HIV TRANSMISSION: Allegations Raise Fears of Backlash Against AIDS Prevention Strategy
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.
CREDIT: MALCOLM LINTON
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
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."