This 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. Tramont censored reporting of thousands of toxic reactions and at least 14 deaths in the ongoing Nevirapine study in Uganda.

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, wanted to get the drug into the US market for use in pregnant HIV-positive women. But the drug’s toxicities were so great, they pulled it out of the FDA approval process. Then they did what all drug companies do with their garbage – dump it into impoverished foreign markets and tell the soft-headed liberal media that it’s an AIDS drug.

The Ugandan study that Tramont helped bury was overseen by Dr. Laura Guay, a US 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 in "The Trouble With Nevirapine" first published in April 2002, and updated this year. Dr. Fishbein tracked down Brink, whose study he described as "an expertly written piece about this very dangerous drug."

There’s not a word in the current NIH mea culpa that Brink didn’t outline in greater detail a year and a half ago.

The Ugandan study started like all AIDS drug trials do. Dr.Guay discarded the study controls. There was no placebo group to compare the Nevirapine group to. 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, creates positive HIV test results. You’ll find this over and over again in the medical literature. But it was ignored in Uganda (as it is in the US, 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 “passive transmission of maternal antibodies” that can trip up the hyper-reactive HIV tests.

So, what are we trying to prevent transmission of? Antibodies? Pregnancy? Who knows.

In order to get around the standard tests’ short-comings, the babies were instead tested with a genetic kit called PCR. But here’s the joke. 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. There’s no standard to measure it against.

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 it to DN, several times, and apparently, they can’t be bothered with it. After all, how could the medical establishment be wrong?

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. In the absence of a controlled, well-observed study, participants 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 a 20% rate of “serious adverse events” in both the Nevirapine and AZT groups. Patients on the drugs 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.

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. (Dead babies don’t mean much there).

If that doesn’t penetrate your skull, try this. A study was done in 1998 with 561 expectant African mothers to see what the rate of presumed HIV infection was with no drugs, no pills and no placebos. The result – 12%. Less than 13.1? Sure. But where’s the money in not drugging them?



This summer in America, the same drug was being used in an NIH sponsored trial of US 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.

“Ouch! Not much we can do about dumb docs?”

Sure there is. We can take them to court. In droves.

But maybe it’s time that the rest of us got smart, and began to regard the NIH with the same unblinking critical eye that we do any other money-driven corporate entity. The day that the Left stops pretending that the NIH is going to solve the world’s health problems, we might actually start saving some lives.



For more on Nevirapine, see the 2001 European Study photos and link at "Altheal.org":http://www.altheal.org/toxicity/orphans.htm

Sadly Mr Scheff needs to learn some basic medicine, and read the HIVNET012 study protocol.

1. The placenta is designed to prevent maternal and fetal blood from mixing. HIV only rarely infects DURING pregancy. C-section can prevent infection, since it mostly occurs as the baby travels down the birth canal. Treating at the time of birth therefore makes good sense.

2. Pregnancy causes very rare false-positive reactions on the HIV tests. One recent study put it at 0.44% in a "high" rate group. Also the Ugandan study used full US-style testing with confirmatory Western Blot, not just rapid ELISA.

3. The tests used for neonatal diagnosis are used routinely: not every RNA test is unapproved in diagnosis! One was approved in September 2001 by the FDA for the purpose of screening samples. Additionally the infections in infants were actually confirmed by additional RNA tests, virus cultures, and serology after the magical 18 month value Mr Scheff mentions.

4. Nevirapine is still approved to treat HIV, despite what he says in the article. The toxicity problem is no different from, say, Tylenol which also causes fatal liver toxicity. The study problem he rightly enough draws attention to is not one of AIDS drugs, but one of study docs (in this single instance) not paying enough attention to their patients.

The study protocol is freely available online at

http://www.hptn.org/Web%20Documents/HIVNET_Protocols/HIVNET012v2.pdf

There really should be no excuse for mis-representing it.

Bennett

Serious Adverse Events Attributed to Nevirapine Regimens

for Postexposure Prophylaxis After HIV Exposures --- Worldwide, 1997--2000




FROM THE CDC ITSELF



In September 2000, two instances of life-threatening hepatotoxicity were reported

in health-care workers taking nevirapine (NVP) for postexposure prophylaxis (PEP)

after occupational human immunodeficiency virus (HIV) exposure*. In one case, a

43-year-old female health-care worker required liver transplantation after developing

fulminant hepatitis and end-stage hepatic failure while taking NVP, zidovudine, and lamivudine

as PEP following a needlestick injury (1). In the second case, a 38-year-old male

physician was hospitalized with life-threatening fulminant hepatitis while taking NVP,

zidovudine, and lamivudine as PEP following a mucous membrane exposure. To characterize

NVP-associated PEP toxicity, CDC and the Food and Drug Administration (FDA)

reviewed MedWatch reports of serious adverse events in persons taking NVP for PEP received

by FDA (Figure 1). This report summarizes the results of that analysis and indicates

that healthy persons taking abbreviated 4-week NVP regimens for PEP are at risk for

serious adverse events. Clinicians should use recommended PEP guidelines and dosing

instructions to reduce the risk for serious adverse events.

MedWatch is a voluntary reporting system for adverse events and problems

with drugs, medical devices, biologics, and special nutritional products. For this analysis,

a serious adverse event was defined as any event that was life-threatening,

permanently disabling, required or prolonged hospitalization, required intervention to prevent

permanent impairment or damage, or any other event that required medical attention.

Including the two case reports of fulminant hepatitis, FDA received reports of

22 cases of serious adverse events related to NVP taken for PEP from March 1997

through September 2000. These 22 events included hepatotoxicity (12), skin reaction (14),

and rhabdomyolysis (one); four cases involved both hepatotoxicity and skin reaction,

and one case involved both rhabdomyolysis and skin reaction. The median age of

affected persons was 36.5 years (range: 12--50 years; age was not reported for four cases);

12 were female, and 12 occurred in the United States. Reasons for administration of

PEP were occupational needlestick or other sharps injury (12), other occupational

exposure (four), sexual exposure (three), nonoccupational (pediatric) needlestick injury (one),

other nonoccupational exposure (one), and unknown (one).

Nine persons took a maximum NVP dose of 200 mg per day, and 12 persons took

a maximum dose of 200 mg twice per day (the dose of NVP was not recorded for

one person). Among the 12 persons taking a maximum dose of 200 mg twice daily, six

were first given a lead-in dose of 200 mg per day for 3--14 days. Concomitant

antiretroviral agents used with NVP for PEP included zidovudine and lamivudine (10); stavudine

and lamivudine (three); zidovudine and didanosine (two); stavudine and didanosine

(one); stavudine and indinavir (one); didanosine and indinavir (one); stavudine, didanosine,

and ritonavir (one); lamivudine, didanosine, and nelfinavir (one); stavudine,

lamivudine, nelfinavir, and saquinavir (one); and none (one). Among the 12 persons with

hepatotoxic reactions, one developed liver failure (requiring liver transplantation), seven had

clinical hepatitis (e.g., jaundice, fever, nausea, vomiting, abdominal pain, and/or

hepatomegaly), and four had elevations in serum liver enzymes (i.e., alanine aminotransferase [ALT]

and aspartate aminotransferase [AST]) without reports of clinical hepatitis.

Baseline liver function tests were reported for six patients and were within

normal limits. Abnormal liver function tests were reported during PEP for 10 patients;

median

peak ALT was 215 U/L (range: 182--2790 U/L; normal: 10--34 U/L), median peak AST

was 375 U/L (range: 96--2370 U/L; normal: 10--34 U/L), and median peak total bilirubin was

7.5 mg/dL (range: 2.0--33.7 mg/dL; normal: 0.2--1.0 mg/dL). The median time from

initiation of NVP use to first abnormal liver function tests was 21 days (range: 13--36 days). In

six cases, hepatitis A, B, and C serologies were reported; all were negative. Eleven

persons reported symptoms, including fever, malaise, and abdominal pain. The median onset

of these symptoms was 14 days after beginning NVP for PEP (range: 3--36 days). The

14 reports of skin rash included one documented and two possible cases of

Stevens-Johnson syndrome. The median onset of rash occurred 9 days after beginning PEP (range:

6--36 days).

Reported by: D Boxwell, Pharm D, Office of Postmarketing Drug Risk Assessment; H

Haverkos, MD, S Kukich, MD, K Struble, Pharm D, H Jolson, MD, Div of Anti-Viral Drug Products, Center

for Drug Evaluation and Research, Food and Drug Administration. Prevention and Evaluation

Br, Div of Healthcare Quality Promotion [proposed], National Center for Infectious Diseases, CDC.

Editorial Note:

Severe, life-threatening, and fatal cases of hepatotoxicity and

skin reactions have occurred among HIV-infected patients treated with NVP

(2,3) and are described in a box warning on the NVP label (Viramune™ [package

insert]†, Boehringer Ingelheim/Roxane Laboratories, Inc., Ridgefield, Connecticut, 1998). This report

suggests that persons taking NVP regimens for PEP after HIV exposures also are at risk

for serious adverse events.

In 1996, the U.S. Public Health Service (PHS) first recommended PEP after

certain occupational exposures to HIV (4). These recommendations, updated in 1998

(5), are being revised to include other antiretroviral agents that have been approved by FDA

for use in HIV-infected persons. NVP is not recommended for basic or expanded PEP

regimens. However, data on the safe and effective use of single-dose NVP to prevent

perinatal HIV transmission (6,7) and a theoretical advantage of more rapid activity (i.e.,

NVP does not require phosphorylation for activation) have prompted clinicians to include

NVP in PEP regimens following HIV exposures. In the HIV PEP registry, which collected data

on occupational HIV PEP use from October 1995 through March 1999, six cases of

serious adverse events related to PEP were reported among 492 registered participants; a

severe skin reaction occurred in one of 11 health-care workers taking a regimen

that included NVP (8).

Because most occupational HIV exposures do not result in transmission of HIV

(9), clinicians considering prescribing PEP for exposed persons must balance the risk for

HIV transmission represented by the exposure and the exposure source against the

potential toxicity of the specific agent(s) used

(4). In many circumstances, the risks

associated with NVP as part of a PEP regimen outweigh the anticipated benefits. When PEP is

prescribed, the manufacturer's package insert should be consulted for dosing

instructions, possible side effects, and potential drug interactions.

The findings in this report are subject to at least three limitations. First, MedWatch

is a voluntary, passive reporting system, and it is unlikely that all serious adverse events

in persons taking NVP for PEP have been reported. Second, data about administration of

a lead-in dose and results of baseline liver function tests and hepatitis serologies were

not included in all reports. In six cases, the initial dose of NVP was 200 mg twice daily

without the recommended 2-week dose escalation, which may have increased the likelihood

of adverse events (10). Third, available denominator data about the use of NVP for

PEP were insufficient to calculate accurate rates of adverse events.

The findings in this report do not apply to NVP use in other settings. Single-dose

NVP is one of the regimens recommended by PHS for prevention of perinatal HIV

transmission (7). No serious toxicity has been reported among mother-infant pairs using

this regimen. Combination antiretroviral regimens containing NVP may be used in HIV-

infected persons after weighing the risks and benefits and monitoring adverse

reactions.

Health-care providers and the public can assist in monitoring the safety

of antiretrovirals and other agents by reporting adverse reactions to the FDA

MedWatch program: telephone, (800) 332-1088, fax, (800) 332-0178, World-Wide Web,

http://www.FDA.gov/medwatch, or mail, MedWatch, HF-2, FDA, 5600 Fishers Lane,

Rockville, MD 20857.

References

1. Johnson S, Baraboutis JG, Sha BE, Proia LA, Kessler HA. Adverse effects associated

with use of nevirapine in HIV postexposure for 2 health care workers [Letters].

JAMA 2000;284:2722--3.

2. Cattelan AM, Erne E, Slatino A, et al. Severe hepatic failure related to nevirapine

treatment. Clin Infect Dis 1999;29:455--6.

3. Sidley P. South Africa to tighten control on drug trials after five deaths. Br Med

J 2000;320:1028.

4. CDC. Update: provisional Public Health Service recommendations for

chemoprophylaxis after occupational exposure to HIV. MMWR 1996;45:468--72.

5. CDC. Public Health Service guidelines for the management of health-care worker

exposures to HIV and recommendations for postexposure prophylaxis. MMWR

1998;47(no. RR-7).

6. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose

nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1

in Kampala, Uganda: HIVNET 012 randomized trial. Lancet 1999;354:795--802.

7. US Public Health Service. Public Health Service Task Force recommendations for use

of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and

interventions to reduce perinatal HIV-1 transmission in the United States. Available at

http://hivatis.org/guidelines/perinatal/Nov_00/text/index.html. Accessed January 2001.

8. Wang SA, Panlilio AL, Doi PA, et al. Experience of healthcare workers taking

postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure

Prophylaxis Registry. Infect Control Hosp Epidemiol 2000;21:780--5.

9. Bell DM. Occupational risk of human immunodeficiency virus infection in

healthcare workers: an overview. Am J Med 1997;102:9--15.

10. Soriano AP, Jiménez-Nácher I, Rodriguez-Rosado R, Dona MC, Barreiro PM,

González-Lahoz J. Incidence of rash and discontinuation of nevirapine using two different

escalating initial doses [Letter]. AIDS 1999;13:524.

* Information included in this report does not represent Food and Drug Administration

approval or approved labeling for the particular product or indications in question.

† Use of trade names and commercial sources is for identification only and does not

constitute endorsement by CDC or the U.S. Department of Health and Human Services.

AP: U.S. Officials Knew of AIDS Drug Risks

Mon Dec 13, 3:11 PM ET

 White House - AP

By JOHN SOLOMON, Associated Press Writer

WASHINGTON - Weeks before President Bush (news - web sites) announced a plan to protect African babies from AIDS (news - web sites), top U.S. health officials were warned that research on the key drug was flawed and may have underreported thousands of severe reactions including deaths, government documents show.

AP Photo

AP Photo

Slideshow: HIV/AIDS

 

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 (news - web sites), the government's premiere 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 (news - web sites).

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 (news - web sites).

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 0 million plan to push nevirapine across Africa to slow the AIDS epidemic, the Health and Human Services (news - web sites) Department sent a nine-page letter to Ugandan officials identifying violations of federal patient protection rules by NIH's research.

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.

Africa accounts for more than two-thirds of the world's AIDS cases, with 27 million infected, and the United States sought to help slow the disease's spread across the continent.

Nevertheless, NIH officials told AP they remain confident after re-reviewing the Uganda study and other research that nevirapine can be used safely in single doses by African mothers and children to prevent HIV (news - web sites) transmissions during birth. But they acknowledged their Uganda research failed to meet required U.S. standards.

As a result, NIH recently asked the National Academy of Sciences (news - web sites) to investigate its science in the case, and has spent millions in the last two years improving its safety monitoring and record keeping.

"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," said Dr. H. Clifford Lane, NIH's No. 2 infectious disease official.

One lesson derived from a closer review of the Uganda research 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, Lane said.

"It was unexpected, and what it means is nevirapine probably shouldn't be a drug of first choice if other options are available," Lane said.

Lane 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 0 million plan in 2002 to send nevirapine to Africa. Bush approved .9 billion for global AIDS fighting next year.

"The president's mission is to try to stop the spread of AIDS in Africa and to come at it from a new angle, and that is what this is all about," spokesman Trent Duffy said.

 

Nevirapine is an antiretroviral drug marketed in the United States as Viramune that 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.

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.

But by early 2002, an NIH auditor, the agency's medical safety experts and the drug's maker all disclosed widespread problems about the U.S.-funded research in Uganda.

Boehringer Ingelheim, the Connecticut-based company that makes nevirapine, told NIH it identified 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.

"It appeared likely, in fact, that many adverse events and perhaps a significant number of serious adverse events for both mother and infant may not have been collected or reported in a timely manner," Westat Corp. reported in March 2002. Westat is a professional medical auditing firm hired by NIH to visit and audit the Uganda site.

Westat reported 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.

Officials said the problems began when NIH converted the research from determining the drug's usefulness to supporting FDA (news - web sites) approval for the drug. Paperwork in Uganda wasn't kept to the FDA standards, they said.

"We may not have reported exhaustively, but we reported all serious side effects," said Professor Francis Mmiro, a lead doctor in the Uganda study. "What you may call a serious side effect in the U.S. is not a serious side effect in Kampala."

NIH officials reviewed the bad news in early March 2002.

Meeting minutes, written in shorthand, raised broad concerns: Half the babies in the study were also enrolled in a vitamin A study that could have affected the outcome, and medical staff running the trials didn't follow procedures for divulging serious adverse events (SAEs).

"No mtg minutes, no training doc(umentation), site used their own criteria for grading SAEs. No lab normal values & serious underreporting of SAEs," the minutes stated.

The minutes quote an NIH official who visited Uganda as saying, "The site staff doesn't know what they don't know."

But Tramont, the AIDS research chief, and other top NIH officials repeatedly dismissed the concerns as preliminary or overblown, and sought to salvage the flawed research's underlying conclusions rather than start over.

"There is presently no evidence that the study's scientific results are invalid," said a report Tramont sent to his staff less than two weeks after getting the March 2002 Westat audit.

In January 2002, Boehringer sent NIH an early copy of its report. But the drug maker, fearing publicity about the report might destroy its chance to get the FDA approval of the drug for domestic use, asked NIH to destroy it before FDA regulators could learn about it.

"Sensitive information. Asked for it to be destroyed when audit is upon us," NIH official Mary Anne Luzar wrote on the cover page of Boehringer's report.

Boehringer says it never requested the document be destroyed, saying "our actions throughout the study evaluation were proactive and forthcoming."

Lane said the request to destroy the report was inappropriate and NIH never complied. But he conceded his agency inappropriately kept the audit from FDA for weeks, saying, "It shouldn't have happened that way."

NIH at first sought to postpone the FDA review of nevirapine, then top NIH and FDA officials arranged for the drug maker to pull its U.S. application rather than risk a public rejection that might scare African countries looking for U.S. guidance on the drug.

Unaware of the internal NIH concerns, Bush announced in June 2002 a 0 million effort to fight the spread of AIDS in Africa and the Caribbean. The plan's centerpiece was nevirapine.

"This major commitment of my government to prevent mother-to-child HIV transmission is the first of this scale by any government, anywhere," Bush said in a Rose Garden announcement. The White House hoped the initiative would reach up to 1 million women a year and cut mother-to-child transmission of HIV by up to 40 percent.

Two years later, after hundreds of thousands of doses of nevirapine have been distributed to African mothers and children, the FDA has recommended NIH stop using the drug with certain patients. It also has demanded stronger warnings to doctors and patients about possible lethal liver damage and rashes in patients who take nevirapine for longer periods of time.

African health officials are having second thoughts. South African officials in July recommended ending the single-use treatment because of the new concerns about drug resistance.

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.

"It's not ideal, but it works," said Dr. Ashraf Coovadia of Coronation Mother and Child Hospital in Johannesburg, South Africa. Without it, "many, many more babies would be born with HIV."

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, like Thailand and South Africa, showing single dose usage at birth is safe and effective.

"The bottom line is there were these procedural issues, such as the speed of reporting adverse events, and the like. But the important scientific data was intact, and found to be valid," said Dr. Patrick Robinson, a top Boehringer AIDS specialist.

Still, the German-owned company no longer is seeking FDA permission to use nevirapine for protecting U.S. infants because better treatments have emerged, he said.

___

AP reporter Alexandra Zavis in Johannesburg, South Africa, contributed to this story.

On the Net:

Documents gathered by AP for this story are available at: http://wid.ap.org/nevirapine1.html

National Institutes of Health: http://www.nih.gov

Boehringer Ingelheim: http://www.boehringer-ingelheim.com