Newsday - February 15, 2000
Laurie Garrett, Staff Correspondent

It's a concept that flies in the face of all previous advice regarding AIDS treatment, defies worries about promotion of drug-resistant viruses and is far from a proven or clearly safe option. Yet at the recent Conference on Retroviruses in San Francisco, the phrase "treatment interruptions" was on every clinician and patient advocate's lips. It was, in short, the main buzz at this, the largest American AIDS meeting.

"I'm not sure the case is proven yet, but clearly my friend wouldn't be with us if he hadn't stopped taking his meds for a few months and then started again," said New Yorker Gregg Gonsalvez, of the patient organization Treatment Action Group. The group is spearheading a move to conduct large-scale, National Institutes of Health-funded clinical trials of various strategies of treatment interruption.

The problem physicians and clinicians hope to address is straightforward. When people become HIV-infected, they are immediately urged to begin a daily combination of three or four potent drugs, from a list of 14 anti-HIV medications. If the patient is infected with an HIV strain that is susceptible to the highly active antiretroviral therapies, or HAART, the viruses will seemingly disappear from the bloodstream.

But the viruses aren't really gone; they've simply been sequestered in cells and tissues that HAART cannot reach. In most patients, after months or years on HAART, either the virus levels rise again or the drug toxicities become intolerable. HAART, in and of itself, is neither a cure nor a safe enough medication that can realistically be taken for a decade or more. Many patients are now approaching their fifth years on HAART, and strange ailments are turning up, including diabetes, cholesterol-associated heart and liver diseases, and a host of cancers.

Some scientists theorize that going off HAART briefly would bring HIV out of hiding, allowing the immune system to see and attack the viruses. The patients go back on HAART - and pow! The drugs would kill the viruses. That's the theory.

The clinical evidence offers a more confusing picture.

First, virtually no HAART patients make immune responses against HIV once their medicines knock the virus out of their bloodstreams and into hiding. That is contrary to what is seen with most other viruses. For example, if an individual survives a bout of yellow fever, measles, polio or a particular flu strain, the person's immune system thereafter remembers those viruses. And if those particular microbes again infect that person, no illness results because the cells and antibodies of the immune system immediately recognize and destroy the invaders.

Not so with HIV. When the virus disappears, so does the immune defense against it. Many laboratories have tried to find anti-HIV antibodies or immune system T-cells in HAART patients whose viral levels in the blood are at zero. The disease fighters aren't there.

In the mid-1990s, Dr. Francis Plummer and a team of University of Nairobi researchers stunned scientists when they announced discovery of a group of Kenyan female prostitutes who appeared resistant to HIV infection, surviving infection for years despite more than six customers a week without condom protection, in a society where upward of 20 percent of their customers were likely to be HIV-positive. Vaccine researchers were ecstatic because the Plummer discovery offered evidence that people could successfully become immune to HIV - something cynics had argued might be impossible.

But at the San Francisco meeting, Plummer's group had distressing news: 10 percent of the "resistant" prostitutes became HIV-positive from 1996 to 1999. And their infections coincided with the women's decisions to decrease their exposure to HIV by having fewer customers or insisting that the men wear condoms.

"It suggests that HIV antigen stimulation is required for the maintenance of resistance," the Centers for Disease Control and Prevention's top HIV specialist, Dr. Kevin De Cock, said in an interview.

Does it imply, De Cock continued, that the human immune system is absolutely incapable of "remembering" HIV without constant reminders in the form of viruses or, in the case of vaccines, of viral pieces or particles? If so, vaccination would have to be constantly boosted throughout life, possibly on some monthly or weekly schedule.

On the other hand, De Cock noted, the Nairobi observation means that "if treatment interruption actually has a beneficial effect, presumably it's an immunological effect."

One case propels all optimism - the so-called Berlin Patient. One of the first HAART patients, this man (whose identity has never been released) decided in 1996 to stop taking his medicine. And his immune system surged forward. Vital T-cells came to the man's rescue and, to date, he has been apparently free of HIV. The Berlin Patient declared himself cured and disappeared from scientific scrutiny last year.

One of his physicians, Dr. Franco Lori of the Private Research Institute for Genetic and Human Therapy in Washington, has followed up, putting 17 patients on deliberately intermittent HAART or a combination of one HAART drug and a cancer treatment called hydroxyurea, which seems to attack the virus. Although the interrupted therapy did not, in the long run, block HIV entirely, it did prompt elevated immune system T-cell levels, Lori reported at the San Francisco meeting. He did not, however, demonstrate whether those T-cells were capable of "remembering" and attacking HIV.

Two studies conducted by the Aaron Diamond AIDS Research Center in Manhattan offered more detailed insight into what happens when HIV patients go on intermittent HAART. In one case, seven patients whose HIV blood loads had for more than a year stayed below detectable levels - meaning, they were very successful HAART subjects - went on a schedule of stopping and restarting their medications three times over the course of a year. Each time the patient stopped HAART, the viruses surged by the billions into their bloodstreams. But the level of those surges decreased each time. And, more importantly, five of the seven patients were, by the third HAART cessation, making T-cells that could remember, attack and kill HIV.

The observation left open the question of what might happen if such intermittent therapy were continued for another year or two, scientist Felipa Garcia of the Aaron Diamond Center said at the meeting, "but this data may be a proof of the concept."

Another Aaron Diamond scientist, Xia Jin, tried to boost patient immune systems during HAART interruptions by giving four people an HIV vaccine each time they stopped taking their medications. He was unable to elicit any clear immune responses against the virus, but in two of the patients viral surges during their drug holidays grew smaller, and took three to four times longer to appear after each cessation. Jin saw that as good news.

The most striking study came from Dr. Steven Deeks' team at the University of California in San Francisco, because it addressed the No. 1 concern about intermittent HAART - promotion of drug resistance by the virus. It has long been known that patients who fail to take their medicines regularly are likely to develop drug-resistant forms of HIV. Those viruses eventually render HAART useless and kill the patients.

Would deliberate drug interruptions, therefore, cause massive drug resistance?

Deeks studied 18 San Francisco patients who had done well on HAART for about three years. He put the men on various interruption schedules and regularly sampled their blood to see what types of HIVs were present. What he found was startling: Drug-resistant, mutant forms of HIV disappeared after a year in half the patients, with wild type, drug-susceptible forms taking over. Deeks' interpretation was that wild type HIVs are stronger, tougher viruses, and in the absence of drug pressure will prevail over the weaker-but-drug-resistant forms of HIV.

Because Deeks didn't conduct immune-response studies of those patients, he could not tell whether in the long run this dominance of wild type HIV was beneficial for the patients.

ILLUSTRATION/PHOTO: Photo by Molecular Histology, Inc. - Left, red signals HIV's presence in the lymph tissues of an untreated patient. At right, another lymph node taken from the same patient, weeks after HAART therapy.

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