THE RASH RESULTS
OF NEVIRAPINE

Data from clinical trials, indicate the
risk of serious side-effects in patients
who take Nevirapine for the first time
may be double the manufacturer's
flagship claim.

by Fintan Dunne, Editor
SickofDoctors.com

14th April 2002

The FDA and Nevirapine manufacturers Boehringer Ingelheim are currently examining irregularities in a Ugandan clinical trial to determine if Nevirapine (sold as Viramune) can be mass-marketed for use in preventing mother-to-child transmission of HIV in the United States.

But another African trial involving "irregularities" also has serious implications for Nevirapine. In fact, tragic underestimation of Nevirapine's side-effects on patients using Nevirapine as their first anti-HIV drug, led to five deaths which halted a drug trial in 2000, at the Kalafong Hospital in Pretoria, South Africa.

Indeed, Nevirapine was originally approved unanimously by a Federal Drug Administration committee, despite evidence that in treatment-naive individuals, the incidence of side-effects was considerably higher than in patients already medicated with other antiretroviral drugs.

These side effects emerge within weeks of commencing Nevirapine, with one clinical trial finding 'rash' affecting 50% of patients. Given this level of adverse reaction, even the single dose use of Nevirapine in preventing mother-to-child transmission may expose mothers, and especially infants, to sub-clinical side-effects at an unacceptable rate -- compared to other anti-HIV medications.

MORE THAN
MERE RASH

Stevens-Johnson syndrome (SJS) killed three the five women who died in the South African trial. SJS can cause all the skin can be sloughed off; mouth and trachea to blister; and lungs and intestines to shed layers inside the body. Despite emergency intervention, Nevirapine can cause serious lifetime disability, or death.

The South African trial was halted, but 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.

Yet, here is what Boehringer said in a 2001 Nevirapine data sheet

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. Fatal cases of SJS, TEN and hypersensitivity reactions have been reported.

Describing this side-effect of Nevirapine as a 'rash' is a laughable understatement. The severe form of the Nevirapine Stevens-Johnson effect, progresses in ways that defy the 'rash' description:

"[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.
Meaning, every mucous tissue also can blister and detach.

"Gastrointestinal involvement may occur because of mucosal sloughing of the mouth, esophagus, stomach, and rectum... "Ocular involvement may occur in 40% to 50%....and progress to more severe complications, including blindness."


REGULATORY 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 favor. The first ever unanimous vote.

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 favorable results from the last trial with subjects who were using HIV medication for the first time. From then on, in all public information, Boehringer Ingleheim trumpeted the combined trials 'rash' incidence of 35%.

No wonder the combined figure from all trials was always spotlighted. Who would want to highlight the worrying data in the last trial: BI 1046 ?

In treatment-naive BI 1046 patients:
• The overall incidence of adverse side-effects was doubled.
• Serious gastrointestinal side-effects appeared.
• Rash affected 50% of subjects -not 35%.

Below 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 center columns.

It's a startling contrast.
                                             
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.

Laura Guay :     -Medical Researcher   "Investigators and mothers were not masked to treatment status or outcome after randomization." Anthony Brink :   -Barrister   "She could have put it more plainly:   We fucked it up from the word go." Read South African barrister and AIDS expert, Anthony Brink. A devastating critique: THE TROUBLE WITH NEVIRAPINE

It is even harder to explain how the FDA authorities continue to approve nevirapine for infants -- against a background of regulatory caution over it's use in adults. The Centers for Disease Control and Prevention have highlighted their "serious concern" about life-threatening side-effects among health care workers taking nevirapine after occupational exposure to HIV.

JUSTIFIED RESERVATIONS

No wonder the South African Government and President Thabo Mbeki have reservations about Nevirapine. In fact, Dr. Val Turner, a member of the president's AIDS advisory panel has bluntly stated that the coyly-named "irregularities" in the Nevirapine HIVNET are explicable thus:

"It doesn't work!" he maintains, citing the Nevirapine review by the so-called Perth Group of AIDS dissidents, to which he belongs, as the reason behind the FDA's trepidation.

South African barrister, Anthony Brink, is even more blunt. He rephrases the admission in the clinical trial report that the trial was quickly unblinded. He thinks the report should state: "We fucked it up from the word go."

Brink's meticulously researched critique of the HIVNET 012 trial is deeply damaging to the FDA review process currently underway. He reports that the trial was neither placebo-controlled, nor double-blind. Maternal plasma HIV-1 RNA levels were not significantly different at delivery from baseline. Which is hard to reconcile with claims that the drug worked as hoped.

The original case records are missing, which makes review of adverse effects from Nevirapine impossible. Furthermore, Brink also cites "professional differences of opinion" between researchers and the hospital staff concerning what constituted a "serious adverse event."

It's time for the FDA to rethink Nevirapine -- from the ground up.


Trial BI 1046 Summary:
click here for
full data table


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