AIDS and the corruption of medical science

By Celia Farber

Joyce Ann Hafford was a single mother living alone with her thirteen-year-old son, Jermal, in Memphis, Tennessee, when she learned that she was pregnant with her second child. She worked as a customer service representative at a company called CMC Call Center; her son was a top student, an athlete and musician. In April 2003, Hafford, four months pregnant, was urged by her obstetrician to take an HIV test. She agreed, even though she was healthy and had no reason to think she might be HIV positive. The test result came back positive, though Hafford was tested only once, and she did not know that pregnancy itself can cause a false positive HIV test. Her first though was of her unborn baby. Hafford was immediately referred to an HIV/AIDS specialist, Dr. Edwin Thorpe, who happened to be one of the principal investigators recruiting patients for a clinical trial at the University of Tennessee Medical Group that was sponsored by the Division of AIDS (DAIDS)-the chief branch of HIV/AIDS research within the National Institutes of Health.

The objective of the trial, PACTG 1022, was to compare the "treatment-limiting toxicities" of two anti-HIV drug regimens. The core drugs being compared were nelfinavir (trade name Viracept) and nevirapine (trade name Viramune). To that regimen, in each arm, two more drugs were added-zidovudine (AZT) and lamivudine (Epivir) in a branded combination called Combivir. PACTG 1022 was a "safety" trial as well as an efficacy trial, which means that pregnant women were being used as research subjects to investigative "safety" and yet the trial was probing the outer limits of bearable toxicity. Given the reigning beliefs about HIV's pathogenicity, such trials are fairly commonplace, especially in the post-1994 era, when AZT was hailed for cutting transmission rates from mother to child.

The goal of PACTG 1022 was to recruit at least 440 pregnant women across the nation, of which 15 were to be enrolled in the University of Tennessee Medical Group. The plan was to assign the study's participants to one of two groups, with each receiving three HIV drugs, starting as early as ten weeks of gestation. Of the four drugs in this study, three belong to the FDA's category "C," which means that safety to either mother or fetus has not been adequately established.

Joyce Ann Hafford was thirty-three years old and had always been healthy. She showed no signs of any of the clinical markers associated with AIDS-her CD4 counts, which measure the lymphocytes that are used to indicate how strong a person's immune system is, and which HIV is believed to slowly corrode, were in the normal range, and she felt fine. In early June 2003, she was enrolled in the trial and on June 18 took her first doses of the drugs. "She felt very sick right away," recalls her older sister, Rubbie King. "Within seventy-two hours, she had a very bad rash, welts all over her face, hands, and arms. That was the first sign that there was a problem. I told her to call her doctor and she did, but they just told her to put hydrocortisone cream on it. I later learned that a rash is a very bad sign, but they didn't seem alarmed at all."

Hafford was on the drug regimen for thirty-eight days. "Her health started to deteriorate from the moment she went on the drugs," says King. "She was always in pain, constantly throwing up, and finally she got to the point where all she could do was lie down." The sisters kept the news of Hafford's HIV test and of the trial itself from their mother, and Hafford herself attributed her sickness and nausea to being pregnant. She was a cheerful person, a non-complainer, and was convinced that she was lucky to have gotten into this trial. "She said to me, 'Nell'-that's what she called me-'I have got to get through this. I can't let my baby get this virus.' I said, 'Well, I understand that, but you're awful sick.' But she never expressed any fear because she though this was going to keep her baby from being HIV positive. She didn't even know she was in trouble."

On July 16, at her scheduled exam, Hafford's doctor took note of the rash, which was "pruritic and macular-papular," and also noted that she was suffering hyperpigmentation, as well as ongoing nausea, pain, and vomiting. By this time all she could keep down were cans of Ensure. Her blood was drawn for lab tests, but she was not taken off the study drugs, according to legal documents and internal NIH memos.

Eight days later, Hafford went to the Regional Medical Center "fully symptomatic," with what legal documents characterize as including: "yellow eyes, thirst, darkening of her arms, tiredness, and nausea without vomiting." She also had a rapid heartbeat and difficulty breathing. Labs were drawn, and she was sent home, still on the drugs. The next day, July 25, Hafford was summoned back to the hospital after her lab reports from nine days earlier were finally reviewed. She was admitted to the hospital's ICU with "acute and sub-acute necrosis of the liver, secondary to drug toxicity, acute renal failure, anemia, septicemia, premature separation of the placenta," and threatened "premature labor." She was finally taken off the drugs but was already losing consciousness. Hafford's baby, Sterling, was delivered by C-section on July 29, and she remained conscious long enough not to hold him but at least to see him and learn that she'd had a boy. "We joked about it a little, when she was still coming in and out consciousness in ICU," Rubbie recalls. "I said to her, 'You talked about me so much when you were pregnant that the baby looks just like me.'" Hafford's last words were a request to be put on a breathing tube. "She said she thought a breathing tube might help her," says Rubbie. "That was the last conversation I had with my sister." In the early morning hours of August 1, Rubber and her mother got a call to come to the hospital, because doctors had lost Hafford's pulse. Jermal was sleeping, and Rubbie woke her own daughter and instructed her not to tell Jermal anything yet. They went to the hospital, and had been there about ten minutes when Joyce Ann died.

Rubbie recalls that the hospital staff said they would clean her up and then let them sit with her. She also remembered a doctor who asked for their home phone numbers and muttered, "You got a lawsuit." (That person has not resurfaced.) They hadn't been sitting with Hafford's body long when a hospital official came in and asked the family whether they wanted an autopsy performed. "We said yes, we sure do," she says. The hospital official said it would have to be at their expense-at a cost of $3,000. "We said, 'We don't have $3,000.' My sister didn't have any life insurance or anything," says Rubbie. "She had state health care coverage, and we were worried about how to get the money together to bury her." There was a liver biopsy, however, which revealed, according to internal communiqués of DAIDS staff, that Hafford had died of liver failure brought on by nevirapine toxicity.

And what was the family told about the cause of Hafford's death? "How did they put it?" Rubbie answers, carefully. "They told us how safe the drug was; they never attributed her death to the drug itself, at all. They said that her disease, AIDS, must have progressed rapidly." But Joyce Ann Hafford never had AIDS, or anything even on the diagnostic scale of AIDS. "I told my mom when we were walking out of there that morning," Rubbie recalls, "I said, 'Something is wrong.' She said, 'What do you mean?' I said, 'On the one hand they're telling us this drug is so safe, on the other hand they're telling us they're going to monitor the other patients more closely. If her disease was progressing, they could have changed the medication.' I knew something was wrong with their story, but I just could not put my finger on what it was."

When they got home that morning, they broke the news to Jermal. "I think he cried the whole day when we told him," Rubbie recalls. "My mom had tried to prepare him. She said, 'You know, Jermal, my mom died when I was very young,' but he was just devastated. They were like two peas in a pod those two. You could never separate them." Later on, Jermal became consumed with worry about how they would bury his mother, for which they had no funds and insurance. The community pitched in, and Hafford was buried. "I haven't even been able to go back to her grave since she passed," says Rubbie.

Rubbie King is haunted by many questions, including whether her sister was really infected with HIV (1), and also what the long-term damage might be to Sterling, whom Rubbie is now raising, along with Jermal and her own child. Sterling, in addition to the drugs he was exposed to in the womb, was also on an eight-week AZT regimen after birth. One of the reasons the family suspects Hafford may have been a false positive is that St. Jude's Children's Research Hospital has not released Sterling's medical records, and although they have been told that he is now HIV negative, they never had any evidence that he was even born positive. (All babies born to HIV-positive mothers are born positive, but most become negative within eighteen months.)

Hafford's family was never told that she died of nevirapine toxicity. "They never said that. We never knew what she had died of until we got the call from [AP reporter] John Solomon, and he sent us the report," says Rubbie King. "It was easier to accept that she died of a lethal disease. That was easier to handle." The family has filed a $10 million lawsuit against the doctors who treated Hafford, the Tennessee Medical Group, St. Jude's Children's Research Hospital, and Boehringer Ingelheim, the drug manufacturer (2).

Rubbie King made a final, disturbing discovery when she was going through Hafford's medical records: In addition to discovering that her sister had only ever been given a single HIV test, she also came across the fifteen-page consent form, which was unsigned.

On August 8, 2003, Jonathan Fishbein, who had recently taken a job as the director of the Office for Policy in Clinical Research Operations at DAIDS, wrote an email to his boss, DAIDS director Ed Tramont, alerting him that "there was a fulminant liver failure resulting in death" in a DAIDS trial and that it looked like "nevirapine was the likely culprit." He said that the FDA was being informed. He was referring to Joyce Ann Hafford. Tramont emailed him back, "Ouch. Not much wwe can do about dumd docs!"

This email exchange came to light in December 2004, when AP reporter John Solomon broke the story that Fishbein was seeking whistle-blower protection, in part because he had refused to sign off on the reprimand of an NIH officer who had sent the FDA a safety report concerning the DAIDS trial that launched the worldwide use of nevirapine for pregnant women. The study was called HIVNET 012, and it began in Uganda in 1997.

The internal communiques from DAIDS around the time of Hafford's death made it clear that doctors knew she had died of nevirapine toxicity. Tramont's reply to Fishbein could be placed squarely with Hafford's doctors, but it was the NIH itself that had conceived of the study as one that tested the "treatment-limiting toxicities" of HIV drugs in pregnant women.

The conclusion of the PACTG 1022 study team was published in the journal JAIDS in July of 2004. "The study was suspended," the authors reported, "because of greater than expected toxicity and changes in nevirapine prescribing information." They reported that within the nevirapine group, "one subject developed fulminant hepatic liver failure and died, and another developed Stevens-Johnson syndrome." Stevens-Johnson syndrome is skin necrolysis--a severe toxic reaction that is similar to internal third-degree burns, in which the skin detaches from the body. Another paper, entitled "Toxicity with Continuous Nevirapine in Pregnancy: Results from PACTG 1022," puts the results in charts, with artful graphics. A small illustration of Hafford's liver floats in a box, with what looks like a jagged gash running through it. Four of the women in the nevirapine group developed hepatic toxicity.

As Terri Schiavo lay in her fourteenth day of a persistent vegetative state, and the nation erupted into classically American moral opera over the sanctity of life, Joyce Ann Hafford's story made only a fleeting appearance--accompanied by a photo of her holding a red rose in an article that was also written by the AP's John Solomon. But soon a chorus of condemnation was turned against those who were sensationalizing Hafford's death and the growing HIVNET controversy to condemn nevirapine, which had been branded by the AIDS industry as a "life-saving" drug and a "very important tool" to combat HIV in the Third World.

(1) HIV tests detect footprints, never the animal itself. These footprints, antibodies, are identified by means of molecular protein weights, and were limited to two in 1984, when the first test was developed and patented, but over the years expanded to include many proteins previously not associated with HIV. Like most Americans, Hafford thought that a single HIV-positive test meant that she "had" HIV--a surefire death sentence. But a majority of HIV-positive tests, when retested, come back indeterminate or negative. In many cases, different results emerge from the same blood tested in different labs. There are currently at least eleven different criteria for how many and what proteins at which band density signal "positive." The most stringent criteria (four bands) are upheld in Australia and France; the least stringent (two bands), in Africa, where an HIV is not even required as part of an AIDS diagnosis. The U.S. standard is three reactive bands. It has been pointed out that a person could revert to being HIV negative simply by buying a plane ticket from Uganda to Australia.

(2) Dr. Thorpe declined to comment, citing ongoing litigation, as did the Tennessee Medical Group, the Regional Medical Center at Memphis, and St. Jude's Children's Research Hospital.

So-called community AIDS activists were sprung like cuckoo birds from grandfather clocks at the appointed hour to affirm the unwarvering AIDS cathechism: AIDS drugs save lives. To suggest otherwise is to endanger millions of African babies. Front and center were organizations like the Elizabeth Glaser Pediatric AIDS Foundation, which extolled the importance of nevirapine. Elizabeth Glaser's nevirapine defenders apparently didn't encounter a single media professional who knew, or cared, that the organization had received $1 million from nevirapine's maker, Boehringer Ingelheim, in 2000 (3). This was no scandal but simply part of a landscape. Pharmaceutical companies fund AIDS organizations, which in turn are quoted uncritically in the media about how many lives their drugs save. This time the AIDS organizations were joined by none other than the White House, which was in the midst of promoting a major program to make nevirapine available across Africa (4).

America is a place where people rarely say: STOP. Extreme and unnatural things happen all the time, and nobody seems to know how to hit the brakes. In this muscular, can-do era, we are particularly prone to the seductions of the pharmaceutical industry, which has successfully marketed its ever growing arsenal of drugs as the latest American right. The buzzword is "access," which has the advantage of short-circuiting the question of whether the drugs actually work, and of utterly obviating the question of whether they are even remotely safe. This situation has had particuarly tragic ramifications on the border between the class of Americans with good health insurance, who are essentially consumers of pharmaceutical goods, and those without insurance, some of whom get drugs "free" but with a significant caveat attached: They agree to be experimented on. These people, known in the industry as "recruits," are pulled in via doctors straight from clinics and even recruited on the Internet into the pharmaceutical industry and the government's web of clincal trials, thousands of which have popped up in recent years across the nation and around the world. Such studies help maintain the industry's carefully cultivated image of benign concern, of charity and progress, while at the same time feeding the experimental factories from which new blockbuster drugs emerge. "I call them what they are: human experiments," says Vera Hassner Sharav, of the Alliance for Human Research Protection in New York City. "What's happened over the last ten to fifteen years is that profits in medicine shifted from patient care to clinical trials, which is a huge industry now. Everybody invovled, except the subject, makes money on it, like a food chain. At the center of it is the NIH, which quietly, while people weren't looking, wound up becoming the partner of industry."

(3) "Our mission of eradicating AIDS is always informed and driven by the best available science, not by donations," said Mark Isaac, Elizabeth Glaser's vice president for policy, when asked to comment. "The full body of research, as well as our extensive experience, validates the safety and efficacy of single-dose nevirapine as one of several options to prevent mother-to-child transmission of HIV."

(4) Africa, as the news media never tires of telling us, has become ground zero of the AIDS epidemic. The clinical definition of AIDS in Africa, however, is sunningly broad and generic, and was seemingly designed to be little other than a signal for funding. It is in no way comparable to Western definitions. The "Bangui definition" of AIDS was established in the city of Bangui in the Central African Republic, at a conference in 1985. The definition requires neither a positive HIV test nor a low T-cell count, as in the West, but only the presence of chronic diarrhea, fever, significant weight loss, and asthenia, as well as other minor symptoms. These happen to be the symptoms of chronic malnutrition, malaria, parasitic infections, and other common African illnesses. (In 1994 the definition was updated to suggest the use of HIV tests, but in practice they are prohibitively expensive.) Even when HIV tests are performed, many diseases that are endemic to Africa, such as malaria and TB, are known to cause false positives. The statistical picture of AIDS in Africa, consequently, is a communal projection based on very rough estimates of HIV positives, culled from select and small samples, which are extrapolated across the continent using computer models and highly questionable assumptions.

By June 2004, the National Institutes of Health had registered 10,906 clinical trials in ninety countries. The size of these trials, which range from hundreds to more than 10,000 people for a single study, creates a huge market for trial participants, who are motivated by different factors in different societies, but generally by some combination of the promise of better health care, prenatal care, free "access" to drugs, and often--especially in the United States--cash payments. Participating doctors, whose patient-care profits have been dwindling in recent years because of insure-company restrictions, beef up their incomes by recruiting patients.

Dr. Jonathan Fishbein is hardly a rabble-rouser. But he is a passionate advocate of "good clinical practice," or GCP, a set of international standards that were adopted in 1996, as clincal-trial research boomed. The GCP handbook states: "Compliance with this standard provides public assurance that the rights, safety, and well-being of the trial subjects are protected, consistent witht he principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible." During the decade prior to his arrival at DAIDS, Fishbein had overseen and consulted on hudreds of clinical trials for just about every pharmaceutical company. Fishbein kenw, before he took his job as director of the Office for Policy in Clinical Research Operations at DAIDS, that there was a troubled study haunting the whole division. Nobody was suppposed to talk about it, but it hung heavily in the air. "Something about Uganda, that's all I knew," he says. There was a trial staged there, a big one, that had been plagued with "problems," and there was also a lot of talk about one particular employee connected to this trial who would need to be disciplined. Soon he discovered just how bad the sitution was. "The HIVNET thing," he recalls, "it hit me like a fire hose when I walked in there."

Fishbein's position was new. "It sounded like a very imporant position," he says. "I was to oversee the policies governing all the clinical-research operations, both here and abroad." He was told he would have a "go-no go" authority over individual trials. It wasn't long before Fishbein realized that he was, in effect, taking a job that was the equivalent of piloting an already airborne plane. "They had all these trials going on, and hundreds of millions of dollars flowing in every year, but there was apparently no one in a senior position there who really had clincal expertise -- who knew all the nuances, rules, and regulations in the day-to day running of clinical trials." DAIDS, when Fishbeing came to work there in 2003, was running about 400 experimental trials both in the United States and abroad.

A DAIDS project officer close to the HIVNET study closed the door when she had her first meeting with Fishbein. She had also crossed over from the private sector, and so she and Fishbein shared a disillusionment over how much shoddier and more chaotic the research culture was within the govenment, compared with industry. "I'm really frightened about the stuff that goes on here," she told him. "We really need somebody." This project officer, who for her own protection cannot be named, told Fishbein that the division's flagship study in Africa--HIVNET 012--had been wracked with problems and completely lacking in regulatory standards. She told Fishbein that the trial investigators were "out of control," and that there was no oversight of them, and nobody with either the inclination or the authority to make them adhere to safety standards. What Fishbein subsequently learned entangled him in a story with eerie echoes of John Le Carre's Constant Gardener.

For our purposes, the story of nevirapine begins in 1996, when the German pharmaceutical giant Boehringer Ingelheim applied for approval of the drug in Canada. The drug had been in development since the early 1990s, which was a boom time for new HIV drugs. Canada rejected nevirapine twice, once in 1996 and again in 1998, after the drug showed no effect on so-called surrogate markers (HIV viral load and CD$ counts) and was alarmingly toxic. In 1996, in the United States, the FDA nonetheless gave the drug conditional approval so that it could be used in combination with other HIV drugs (5).

By this time, Johns Hopkins AIDS researcher Brooks Jackson had already generated major funding from the NIH to stage a large trial for nevirapine in Kampala, Uganda, where the benevolent dictator Yoweri Museveni had opened his country to the lucrative promise of AIDS drug research, as well as other kinds of pharmaceutically funded medical research. HIVNET 012, according to its orginal 1997 protocol, was intended to be a four-arm, Phase III, randomized, placebo-controlled trial (6). It's sole sponsor was listed as the National Institute of Allergy and Infectious Diseases (NIAID), though one of the investigators was a Boehringer Ingelheim employee. The "sample size" was to be 1,500 HIV-1 infected Ugandan women more than thirty-two weeks pregnant. The four arms they would be divided into were 1) A single dose of 200mg of nevirapine at onset of labor and a single 2mg dose to the infant forty-eight to seventy-two hours post-delivery, and 2) a corresponding placebo group; 3) 600mg of AZT at onset of labor and 300mg until delivery, with a 4mg AZT dose for the infant lasting seven days after birth, and 4) a corresponding placebo group. There were to be 500 women in each "active agent" arm and 250 in each placebo arm. The study was to last eighteen months, and its "primary endpoints" were to see how these two regimens would affect rates of HIV transmission from mother to child, and to examine the "proportion of infants who are alive and free of HIV at 18 months of age." Another primary objective was to test the "safety/tolerance" of nevirapine and AZT. HIVNET's architects estimated that more than 4,200 HIV-positive pregnant women would deliver at Mulago hospital each year, allowing them to enroll eighty to eighty-five women per month. Consent forms were to be signed by either the mother or guardian, by signature of "mark." One of the exclusion criteria was "participation during current pregnancy in any other therapeutic or vaccine perinatal trial."

Although HIVNET was designed to be a randomized, placebo-controlled, double-blind, Phase III trial of 1,500 mother mother/infant pairs, it wound up being a no-placebo, neither double- nor even single-blind Phase II trial of 626 mother/infant pairs. Virtually all of the parameters outlined for HIVNET 012 were eventually shifted, amended, or done away with altogether, beginning with perhaps the most important--the placebo controls. By a "Letter of Amendment" dated March 9, 1998, the placebo-control arms of HIVNET were eliminated. The study as reconstituted thus amounted to a simple comparison of AZT and nevirapine. On September 4, 1999, The Lancet published HIVET's preliminary results, reporting that "Nevirapine lowered the risk of HIV-1 transmission during the first 14-16 weeks of life by nearly 50 percent." The report concluded that "the two regimens were well-tolerated and adverse events were similar in the two groups." The article also reported thirty-eight babies had died, sixteen in the nevirapine group and twenty-two in the AZT group. The rate of HIV transmission in the AZT arm was 25 percent, while in the nevirapine group it was only 13 percent. As Hopkins Medical News later reported, the study was received rapturously. "The data proved stunning. It showed that nevirapine was 47 percent more effective than AZT and had reduced the number of infected infants from 25 to 13 percent. Best of all, nevirapine was inexpensive--just $4 for both doses. If implemented widely, the drug could prevent HIV transmission in more than 300,000 newborns a year."

With the results of the study now published in The Lancet, Boehringer, which had previously had shown little interest in HIVNET, now pressed for FDA approval to have nevirapine licensed for use in preventing the transmission of HIV in pregnancy.

(5) Asked to comment about the Hafford case, HIVNET 012, and the larger nevirapine controversy, Boehringer Ingelheim provided the following statement: "Viramune (nevirapine) was an innovation in anti-HIV treatment as the first memeber of the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of drugs. Now in its tenth year of use, Viramune has been used as a treatment in more than 800,000 patient-years worldwide."

(6) The study was originally titled "HIVNET 012: A Phase III Placebo-Controlled Trial to Determine the Efficacy of Oral AZT and the Efficacy of Oral Nevirapine for Prevention of Vertical Transmission of HIV-1 Infection in Pregnant Ugandan Women and their Neonates." "Randomization" means that people are randomly chosen for one arm of the study or another, a procedure that is supposed to even out the variable that could affect the outcome. "Placebo controls" are the bedrock of drug testing and are the only way to know whether the treatment is effective. Phase I trials involve a small group of people, twenty to eighty, and are focused on safety and side effects. In Phase II trials, the drugs are given to an expanded cohort, between 100 and 300, to further evaluate safety and begin to study effectiveness. Phase III drug trials expand further the number of people enrolled, often to more than 1,000 and are meant to confirm a drug's effectiveness, monitor side effects, and compare it with other treatments commonly used. A small Phase I trial preceded HIVNET 012 that studied the safety, primarily, of nevirapine in pregnant women but also looked at efficacy. It was called HIVNET 006, and it enrolled twenty-one pregnant women for initial study. Of twenty-two infants born, four died. There were twelve "serious adverse events" reported. The study also showed that there was no lowering of viral load in the mothers who took the study drug (the industry's agreed upon standard for interrupting maternal transmission). community.livejournal.com