IBT: Finding A New Way To Beat HIV

We need better drugs or another way to control HIV! It's not that we are ungrateful that the age of weekly funerals of friends has ended. It is just that the current drugs don't cure the disease and are user-hostile.

Across the country there are anecdotes about people just stopping therapy, either unable to cope with the side effects, or sick of being chained to the demands of a pill box. Between rashes, lipodystrophy syndrome, problems with bureaucracies filling prescriptions on time, accidents, the famous protease moments that make users fear being more than a short distance from a bathroom, diabetes, allergic responses, hallucinatory episodes, mitochondrial toxicities, drug/drug interactions, and confusion over cholesterol levels that frighten doctors, it's amazing more people have not stopped taking their medicine. We need alternative therapies!

At the moment, however, there are none that have been proven to work. But there are important studies and impressive research that's pointing toward one way of jumping out of the constant cocktail glass. Immune-Based Therapies (IBT) begin with the observation that in most cases the immune system controls HIV for over a decade with no help from any drugs, and suggests that learning how to help the body be more effective at doing what it does so well would be a powerful addition to our therapeutic armamentarium.

The core IBT strategy starts by using drug cocktails to suppress HIV replication to the point where the virus is undetectable for a sustained period -- at least a few months to a few years. Somewhere during this time, scientists are trying to develop ways to get the body's immune system to fight HIV more powerfully.

Among the efforts there are:

  • using HIV-specific vaccines to teach the newly produced T-cells how to fight HIV;

  • using IL-2 (a substance the body makes which causes our fighter cells, the T-cells, to reproduce) to hopefully give people so many T-cells that opportunistic infections can be avoided; and

  • interrupting therapy for short periods of time to expose the body's killer cells to a small amount of HIV for a short period of time in the hopes this will lead to a better immune response against HIV.

Some scientists are using combinations of these approaches to better stimulate the patients' immune responses against HIV. There's enough science and early patient testing to suggest the possibility of potentially viable alternatives to round-the-clock pill therapy, certainly enough data to warrant large study trials that are now enrolling people who want to participate in finding conclusive answers.

Structured Interruptions

One major impetus for Immune-Based Therapy comes from results of studies of the effects of stopping an antiviral cocktail that have successfully suppressed the virus to undetectable levels for several months. Formal studies are already underway to look at what happens when there are strategic interruptions of an antiviral regimen, but, unfortunately, people are trying out interruptions on their own without consulting their doctors or joining a study. Some folks on an antiviral treatment are sick of pill bondage or sick of the side effects the pills cause. However, to be absolutely clear: Stopping an antiviral regimen is NOT generally recommended by Search for a Cure or anyone else in the medical community. But some people toss their cocktails anyway. Don't do this! Consult a doctor and join a study.

Regardless of why interruptions occur, researchers discovered that some people who stopped taking a successful antiviral combination don't suffer an immediate surge in HIV reproduction. In effect, their immune systems were able to "pick up the slack" and control the virus for periods of time without the medications in the standard antiviral arsenal.

It's unclear why "Structured Treatment Interruptions" -- to use the current jargon -- actually works for some people. There are various theories: one is that after antivirals get rid of most HIV, small interruptions allow for a little HIV to come back getting the body primed to fight against the virus so that when a second interruption in therapy occurs, the immune system fights to keep the amount of virus production down. This has been seen in persons recently infected (acute HIV), but over time the virus wears down the body's defenses. An antiviral treatment interruption or other immune stimulation may, in some people, help to get the body's defenses back up. Perhaps an initial HIV exposure effectively inoculates the body's immune system so it's now able to recognize HIV if it re-appears at low levels after being initially "zapped" with antivirals.

The best way to use treatment interruptions and immune boosters is not yet known. One popular idea is to create a cyclical method: first use antiviral cocktails to get rid of most HIV, then use boosters (immune stimulants, e.g., vaccines, IL-2, etc.) and then stop using the antiviral cocktail. When HIV reaches a certain threshold, hit it back down with the same antiviral cocktail you started with. Each time this is done, some data indicates it will take longer for the virus to reach the "hit it back down" threshold. The aim is to control HIV without drugs for long periods of time.

Research physicians and microbiologists find variations on this strategy important and promising. Indeed, there are government studies dedicated to finding out if there is a way to safely manage structured treatment interruptions. To learn more, please contact us at Search For A Cure or check our website www.searchforacure.org.

Throwing Away the Crutches

Once it became clear that most patients manage to keep HIV infections in check by smashing the virus down to undetectable levels using antiviral cocktails, researchers started asking the next question: How can we help the immune system do an even better job -- perhaps containing HIV without the drugs?

This is especially important for those who have had the disease for a long time, for HIV over time destroys critical disease fighting cells, called CD4+ T-cells, to the point that the immune system is seriously compromised or outright disabled.

Therapeutic Vaccines: Remune

One way of tweaking up the body's defense system is through immune stimulants or "immune modulators." One type of modulator is vaccines such as Remune (which is HIV that has been killed and inactivated). Vaccines used to help fight a disease, are usually called "therapeutic" -- as opposed to the traditional "preventative" vaccines, such as polio or measles -- where the vaccine is introduced into the bloodstream before a person is exposed to the germ.

Doctors Fred Valentine at New York University and Bruce Walker at Massachusetts General Hospital are finding that people who are vaccinated with "dead" (i.e., harmless, defective) HIV acquire an energetic response to the virus. It is hoped that using a dead virus first before getting off of antivirals might help the immune system get ready to fight the real enemy when the antivirals are stopped.

There is a synergistic effect too. In one study, people who were vaccinated in Dr. Fred Valentine's New York research clinic kept the level of virus lower than those who were not. Valentine, in particular, noticed that since both groups used antivirals, these results suggest that some types of immune-based therapies may help antivirals do their job better. (More about Remune and vaccine therapy in next month's Reasons for Hope column.)

A Big Winner: Interleukin-2

It is widely believed that people get sick from HIV because the virus causes people to lose CD4+ T-cells. IL-2 causes the body to grow new T-cells in large numbers. In fact IL-2 can get the number of T-cells back to normal levels. We now know that these new T-cells seem to function normally. In addition, IL-2 used together with antivirals may reduce HIV to somewhat lower levels than when antivirals are used alone. This may be because IL-2 used together with powerful antivirals not only grows back T-cells to normal levels, but also it might activate latent virus so that the antivirals are effective in inhibiting their replication.

Interleukins are a type of unique cellular protein, called a cytokine, which the body produces and which have wondrous properties. Interleukin-2, for example, causes T-cells to reproduce. On one level, that's very bad, because when infected cells make copies of themselves, they also manufacture HIV as a byproduct. But this may also turn out to be an asset because it could leach out HIV from hidden sanctuaries exposing it to effective antiviral therapy.

Lots of data suggests that receiving intermittent courses of IL-2 can reconstitute damaged immune systems by stimulating CD4+ T-cells to grow in large numbers. So people whose T-cells have fallen down to 200 copies or lower can get large boosts in their CD4 cell counts, often returning them to normal levels.

To be sure, the subject of IL-2 is complex and fascinating -- worthy of several follow-up reports. One raging controversy surrounding this therapy is the dosing level. At certain concentrations, IL-2 can cause flu-like symptoms when it's taken as an injection every few months. So the search is on to find an optimal dosing to ratchet up the immune system enough to squelch HIV but minimize unhappy side effects. The dosing levels in large clinical trials now going on have minimal side effects that can be managed with simple medicines like Tylenol.

A different line of research is being studied by Cornell Medical Center's Dr. Kendall Smith, the person who discovered the IL-2 molecule. Data from Smith's research lab shows that frequent daily low doses of IL-2 -- about a bee sting's worth -- during and after a treatment interruption of antiviral cocktails may help generate cells which fight HIV. Side effects at this level are negligible.

Smith found that nine patients who stopped all antiviral therapy but continued IL-2 microdosing had an initial rise in HIV levels in their bloodstream, followed by a fall in HIV replication back down below what it was before they started antiviral therapy. Smith's method still needs larger controlled studies, which hopefully occur this spring.

New Style Combination Therapy

Studies will continue looking at both therapeutic vaccines such as the late Jonas Salk's "Remune" product. Meanwhile, large, elaborate clinical trials of IL-2 have been launched. But the really intriguing set of research being planned uses both IL-2 and a therapeutic vaccine together with planned interruptions of antiviral cocktails. The goal is to see if it's possible through a multi-stepped process to induce people who are chronically infected to control their virus for a long time without any antivirals at all save for the initial hit or which may prolong the benefit of antiviral therapy. Or perhaps to achieve the ultimate prize: Total Viral Clearance.

With the beginning of the third decade of the AIDS Epidemic, Immune Based Therapies are dominating the research agenda. Yet big questions remain: Is it possible that by using IL-2 and other immuno-modulators we can better suppress HIV replication? What's the best way of using 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, permanently? Could they even lead to safe drug holidays of months or even years for many people? Could using vaccines and cytokines together work better than either therapy acting alone?

Just as in the early Nineties there was evidence that combination antiviral therapies -- especially those using protease inhibitors -- could slow HIV replication and save millions of lives, today the tide of research is pointing towards minimal drug strategies that will help defeat HIV, or perhaps keep this deadly bug harmlessly at bay.

For more information call Search For A Cure at (617) 536-2474, e-mail us at hope@sfac.org, or check out our website, www.searchforacure.org. Two uniquely informative and easy to understand educational pieces on immune based therapies and IL-2 are available: Community Prescription Service (CPS), the HIV positive owned and operated mail-order prescription service, is producing the "Immune City" issue of InfoPack (bound by POZ) and a booklet called "Immune Restoration in HIV: The IL-2 Handbook." To obtain free copies, call CPS at (800) 842-0502 or go to their website, www.prescript.com, for download of both.

David Scondras is the founder and chairman of Search For A Cure. Scondras developed the nationally recognized HIV treatment series, "Reasons for Hope." All articles in the series are reviewed by expert HIV doctors and scientists and an HIV positive and negative focus group for accuracy and understandability. The ideas expressed in this article are those of Search For A Cure, and do not necessarily reflect the opinions of the review panel or AIDS Survival Project.

Search For A Cure is a not-for-profit organization providing education, promote access and advocating the basic human right to safe and effective treatment for all people living with AIDS.