Bay Area Reporter - November 11, 1999
Jeff Gustavson ACT UP/Golden Gate Writers' Pool

Additionally, last week, Dr. Roger Pomerantz and his colleagues reported the were able to find very low levels of viral replication in samples declared "undetectable" irrespective of the lower limit of detection. This is consistent with Dr. David Ho's observation of genetic drift in the latently infected pool (where virus is integrated, but not actively produced) which indirectly presumed low level replication as well.

Less is not more

In the yin yang of treatment dogma, the formerly anathemic idea of stopping antiretroviral treatment for HIV has garnered serious interest from both the community and clinical researchers alike. This contrasts sharply with the largely failed concept of induction/maintenance. This incomplete halt of therapy studied people who were successful (undetectable viral load) on triple or quadruple therapy and asked what happened when given dual or monotherapy which lacked much community support.

Two studies highlighted that induction/maintenance did not work. Allowing ongoing viral replication in the presence of suboptimal antiretroviral therapy would produce resistance constituted a major concern for safety. In the AIDS Clinical Trials Group (ACTG) Trial 343, 23 percent of participants randomized to "maintenance" therapy of one or two antiretroviral medications, after a twenty-four week induction period of undetectability on triple therapy, experienced a rapid rise in virus above 200 copies per milliliter. This trial was stopped by an Interim Review Committee for safety reasons. In the ADAM trial from Amsterdam, 9 of 14 persons who were switched from four drugs to two had viral rebound. In theory, generation of resistance should be much less without the selective pressure of any antiretrovirals in a structured treatment interruption.

None may be better

Larry Fox, M.D., works as a Medical Officer with the HIV Treatment Research Program at the Division of AIDS at the National Institute of Allergies and Infectious Diseases, one of the Institutes that make up the National Institutes of Health. "A structured treatment interruption may be of benefit to three different populations of persons with HIV infection. First, there are those who successfully began treatment in early infection. Three patients who began to receive treatment soon after being infected have now been reported to interrupt therapy without viral rebound. The so-called 'Berlin Patient' reported by Dr. Franco Lori as well as two people from a Brussels cohort. In the case of the Berlin patient, there were successive periods of therapy withdrawal followed by reintroduction of therapy."

These reports are anecdotal but greatly encouraging. The question that needs to be asked in a prospective fashion is if it's possible to treat someone for a period of time and allow the immune system to gain the upper hand and be able to control infection". ACTG 371, a study of early infection enrolling locally at the Positive Health Project (formerly known as Ward 86), is planning a withdrawal of medicine after two years of undetectability (< 200 copies).

Stuck in the middle

The second group for which interruption may be of benefit is the more chronically infected, but successfully treated on HAART. Dr. Fox explains "Individuals in this category are being studied by the intramural group here at the NIH. We will take individuals with CD4 counts above 300 and viral loads less than 50 and follow them for two years to see if there is a clinical difference to remaining on therapy or if equivalence can be achieved with treatment interruption." Those in the treatment interruption arm will have one month off therapy followed by two months on. "This is more along the lines of chronic cancer treatment where therapy is not expected to be continuous", Fox says.

At the End of the Line

Fox continues "At the other end of the spectrum, there are people whose virus which has multiple resistance mutations and for whom antiretroviral therapy has failed. Dr. Veronica Miller from Frankfurt, Germany has reported on her cohort of patients who stopped treatment for a variety of reasons. She reported that in two thirds of those who stopped, their virus had reverted to wild type [no mutations]. Presumably, however, mutant virus is still there, just not being picked up in the assay."

Dr. Miller was able to resuppress in some of her patients using mega-HAART, regimens that use five or more drugs. However, Dr. Fox warns "A note of caution: Fully one half or the patients in the Frankfurt cohort did not see their CD4s [T-helper cells] return to the levels that they were before going off therapy. This may have something to do with the fact that the were low to start, but it does raise flags."

Prove it All Night

Unfortunately, all the information gathered so far has been out of he context of a prospective randomized trial. However, soon we may know more. The first such trial of treatment interruption is being conducted by Steve Deeks, M.D. here locally at UCSF/San Francisco General Hospital in collaboration with Drs. Marc Hellerstein of UC Berkeley, and Mike McCune and Bob Grant of the Gladstone Institute of Virology and Immunology and coordinated by the fabulous Becky Hoh discussed in an earlier Writer's Pool column (see "You can do something about protease inhibitor failure"). This trial has fully accrued and will likely be presented at the Human Retrovirus conference early next year here in San Francisco.

The Community Program for Clinical Research on AIDS (CPCRA) has a two arm trial in development for people in salvage situations. Participants in the the MDR HIV Drug trial must be able to construct a genotypically viable regimen will be randomized to either an immediate switch to that therapy or an interruption (what used to be called a "washout"). They will then be followed to see which group does better.

Undetectable is not Enough

The ACTG is planning two treatment interruption studies, A5024 and A5068. A5068, currently completing development, is being chaired by Jeff Jacobson, M.D. of Mount Sinai Medical Center in New York City. Dr. Jacobson explains "There is a growing realization that antiretroviral success [in terms of suppression of viral load] has failed to restore HIV-specific immunity. We are hoping to stimulate more long lasting health by boosting the person's own immunity through both introduction of an exogenous [from the outside] vaccine, and auto-immunization using the patient's own virus like a vaccine."

Dr. Jacobson elaborates "Our study will enroll eighty relatively healthy individuals with CD4 counts above 500 and an undetectable viral load of less than fifty copies for the last six months prior to entry. We have built in safety features such as frequent viral load monitoring and are on guard for any precipitous CD4 cell decline. This four arm study will compare no interruption against an arm that has three two week interruptions, an arm that will receive vaccination with canary pox vaccine and an arm that has both cycles of interruption and the vaccination. The comparison will be made at the end when all four arms will go off treatment for six weeks and use the new viral set point as read out." It is hoped that the set point would be lower after either or both kinds of immunization.

Don't try this at home

These studies all pose interesting questions as well as help to determine whether there is any clinical benefit to treatment interruption. Nevertheless, it is too early to tell whether interruption is useful. This should not in any way be confused with a one or several day long drug holiday which no one recommends. Structured treatment interruption studies are being conducted with intense safety monitoring for CD4 and viral load changes. Interruptions are not being recommended outside of a trial setting due to all the safety concerns.

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