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AIDS Treatment News
1995 Outlook: Research Strategy
John S. James
January 20, 1995
AIDS TREATMENT NEWS #215, January 20, 1995

As 1995 begins, we have more opportunities for progress toward major improvement in AIDS/HIV treatments than ever before. And we have clear, feasible paths to follow -- of safe, rapid, low-cost, high-quality treatment trials in people, to get solid preliminary information on how certain potential treatments work in practice. Researchers now have better tools to run these trials than in the past -- and some of the new tools, especially tests for plasma HIV RNA, are also available to individual physicians and patients.

Also, we are hearing more cases of unexpected improvement in people with HIV or AIDS -- sometimes beyond what would be thought possible. The most dramatic examples are usually from clinical trials of experimental treatments such as protease inhibitors. But there are others who are lucky enough to do quite well with approved treatments or treatment combinations which happen to work for them. And some do well with "alternative" treatments, or their own combinations of approved, experimental, and/or alternative approaches. We have long believed that the best strategy available is to try many different treatments, keeping the ones that seem to work for oneself, and discarding the ones that seem not to work.

Strategy, Part I: Small, Rapid Screening Trials These success stories are not the answer, however. They do not work for everyone, and usually there is no way to predict who will benefit. Also, no one knows how long the successes will last -- although often they seem to work for years, with no evidence of failure in sight.

These success stories, instead, should be seen as treatment leads, entry points for further research. For each lead, physicians and scientists should use their best judgment to try to define a class of patients who might reproducibly benefit. The next step is to run a small, rapid "proof of principle" trial -- usually in only a few patients, perhaps ten to 20 -- looking for consistent changes in measurable indicators of improvement. There might or might not be a control group in this trial.

What would happen then? Most of the proposed treatments tested this way, perhaps 80 or 90 percent, would probably be found not to work. But there are dozens of good-quality leads waiting for such a test, and a number of them would come out with strong support. These would then have the social/political momentum needed to move rapidly into further research.

This proposal for many short, rapid screening trials is not controversial, but is generally accepted as something that can and should be done. The cost and other resource requirements would be modest. The problem today is finding the political and institutional will to make the research happen.

Strategy, Part II: A New Way to Prove Clinical Benefit The next step after the screening trials is more controversial. Those short trials will look for a measurable, reproducible improvement, usually in blood work. But what then? Change in a blood test may not prove that the treatment actually benefits patients. Usually we need other kinds of trials to show this.

Here we face a serious problem. The prevailing thinking so far has focused on a kind of clinical-benefit trial design which will take hundreds of patients for each drug studied, and take years to produce conclusive answers. This kind of trial randomly assigns the treatment being tested to some patients, while others are assigned to standard treatment instead. Then both groups are observed to see which one gets sick faster. It takes a long time because AIDS progresses slowly; even if the new treatment being tested were a complete, instant cure, the trial might still take years, because it would have to wait for a statistically significant number of those on the standard treatment to get sick or die. And even aside from the time required to run the study itself, it usually takes years to politic for, finance, design, organize, and recruit for such a large trial (in addition to the time to analyze the data, distribute the results, and get them into standard medical practice). Even aside from the problem of making people wait for years to get better treatments, it is clear that there will not be enough patients available, let alone enough money or trained researchers, to test more than a few of the treatments which are likely to pass the small screening trials.

There is a better approach. The treatments which pass the small screening trials in all probability do benefit patients -- the difficulty is in finding a feasible way to prove that conclusively. What we suggest is combining a number of treatments which work well in the screening trials, until the cumulative benefit of all of them is great enough to be clearly visible -- not only in delaying illness, which takes a long time to see, but also in getting sick people well, which usually happens much more quickly. When patients regularly get out of bed and go back about their lives, when those who were disabled can work again, when chronic infections disappear with no further need for antibiotics or other specific treatments, then the value of the AIDS/HIV treatment will be unambiguous. Statistical proof could be rapidly obtained, through small, rapid trials (much like the screening trials) which compare immediate vs. delayed therapy -- for example, randomly assigning volunteers to either start the treatment now, or to start it in six weeks. Long-term followup would of course be included, to make sure that the benefits last, and to watch for long-term side effects.

This research strategy offers definitive proof of clinical benefit in small, rapid, inexpensive trials -- instead of the huge years-long trials that are usually believed necessary to prove clinical benefit. It may not prove the benefit of each individual treatment -- only of a certain, partly-arbitrary combination. But the information available today suggests that this strategy could quickly provide relief and save lives; those who want more refined information could pursue it later.

This approach to proving clinical benefit, unfortunately, is not yet part of the ongoing conversation on how to improve AIDS research. We have never heard it discussed or proposed anywhere. Hopefully our readers will help to get this idea onto the table, to be considered professionally and accepted or rejected on its merits. None of the alternatives offers an acceptable outcome.

This proposal for proving clinical benefit turns the small, rapid screening trial into part of a complete strategy for going from where we are now to where we need to be to save lives. Let's further develop and improve this strategy, and use it as an organizing tool to get the research done.

Strategy, Part III: New Mechanisms of Action A third potential research strategy would seek to develop treatments which control HIV through new, previously-unknown mechanisms of action.

This could be done through intensive research into what might be called mystery treatments -- accidental or lucky discoveries of drugs or other treatments which seem to be helping in some way, but which have no known mechanism of action. Mystery treatments may include prescription drugs (one possible example is sulfasalazine), certain nutrients (see "Some Vitamins Associated with Decrease Risk of AIDS and Death," AIDS TREATMENT NEWS #214, January 6, 1995), or other approaches such as exercise. The goal is not so much to develop these treatments themselves, as to discover how they might work. If a new mechanism of action is found, then a whole new approach to AIDS treatment would become possible.

The key is to direct more research attention and resources into investigations of mystery treatments, which could lead to potentially major advances in understanding and treating HIV disease. This is the opposite of what happens now, which is that potential treatments without a known mechanism of action are largely ignored.

How does one begin to study a possible treatment with no known mechanism of action? One way is to look for consistent changes in any of the virological, immunological, and other tests which are available. Any repeatable, predictable treatment effect could serve as a lead or clue. And of course this research would be done in collaboration with specialists, usually outside the AIDS field, with expertise in the treatment being studied; they can help to identify and evaluate research leads.

Political Strategy: Organizing National Will AIDS research and AIDS prevention have always suffered from a lack of full national commitment to AIDS. Today this problem is becoming more critical than ever before. As it affects research, it takes many forms: * AIDS research has long overemphasized large, high-tech, complex, and product-oriented projects, because those are the ones people get paid to do, the ones that build a politically powerful constituency (lobby). Corporate research is almost always oriented toward proprietary products; in theory, government and foundation research should fill in the gaps by doing necessary work which companies will not do -- including basic research, and also including the small trials that we suggested above, for those treatment leads which are not products that corporations will study. But due to conflict of interest, revolving-door employment, and increasing reliance by academic institutions on entrepreneurial funding, non- corporate institutions have not adequately set their own agendas. As a result, academic, government, and foundation researchers have tended to study the same drugs and approaches that corporations already are studying, or should be.

Part of the problem is the ever-increasing difficulty of making anything happen in clinical research (due to ever- growing costs and regulatory requirements, as well as increasing scarcity of funds). This creates a conservative bias, by making it hard to get any trial off the ground unless it has a large, pre-existing constituency. Since new ideas almost never come into being with a large constituency, they almost always suffer great delays while the necessary professional/commercial/regulatory momentum develops.

In other circumstances, it would be possible to correct these structural defects. But due to the widespread attitudes around AIDS, the nation has not found the will to do so.

* The recent elections have created new and serious problems. Many members of Congress seem to be interested in representing only one group of people -- white, heterosexual men with good incomes -- and have little interest in anyone else's concerns. (A more accurate statement would be that they represent the frustrations of certain voters, and the interests of multinational big business.) Since relatively few such people have AIDS, money may be taken from AIDS for tax reduction, military spending, and other rewards for those who financed the recent political campaigns.

* Recently we spoke with two business reporters not connected with AIDS, and found a well-developed ideology of fatalism tailor-made to justify not bothering with AIDS research. One compared AIDS research to a swamp, in that the farther you go in, the deeper you get, without end. The other compared AIDS to the common cold -- more serious, he acknowledged, but similar in that despite ongoing progress, we do not expect to ever see a time when people do not get colds (or, by obvious analogy, a time when people do not die of AIDS).

These images did not come from their personal experience, but from somewhere else. This ideology does not reflect anyone's experience, but appears to have been constructed for a purpose -- to justify abandoning people with AIDS or HIV.

* Other national-will problems are closer to home. AIDS service organizations have never shown much interest in research -- and neither has organized medicine. And public- policy experts, in Washington and elsewhere, seldom understand science and technology issues, or have any serious interest in them.

* Also close to home is the lack of popular mobilization on AIDS. Most people affected by HIV do nothing, ever, to help the cause of AIDS research. One major reason is that organizers have not created effective channels for them to use in doing so. In most locations, the only options, the only ways to interact with the issue, are to send a check to a distant national organization -- or possibly to sit through many hours of high-tension, ego-battle meetings, before the new person is allowed to actually do anything which contributes. Many people want to meet with friends and neighbors to write and call Congress to support AIDS funding -- perhaps the most important thing they could be doing now -- but nobody has organized to give them the information they need.

The public motivation certainly does exist; as we pointed out in the last issue of AIDS TREATMENT NEWS, at least 50 million people in the U.S. alone have a relative, friend, or acquaintance whom they know has AIDS or HIV. What must be done is to establish a social movement so that these millions of people can make their voices heard, instead of remaining silent as is almost always the case today.

In summary, we now have excellent opportunities for progress in treating AIDS. But they are not being exploited effectively. Solutions have been identified; it is up to us to organize and insist that they be implemented.