Pregnant Woman Enrolled in NIH Study Died of Liver Failure Likely Caused by Antiretroviral Drug Nevirapine

An HIV-positive pregnant woman enrolled in a NIH study examining the ability of the antiretroviral drug nevirapine to prevent mother-to-child HIV transmission died of liver failure that likely was caused by the drug, the AP/Las Vegas Sun reports. Joyce Ann Hafford died Aug. 1, 2003, less than 72 hours after giving birth by emergency caesarean section to an HIV-negative infant. Hafford enrolled in the study -- which was an "outgrowth" of previous research conducted in Uganda and required multiple doses of nevirapine -- to reduce the risk that her infant would contract HIV, according to the AP/Sun (Solomon/Herschaft, AP/Las Vegas Sun, 12/15). NIH in 1997 began studying the use of nevirapine in single doses among HIV-positive pregnant women in Uganda to determine the drug's ability to prevent vertical HIV transmission. The initial results showed that the drug prevented HIV transmission to newborns in as many as 50% of births. However, by early 2002, medical safety specialists and an auditor with NIH as well as the drug's manufacturer Boehringer Ingelheim all cited "widespread" problems with the research in Uganda -- including a failure to receive participants' consent about changes in the study, administration of incorrect doses, and delays and underreporting of fatal and life-threatening reactions to the drug. Because of the reported problems, NIH suspended the research for 15 months from spring 2002 to summer 2003 in order to review the trial and take corrective steps (Kaiser Daily HIV/AIDS Report, 12/15).

Liver Failure
NIH documents obtained by the Associated Press show that Hafford could have survived if doctors had ceased administering nevirapine when her bloodwork indicated liver problems two weeks before her death, the AP/Sun reports. Since 2000, the government has warned that nevirapine can cause lethal liver damage or rashes in patients who take the drug in multiple doses over extended periods of time. "This case was particularly unfortunate b/c (because) the PI (principle investigative doctor) didn't stop drug when grade 3 liver enzymes were reported," Dr. Jonathan Fishbein, a specialist hired by NIH to improve the agency's research practices, wrote in August 2003 in an e-mail to Dr. Edmund Tramont, director of the National Institute of Allergy and Infectious Diseases Division of AIDS, who has admitted to altering a report on the Ugandan trial because he thought reports of problems with the study were exaggerated, according to the AP/Sun. An official NIH review concluded that the Memphis, Tenn., hospital where Hafford was being treated "failed to react" to laboratory results showing that her liver failure began "well before" she died, according to the AP/Sun. "The site had identified that there was a delay in reviewing laboratory evaluations from the clinic visit the week before she presented with clinical hepatitis," the report concluded. NIH since has changed research rules in nevirapine studies to "ensure the early detection" of liver problems, the AP/Sun reports.

NIH Reaction
Hafford's case "reverberated among the government's top scientists," who had been monitoring reports on her deteriorating health since she had given birth, according to the AP/Sun. NIH officials "quickly" suspected that the study's drug regimen might have contributed to her liver failure because it included nevirapine, the AP/Sun reports. "Ouch! Not much wwe (we) can do about dumd (dumb) docs," Tramont wrote in an e-mail responding to reports from his staff that doctors continued to administer the drug regimen to Hafford even after signs of liver failure. NIH officials since have said that experimental drugs, likely nevirapine, resulted in Hafford's death, according to the AP/Sun. However, Hafford's family has said they were never told that NIH had concluded that the study's drug regimen likely caused her death until the Associated Press obtained copies of the case file. "They tried to make it sound like she was just sick. They never connected it to the drug," Rubbie King, Hafford's sister, said, adding, "If it were the disease, solely the disease, and the complications associated with the disease, that would be more readily acceptable than her being administered medication that came with warnings that the medical community failed to get ... to her." According to NIH officials, the agency generally "leaves disclosures like that to the doctors who treated her," the AP/Sun reports. Hafford's family has begun to pursue litigation in order to obtain more information on her death, the AP/Sun reports.

Consent Form
According to Dr. Clifford Lane, acting deputy director of NIAID, Hafford upon agreeing to participate in the study should have signed a 15-page, NIH-approved consent form that specifically warned of the risk of liver failure. However, her family said that she "seemed unaware of the liver risks" and has kept a bottle of the drug to demonstrate that it included no safety warnings, according to the AP/Sun. However, according to Lane, the bottle should not have had any warnings because the study's rules require that participants be unaware of the drug's effects to avoid possible influences on the results. Therefore, the consent form would have been Hafford's "lone warning about potential liver problems," Lane said, the AP/Sun reports. The warnings concerning potential liver problems appear on the sixth page of the consent form, which is "chock full of complex medical terms," according to the AP/Sun. The form says that liver inflammation is possible and "rarely may lead to severe and life-threatening liver damage and death," the AP/Sun reports.

Reaction
According to Fishbein, Hafford's death is "attributable to a bigger problem in government research," the AP/Sun reports. "This is not just a clinical trial issue, this is a health care issue. The public expects that diagnostic test results are promptly evaluated and acted on, if need be. Sadly, this is but one example where an assessment was not done quickly and it cost this young mother her life," Fishbein said. Jim Kyle, a lawyer representing Regional Medical Center at Memphis -- where Hafford died -- declined to comment because of her family's pending litigation. "We feel horrible that something like this would happen to anyone in any circumstance," Lane said, adding, "There are risks in research and we try to minimize them" (AP/Las Vegas Sun, 12/15).

Nevirapine Use
According to a NIAID release, the agency is "confident" that previous studies indicating that nevirapine is safe for use in HIV-positive pregnant women to reduce the risk of vertical HIV transmission "will be upheld." "The simple and cost-effective nevirapine regimen has been used in developing countries to prevent HIV infection in thousands of infants; it represents a major public health advance and is one of the true success stories in HIV prevention," the release said, adding that no new data exist to "suggest that current recommendations regarding use of this regimen should be changed" (NIAID release, 12/14). The South African HIV/AIDS treatment advocacy group Treatment Action Campaign said in a release that the "criticisms leveled by the parties involved in the NIH news story ... do not provide evidence questioning the safety or efficacy of short-course nevirapine" and the reported problems are related specifically to NIH trial management (TAC release, 12/15). The "questions raised about the Uganda trial do not ultimately raise real concerns about the safety or effectiveness of single-dose nevirapine," Project Inform, a national HIV/AIDS treatment information and advocacy organization, said in a release, adding, "Exaggerated reports and emotional language in the media can only exacerbate the difficult challenges facing the world in its efforts to bring HIV infection under control in resource-poor settings" (Project Inform release, 12/15).