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HIV TRANSMISSION: Allegations Raise Fears of Backlash Against AIDS Prevention Strategy

Science 24 December 2004
Vol. 306. no. 5705, pp. 2168 - 2169
by Jon Cohen

Much to the dismay of AIDS researchers and clinicians around the world, the Associated Press (AP) ran a series last week that has reignited debate about the safety of one of the most heralded interventions in AIDS prevention: use of the drug nevirapine to prevent HIV transmission from an infected mother to her infant. This treatment likely has spared tens of thousands of children from the disease. Experts insist that, although the drug is not problem-free and some irregularities occurred during one clinical trial, nevirapine's benefit far outweighs the risks.

The AP stories focus on a study in Uganda, which revealed in September 1999 that a single dose of nevirapine given to an HIV-infected mother in labor and to her infant could halve transmission rates. The finding, later confirmed by other studies, led to the widespread use of this cheap, simple intervention in poor countries. The AP series alleges that officials at the National Institute of Allergy and Infectious Diseases (NIAID), which funded the so-called HIVNET 012 study, downplayed problems that surfaced in 2002, did not promptly communicate them to the Food and Drug Administration (FDA) and the White House, and steamrolled over concerns of its staff, one of whom has gone to Congress with charges of an alleged "cover-up."

The study had "irregularities with record keeping" at its headquarters in Kampala, Uganda, acknowledges Clifford Lane, NIAID's deputy director. But he stresses that "there has been nothing to refute the claims of safety and efficacy with regard to single dose nevirapine treatment to prevent the transmission from mother to infant." And he worries that "this particular news story may cause people to stop using nevirapine, and infants could be infected and die needlessly."

In the wake of the story, Rev. Jesse Jackson, a former U.S. Presidential candidate, decried NIAID's actions as "a crime against humanity" and called for Congress to investigate "this catastrophe." In South Africa, where President Thabo Mbeki's government has been criticized for its slow adoption of nevirapine to prevent mother-to-child transmission (MTCT), the political online publication ANC Today said the AP stories proved the hesitation was "fully justified," and it assailed NIAID for using Africans as "guinea pigs."

Nonprofit organizations that provide nevirapine to prevent maternal-infant transmission in developing countries have struck back on their websites. The Elizabeth Glaser Pediatric AIDS Foundation in Los Angeles notes that the drug has been used hundreds of thousands times "without any significant toxicities for mothers or babies." A statement from Global Strategies for HIV Intervention, based in San Rafael, California, says six other MTCT studies confirm the safety and efficacy of nevirapine and stresses that the problems at the Ugandan site have been known for years. "This is not new news," says the statement.


In fact, Boehringer Ingelheim, the drug's manufacturer, first uncovered problems with HIVNET 012, which involved 645 mother-infant pairs. Nevirapine is an FDA approved drug to treat HIV infection, but the Uganda results led Boehringer to seek FDA endorsement for its use in preventing MTCT, explains principal investigator J. Brooks Jackson of Johns Hopkins University, which collaborated with researchers from Makerere University in Kampala. As part of the process, Boehringer audited the Uganda site in January 2002 and discovered discrepancies in the records. A Boehringer representative said the audit turned up "a lot of pin pricks but no show stoppers,'" recalls Jackson.

When advised of the problems later that month, NIAID's Division of AIDS should have informed FDA within 3 days but did not. "That was an error," concedes Edmund Tramont, who heads NIAID's Division of AIDS and who did not learn about the discrepancies until March 2002. At that point NIAID informed FDA, shut down the site for new studies, and notified the public, triggering a flurry of press coverage. NIAID also hired a contractor to audit the site. That second audit revealed serious unreported incidents, including deaths and "thousands" of less serious "adverse events." Tramont's worries were assuaged when he learned that the unreported deaths, which were not related to the drug, had in fact been recorded, and that the unreported adverse events were also unrelated to the drug and involved diseases like malaria and tuberculosis.

Because an initial review of the discrepancies uncovered no safety issues, NIAID officials say they saw no reason to give the White House a detailed briefing about their concerns. That June, President George W. Bush announced a $500 million program to prevent MTCT in developing countries that would rely heavily on nevirapine. The AP alleges that NIAID "chose not to inform the White House" about its internal concerns for fear of "scuttling the use of nevirapine in Africa." Tramont sent over yet another audit team. This third audit compared the hospital records of 80 mother-infant pairs to the information in the database---a statistically significant sample. It found discrepancies, but they were relatively infrequent. In early April 2003, when NIAID was wrestling with whether to reopen the Ugandan site for research, NIAID's Betsy Smith wrote a report for FDA that sharply criticized the study's adverse event reporting. "Subject records on site were of poor quality and below expected standards of clinical research considered at the forefront of medical research," Smith concluded. Tramont edited the report and removed that detail and other critical aspects, a move the AP reported led to "disbelief" among some staffers. Tramont says he made the changes because he felt Smith relied too heavily on the misleading second audit. Jonathan Fishbein, the NIAID staffer who has gone public with his concerns, became embroiled in what was then a backroom dispute in July 2003, shortly after he was hired by the Division of AIDS to improve clinical trials. Fishbein wanted more time to review the issues before allowing the Ugandan site to reopen for new clinical studies, but Tramont was impatient. "I want this restriction lifted ASAP because the site is now the best in Africa run by black Africans," Tramont e-mailed Fishbein. "The site was shut down for 15 months," says Tramont. "It was stupid and bureaucratic not to reopen it." In February 2004, with office tensions mounting, Fishbein received notice that he was being terminated for "non-performance." He took complaints of what he viewed as his mistreatment and the scientific cover up to many officials, including the head of the National Institutes of Health (NIH). He also sought whistleblower status. Although NIH will not discuss Fishbein by name, deputy director Raynard Kington says a research integrity officer reviewed what he called allegations of "scientific misconduct" and determined they were "erroneous." NIH did ask the Institute of Medicine to review the scientific issues surrounding HIVNET 012, and that panel plans to issue a report in March 2005. Meanwhile, Fishbein says he is "not is disagreement" that nevirapine saves lives. "My issue is not nevirapine, but the process."