Woman died during anti-HIV drug study

Ann Hafford died without ever holding the son she had tried to save from AIDS by taking an experimental drug regimen administered by government-funded researchers during her pregnancy. But even before her stunned family could grieve, the death of the 33-year-old Memphis, Tenn., woman was reverberating among the government's top scientists in Washington, D.C. They quickly realized the drugs she was taking likely caused the liver failure that killed her. Reports of her declining health were being monitored in late July 2003 at the National Institutes of Health as she lay on a respirator, and the case eventually reached the nation's chief AIDS researcher, according to documents obtained by the Associated Press. "Ouch! Not much we can do about dumb docs," Edmund Tramont, NIH's AIDS Division chief, responded in an e-mail after his staff reported that doctors continued to administer the anti-HIV drugs nevirapine, sold in the United States as Viramune, and Combivir to Hafford despite signs of liver failure. Nevirapine is an antiretroviral drug used since the mid 1990s, and the government has warned since at least 2000 that it could cause lethal liver problems or rashes when taken in multiple doses over time. Hafford's family says they were never told NIH had concluded that the experimental drug regimen likely caused her death until AP gave them copies of NIH's internal case documents this month. They were left to believe Hafford had died from AIDS complications but began pursuing litigation to learn more. "They tried to make it sound like she was just sick. They never connected it to the drug," said Rubbie King, Hafford's sister. "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." NIH officials acknowledge that experimental drugs, most likely nevirapine, caused her death, and that keeping the family in the dark was inappropriate. But NIH usually leaves disclosures like that to the doctors who treated her. "We feel horrible that something like this would happen to anyone in any circumstance," said H. Clifford Lane, NIH's number 2 infectious disease specialist. "There are risks in research and we try to minimize them." The study during which Hafford died recently led researchers to conclude that nevirapine poses risks when taken over time by certain pregnant women. "Continuous nevirapine may be associated with increased toxicity among HIV-1 infected pregnant women" with certain liver cell counts, the study concluded. Lane said Hafford should have signed a 15-page, NIH-approved consent form at the start of the experiment specifically warning her of the risks of liver failure. The family says Hafford seemed unaware of the liver risks. They even kept the bottle of nevirapine showing it had no safety warnings. Lane confirmed the nevirapine bottle Hafford received likely wouldn't have had safety warnings, because the experiment's rules called for the patient to be unaware of the exact drug effects to avoid the placebo effect, or patient influence, on the test results. That means the consent form would have been her lone warning about potential liver problems, he said. And that 15-page, single-spaced consent form is chock-full of complex medical terms like "hypersensitivity reactions" and "pharmacokinetic test." The warning about potential liver problems shows up on the sixth page, where it says liver inflammation is possible and that it "rarely may lead to severe and life threatening liver damage and death." Hafford, who was HIV-positive but otherwise healthy, agreed to participate in the NIH-funded research project that provided her multiple doss of nevirapine to protect her soon-to-be-born son, Sterling, from getting HIV at birth. The project was an outgrowth of earlier research in Africa that concluded the drug could be taken in single doses safely to protect newborns half the time. Hafford died August 1, 2003, less than 72 hours after giving birth. Sterling was delivered prematurely by cesarean section as his mother was dying. Though premature, he was spared from HIV and is healthy. NIH's documents suggest Hafford's life might also have been spared if the drug had been stopped when the first liver problems showed up in her blood work two weeks before death. NIH's official review determined the Memphis hospital failed to react to lab results that showed her liver failure was starting well before she died. The official investigative files cited "drug-induced hepatitis" of the liver as the cause of death. Hafford's case has come to light in the midst of reports by the Associated Press of a possible cover-up by NIH officials of problems with a study of nevirapine in Uganda, including unreported adverse reactions to the drug, in the weeks prior to the launch of a $500 million U.S. project to provide nevirapine to pregnant HIV-positive women in Africa. Tramont has admitted to changing a report by medical investigators that originally warned of problems with the Uganda study and contained safety questions about nevirapine. Tramont changed the report's conclusion to state that nevirapine use was safe. He says he changed the report because of his greater expertise with AIDS issues than other NIH staff members and because he disagreed with the original safety conclusions.