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A new model for AIDS treatment activism

Two years ago, author-activist Larry Kramer had a scare. Kramer is blessed with an extremely low amount of virus in his blood--in lab tests it's undetectable--but suddenly it flared up. "I thought, 'Oh my God,' " he recalls. "What happens if my virus is on its way up? What drugs would I take? I didn't know then and I still don't know."

Luckily, Kramer's virus receded on its own, so he didn't have to decide which of the new protease-inhibitor drugs to take, a decision that's frightening and confusing. There are 11 approved drugs that fight HIV, and two more about to be released. But no one is sure how to use them.

Patients usually take a cocktail of three medicines. With 11 to choose from, there are 165 possible combinations, and when the two new drugs come on line, that number will soar to 286. Add in the regimens of two, four, and even five drugs, which are becoming more popular, and the number of options exceeds 2300. Which is best? And if the first combination fails--as currently happens with a quarter or more patients--what is the optimal "salvage regimen"?

The most precise way of answering these questions is to run controlled clinical trials--but with so many options to choose from this is impractical. What's more, such trials take years, by which time new drugs are likely to become available, rendering the outcome obsolete.

Yet hundreds of thousands of patients are playing what Kramer has dubbed "drug-combo roulette," choosing regimens without full knowledge in a desperate bid to keep AIDS at bay. What Kramer realized, even before his own scare, was that these patients are participants in a vast medical experiment that, unfortunately, no one is tracking. "What a waste, all this data going down the toilet," Kramer says. "And so it just sort of came to me that patients should be able to put their information on the Internet," allowing them and their doctors to log in and find out, in real time, how patients are doing on any drug combination.

Two years later, Kramer's idea has grown into the multimillion-dollar HIV Treatment Data Project (TDP). Field testing is scheduled to begin in New York City and California next month, and Kramer sees it as the next step in AIDS activism--patients collecting and recording the scientific data that might help save their lives. "We're all waiting for someone to tell us what drugs to take," says Kramer. "That's not going to happen. We'll have to find these answers for ourselves. It's time to hit the keyboards like we hit the streets."

Not quite yet, because TDP might not be fully available for a year. There's also debate about how reliable the information it provides can ever be. Though leading activists and researchers raised plenty of questions about the project, almost no one opposed it. "It's worth a try," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "It may turn up useful information."

Treatment Action Group's Mark Harrington, who won a MacArthur "genius" grant for his activism, predicts that TDP will have limited use, because only clinical trials can prove what drugs are effective. Still, he thinks the project could uncover hidden trends: "What happens if everyone's failing nelfinavir [a leading protease inhibitor] and we didn't know it?" There's little love lost between Harrington and Kramer, but, Harrington says, TDP "might well be the most constructive thing Larry's done in five years."

Kramer's old friend Rodger McFarlane, the indefatigable former head of Gay Men's Health Crisis and Broadway Cares/Equity Fights AIDS, is TDP's director. Mike Stocker, president and CEO of Empire Blue Crossand Blue Shield,helped convince the American Association of Health Plans, a managed-care industry group, to get involved, and it provided more than a million dollars in funding. High-caliber AIDS doctors and statisticians--led by Sherrie Kaplan of New England Medical Center and Tufts University--are designing the questionnaire and the data crunching. But maybe the biggest break came when an executive at the software company Lotus read an article by Kramer that described the project and called for volunteers.

Bruce Brothers had moved to Colorado, where his parents live, to die of AIDS. Lymphoma raged in his body. For three months, he recalls, he was in the hospital "almost constantly." His T-cell count, an important gauge of the immune system, plummeted to 19 (a healthy person has 1000). Death was more than just knocking; it was banging down the door.

Brothers was rescued by one of the new three-drug regimens, allowing him to return to work. That's the Lazarus story that has become so commonplace in AIDS. But just as common is what happened next: HIV mutated, escaping the powerful drugs, and Brothers faced the dilemma of what medications to take next, something no clinical trial had solved. Just when Brothers "realized this great ride and recovery was not a sure thing," he read Kramer's article in the AIDS magazine POZand called the publication, saying, "I'm the person Larry is looking for."

Brothers, who has never before been involved in activism, says he wanted to "add value" to the project. That he has. Lotus estimates it has already donated more than $1.5 million in staff time and resources, and Kramer calls the company's work "fucking unbelievable." (The company's motivation? Partly, it's helping Brothers, but if the project succeeds, Lotus could use the PR to land new contracts in the healthcare business.)

Lotus has designed a Web site, in English and Spanish, that is attractive yet simple enough to run on low-grade computers. Scientists and activists created a questionnaire with enough queries to get important scientific answers but not, they hope, too many to scare patients away. Confidentiality has been assured by Lotus's top-of-the-line encryption. And the questionnaire is smart: different answers track the user down appropriate paths. What about patients who don't know much about their treatment, not even the name of their drug? A picture of the pill is just a click away.

It sounds great, but everyone involved is nervous about the upcoming test. Will patients sign on? Will they trust the encryption security? Will they enter their data correctly--and consistently every three months? Can this high-tech experiment attract people who don't own computers and may never have used them--in short, the poor and marginalized who bear the brunt of the epidemic?

"The problem with a lot of my patients," says Jeannine Bookhardt-Murray, medical director of HIV services at Morris Heights Health Center in the Bronx, "is that they're hungry. Hungry! We're constantly on the phone calling the Food Force," a local agency that battles hunger.Before coming to Morris Heights last year, Bookhardt-Murray worked for 13 years at Harlem Hospital, but, she says, "I never saw poverty in Harlem like I do here." According to the last census, the median income in the clinic's zip code is less than $14,000 per household.

Bookhardt-Murray's clinic sees about 300 HIV patients regularly, and another 100 off and on. (Only two died last year, a testament to the quality of care.) About half are Hispanic, a third are African American, and about 15 percent don't speak English fluently. How many have access to the Web? "Oh, very few, zero to 5 percent," says Bookhardt-Murray. "Most have probably never even used a computer."

While some of her patients are "very sophisticated" about AIDS and its treatments, poverty, Bookhardt-Murray says, often creates a mind-set of "feeling trapped, helpless, not knowing how to get what you need." That's why she's so excited that her clinic is one of the four test sites for TDP. She sees it as an opportunity not only for her to obtain scientific information, but also for her patients to learn more about their care.

Patients don't just input data. The program saves all the information they enter in a simple, clear, and confidential home page, links them to other high-quality Web sites, and allows them to communicate with other participants through a "chat" room. Planners also hope to create an automatic feedback system. For example, if patients are on a substandard regimen, the program might let them know. "A major goal of this whole thing is education," says Kaplan, TDP's principal investigator. "We want to help patients amass as much information as possible, so they can talk more rationally with their doctors."

Lotus is setting up three terminals at Morris Heights, and AAHP is funding a coach to help patients use the computers. The other New York test site is Dr. Howard Grossman's private practice in Chelsea, consisting mainly of middle-class gay men. The mix was designed not for political correctness, says McFarlane, but to get a representative sample. For example, poor people often have secondary diseases, such as diabetes and high blood pressure, which usually disqualify them from clinical trials but might very well affect their response to HIV drugs.

The first phase of testing is designed to see how user-friendly the system is and to find out whether patients can accurately and reliably enter their own medical data. But there are plenty of potential pitfalls.

"I have patients who really know their data, and others who don't keep a tab," says Wafaa El-Sadr, chief of Harlem Hospital's infectious disease division. While she thinks the database "would be really useful," she speculates that participants in the project are likely to be the ones who know their data, skewing the results. She thinks the project might also end up being biased toward the healthy, because "when people are sick, probably the last thing they want to do is enter data." And what about fraud, a drug company logging in fictitious patients doing well on their product?

Then there are the technical hurdles. The pharmaceutical giant Glaxo Wellcome has spent millions developing a similar database, called CHORUS, that tracks patients through medical records. "We underestimated what it would take to make the system work," says CHORUS coordinator Ebere Igboko. "We did not and could not anticipate bugs that had to be worked out and still are." The system automatically checks for errors--and finds them, even though participating doctors and nurses underwent "a lot of training." Igboko supports the Treatment Data Project: "It would be a really useful thing, but it sounds extremely ambitious."

TDP hasn't yet tackled how to analyze its data. The plan is for anyone to be able to log in and formulate any question, such as, "How are women in late-stage disease who have already taken medications A, B, and C faring on drug regimen X, and what side effects are they experiencing?" Making such a program easy enough for overworked doctors and nurses, not to mention patients, will be no easy feat.

If all these hurdles are cleared, exactly what might the database reveal? Figuring out whether drugs are effective--let alone which combinations have an edge on others--can be surprisingly difficult, even in a carefully constructed clinical trial. By their nature, "observational databases," as scientists call studies like TDP, aren't controlled or randomized.That makes it hard--some say impossible--to deduce whypatients are doing well on any given drug regimen. Maybe their good fortune is due to the drugs, but maybe it's because of some other factor. "The danger of drawing incorrect conclusions is greater," says Sam Bozzette, a heavyweight researcher from the University of California at San Diego. If that happened, he says, spurious findings could be accepted as fact, and actually harm patients.

Yet Bozzette is a self-described "cheerleader" for the project: "It might be a very good way to pick up side effects, unusual occurrences, patterns in the data. That could be quite valuable." Indeed, it could push researchers to conduct more precise clinical trials. And a rigorous study design "doesn't inoculate you against the wrong inference," he says, citing a heart medication that, in a controlled clinical trial, was shown to allay abnormal heartbeats. It also caused cardiac arrest and death, a fact that was only discovered, he notes, through "an observational approach."

Indeed, clinical trials usually exclude people with messy treatment histories and complicating health problems. That's one reason drugs almost always work better in clinical trials than in the real world. Observational databases, on the other hand, describe what's happening on the ground. And if they amass enough participants, statisticians can provide evidence about what's working--and what's not--for various subgroups.

Bozzette insists that TDP's real use will be for the patient or doctor who doesn't have time to wait for pristine answers but is "sitting there saying, 'Shit, I've got to do something.' " Through TDP, he says, patients will "be able to ask 10,000 friends, and that would be powerful." If Bozzette were with a patient who had a complicated history of failing various regimens, "I might think of some combinations and pump them into this database just to see if anyone had any experience with them. Who knows? It might have been taken by seven people and in five cases their hair fell out."

Finally, if the project were to succeed, how would the database be used? Would managed-care companies look to it for reasons to limit treatment options? Not likely, says Empire Blue Cross's Stocker, since even the most expensive drug regimens are cheaper than hospital stays. McFarlane hopes to tap pharmaceutical funding; will these companies try to control access to the data, or determine the research agenda?

Kramer has a history of turning on groups he founded; he has excoriated GMHC and ACT UP. How long will it be before he attacks TDP? Kramer laughs. "I'm 63 years old now," he says. Then, getting serious, he vows he won't turn on the project "as long as it works well and no one tries to put anything over on anyone."

Ultimately, the whole enterprise depends on patients. "Patients will have to be extremely involved and very dedicated to putting their data in over a long period of time, in a way the pros would say is very unlikely--nutty, in fact," says Bozzette. "But nobody on my side of the fence is in a position to tell Rodger and Larry what the community can and can't do. I'd love this to work."

"My instinct is that patients will do a lot better job than we think they'll do," says Empire Blue Cross's Stocker. "That's based on my experience as a physician. Patients have a totally different motivation than doctors. There's usually a genuine desire on their part to help other patients. So I'm kind of hopeful."

"GMHC and ACT UP were both grounded in a notion of patient empowerment and this seems like the next step," says Kramer. While everyone else on the project tries to downplay expectations, Kramer wants to "revolutionize how medical data is collected." He hopes to enlist a quarter-million HIV patients. "Size does matter," says McFarlane, but he adds that the project could yield useful data with just 1 percent of Kramer's goal.

Does Kramer think TDP is going to work? "I never doubted from day one, when I helped start GMHC, that there wasn't a cure for AIDS. I never thought it would defeat us totally. I've always thought that if we fought long enough and hard enough, we could get to the top of the mountain."

Research assistance: Tyler Schnoebelen

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