With HIV infection, there are two kinds of t-cells -- cells which are not infected, and infected cells which, when activated, act like HIV factories producing virus that infects new cells. With the use of powerful new drug combination therapies, cells which are infected with HIV slowly die. Uninfected cells are kept safe. For this reason, antiviral therapies gave us hope that we could eradicate the virus. By calculating how fast infected cells die, scientists can estimate how long it would take to get rid of every last one of them.
Unfortunately the last few infected cells live a long time. Data were presented at the annual Retrovirus Conference in Chicago this February that show these last few cells -- a small fraction of a percent of the original number of infected cells -- will live for 20 or 30 years and antiviral therapy therefore would take that long to clear out the virus. This makes scientists less optimistic that the virus can be eradicated with antivirals alone.
For many years it was unclear how to stop HIV from reproducing because it made so many different copies of itself. When a drug was used to stop it, eventually one of those different copies would, by chance, be able to get around the drug. Soon the body would be filled with this new "resistant" type of HIV.
But when several kinds of antiviral drugs were used in combination, they created such a powerful blockade that the virus was unable to reproduce quickly, and so resistance could be avoided or postponed. Many people who can tolerate the new medicines have levels of virus so low that even the most sensitive of tests cannot measure them. As long as the medicines are taken on schedule, t-cells come back, and some healing of the damage caused by the virus takes place.
Unfortunately the combination drug therapies don't work for everyone -- although new ones being developed look very promising for many people who have lost the benefit of existing medicines. Side effects cause some people to stop taking the medicines. In other people, the difficulties of taking every pill on time every day may lead to on-again, off-again therapy which can cause resistance. Some combinations may not be completely effective at reducing super high levels of virus down to the very low amounts needed to avoid resistance. Occasionally, a person may have been infected with a "resistant" type of virus that does not respond well to some of the medicines.
We have not used antiviral combinations very long -- they are a new invention. It is therefore reasonable to be concerned how long even at very low levels of virus, the drugs can keep the virus at bay.
Finally, there is fear that some long term side effects, such as high levels of cholesterol, or fat redistribution, or diabetes created by drugs, may slowly get worse and limit the length of time people can use some drug combinations, even if the treatments stop HIV effectively.
For these reasons, as well as the cost of continuous medication and the psychological burden of constant compliance with drug scheduling, it is important to see if there is a better way to manage the illness.
It is a mistake to assume that the new antiviral drugs are the only thing that stops HIV from reproducing and causing damage. In fact, when the body is first infected with HIV, the virus grows quickly out of control, and tens of billions of copies are made as it seeds cells in virtually every part of the body with instructions on how to make more of itself. It is the body's own immune system which clears out most of this virus at the beginning, and if it were not for the fact that HIV somehow damages the body's ability to attack it, the immune system would probably take care of the infection without any help. The most powerful antiviral is the body's own immune system, when it is working as it should.
Perhaps 5% of people infected with HIV can control it without any drugs. These people have been called "Long Term Non-Progressors" (LTNPs) because they show no signs of progressing to AIDS. They have one other thing in common: their immune system cells are aggressive in attacking HIV. People who have HIV, but are not LTNPs, have cells which do not seem to recognize or attack HIV with any energy.
So it makes sense that one approach to control of HIV might be to get the body to turn on its own immune system defenses after the drugs keep the virus which has damaged that system in check. The hope would be that the drugs could protect the immune system while it regenerates the ability to control HIV, and with the amount of virus being very small, perhaps the immune system could control it without the drugs for long periods of time.
The best evidence that this can be done is that some people have done it. It has worked in a very few people, and the actual ability to control HIV without drugs for some period of time has been demonstrated only in people who have tried one or another of these methods soon after they were infected. The purpose of continuing the work is to understand why this can sometimes be done. Understanding why might lead to a method most people can use.
Dr. Franco Lori has begun interrupting antiviral therapy in three people who had undetectable levels of virus. He allowed the virus to come back up until it reached 5,000 RNA copies. Each time the three people interrupted their therapy, the virus came back, but each time it took much longer. During the first interruption it took seven days on average for people to get back to 5,000. Then they went back on therapy for 90 days and interrupted it again. This time it took an average of 14 days to get back to 5,000. Treatment again for 90 days and then the third time it took 37 days to reach 5,000! This process is continuing. It seems that each time a little HIV is allowed to grow, the body's immune system learns how to fight it, much like a vaccine would do. This process is being called "self-vaccination."
Other doctors, like Fred Valentine at New York University and Bruce Walker at Massachusetts General Hospital, are finding that people who are vaccinated with dead HIV are getting back some of ability to fight HIV that they lost. At the Aaron Diamond Research Center in New York City, there is an example of two patients who had interruptions of therapy and have been off all antivirals for over a year with viral levels below the limits of detection. Others have been able to control the virus for shorter periods of time.
There are many studies being planned using all of these methods to see if there is a way to control HIV without the constant use of drugs.
In Dr. Fred Valentine's work in New York, those people who were vaccinated kept the level of virus lower than those who were not. Since both groups used antivirals, it suggests that some immune-based therapies may help antivirals do their job.
There is an effort underway to clear out those last few cells which harbor HIV. There are chemicals which the body produces, like "interleukin-2," which causes t-cells to make copies of themselves. When those long lasting cells that hide HIV make copies of themselves, they also make HIV and if a person is protecting all his other cells from infection by using powerful antivirals, when these long lasting cells are forced to divide by IL-2, they are killed off. This may explain two people at the National Institutes of Health who have stopped taking drugs after completing IL-2 and antiviral therapy and in whom scientists cannot yet detect any virus.
We do not yet know how to use these and other new ideas. Nobody should be tempted to try them out on their own -- join a trial so that all of us benefit from your experiences! With the help of volunteers, we will figure out how to use these new "immune-based" therapies, and just maybe figure out how to end the tyranny of pills. IL-2. Vaccines and immunogens. Immune Restoration. Self-vaccination. These may become the buzzwords of the future.
Is it possible that by using IL-2 and other chemicals we can clear out the last infected cells? Can we use vaccination to turn on the body's ability to fight HIV by itself? By cycles of interrupting and restarting therapy can we get the body to fight HIV even more powerfully? Would these methods help antivirals keep the amount of virus down? Could they even lead to drug holidays of months or even years for many people?
There is reason to hope that at least for some people, the answer to these questions will be "yes."
This Boston AIDS Writers Group panel consisted of David Scondras, Robert Krebs, and Jon Hultgren from Search For A Cure. The Review Panel for this article consisted of Dr.Cal Cohen, Research Director of CRI, New England; Dr. Stephen Boswell, Medical Director at The Fenway Community Health Center; Dr. Alfred DeMaria, Assistant Commissioner, Massachusetts Department of Public Health; Stewart Landers, Senior Consultant at John Snow Inc.; John James of AIDS Treatment News; Dawn Fukuda of AIDS Action Committee; and Robert Folan of ACT-UP Boston. The ideas expressed in this article are those of the Boston AIDS Writers Group panel and do not necessarily reflect the opinions of the Review Panel or the AIDS Survival Project. You can contact Search For A Cure at 58 Burbank Street, Boston, MA 02115, phone: 617-536-2474, fax: 617-266-0051, e-mail at firstname.lastname@example.org, website: www.sfac.org.