Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

Effects of Prolonged Discontinuation of Successful Antiretroviral Therapy
     Written for NATAP by Michael Norton, PA

Design
- Retrospective analysis of individuals who chose to discontinue antiretroviral therapy for at least 12 weeks after being successfully suppressed to determine the predictors of the slope of decay in CD4+ T-cells.

Baseline Characteristics

- N = 72
- 62% male
- Median nadir CD4+ cells prior to Rx = 272 cells/mm3
- Median VL prior to therapy = 5.0 log copies/ml
- Median time undetectable = 36 months
- Median CD4+ cells at time of discontinuation = 571 cells/mm3
- Patients chose to discontinue therapy most commonly due to preference for such and/or drug toxicity

Results

- Mean follow-up after stop of therapy = 45 weeks
- Median slope of decay in CD4+ was 16 cells/mm3 per month
- Using Multivariate analysis: CD4+ gain on therapy was the only significant predictor of the slope of decay in the CD4+ cells after discontinuation of therapy. (Those who had gained the most while on therapy, quantitatively lost the most CD4+ cells and lost them in the shortest amount of time when they discontinued therapy.)
- Median VL went back to equivalence when looking at the cohort, went back to original setpoint (viral load prior to therapy). Looking at individuals, they went to within .5 log copies of where they were prior to therapy.
- No retroviral syndromes reported
- 13 out of the 72 patients re-started therapy. 11 re-suppressed. 2 virologically failed, no genotypic information was provided.
- 4 patients developed AIDS defining events, 2 of those were PCP.

Discussion

Pablo Tebas presented this on behalf of his collaborators at 4 centers across the U.S. He noted that the current paradigm of continuous ARV therapy is being challenged due to:

--Challenge of adherence
--High virologic failure rate
--Increasing long-term complications associated with continuous, lifelong therapy.
But he also pointed out that there are potential disadvantages to stopping ARV therapy and allowing viremia to robustly rebound:
--Virologically successful reintroduction of therapy will not be
possible in all
--When one stops therapy there may be a loss of immunologic
repertoire
--When one stops therapy there is an increased potential for HIV
transmission

--When one stops therapy there is greater potential for HIV related symptoms or AIDS defining illness.
(Editorial note: in July AIDS Journal, Steve Deeks published article finding unexpected viral load repopulation pattern in CSF after interrupting HAART, suggesting potential harmful effect. See Cerebrospinal fluid response to structured treatment interruption after virological failure, with PDF attached)

He also noted that the ACTG and the CPCRA are both going to do studies looking at stopping or interrupting therapy and comparing the outcomes to continuous therapy. An additional component that is also receiving clinical trial investigation is the use of IL-2 during interruptions or after stopping to see if it

--prevents or slows CD4+ depletion
--preserves immune function
--aids in the development of HIV specific responses (aids in autoimmunization).

(Editorial note: the use of several different therapeutic vaccines to control HIV during an interruption in chronic HIV is also being studied).

Dr. Clotet from Spain stood up and stated that Europe is doing a similar study. In their study he reported that they have seen a 5-6% prevalence of retroviral syndrome [during interruption]. He also suggested that patients participating in these studies, whose VL rebounds to >5.0 log copies/ml be able to re-start ARV therapy immediately.

Commentary
Whether it is Fauci’s STI’s with the goal of less total time on therapy, or Walker’s STI’s in acute seroconverters leading to possible immunologic control, or this studies look at completely stopping therapy, or the fight over when to start therapy, these are the current discussions going on among many of the experts in HIV medicine. As a clinician, I can tell you that patients have and will continue to make individual choices regarding the taking and not taking of their medicines. Hopefully this current focus will further help patients and clinicians clarify the risks or possible benefits of these new approaches.