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 W