - FTC or lamivudine (3TC) with stavudine and nevirapine.

In an interview with The Natal Witness, De Lille said, “One patient developed a rash all over the body and still has marks on the face. He told Dr. Botes that this had happened since using the drugs, but the doctor said it was not the drugs causing the rash, but the HI virus. “

The Natal Witness also reported De Lille saying one woman went completely blind for two weeks, but regained her eyesight after discontinuing the drugs. Another patient could not sleep; was vomiting and suffering from depression.

Recently, a 'Carte Blanche' investigation of the Nevirapine trial by Vivienne Vermaark, was broadcast on M-NetTV in South Africa. The documentary describes symptoms consistent with SJS in 'Lucy' -one of the five women who died.

Before De Lille's remarks were even reported, Minister of Health, Tshabalala-Msimang announced that further recruitment for clinical trials using the drug Nevirapine in SA would be halted. Tshabalala-Msimang told Parliament that two of the women died of liver damage, and there was “probable” causal association with Nevirapine in the other three cases.

Kevin McKenna, a spokesman for Nevirapine manufacturers Boehringer Ingelheim, wasn't about to own up- “My information is that the actual link to Nevirapine is inconclusive, and that the company involved [are] examining the [deaths] and establishing the reasons,” he said at the time.

Inconclusive evidence, perhaps -but very strongly circumstantial, nevertheless. Here is what Boehringer says on a New Zealand Government site in their Nevirapine data sheet

(Why NZ? Well, Boehringer are a bit coy about detailed drug
information on most of their worldwide Internet sites
-offering toll-free information by phone instead.)

Boehringer Ingleheim
Nevirapine Data Sheet

"The major clinical toxicity of VIRAMUNE is rash.
....occurring in 16% of patients in combination regimens in Phase II/III controlled studies..
...35% of patients treated with VIRAMUNE experienced rash compared with 19% [ ] treated in control groups of either AZT + ddI or AZT alone.

Severe or life-threatening rash occurred in 6.6%
of VIRAMUNE-treated patients compared with 1.3% of patients treated in the control groups. Overall, 7% of patients discontinued VIRAMUNE due to rash.

Rashes are usually mild to moderate,
maculopapular erythematous cutaneous eruptions, with/without pruritus, on trunk, face and extremities.

Severe and life-threatening skin reactions
have occurred in patients treated with VIRAMUNE, including SJS and TEN (toxic epidermal necrolysis). Fatal cases of SJS, TEN and hypersensitivity reactions have been reported.
VIRAMUNE must be discontinued if patients experience severe rash

Severe and life-threatening hepatotoxicity, including fatal fulminant hepatitis, has occurred in patients treated with VIRAMUNE. Some of these cases began in the first few weeks of therapy. Monitoring of liver function tests is strongly recommended especially during the first six months of VIRAMUNE treatment.

Official Boehringer data sheet on
New Zealand Medicines Safety Authority website

The "hepatoxicity" arises partly because the liver is the organ that must metabolise Nevirapine. Deaths from liver failure are not unheard of in such a clinical trial -but are certainly minimised by proper monitoring.

So, two of the five deaths that occurred on this Nevirapine trial can be accounted for by "hepatotoxicity" -as Minister Tshabalala-Msimang indicated in parliament. But what of the three deaths described as 'inconclusive' by the Boehringer spokesperson?

More than a mere rash?

Describing this side-effect of Nevirapine
as a 'rash' is downright misleading. In the same way as describing the visible septicemia of viral meningitis as a rash would fail to tell the whole truth. Because, in both cases, the 'rash' is not cutaneous, nor arising from localised causes -but systemically driven and means the body is signaling a very serious illness. In the severe forms of the Nevirapine effect, the reaction progresses in ways that depart from any known 'rash.'

Bear in mind that the SJS/TEN syndrome we will now describe is preponderantly due to adverse drug reaction. It is an iatrogenic syndrome to which no human being should be lightly put at risk.

Kathy Supple and Julie Liberio are critical care nurses, with experience of multi-causal SJS/TEN, where the:
"definitive characteristic is massive epidermal sloughing
at the dermo-epidermal junction, leading to a completely denuded dermis"

Meaning, the skin detaches from the body.

"The extent of multisystem involvement and complications
varies with each patient. Universal involvement of mucous membranes varies according to the level of involvement
in each area: eyes, mouth, airway, esophagus,
rectum, vagina, and urethra"

Meaning, every mucous tissue also can blister and detach.

"Gastrointestinal involvement may occur because
of mucosal sloughing of the mouth, esophagus,
stomach, and rectum, [ranging in effect] from anorexia to development of a necrotic bowel"

"Ocular involvement is due to conjunctival sloughing
and may occur in 40% to 50%. Involvement may be
manifested initially as a mild conjunctivitis and progress
to more severe complications, including blindness. The
extent of ocular involvement is unpredictable and is not necessarily related to the initial severity."

Let us recall the witnesses who spoke to Patricia de Lille, MP about the side effects of the trial drugs:
"one...developed a rash all over the body"
"one woman went completely blind for two weeks"

Recall those who spoke on the Carte Blanche program:
' “What happened to her sight after she took the pills?”
Rebecca: “She started to change. Blind…
not to hear nicely… not to speak properly.”
Rebecca also witnessed other symptoms,
including anal bleeding, sores that wouldn't heal,
abdominal pains, weight loss, fevers and pneumonia...
These could all be typical Aids symptoms, but Rebecca remains convinced it was the drugs - not the virus. '

These were no Aids symptoms.
• The rashes and sores observed -were classic Nevirapine rash.
• The anal bleeding and abdominal pains bore testimony to Nevirapine's predilection for affecting the gastrointestinal
system -as seen in the comparable clinical trial which
ushered in FDA approval.
• The full blindness was untreated SJS ocular sloughing.
• The blindness which, tellingly, healed on stopping
medication -was a reversal of SJS syndrome.

All five women clearly died of known and preventable side-effects of Nevirapine. How could this possibly happen?

High-level rashness

The FDA's Antiviral Drugs Advisory Committee
met on June 7, 1996 to consider Nevirapine for approval.
It was a doubly historic day. This was the first ever nonnucleoside reverse transcriptase inhibitor (NNRTI) to be approved. The committee practically stood on chairs and cheered for Nevirapine. The vote was a unanimous 8-0 in favour. The first ever unanimous vote. Nevirapine was approved under the FDA's accelerated approval program June 24, 1996

NNRTI's came on the scene in the interregnum between first generation antiretrovirals like AZT, and and the current, now failing, Protease Inhibitors drugs. By binding to reverse transcriptase at a site different from the one used by nucleosides they promised to augment the existing drugs.

But clinical trials of Nevirapine showed only modest changes in CD4 count and viral load when used by patients already on first generation antiretrovirals. What really swayed the committee were more favourable results from the last trial with subjects who were 'treatment-naive' -using HIV medication for the first time. Those results secured approval of Nevirapine at 400mg/day.

From then on, in all public information, Boehringer Ingleheim trumpeted the combined trials 'rash' incidence of 35%, with an openly acknowledged 'severe rash' rate five times that of AZT
(6.6% v 1.3%), and offered suggestions for moderating severity and monitoring patients carefully. Laudable enough.

But, no wonder the combined figure from all trials was always spotlighted. For, who would want to highlight the worrying data in the last trial: BI 1046 ?

Here is a summary version of the trials data table. Compare the severity of reaction in the BI 1046 treatment-naive columns
- with the earlier trials on patients already exposed to antiretroviral drugs -in the centre columns

It's a startling contrast.
click table for larger version
click here for full data table

In treatment-naive patients:
• The overall incidence of adverse side-effects is doubled.
• Serious gastrointestinal side-effects appear.
• Rash affects 50% of subjects -not 35%
• Nivirapine & AZT used together produce side-effects
at a rate that diverges strongly from the average of all trials

It seems hard to justify Boehringer Ingelheim boldtyping the particular dangers of rash -above other toxicity's, yet failing to spotlight the need for additional caution in the treatment-naive. Even harder to justify the failure to warn of the need for caution with the Nivirapine & AZT combination.

The higher gastrointestinal adverse effects could arise from low tolerance to medications in those using them for the first time- but even this were a factor, it might also be that a rash-type effect is selectively targeting gastrointestinal or, for that matter oracular tissues. Though called a 'rash,' the SJS-effect can manifest invisibly inside the body as well as on the skin.

These concerns are taken very seriously
in the European Union.
Advised by it's expert group on antiretrovirals, the
European Agency for the Evaluation of Medicines,
on April 12, 2000, decided (PDF)
to maintain Nevirapine in it's
"under exceptional circumstances" category.

The agency issued an urgent
safety restriction (PDF)

on Nevirapine to include new warnings on
"life-threatening cutaneous and hepatic reactions"
-citing continuing reports of incidents of these very severe reactions in 1999/2000.

These warnings are not new.
So any prudent person would take a considerably more caution with treatment-naive individuals and might even rule out many for treatment based on sensitivity testing.

The US versions of the SJS syndrome warning advises patients to "Dial 911 or rush to the nearest ER." on suspicion of an SJS reaction. A prudent person would also wonder if medication requiring this level of support services, was in any way appropriate for Africa. Or, wonder if the fatality rate might increase were this factor ignored.

TRIAL DESIGN and SUPERVISION

Still, despite the obsfucation over clinical trial data, could not the South African oversight and review structures, in conjunction with clinical trial administrators, surely be relied upon to ensure that a catastrophe could not occur?

Techniques exist to mediate the worst effects of the Nivirapine toxicity. Antihistamines and even prior dosing with cortico-steriods can diminish 'rash' severity, albeit at the risk of masking long-term damage. Immunoglobulins can be effective in reversing full-blown SJS. Clearly defined monitoring procedures can detect severe reactions while still nascent. Sensitivity testing could eliminate risk to susceptible individuals.

WHAT NEXT?

There are serious civil and possibly, criminal implications for all who are party to the supply of medication in such a way as leads to avoidable death. There are valid reasons for believing that procedures broke down at one or more levels and that some of those breakdowns could involve criminal neglect.

Against that backdrop, the documents that recorded the trial could be important evidence. So it is worrying that the Carte Blanche investigation reported problems with access
to medical files:

Nelly: “They say the file is missing.”
The hospital registry told Nelly that her files
were removed from the registry"

If those reports are accurate, in the light of prime facie evidence, early action should be taken to secure the evidentiary basis of any possible criminal prosecutions.

END

See our coverage of the Carte Blanche report here

** All photos are of USA-based victims of SJS side-effects
caused by supha-based drugs (mostly antibiotics)
in normal clinical practice.

We do not imply that these persons have suffered from Aids,
but they suffered an SJS syndrome which presents
substantially an identical clinical profile
when caused by antiretroviral drugs.