In Last Part of Series, Kaiser Daily HIV/AIDS Report Reviews the History of HIV Treatment
On June 5, 1981, the CDC introduced the world to the disease that eventually became known as AIDS. Although the disease had been present in the United States and elsewhere before this time, it was the first known mention of AIDS in a media report. Over the years, media coverage of AIDS has evolved from having an air of mystery to reports of panic, stigma and homophobia; from domestic epidemiology and policies to international crises and drug access. This week, the Kaiser Daily HIV/AIDS Report has featured stories on different aspects of the media's coverage of the disease over the past 20 years, including federal legislation, public fear and stigma and AIDS in the arts. The following report, the last in our series, reviews the history of HIV treatment in the United States, with a special focus on how the media portrayed treatment research and advances and the public's response. The story does not address the search for a vaccine, a separate large-scale research effort.
No 'Magic Bullet'
When doctors in Los Angeles and New York first recognized Kaposi's sarcoma and Pneumocystis carinii pneumonia in young gay men, the underlying cause of the immune deficiency making these otherwise healthy men susceptible to such "opportunistic infections" was unknown, and doctors could only treat the individual diseases. When the term AIDS first appeared in the MMWR in 1982, it was used to describe "a disease, at least moderately predictive of a defect in cell-mediated immunity, occurring with no known cause for diminished resistance to that disease" ("The Relationship Between HIV and AIDS," NIAID, 6/2000). Although by 1983 doctors suspected a "bloodborne virus is to blame" for AIDS, the cause of the disease had not yet been identified (Killackey, Daily Oklahoman, 6/16/83). As time passed, researchers identified the virus, eventually named HIV, and learned about its abilities to destroy the immune system, opening doors to experimentation with different compounds that showed antiviral properties. In April 1985, the Washington Post reported that "several drugs" showed "promise" in fighting HIV infection. However, it was not until July 1985, when actor Rock Hudson was hospitalized for an AIDS-related liver condition in Paris -- then "known as the foremost center for AIDS research" -- that AIDS treatment received major news coverage. Americans began seeking treatment in France, but French doctors "warned that Paris is no mecca for cures and that treatment in a strange environment could prove traumatic" (Ganley, Associated Press, 7/27/85). By September, the drug "that drew Rock Hudson and other patients to Paris," HPA 23, was undergoing clinical trials in the United States (Kronholm, Associated Press, 9/18/85). The "avalanche of publicity" surrounding Hudson and the drug prompted the FDA to "move into high gear" human clinical trials for potential AIDS treatments. At the end of 1985, NIAID was establishing "a network of medical centers around the country" to conduct drug trials, and at least four compounds were in "limited clinical trials": suramin, used to treat African sleeping sickness; azidothymidine (AZT), an antiviral first developed as a cancer treatment; ribavirin, an antiviral; and HPA 23, an antiviral that could cause bleeding disorders. Other compounds, including AL 721, ansamycin and cyclosporine, were in laboratory testing. In addition, several immune-boosting drugs such as isoprinosine, alpha-interferon and interleukin-2 had been tested in humans with the virus but "with little or no clinical success" (Norman, Science, 12/20/85).
In March 1986, the AP/New York Times reported that AZT had "bolstered the immune systems of 15 of the first 19 patients to receive" the drug and had improved some of their symptoms. The study, published in the Lancet, stressed that AZT, manufactured by Burroughs Wellcome (which later would become Glaxo Wellcome), was not a cure, had side effects "such as mild headache and upset stomach and in large doses was toxic to the bone marrow" (AP/New York Times, 3/14/86). A larger placebo-controlled clinical trial of the drug was stopped in September after it "proved effective" at slowing disease progression (Berg, Washington Post, 12/23/86). The success of AZT "shattered" the belief that stopping HIV replication "without damaging the patient" would be "impossible," Dr. Samuel Broder of the National Cancer Institute said (Thompson, Washington Post, 12/30/86). In March 1987, AZT received FDA approval under the agency's new "1-AA priority review designation," designed to give AIDS drug reviews "top priority" (HHS release, 3/20/87).
Still A Lot to Learn
AZT became "a turning point in the battle to change AIDS from a fatal disease to a treatable one," then-HHS Secretary Louis Sullivan said in 1989 (Hilts, New York Times, 8/18/89). But the drug had potentially serious side effects such as anemia, fever and nausea; was expensive; and required patients to take the drug every four hours around the clock. Marketed under the name Retrovir, the drug was initially "restricted" to AIDS patients suffering from pneumonia or severely depressed immune systems because of a "limited supply" (McCabe, San Francisco Chronicle, 3/21/87). However, once the drug became readily available, some physicians prescribed the drug to HIV patients who did not yet show symptoms of AIDS, although the drug's effectiveness was unproven in this population (Kolata, New York Times, 12/21/87). But some patients chose not to take the drug due to the potential side effects, and because they had watched others who took the drug continue to deteriorate, sometimes getting worse due to the side effects (McCabe, San Francisco Chronicle, 3/21/87). Experts debated how early to start treatment, as several studies showed that patients who began taking AZT after developing symptoms did not live as long as those who took the drug before developing AIDS symptoms (Kolata, New York Times, 2/15/91).
When it was approved, AZT cost about $12,000 per patient per year, making it "one of the most expensive drugs ever sold." However, in December 1987, Burroughs Wellcome cut the cost of AZT by 20%, saying it could now produce "large quantities of AZT at lower costs." Rep. Henry Waxman (D-Calif.) said of the new price, "I'm delighted to see this move by the company. ... [But] I'm afraid many people are still going to have a hard time getting access to this drug." Jeffrey Levi, then executive director of the National Gay Rights Task Force, said, "Burroughs has a monopoly and they still have not justified their pricing structure. We can only hope this [price-cutting] trend will continue" (Specter, Washington Post, 12/15/87). Pat Christen of the San Francisco AIDS Foundation said, "Unless [patients] have the insurance to cover it ... AZT is going to cost a lot of money for the indigent" (San Francisco Chronicle, 3/21/87). However, on July 11, 1987, Reagan signed a supplemental appropriations bill that allocated $30 million to create the AIDS Drug Assistance Programs (ADAPs), emergency funds to help low-income patients purchase the drug (Kaiser Daily HIV/AIDS Report, 6/7).
"Prominently citing" a request by Vice President and Republican presidential candidate George Bush, the FDA announced on Oct. 19, 1988, interim regulations that would shorten the approval process for drugs used to treat "life-threatening or seriously debilitating diseases," including HIV/AIDS. Then-FDA Commissioner Frank Young said that by implementing the new regulations, "We could reduce ... the time involved in clinical investigation by about one-third to 50% of the time for promising drugs" (Scripps Howard/AP/Seattle Times, 10/20/88). In moves "closely tied" to the new approval process, pharmaceutical companies began "giving away" experimental drugs that were still in the early phases of testing. The New York Times reported that the give-aways also stemmed "partly from public protests over the high price that Burroughs Wellcome Company charges for AZT." In 1989, Bristol-Myers announced a program to provide for free its drug ddI, which had "shown promise [of slowing HIV progression] in early tests" (Freudenheim, New York Times, 10/21/89). Two years later, in October 1991, the FDA approved ddI, sold under the brand name Videx, for patients with advanced HIV infection who were unable to tolerate AZT or whose health "significantly deteriorated" while taking AZT (FDA release, 10/1/91). David Kessler, then FDA commissioner, said that the expedited approval of ddI "sets an example for the approval of other drugs for AIDS" (Kolata, New York Times, 7/20/91).
Improving the Approval Process
In April 1992, Vice President Dan Quayle and HHS Secretary Sullivan announced four new FDA initiatives to "speed access to new drugs and improve the drug review process." The four initiatives included:
- Accelerated Approval: Instead of using endpoint markers such as death, the FDA agreed to use "surrogate endpoints that indicate that a drug is effective," such as increased or stable CD4 cell counts in AIDS patients. Additional testing to "confirm" the drug's effectiveness would be performed after marketing approval. This "accelerated" process would allow drugs to reach market one to three years sooner than under the previous process.
- Parallel Track: Under this initiative, AIDS drugs would be made available to patients unable to participate in clinical trials "as early as possible in the drug development process -- a departure from the current practice of making investigational drugs available initially only through controlled clinical trials." Although the program was restricted to AIDS drugs, officials said other drugs might be considered in the future.
- Safety Testing Harmonization: Through a cooperative agreement among the European Community, Japan and the United States, researchers could use consensus guidelines for their research and submit to any country within the group animal safety data, eliminating the need to duplicate "valid animal testing."
- Outside Expert Reviews: The FDA would contract with outside reviewers to "reduce the backlog of new drug applications." Although the FDA would maintain "full final approval authority," outside reviewers would "assume much of the burden of analyzing the data in these applications" (FDA release, 4/9/92).
The Concorde Study
Almost a year after the FDA announced its accelerated approval process, the initiative came under fire after a letter in the April 3 Lancet described initial results of a European study that examined the use of AZT in HIV patients without symptoms. The study, called the Concorde trial, showed that after three years of follow-up, researchers saw "no differences in the cumulative risk of death or disease progression between HIV-infected individuals given immediate AZT therapy and those who were not treated until they developed decreases in the numbers of certain immune system cells or at the time that AIDS-related symptoms occurred" (FDA release, 4/1/93). The New York Times reported that the study "challenged the validity of using the CD4 count as a surrogate marker for AZT among symptomless [HIV-positive] individuals," noting that the FDA "has put great emphasis on surrogate markers" since the implementation of its accelerated approval process. Surrogate markers had been used in the approval of both ddI and ddC, another anti-HIV drug approved in June 1992. The Times noted the government's Catch-22: "If government officials are overly cautious and too rigid in demanding proof of a drug's effectiveness, patients may die before getting a chance to benefit from it. But if a drug is approved too quickly, patients may suffer unexpected harm and those who pay the bills may waste millions of dollars" (Altman, New York Times, 4/6/93). But in July, Australian researchers released study data showing that AZT "significantly slows the progression toward full-blown AIDS," confirming U.S. officials' belief that "AZT is a moderately useful drug that can slow the course of AIDS in some patients for a limited period of time." Johns Hopkins University AIDS researcher John Bartlett said, "This is a field filled with broken dreams, and there have been a lot of very great disappointments ... But even with all that ... I'd say there are some compelling reasons to start [therapy] early" (Angier, New York Times, 7/29/93). This attitude would drive HIV treatment theory through the advent of protease inhibitors.
In 1994, the FDA approved AZT for use in pregnant women to reduce the risk of mother-to-child HIV transmission. In a landmark study, called ACTG 076, AZT was administered orally to pregnant women daily during pregnancy and intravenously during labor, and the newborn infant received oral AZT within 24 hours after birth and for six weeks. The study was stopped when preliminary results showed that the rate of HIV transmission in the group receiving treatment was reduced by about two-thirds, from 25.5% to 8.3% (FDA release, 8/8/94). This was "the first indication that mother-to-child transmission of HIV can be at least decreased, if not prevented," Dr. Harold Jaffe of the CDC said. Jaffe added that the findings gave health officials "a real impetus" to identify HIV-positive pregnant women. The finding was also expected to have "worldwide implications," Dr. James Curran of the CDC said, especially in Africa where HIV transmission to infants was a "much bigger public health problem" than in the United States (Altman, New York Times, 2/21/94). The treatment regimen, however, remained expensive, and access to the drug in developing countries was limited. In 1999, the use of a short-course regimen of the drug nevirapine, approved in June 1996, was proven to reduce the risk of HIV transmission from mother to child with just two doses -- one for the mother and one for the infant, given during labor and immediately following birth, respectively -- at a cost of $4, compared with $268 for the similarly effective AZT regimen (Altman, New York Times, 7/15/99).
The first protease inhibitor, a new class of drugs that targeted the protease enzyme that HIV uses to make new copies of itself, was FDA-approved in December 1995. The drug, called saquinavir, was approved for use in combination with older drugs, such as AZT. "Today's approval introduces a new class of drugs for treating AIDS. This drug was approved in just 97 days -- evidence that FDA is carrying through on the Clinton administration's priority to review new drugs ... on the fastest possible track consistent with safety," then-HHS Secretary Donna Shalala said (FDA release, 12/7/95). Soon after, reports of HIV treatment success with other experimental protease inhibitors began to pepper the media, and by the end of March 1996, two more protease inhibitors, ritonavir and indinavir, had been approved for use in combination with older HIV drugs, bringing the total number of approved HIV drugs to nine (FDA release, 7/1/96). Results from several studies using different three-drug combinations incorporating new and old drugs were presented that summer at the Vancouver International AIDS Conference. The New York Times reported that the positive results represented a "clear watershed in the treatment of AIDS, since the available drug therapies have gone almost overnight from the unspectacular to the possibly significant." After their experiences with the ups and downs of AZT, researchers and HIV patients "were generally thrilled by the new hope in AIDS treatment," but "many cautions" remained, including the "fear that the virus may in time develop resistance to the new drugs just as it has done to older ones" (Altman, New York Times, 7/12/96).
The Media Declares 'The End'
Although many doctors were skeptical about the long term effectiveness of the new treatments, the media was captivated by the positive news of HIV patients with "no measurable trace of the virus" in their blood. For Newsweek's Dec. 2, 1996, edition, the magazine featured a cover story headlined, "The End of AIDS?" Though it noted in its subheadline and in the story that "[t]he plague continues" and "[t]his is not the end of the plague," Newsweek did report, "[T]his year's breakthroughs do mark the end of our long-established way of thinking about the virus. Doctors are starting to consider HIV a chronic, manageable disease rather than a death sentence. Huge swaths of the American psyche -- how we view sex, trust, responsibility -- will have to change." The success of drug combinations in bringing people back from the brink of death was even termed "the Lazarus effect" (Leland, Newsweek, 12/02/96). In addition, Time magazine named AIDS researcher David Ho of the Aaron Diamond AIDS Research Center its 1996 man of the year. Newsday declared, "It's hard to imagine a more fitting choice. Ho is at the forefront of a remarkable scientific achievement. After 15 frustrating years, he and his fellow scientists are closing in on HIV" (Newsday, 12/28/96). Ho said of the honor, "I'm just a poster boy for AIDS research," noting that being chosen for the cover was a "great source of anxiety" for him, as he was "concerned about the hype and the publicity. One could bake in the spotlight [instead of] basking in it."
In a January 1997 Science commentary, longtime AIDS reporter Jon Cohen, noting the several 1996 stories on the "dramatic strides" made in HIV treatment, wrote, "A casual browser of recent newsstands might conclude that AIDS is now all but cured." He added, "[A] growing number are concerned that many popular media stories cross the line that separates hope from hype." Cohen said that "from the moment researchers first reported these data ... they have raised red flags." The studies were "small and ongoing"; even those with "undetectable" amounts of virus in their bloodstream "harbor[ed] masses of HIV"; drug-resistant strains were beginning to emerge and had "already taken over in some patients"; and "serious toxicities" were "certain to surface" over time (Cohen, Science, 1/17/97). In addition to medical problems with the drugs, some experts said that the positive news was causing people to be "less careful." Florida International University Professor William Darrow said, "Significant numbers of gay men may believe that there is a cure," noting that results from a study he conducted showed that "gay men are reacting to this bit of news by throwing caution to the wind" (Striphas, St. Petersburg Times, 3/30/97). News of HIV-positive basketball star Magic Johnson's "miracle recovery" on protease inhibitors caused "[s]ome young people [to] think if Johnson can overcome the disease, they can do the same or don't have to worry about safe sex." The Chicago Tribune reported, "Indeed, the concept of an end to the AIDS epidemic appears highly premature, and it can have unfortunate consequences" (Condor, Chicago Tribune, 4/13/97).
'Buffalo Hump' and 'Protease Paunch'
By June 1997, only a year after the Vancouver International AIDS Conference, where protease inhibitors had been heralded, the combination therapies, which had come to be known as highly active antiretroviral therapy, or HAART, were causing potentially fatal side effects in HIV patients. The FDA issued a health advisory warning physicians that protease inhibitors "may contribute to increases in blood sugar and even diabetes" in patients on the therapies. But the advisory said that "none of the data [received by FDA] definitively demonstrates that the drugs caused the condition" and noted, "While diabetes is a very serious condition, the agency believes these events occur relatively infrequently ... and does not recommend that patients forego protease inhibitor therapy" (FDA release, 6/11/97). The government also released HIV treatment guidelines to "help end confusion among doctors and patients who must make life-and-death choices among 11 antiviral drugs that can be taken in 320 different combinations." At a press conference to announce the guidelines' release, experts "warned" that if taken improperly, the treatments could "do more harm than good" (Recer, AP/Pittsburgh Post-Gazette, 6/20/97). Although AIDS death rates were dropping due to the success of HAART, for some HIV patients the "drugs d[id] not work at all." Research showed that up to one-third of patients did not improve on the combination therapies. Some patients were unable to follow the regimented schedule of taking daily up to 40 pills, many of which had specific dosing instructions, such as taking on an empty stomach (Hanrahan, Los Angeles Daily News, 12/1/97). By the Geneva International AIDS Conference in June 1998, more side effects of the protease inhibitors were emerging. Termed "lipodystrophy syndrome," the side effects included muscular wasting in the face, arms and legs, dry skin, cracked lips, overall weight loss and changes in fat metabolism. For unknown reasons, fat was redistributed in the body to the back of the neck and stomach, conditions known as "buffalo hump" and "protease paunch," and to the breasts of women. The New York Times reported that the syndrome had "caught AIDS experts by surprise" and that the "side effects have become a very large problem," according to Australian researcher Dr. David Cooper. As the problems became more apparent, many patients stopped taking the drugs or refused to begin the therapy in the first place, as they "weigh[ed] the disfigurement and the unknown longer-term risks of protease inhibitors against the possibility of a steady decline in [their] condition" (Altman, New York Times, 7/7/98). The 1998 International AIDS Conference ended in a "somber mood," with "many participants thinking that their best hope against the epidemic was the strategy they had since it began: prevention."
'Bridging the Gap'
The 1998 International AIDS Conference was themed "Bridging the Gap," with reference to the divide between developed and developing countries, where the virus was causing "a runaway epidemic," according to UNAIDS Executive Director Peter Piot (Altman, New York Times, 7/5/98). Despite concerns over drug resistance and side effects raised at the conference, international focus on the disease soon shifted from prevention to drug access. Newspapers began reporting that AIDS activists around the world were pressuring big pharmaceutical companies to provide discounted drugs to HIV-positive individuals in developing countries, as the success of countries such as Brazil, where the government manufactures and provides patients with generic AIDS drugs, in controlling disease spread. With this push, more AIDS patients around the world are gaining access to drugs that could prolong their lives. But with more drugs entering areas of the world that do not have adequate health infrastructures to handle the complex treatment regimens, officials are growing concerned that improper drug use could lead to the emergence of drug-resistant HIV strains. One recent study led by Dr. Susan Little of the University of California-San Diego showed a 14% increase of drug-resistant strains among new HIV cases in the United States and Canada (Altman, New York Times, 2/8). This week, Piot expressed regret that the focus of the HIV/AIDS issue had shifted from prevention to treatment, adding that "we are certainly not at the end" of the "largest epidemic in human history" (Kaiser Daily HIV/AIDS Report, 6/6).
This concludes the Kaiser Daily HIV/AIDS Report's weeklong series examining 20 years of media coverage on HIV/AIDS. Contributors to the series include: Meredith McGroarty (Day 1); Ingrid Dries-Daffner, Melissa Keefe and Meredith Weiner (Day 2); Heather Schomann and Laura Menge (Day 3); Darryl Drevna, Leslie Isenegger and Amanda Wolfe (Day 4); and Alyson Browett (Day 5).
The other parts of the Kaiser Daily HIV/AIDS Report 20th anniversary series are available online:
- The June 4 article examines early media coverage of the epidemic.
- The June 5 article examines the stigmas surrounding HIV/AIDS.
- The June 6 article looks at HIV/AIDS in the arts.
- The June 7 article examines 20 years of legislation and policies on HIV/AIDS.