Health Supreme Update: Africa - Nevirapine For AIDS Mothers: U.S. Hid Research Concerns
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According to a recent article in the Indy Star, the National Institute of Health did not inform presidential aides about safety concerns that emerged during testing of nevirapine in Uganda. As a result, a U.S. led program distributed the drug to hundreds of thousands of pregnant mothers in Africa. The aim was to stem mother-to-child transmission of HIV, a retro-virus widely believed to cause the symptoms of Aids.
U.S. Senator and Finance Committee Chairman Charles Grassley asked the Justice Department to investigate NIH's conduct. In a letter released Monday, Grassley said he was compelled to do so by "the serious nature of these allegations and the grave implications if the allegations have merit."
The Ugandan research, according to Boehringer Ingelheim, the producer of the drug, was plagued by "serious" and "major" issues but NIH officials at the time dismissed the problems as overblown and let the drug distribution program go ahead because of what NIH's AIDS research chief, Dr. Edmund Tramont called "the enormity that this decision could have on the worldwide use of nevirapine to interrupt mother-baby transmission". So because it was thought of paramount importance to provide a drug to pregnant African women classified as suffering from AIDS, the safety concerns were disregarded.
It is one of the great tragedies of our time that a highly toxic and potentially damaging drug is given to pregnant mothers in order to prevent mother-to-child transmission of a virus that, according to independent virologists, has not been properly isolated, and has not been proved in scientific studies to be the cause of the AIDS symptoms. Insistence to drug pregnant mothers is more tragic still as the classification of "HIV infection" in Africa is uncertain and has led to exaggerated numbers of mothers to be needlessly classified as suffering from AIDS.
. . .
U.S. knew of AIDS drug concerns
Health officials kept mum on flaws in research for nevirapine, sent to Africa to protect newborns.
By John Solomon
Associated Press
December 14, 2004
WASHINGTON -- Weeks before President Bush announced a plan to protect African babies from AIDS, top U.S. health officials were warned that research on the key drug was flawed and may have underreported severe reactions including deaths, government documents show.
The 2002 warnings about the drug, nevirapine, were serious enough to suspend testing for more than a year, let Uganda's government know of the dangers and prompt the drug's maker to pull its request for permission to use the medicine to protect newborns in the United States.
But the National Institutes of Health, the government's premier health research agency, chose not to inform the White House as it scrambled to keep its experts' concerns from scuttling the use of nevirapine in Africa as a cheap solution, according to documents obtained by The Associated Press.
"Everyone recognized the enormity that this decision could have on the worldwide use of nevirapine to interrupt mother-baby transmission," NIH's AIDS research chief, Dr. Edmund C. Tramont, reported March 14, 2002, to his boss, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
The documents show Tramont and other NIH officials dismissed the problems with the nevirapine research in Uganda as overblown and were slow to report safety concerns to the Food and Drug Administration.
An audit of the Uganda research showed that 14 deaths were not reported in the study database as of early 2002 and that the top two researchers in Uganda acknowledged "thousands" of bad reactions weren't disclosed.
NIH said that most of those bad reactions were likely caused by poor health of the patients, not the drug itself.
Nevirapine, marketed in the United States as Viramune, has been used since the 1990s to treat adult AIDS patients and is known to have potentially lethal effects like liver damage and severe rashes when taken over time.
NIH's nevirapine research in Uganda was so riddled with sloppy record-keeping that NIH investigators couldn't be sure from patient records which mothers got the drug. Instead, they had to use blood samples to confirm doses, the documents show.
Less than a month after Bush announced a $500 million plan to push nevirapine across Africa to slow the AIDS epidemic, the Health and Human Services Department sent a nine-page letter to Ugandan officials identifying violations of federal patient protection rules by NIH's research. Africa accounts for more than two-thirds of the world's AIDS cases, with 27 million infected.
The NIH research "may have represented a failure to minimize risk to the subjects," the Office of Human Research Protections told Ugandan authorities in summer 2002.
Senate Finance Committee Chairman Charles Grassley, R-Iowa, has asked the Justice Department to investigate NIH's conduct. In a letter released Monday, Grassley said he was compelled to do so by "the serious nature of these allegations and the grave implications if the allegations have merit."
Dr. H. Clifford Lane, NIH's No. 2 infectious disease official, said NIH officials were aware in spring 2002 about the impending White House announcement on nevirapine but did not tell presidential aides of the problems because they were confident, even before reviewing the Uganda research, that the underlying science was solid.
The White House -- though unaware of the NIH concerns -- also remains confident in Bush's $500 million plan in 2002 to send nevirapine to Africa. Bush approved $2.9 billion for global AIDS fighting next year.
In 1997, NIH began studying in Uganda whether it could be given safely in single doses to stop mother-to-baby transmissions. That research showed it could reduce transmission in as many as half the births.
By early 2002, an NIH auditor, agency medical safety experts and the drug's maker all disclosed widespread problems with the U.S.-funded research in Uganda.
Boehringer Ingelheim, the Connecticut-based company that makes nevirapine, told NIH it found at least one "critical compliance issue" that compromised the integrity of the study and more than four dozen issues it described as "serious" and "major."
Boehringer and NIH auditors cited concerns such as failing to get patients' consent about changes in the experiment, administering wrong doses and delays and underreporting of "fatal and life threatening" problems.
Westat, a professional medical auditing firm hired by NIH to visit and audit the Uganda site, reported in March 2002 that there were 14 deaths not reported in the study database as of early 2002 and that the top two researchers in Uganda acknowledged "thousands" of bad reactions that weren't disclosed.
NIH said the subsequent review whittled that list down significantly, all deaths were eventually recorded and the majority of bad reactions are believed to have been caused by the poor health of patients, not the single dose of nevirapine. But they conceded it was incumbent on a U.S. research project to fully and quickly disclose them.
"We may not have reported exhaustively, but we reported all serious side effects," said Professor Francis Mmiro, who led the Uganda study. "What you may call a serious side effect in the U.S. is not a serious side effect in Kampala."
African doctors said they weren't aware of the full extent of NIH's concerns but feel comfortable -- at least until better options emerge -- administering it in single doses to AIDS-sickened mothers who have few other choices to protect newborns.
Boehringer Ingelheim said it has donated enough doses to treat more than 411,000 mothers and infants in Africa, and self-disclosed the problems it found with the Uganda research. But it says it has research from other locations, including Thailand and South Africa, showing single-dose usage at birth is safe and effective.
Still, the German-owned company no longer is seeking FDA permission to use nevirapine for protecting U.S. infants because better treatments have emerged, said Dr. Patrick Robinson, a top Boehringer AIDS specialist.
About Nevirapine
*The drug:* Nevirapine, an AIDS drug pronounced Nee-VERA-peen, is made by Boehringer Ingelheim Corp. and is marketed under the brand name Viramune. There are two generic versions, Nevimune, made by Cipla, and Nevirex, made by Aurobindo Pharma.
*How it works:* Nevirapine, a non-nucleoside reverse transcriptase inhibitor, blocks an HIV protein that the virus uses to make new viral particles.
*How it is used:* Nevirapine is generally taken once or twice a day in combination with other anti-AIDS drugs, such as AZT or didanosine.
*Experimental use:* Nevirapine was tested in Uganda, Kenya and Thailand to see whether a single dose to a mother in labor and one later to the newborn could prevent HIV transmission from an infected, pregnant woman to her baby.
*Resistance problems:* Studies found that birthing mothers who received nevirapine could develop an HIV virus resistant to some HIV drugs, including nevirapine. This could make their later AIDS treatment less effective.
*Side effects:* Liver toxicity occurs in some patients. About 16 percent of patients develop a skin rash. Other common side effects include nausea, fatigue, headache, vomiting, diarrhea and abdominal and muscle pain.
Here is a discussion by Vera Hassner Sharav of the AHRP - Alliance for Human Research Protection:
ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
Promoting Openness and Full Disclosure
www.ahrp.org
The Associated Press reports: “Less than a month after Bush announced a $500 million plan to push nevirapine across Africa to slow the AIDS epidemic, the Health and Human Services Department sent a nine-page letter to Ugandan officials identifying violations of federal patient protection rules by NIH's research.”
The AP reports that offficials at the National Institutes of Health (NIH) failed to inform the White House and concealed from FDA officials that the AIDS drug, nevirapine, which the US government was recommending as a “cheap solution” for the protection of African babies from AIDS had in fact been found to cause “thousands of severe reactions including deaths.”
The AP investigative report indicates that documents show that top NIH officials including Dr. Edmund Tramont and Dr. Anthony Fauci, “dismissed the problems with the nevirapine research in Uganda as overblown and were slow to report safety concerns to the Food and Drug Administration.”
Dr. H. Clifford Lane, NIH's No. 2 infectious disease official is quoted stating: "I would say there are many lessons that we have learned from this review that will help us do our clinical research, both domestically and internationally, much better."
One lesson derived from a closer review of the Uganda research, Dr. Lane acknowledges, “is that even single doses of nevirapine can create instant resistance, meaning patients may not be able to use the drug or others in its class again when their AIDS worsens.”
NIH documents show that the same drug was used in Phase I clinical trials that were conducted in New York City on vulnerable infants and children at the City licensed foster care facility, Incarnation Children’s Center (ICC). In the absence of parents to protect these foster care children from harmful drug experiments, the City of New York “consented” to drug experiments on their behalf.
At least three experiments conducted at ICC involved nevirapine--one of these involved 7 drugs “some of them given at higher doses than normal.”
The Alliance for Human Research Protection asks:
What adverse effects did the foster care children in NYC suffer as a result of these AIDS drug experiments?
What “lessons” justified exposing foster care childen to suffer in Phase I drug experiments?
See: BBC 2 expose of the ICC experiments
See: AHRP’s letter of complaint to the FDA and OHRP
Vera Hassner Sharav
212-595-8974
[email protected]
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More recent development:
ASSOCIATED PRESS (Article in Daily Breeze)
AIDS Research Chief Rewrote Safety Report
USA TODAY - 14 Dec 2004
AIDS drug worth the risk, federal health official says
ANC accuses US of using Africans to promote nevirapine AIDS drug
18 Dec 2004
Thabo Mbeki's ruling party of South Africa, the ANC (African National Congress), has attacked top US officials and accused them of using African women and babies as human guinea pigs to promote nevirapine, a controversial AIDS drug. They have accused US officials of lying.
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To get some of the real background of this scandal, here is an excellent article by Liam Scheff, the journalist who blew the whistle on the Aids drug experiments on orphans at the New York Incarnation Children's Center:
Exclusive: The Truth about Nevirapine
Mon, 20 Dec 2004
(original on GNN.TV)
By Liam Scheff
Stepping over bodies on the way to market
Last week, Dr. Edmund Tramont, Head of the National Institutes of Health (NIH) AIDS division, was outed by fellow NIH AIDS researcher Dr. Jonathan Fishbein, for burying evidence of drug toxicity in an African drug trial. Documents obtained by the Associated Press show that Tramont censored reporting of thousands of toxic reactions and at least 14 deaths in the ongoing Nevirapine study in Uganda. Nevirapine is the key component of George W. Bush’s $500 million donation to get AIDS drugs to Africans.
South African President Thabo Mbeki accused the U.S. of using Africans as “guinea pigs.” The Rev. Jesse Jackson echoed the statement, calling the cover-up “an outrage.”
The media has seized on this like it’s news, but the truth about Nevirapine was known in 2000, when the FDA put a black-box label on the drug, warning of the drug’s ability to cause fatal liver damage and bloody rupturing of skin and flesh.
The drug’s manufacturer, Boehringer Ingelheim, had originally slotted the drug for pregnant HIV-positive women in the U.S. But Nevirapine’s toxicities were so great, they pulled it out of the FDA approval process. Then they did what all AIDS drug manufacturers do with their garbage – dump it into the gay, Black or foreign market and tell the soft-headed liberal media that it’s an “antiretroviral” that will stop AIDS.
The Ugandan study that Tramont helped bury was overseen by Dr. Laura Guay, a U.S. doctor from Johns Hopkins University School of Medicine. Under Dr. Guay, the drug found its approval overseas. How does a drug that kills Americans save Africans?
South African lawyer and journalist Anthony Brink scrutinized the study and approval process in his 2002 online publication, “The Trouble with Nevirapine.” Brink’s work on the drug AZT was widely read by South African leadership, and prompted President Thabo Mbeki’s early criticism of the drugs being used in AIDS care. Dr. Fishbein tracked down Brink, whose Nevirapine study he described as “an expertly written piece about this very dangerous drug.”
There’s not a word in last week’s NIH mea culpa that Brink didn’t outline in greater detail a year and a half ago.
The Ugandan study (HIVNET 012 – The Lancet, Sept. 4, 1999) started like most AIDS drug trials do. Dr.Guay discarded the study controls. There was no placebo group to compare the Nevirapine group to. The exclusion of a placebo group is a near-standard protocol in AIDS research trials, where doctors claim that it would be unethical not to offer patients at least one drug. In Guay’s study, Everybody was on one of two cell-killing drugs – Nevirapine or AZT.
The study put pregnant women on one of the two pills at labor. Why at labor? The idea is to prevent transmission of HIV from mother to child. The mother’s HIV status is determined, of course, by what we call an HIV antibody test.
Here’s a clever bit of information left out of the NIH report and the mainstream press coverage – HIV test inserts warn that pregnancy produces antibodies which cause the tests to come up positive. Pregnancy, on its own, can create positive HIV test results. You’ll find this over and over again in the test packets and the medical literature (ex. Arch Fam Med. Sep/Oct 2000; Vironostika HIV-1 EIA Test 2003). But it was ignored in Uganda (as it is in the U.S., every day).
The other line of missing logic in the Ugandan study is that, according to the test manufacturers, no child can be tested for at least 18 months with any certainty, because of normal “acquisition of maternal antibodies” that can trip up the hyper-reactive HIV tests. (Oraquick HIV-1 Antibody test; MedMira Rapid HIV-1 Test 2003)
In order to get around the standard tests’ shortcomings, the babies were instead tested with a genetic kit called PCR. But here’s a minor catch. PCR isn’t validated or approved to diagnose viral infection.
PCR is irreproducible. In the lab, it gives wildly varying results for the same sample material. (MMWR. 2001 Nov 16, 2001) There’s no standard to measure it against (JAMA. May 1, 1996). PCR tests amplify scraps of unidentifiable genetic material in cells. Researchers like to pretend that this material represents some aspect of a virus – but the manufacturer warns specifically against using the test for this purpose:
“The AMPLICOR HIV-1 MONITOR Test….is not intended to be used as a screening test for HIV or as a diagnostic test to confirm the presence of HIV infection.” (Roche PCR HIV-1 Monitor Test)
But that’s exactly how doctors and researchers are using it, to get infants into a drug study.
Where’s the liberal media on this issue – Mother Jones, Democracy Now!? I’ve presented the info to DN, several times, and apparently, they can’t be bothered with it. (After all, how could the medical establishment be wrong?)
[DN didn’t return GNN’s request for comment – ed.]
But even if the tests were accurate, and the drugs weren’t biological weapons, there’s a terrible flaw in these studies. To paraphrase Brink – what’s the purpose of a last-minute drugging to prevent the passage of a retrovirus, when the child and mother have been sharing the same blood, tissue, cells and body for nine months?
Adding insult to injury, the Guay study also became immediately unblinded. Everybody knew who was on Nevirapine, who was on AZT, and who tested positive. From the study: “After randomisation, on-site study staff and investigators became aware of the treatment and infection status of the mother-baby pairs. Mothers also knew to what study group they had been assigned after randomisation and of the infection status of their babies during the study… mothers were not masked to treatment status or outcome after randomization.” In the absence of rigorously-maintained study controls, participants in drug trials tend to give into panic, pill-sharing, over-consuming, and the mixing in of non-study drugs to try to get the HIV-antibody response to go away.
The results of Guay’s study came in with an official recommendation for Nevirapine, but only after recording an 80% rate of “laboratory abnormalities” for mothers and a 20% rate of “serious adverse events” in newborns in both the Nevirapine and AZT groups. These infants had blood and tissue infection, pneumonia, blood cell death, severe rash and insufficient oxygen reaching their tissues.
Thirty-eight babies died. Sixteen on Nevirapine, twenty-two on AZT. But Dr. Fishbein’s outing of internal Boehringer-Ingelheim documents have added at least 16 more deaths, mostly in the Nevirapine group.
The drug was approved because the rate of PCR-inferred viral infection in the Nevirapine infants was 13.1%. Lower than that of the AZT group’s PCR rating. What’s PCR? A non-diagnostic test with no standard that gives different results for every sample.
According to the medical/pharmaceutical establishment, it was enough to get a profitable, deadly drug into the international marketplace.
In “The Trouble with Nevirapine,” Brink points to another transmission study, done in July, 1998 (Journal of AIDS and Human Retrovirology). The study looked at 561 expectant African mothers and newborns to see what the rate of presumed HIV infection was with no drugs, no pills and no placebos. The result – 12%. Less than the 13.1%, with none of the drug toxicities. This result was roundly ignored in the quest to bring Nevirapine to market.
In Africa, the reactions to last week’s revelations was anger. South African President, Thabo Mbeki, who has been roundly vilified in the U.S. press for his criticisms of the drugs and tests, commented in the December 17 ANC Today:
“Clearly, what was important for Dr Tramont was not the health of the African people, but the success of President Bush’s visit to our continent, during which he would market Nevirapine to convince all of us that he is concerned about our health, not knowing that the U.S. state medical research authorities had kept him ignorant about the serious concerns relating to the use of Nevirapine.
In other words, Dr Tramont was happy that the peoples of Africa should be used as guinea pigs, given a drug he knew very well should not be prescribed.”
This summer in the U.S. the same drug was being used in an NIH sponsored trial of U.S. patients. Another expectant mother, Joyce Ann Hafford, had been dosed with Nevirapine (commercially sold here as “Viramune”) because she too had a reaction on an HIV test.
Hafford was 33. Before entering the study, she was healthy and pregnant, but was convinced to go on the drug because of her HIV test result. In early August doctors knew that Hafford’s liver was failing. But they kept her on the drugs.
She died two weeks later due to “drug-induced hepatitis” – fatal liver poisoning. An emergency cesarean-section was performed to get her baby out of her dying body. Neither she nor her family had been given the drug’s boxed warning label prior to her entrance into the study. If she had, she might be here today.
The Nevirapine (Viramune) label:
“Warning: Severe, life-threatening, and in some cases fatal hepatotoxicity [liver poisoning], including fulminant and cholestatic hepatitis, hepatitic necrosis [liver death] and hepatatic [liver] failure, has been reported in patients treated with VIRAMUNE [Nevirapine]…Patients with signs or symptoms of hepatitis must discontinue VIRAMUNE and seek medical evaluation immediately.
Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis [skin death], and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction.
It is essential that patients be monitored intensively during the first 18 weeks of therapy with VIRAMUNE to detect potentially life-threatening hepatotoxicity or skin reactions….In some cases, hepatatic injury has progressed despite continuation of treatment. VIRAMUNE should not be restarted following severe hepatatic, skin, or hypersensitivity reactions.”
Dr. Edmund Tramont, of the NIH, had these thoughtful words to offer on the subject:
“Ouch! Not much wwe (we) can do about dumd (dumb) docs,” he wrote, in an inner-office email, leaked to the Associated Press.
Hafford’s family is currently consulting with lawyers to see exactly how much can, in fact, be done about “dumb docs.”
So far, the major media has covered these stories as though they were exceptions to the rule. Not a single media outlet has questioned the efficacy of HIV tests, even though the test manufacturers clearly do. The guardians of the Left – Mother Jones, Democracy Now!, et al – have, for over ten years, dismissed researchers and journalists who’ve sounded the warning bell about the tests and drugs, as the lunatic fringe. So how do they account for Nevirapine, and the drug it beat out, AZT?
The NIH blow-out has not impacted Washington. On Tuesday, December 14, White House press Secretary Scott McClellan stated that Nevirapine would continue to be used in pregnant women in the US and Africa: “[T]he U.S. Public Health Service guidelines continue to recommend short-term therapy with Nevirapine as an option for women who enter care late in pregnancy.” He described Nevirapine as “a drug that can help save lives.”
McClellan added, “The NIH is taking an appropriate step to ask for further analysis of the drug. That’s what their role is in this.”
On Friday, the NIH fired Dr. Jonathan Fishbein, the AIDS researcher and whistle-blower who exposed Dr.Tramont.
As for “their role” in “further analysis” of the drug, the NIH is “currently recruiting” patients in Africa, India, Brazil, the US and Puerto Rico for trials with titles like “Daily Nevirapine to Prevent Mother to Infant Transmission of HIV,” and “Nevirapine Use to Prevent Mother-to-Child Transmission of HIV.”
It seems that the Bush administration will be able to pay Boehringer to give Nevirapine to pregnant women, after all.
Additional info:
Dr. Fishbein’s webpage: www.honestdoctor.org
Anthony Brink’s Treatment Information Group page: http://www.tig.org.za/
Liam Scheff is an investigative journalist and health advocate who’s been published in the New York Press, LA Citybeat and Boston’s Weekly Dig. His reporting on cell-killing drugs like Nevirapine was recently featured in a BBC documentary.
Family of woman killed by AIDS test drug sues doctors
MEMPHIS (AP) � The family of a pregnant woman who died while taking experimental AIDS drugs to protect her baby from getting the disease is suing the doctors, drug makers and hospitals involved in the study for $10 million.
Are AIDS drugs worse than the disease? Don't ask the people who make them. - By Celia Farber in NYPRESS.COM
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