NEWS

Rethinking HIV therapy

by Bob Roehr Strategic interruption of therapy (STI) is "the flavor of this year," said the eminent Dr. David Ho, vice chair of the 7th Conference on Retroviruses and Opportunistic Infections. While data is skimpy, the hope is that stopping all anti-HIV drugs for some period of time is not only possible, it may even be beneficial.

Who should stop? When should they stop? And how long should they stop? Those basic questions are all unanswered, but the fact that clinical trials are being put together to find answers is cause for optimism among activists" and researchers alike.

This paradigm shift in thinking comes from integrating new pieces of information into a unified whole. The hope that protease inhibitor-based combination therapy would be powerful enough to purge the body of HIV has long waned, while evidence of long-term side effects of these drugs continues to grow. The risk/benefit ratio no longer tilts overwhelmingly to a presumption that everyone should be on therapy at all times.

More recent and less understood are three surprising developments. In late 1998, Veronica Miller, MD, showed that when patients stopped therapy, some types of drug resistant virus tended to fade into the background and the original drug susceptible wild type virus reemerged to become dominate. This virus was more easily suppressed when therapy was restarted.

This year Steven Deeks, MD, a researcher at the University of California at San Francisco, showed that the change from mutant to wild type virus "was abrupt and occurred rapidly. Typically most resistance was lost over a period of 1-2 weeks." Patients passed through that window of change at varying lengths of time, from 2-15 weeks after stopping therapy.

He hypothesized that residual drug effect influenced time to the shift. Some drugs, particularly the NNRTI class that includes Sustiva, stay in the body longer when you stop taking them. Deeks also found that protease-resistant virus reverted to wild type, while resistance to nucleoside analogs diminished but did not disappear.

THE ART OF

Many assume that mutant virus, like wild type, is "archived" in tissue or cell reservoirs. "What we don't know yet is how long it will be before that reservoir of resistant virus breaks out and again becomes the dominant virus," said Daniel Kuritzkes, MD, at the University of Colorado Health Sciences Center.

But researchers looking for archived mutant virus in the usual places have not been able to find them in all patients.

It may be that the detectives and their tools are defective. The more intriguing possibility is that mutants, already less fit to replicate than their wild type siblings, may also be deficient when it comes to archiving.

CTL Rebound

The well-known paradox is that "it takes viral antigen to keep the immune system charged up. Once virus replication is controlled too well, the number of these cells diminishes," explained Kuritzkes. Stop therapy and the viral load explodes, chewing up T-cells in the process.

But in at least some individuals, renewed exposure to high levels of the virus also re-stimulates cytotoxic T-lymphocyte (CTL) killer cells. The immune system seems to not only return to the killing efficiency of before, it actually seems to learn from the experience. Each time it goes through the stop/start cycle of therapy it gets a better handle on controlling HIV replication.

At the "late breaker" closing session of the conference F. Garcia, MD, from the Hospital Clinica in Barcelona, Spain, showed data on ten patients who have been through three cycles of STI. For some of them, the time to viral rebound extended with each cycle. A few showed a spike, then a spontaneous decline in viral load after stopping therapy. Garcia suggested that both of these responses indicated stimulation of a more powerful immune response.

The Aaron Diamond Institute in Manhattan used a "therapeutic vaccine" prior to stopping therapy in an attempt to stimulating CTL response. It found that viral rebound was delayed in two of the four patients. The best CTL response produced the longest delay in viral rebound. However, it is unclear whether part or all of this response should be credited to the

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Dr. David Ho. Photo by Bob Roehr

vaccine or to the fact of stopping therapy as described above.

The hope is that by cycling off and on drugs, with or without the assistance of a therapeutic vaccine, one can boost the immune system's contribution to viral control, and take longer drug holidays.

Kiyoshi's Story

Philadelphia activist Kiyoshi Kuromiya has stopped therapy several times because of anemia and toxicity associated with his regimens. His viral load rebounded from undetectable to 4,000 one time and 14,000 another time before he restarted therapy. That's enough to scare many PWAS, but it is just a bump in the road for this veteran who peaked at 1.2 million copies of HIV in 1994. Each time when he has resumed therapy his viral load returned to an undetectable level, and his CD4 count has risen.

"At the end of my most recent structured treatment interruption [my CD4 count] was higher than it has been in ten years," he says. "It suggests, in my case anyway, that viral rebounds are diminished and I achieve viral control very rapidly after ending my treatment interruption."

Kuromiya acknowledges, "You can't draw conclusions from the small size of the studies" presented at the conference but "a lot of us don't have the luxury of waiting." He believes that if the interruption is well monitored, "there haven't been any dangers that we don't already know about."

"I think that the evidence is good enough that people can feel they won't do themselves irreparable harm" with a moni-

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tored strategic interruption, says James Learned, an educator with the Community Research Initiative on AIDS (CRIA).

New York activist Gary Rose suggests that STI may offer an opportunity to stabilize or even begin to reverse side effects such as lipodystrophy or mitochondrial toxicity. "If nothing else, your liver might be given a little time to breath. That can't be a bad thing."

Currently, data is available on only two or three interruptions cycles, though the trials are continuing. The number of responders seems to increase with each round of interruption. "Could this possibly mean that the number will continue to grow?" asks Rose. "Getting to 100 percent is highly unlikely, but 50 percent might be possible."

"I think there is some promise there," says Kuromiya. "I hope that in three years everybody will not be doing drugs every day but every few weeks or every few months."

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OUTLINES Feb. 23, 2000

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