The road to a cure.

The medical fight against HIV is now well into its third decade. Following the discovery of HIV and proof of its causative role in AIDS, the focus of much AIDS research has been on finding ways to suppress the replication of the virus once it has infected the human host. While this has been a daunting task because of the way HIV integrates itself into cells of the human immune system, science has succeeded grandly in slowing the growth of the virus and the damage it does within the body. This success didn't come in a single leap, however, and many people who receive treatment still suffer today, both from the effects of HIV infection before they began treatment (common in the earlier days of the epidemic but still seen today) as well as from the side effects of many of the drugs used to treat HIV. But particularly for those infected recently who have access to good medical care and the best of the drugs, the ability to manage HIV disease is all but taken for granted. Even for those who were infected long ago and developed resistance to a series of the earlier generations of medications, the options for effective treatment today are striking. The biggest problems in confronting HIV disease today are more political than scientific in nature. If only we could be as successful in providing access to care and treatment as we have been at suppressing the virus itself.

So what do we have to complain about, some ask? On a purely medical or scientific basis, managing a disease, even if it can be done for decades, is not the same thing as curing it. People with HIV are grateful to be able to live longer lives today, but those lives are still dominated by the presence and effects of HIV. Coping with the virus still greatly complicates every aspect of their lives. It still makes those living with HIV dependent on a lifelong regimen of medication, daily dosing requirements, and possible drug side effects. It is not unreasonable for people with HIV to ask for, or even demand, an outright cure for the disease. There are few other illnesses in which society is content to settle for a lifetime of disease management based on the use of wildly expensive drugs and the acceptance of significant drug side effects. A true cure, and nothing less, must always be the goal of treatment activism.

As obvious as this seems, there is in fact little talk of "a cure" at most activist gatherings, AIDS service organizations, and research meetings. Talking about a cure is often considered a false hope or waste of time. The great majority of researchers do not believe that a cure will be possible in the foreseeable future, if ever. Of course, it's hard to forget that similar attitudes were voiced about the possibility of even treating the disease back in the mid-1980s. Such pessimism was proven wrong then, and there is every reason to expect that it will be proven wrong again.

How do we get from disease management to cure? What will it take to change the current expectation of life-long disease management into the demand for a cure? First and foremost, what is required is a change of attitude. It is one thing, after 6 months or even a few years of research, to celebrate today's new drugs that are more potent, last longer, and appear to have fewer side effects. It is quite another to contemplate how people will fare when they must use such drugs for 40 or 50 years. It is wonderful to see the US and other Western governments commit billions of dollars to fund treatment for a million or more people in resource-poor nations. It is quite another thing to contemplate whether the nations of the world are prepared to provide treatment for 40 to 100 million people for the length of their lives.

As activists and people living with HIV, we must remember how we reached the state of successful disease management we are so proud of today. We got there by demanding it. We raised our voices and made it clear to government, scientists, and private industry that we would not accept the status quo, which in the early days was simply a matter of going to an early grave. Over time, we generated enough pressure, and found enough allies in government, media, academia, and private industry to make AIDS research a real priority. That pressure, and the commitments it created, led to breakthroughs in biology, chemistry, immunology, and drug development. Sufficiently prodded, there is no known limit to what mankind can achieve.

So as a first step, we must put the concept of a cure back on the map. We must seek consensus that developing a real cure is as important as creating a vaccine, and perhaps more important than creating an endless string of slightly different drugs that suppress the virus. We don't need countless new drugs of the same kinds, with the same limitations. We need a limited number of very good ones and we are very close to achieving that goal. Yet all but a small percentage of the investment in AIDS treatment research is directed toward finding more drugs to manage disease and endlessly fine-tuning their use. In contrast, the amount spent on developing a potential cure is so small as to be immeasurable. The hope that simply adding more or better antivirals alone will lead to eradication of HIV has withered. Finding a cure requires a different kind of research and different approaches to treatment. To get beyond this roadblock, the once loud voices of people with HIV and their advocates must once again be heard demanding action. Complacency with long-term disease management is not a solution.

Secondly, we must aggressively support research that offers the potential to move beyond disease management. Today, only a handful of scientists are openly working on a cure for HIV disease, and they are often chastised whenever they make public statements about such work. We must be quick to defend them whenever appropriate. This is equally true of the pharmaceutical industry. To the best of my knowledge, only 2 pharmaceutical companies are investing in research that even remotely offers the potential for a cure.

One of these is Tibotec Pharmaceuticals, which also makes the new protease inhibitor Prezista. While Prezista may be one of the best drugs of its type, like other antivirals it cannot cure the disease. But Tibotec is also funding an innovative gene therapy experiment with the hope of creating a new line of immune cells that are essentially themselves immune to the effects of HIV and cannot be infected by it. This general approach has been discussed for more than 15 years, but this is the most advanced study actively testing it.

A second approach is under study at Merck, which makes the new integrase inhibitor MK-0518. As good as it appears to be, the integrase inhibitor is unlikely to lead to a cure. Other research at the company, however, points in that direction. It is widely believed that the biggest obstacle to eliminating HIV from the body is the way in which the virus creates reservoirs of infected cells that are protected from even the best antiviral drugs, as well as from the immune system itself. These reservoirs of infection remain in the body, always ready to maintain the presence of HIV. There are a number of possible ways of reducing or eliminating these reservoirs. Merck is the only company we are aware of that funds both internal research efforts and helps support external research on methods to reduce or eliminate these critical reservoirs of infection.

Both these efforts are surprising developments because it is easy to assume that pharmaceutical companies would not be interested in conducting research that offers the hope not only of curing the disease, but in turn eliminating the market for expensive HIV drugs. The work of these companies, and perhaps others we are not aware of, must be applauded publicly. It is a very good thing that they are doing this. We must encourage them, and encourage other companies to follow their example. If a cure is developed for HIV, there will always be plenty of other illnesses that companies can focus on. The future of the pharmaceutical industry does not depend upon the sale of HIV. But the lives of tens of millions of people do indeed depend on finding a real cure for AIDS.

Thirdly, we must demand that a significant portion of federal research dollars be spent on research seeking a cure. Today, it is difficult to say that any federal research efforts have such a direct focus. The Office of AIDS Research and the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS must put such research on the federal agenda or use some of their modest discretionary funds to help kick-start a program of this type. NIAID has conducted internal research programs of this type but hasn't developed programs to support outside researchers. Recently, the American Foundation for AIDS Research (AmFAR) took on this charge and invited grant applications from researchers who wished to work on reducing the reservoirs of HIV. It funded several such applications, and AmFAR should be acknowledged for this important effort. If AmFAR, with its far smaller research budget than NIAID, can direct funds toward seeking a cure, surely the federal government can do a great deal more.

Fourth, and perhaps finally, if we wish to get on the road towards a cure, we must believe in it ourselves. Far too many people with HIV, as well as their doctors, have accepted the notion that a cure is not likely. No one can be certain that a cure will be found. No one can predict the future. But one thing is certain: if we allow pessimism about a cure to dominate our thinking, we surely won't get one. We get only what we demand, and we demand what we need. The current complacency about HIV is a very dangerous thing. It puts the lives of millions of people in needless jeopardy. We must restore our belief in a cure and make it one of the central demands of our activism.

Martin Delaney is Founding Director of Project Inform, an HIV/AIDS non-profit organization located in San Francisco.