• Strategic Treatment Interruptions: Where Are We?
  Abstract S18
  Authored by B. Hirschel (Geneva Univ. Hosp., Switzerland)
  View the original abstract

Dr. Bernard Hirschel from Geneva talked about structured treatment interruptions, another topic about which we have heard a lot lately. Dr. Hirschel was bright, fresh and funny and gave one of the best overviews about the topic I have heard so far.

There have been multiple structured treatment interruptions trials, most of them quite small, both for patients with acute infection -- where this strategy seems to be most successful -- and for patients chronically infected, where the strategy does not seem to work very well, if the goal of treatment interruption is to autovaccinate the individual against his or her own HIV and make the immune system take control of the virus.

Dr. Hirschel began his talk by summarizing why anybody on earth would want to stop antiretroviral therapy, a therapy that has saved so many lives. The reasons he pointed out are:

• Cost: Therapy is expensive, even more expensive in relative terms in the developing world -- he gave the example of Zimbabwe.

• Side Effects: Therapy has side effects, and they seem to increase with drug exposure. Maybe using therapy intermittently could potentially lead to less drug exposure and decreased toxicity.

• Rebuilding HIV-Specific Immunity: The third main reason was the idea of autovaccination and the attempt to rebuild HIV-specific immunity. The problem with chronically infected individuals is that HIV destroys HIV-specific CD4 cells soon after acute infection, and these cells do not return with treatment.

Dr. Hirschel then discussed in detail the results of the largest study yet to evaluate structured treatment interruptions in chronically-infected patients: The Swiss-Spanish Intermittent Treatment Trial (SSITT). That study enrolled 133 patients. Before starting antiretroviral therapy, the average viral load was around 30,000 and the average CD4 count was 388 cells/mm³. Participants had been taking HAART for over two years. The average CD4 cell count at the time of stopping therapy was 740.

All of the participants had four structured treatment interruption cycles of eight weeks on treatment, followed by two weeks off. After 40 weeks, treatment was stopped through week 52, and at that time the viral load was determined again. The goal was to have a viral load below 5,000 at that point (the primary endpoint of the trial). Only 17 percent of patients did. The main predictors for this result were a low baseline viral load and the absence of viral rebound during the treatment interruptions. This really torpedoed the whole idea of auto-immunization because the patients who did better were those who were less exposed to the HIV antigens. Many patients remained off antiretroviral therapy and their CD4 cell counts remained stable for a variable period of time. Another important finding was that CTL (cytotoxic T lymphocyte) responses did not predict at all which patients would be able to control the virus; something that questions the value of these very sophisticated immunologic tests in clinical practice.

Then Dr. Hirschel declared the death of the autovaccination theory with a slide that showed a tombstone with the words "Here Lies the Autovaccination Hypothesis" that I am sure did not make many investigators in the audience very happy (i.e., those running structured treatment interruption trials in chronically infected patients and still pursuing that theory). He pointed out that new approaches should be tried out to make autovaccination work, like the administration of immuno-modulators, vaccines or cytokines before any treatment interruption to see if that affects the results of the interruption.

He concluded by summarizing four of the major studies currently in progress which evaluate the use of intermittent therapy:

1. The SMART trial from CPCRA evaluates two different strategies, one CD4-driven and another viral-load-driven, for the long-term management of HIV infection.

2. The Staccato trial from Europe, Thailand and Australia evaluating the continuous use of therapy vs. CD4-driven therapy vs. short periods of time on and off therapy.

3. The ACTG trial 5102 evaluating CD4-driven therapy and the role of interleukin 2 in prolonging the intervals off antiretroviral therapy.

4. The European Quest trial evaluating the role of the ALVAC and Remune vaccines in prolonging the times off therapy. At least two ACTG trials are asking similar questions related to the role of vaccines in treatment interruption strategies.

Obviously the issue of intermittent therapy is not dead, but the goals are changing: we clearly do not want to immunize the patients against their own HIV anymore. We just want to decrease drug exposure and cost.