Being Alive Newsletter - March 1999
Walt Senterfitt

The most interesting news coming out of the recent Chicago Retrovirus Conference was about efforts to control HIV without eradicating it. Eradication seems out of the question for now and perhaps control is better anyway. Several strategies to achieve control of HIV are being explored.

The most exciting of these strategies is also the most easily given to oversimplification and sensationalism. Based on the experiences of a few patients so far, it may be possible to preserve the body's powerful initial response to HIV that is usually lost after a few months, by starting HAART early. ("HAART" refers to highly active retroviral therapy, meaning combination therapy with drugs from at least two classes, achieving reduction in viral load below detectable levels). After a period of HAART, it may be possible to stop taking antivirals, let HIV viral load rebound to a limited degree so as to stimulate the immune response that has been preserved, then restart HAART. After several start-restart cycles (perhaps as few as two), the immune system may then be able to control HIV on its own.

Some have taken the headlines about these very preliminary studies to mean, "Oh, good, now I can stop taking my antivirals and my body will control HIV on its own." It certainly is tempting to be instantly rid of the hassles of adherence and the discomforts of side effects, without feeling guilty or self-destructive. Almost everyone who has had to stop taking antivirals for awhile has felt better in the short run-side effects are draining even if we adapt to them. So might it be safe to start taking drug holidays on your own in the hope that you can achieve control this way? No! Or at least, Not yet!

Background-Franco Lori and the "Berlin Patient"

Right before the 1998 Chicago Retrovirus Conference there was a buzz in the media about one or two patients of Dr. Franco Lori who had used hydroxyurea and had eliminated HIV from their bodies entirely. It turned out that total elimination had not been achieved, though it did take the most sophisticated research techniques available to find remaining HIV in this person's body. Still, the case of this patient is so striking that he has achieved a certain notoriety as "The Berlin Patient."

The research that has been stimulated by this case came about, as does so much in science, through serendipity. A young man in Berlin was started on a triple combination (ddI, indinavir and hydroxyurea) three weeks after he was infected, while still in the stage of acute or primary HIV infection (characterized by mononucleosis-like or flu-like symptoms). After two weeks, he had to stop taking his HIV meds because of another serious illness. He re-started the HAART regimen after that illness resolved, but had to stop again four months later, also because of another illness. This time the patient did not want to start antivirals again, so his doctors just observed him closely. Twenty-four months and counting since he stopped his medications, his viral load is below detectable levels and t-cell count is at a normal, non-HIV-infected level.

HIV-Specific CTL Response

In searching for an explanation, researchers looked at one important indicator of the body's immune response to HIV, the "HIV-specific CTL response." Here, serendipity merged with ongoing, targeted research. Various researchers had been studying this immune system phenomenon as a possible key to restoring the body's control of HIV.

I say "restore" because the body's initial response to HIV is phenomenally successful. Initial infection leads to an enormous multiplication and spread of HIV throughout the body which triggers in response an enormous mobilization of the body's resources against the invasion. As with other viral illnesses, this massive infection and the fight against it causes flu-like symptoms of fever, fatigue, aches, diarrhea, sore throat and perhaps a rash, sores in the mouth or more localized symptoms.

After a few weeks the body knocks HIV viral load way down and contains HIV within pockets of the immune system, where it is kept to very slow growth for years. We are not sure, but it is hypothesized that the primary part of this successful first containment is the "HIV-specific CTL response." CTL stands for "cytotoxic [cell killing] T lymphocyte," a form of CD8 or t-8 cell that has been programmed specifically to recognize and destroy HIV and t-4 cells that have become infected with HIV. This response is usually lost after a few months.

By the way, the prospect of the body's controlling HIV without eradicating it would not be unique to HIV. Our bodies already do this with dozens of other viruses, particularly those of the herpes family. When one gets mononucleosis, caused by the Epstein-Barr Virus, the body's EBV-specific CTL response eventually controls it and keeps it suppressed the rest of your life, unless some unusual event disrupts the immune system. Same with varicella zoster, the herpes virus that causes chicken pox and can then come back as shingles. The story's the same for infections with CMV and herpes simplex viruses. Once infected with any of these, you are infected for life. The body just controls them under ordinary circumstances. HIV infection is different so far, most likely because its target is the immune system's recognition and control system.

Researchers looking to explain why some few individuals manage to completely control HIV without drugs discovered that these "long term non-progressors" have kept a robust HIV-specific CTL response. Their immune systems are continuing to recognize and destroy HIV as in early HIV infection, and do the job so well that HIV never rises about a very low level in their bodies. The effort then switched to trying to preserve this response in more than a select few persons, and to restore it in those who have lost it.

The Berlin Patient turned out to have preserved a very strong HIV-specific CTL response after his HAART had to be stopped. Dr. Lori noted that three factors involved in this case might be responsible for the success, and perhaps all three are needed: starting treatment very early, during primary infection; stopping and then restarting treatment (intermittent therapy); the particular regimen of ddI (Videx), indinavir (Crixivan) and hydroxyurea.

Intermittent Therapy Might Provide "Self Vaccination"

Dr. Lori and other have focused on the idea of intermittent or "stop and go" antiviral therapy as perhaps the key ingredient. Why?

Speculatively, it may provide the stimulus or small provocation that the immune system needs to pump up or restore its own natural and powerful response to HIV. Perhaps one reason the CTL response is lost, they say, is because HAART reduces HIV so much, that newly produced "na ve" t-cells (those which have not yet been exposed to any pathogens) don't have an opportunity to become sensitized and fight off HIV. On the other hand, one does not want to run the risk of overwhelming these new t-cells produced in the context of HAART such that HIV runs rampant again. Perhaps intermittent HAART will allow the body to flush out most HIV, rebuild immune system components that have been damaged, and produce enough new "na ve" t-helper (CD4) cells which, when re-challenged with HIV, can successfully contain it for a long period.

So Dr. Lori is now conducting a carefully controlled experiment in Washington, D.C. at Georgetown University. Interestingly, he is including not just those HIV+ persons who started treatment during very early infection, but also those who have been infected for several years. Volunteers in the study must first maintain several months of effective HAART, as indicated by viral loads below the limits of detection. Then they stop their antivirals and have their viral loads measured very frequently. Once viral load rebounds to 5000 copies, then HAART is restarted. In Chicago, Dr. Lori reported on three patients who have thus far stopped medications three times.

Though each patient has seen his viral load rebound each time so far, the period of time without detectable HIV after stopping medications has been gradually increasing. After the first interruption, the period to rebound was just one week. After the second time, it was two to three weeks. After the third interruption, it was six to eight weeks. The study is continuing.

Other Research Findings

Dr. Bruce Walker and his group at Massachusetts General Hospital in Boston have been key players in this area even longer than Dr. Lori, and are more cautious. Dr. Walker is the one who discovered that long term non-progressors have maintained their HIV-specific CTL response, and that this response is ordinarily lost fairly early in infection. His work has centered on the importance of starting treatment early, and then trying to stop and see if the natural response is strong enough to maintain control without drugs.

Dr. Walker currently has 20 individuals in his study who started treatment during primary infection. The group has all reached viral loads below the limits of detection, on average by 10 weeks after starting treatment. (Interestingly, the one person who took six months to reach undetectability was found to have been infected by a drug-resistant virus in the Boston area.)

While continuing HAART, Dr. Walker tests each participant regularly for their HIV-specific CTL responses. Only three had these responses before starting treatment; the others had already lost them, although all were within the first six months of infection. After two months of treatment, 13 of the 17 so far analyzed had the CTL responses, and after six months of treatment, all 11 of the 11 who have been in the study that long have the response.

One person in the study wanted to try stopping his HAART. He initially seemed like a good candidate, reaching undetectability very rapidly, after just three weeks of treatment. However, his viral load rebounded between weeks five and six after stopping, to 17 000 copies, and treatment was restarted. A comparable patient with chronic (long established) infection stopped at about the same time, and his viral load rebounded to 17 000 within seven days and to 120 000 at the end of two weeks. So, the first patient may well be exhibiting a relative ability to control HIV without drugs, and the next interruption may sustain HIV control for longer.

Still, Dr. Walker cautions that we should all go slowly and do these experiments in carefully controlled settings. The ability to measure HIV-specific CTL responses, for instance, only exists in certain highly specialized research institutions right now.

Dr. Ho's Group Weighs In

In a study of early initiation of treatment originally intended to test the eradication hypothesis, Dr. David Ho in New York started a number of individuals on triple therapy (AZT, 3TC, Crixivan) while they were still in the primary infection stage. A number of these patients had adherence problems, and four were studied closely. One patient stopped HAART 120 days after starting, and his viral load spiked right back up. He started HAART again and after the second stop, has maintained control for 14 months and counting. Another of these four has maintained control for over 24 months after two stop-and-starts. Both of them had strong CTL responses.

However, the other two of the four were not able to maintain HIV suppression after stopping. Rebound came fairly quickly and has not improved much on subsequent cycles. They both had weak CTL responses.

Another Strategy

At least one other strategy is under examination: giving an "immunogen" or therapeutic vaccine to persons with chronic infection. The early hopes for therapeutic vaccines were not borne out in clinical trials. However, Dr. Fred Valentine of New York University presented some data on the use of Remune (the "Salk HIV Vaccine"). This study was initially designed for another purpose and was unfortunately stopped early for lack of funds before this new area of investigation became clear. Though not statistically significant, there was a trend toward restoration of CTL response in those participants treated with Remune compared to those given only an "adjuvant" (an enhancing substance added to vaccines to make them more effective). This approach might allow folks who have been infected a long time to have their CTL response boosted before running the risk of stopping antiviral treatment.

Take Home Message

These very preliminary research results are both very exciting and very uneven. The prospect of using treatment selectively to preserve and restore the body's natural defenses is intuitively compelling and powerful. But.

There are the countervailing dangers of losing control of one's HIV infection or inadvertently promoting resistance. Only a very small number of individuals have been involved in these studies.

A lot of careful monitoring in a highly specialized setting is necessary to experiment safely.

My advice is that being smart means being cautious for now, and advocating for more rapid research, including some here in Los Angeles.

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ÆGIS is made possible through unrestricted grants from Roxane Laboratories, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 1999. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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