Update #2 Day 3, Tuesday February 7 from the Retroviruses and Opportunistic Infections National Meeting

Conference - February 7th Transcript

Dr. Eric Daar offers perspectives of interest on topics from the 13th Conference on Retroviruses and Opportunistic Infections (held in Denver, Colorado February 5-8, 2006)

Treatment Interruptions

In a session entitled "Antiretroviral Therapy: New Insights and Treatment Strategies" there were a series of presentations on the topic of treatment interruptions. In fact, several of these have received a lot of attention in the media of late. One such study was called "The SMART Study." SMART was to enroll 6,000 people who had high CD4 cells. They were to be randomly assigned to either continue antiretroviral therapy or discontinue it when CD4 cells were >350 cells/uL and then reinitiate therapy when they declined to below 250 cells/uL. The primary end point of this study was time to clinical events, or progression to AIDS or death. At the time of a recent interim review, the data safety monitoring board terminated the treatment interruption arm of this study because of a highly significant increased risk of clinical events in these subjects. This study was described in some detail, focusing mostly on the primary end points, and recognizing that additional analyses will be performed to address a variety of other very important questions related to tolerability and quality of life. Of the approximately 2,500 people enrolled in each arm they found that most in the treatment interruption group maintained their T cell counts above 250 cells/uL. However, in this group there was nearly a 2.5 times increased risk or clinical endpoints, including progression to AIDS and death. While the outcomes were not related to CD4 cell nadir, it did relate to proximal CD4 cell count and was most notable in those who came into the study with a viral load of less than 400 copies/mL.

In another related study, "Trivacan," they enrolled subjects on a stable regimen with high CD4 cells and randomly assigned them to either continue on their current therapy, to interrupt their treatment with a plan to restart if T cells declined to below 250 cells/uL, or a strategy where they would go off their treatment for 8 weeks and then restart for 8 weeks. The primary endpoint was the percent of subjects who maintained T cells over 350 cells/uL at 24 months as well as the risk of clinical progression. Near the end of 2005 the Data Safety Monitoring Board reviewed the three different arms, and found that there was an increased risk of progression amongst those in the so-called 'CD4-Guided Treatment Interruption Arm.' As a result of this the interruption arm was stopped and the continuous therapy versus the 8 weeks on / 8 weeks off arm were continued, presumably because they didn't see a difference in outcomes between these groups. Data was presented comparing the continuous treatment arm verses the CD4-Guided Treatment. Although baseline characteristics were similar between the groups there was a highly significant increased risk of progression in those of the CD4-guided strategy. Interesting, many clinical events were bacterial infections including bacteremia.

In contrast to these two studies another study that used CD4-guided treatment interruptions called the "Staccato Trial" (performed largely in Asia) reported different results. This study originally had 3 arms, including people with high CD4 cell counts on stable regimens, who either continued their therapy, would start it and restart it every week, or stay off of therapy until their CD4 cells dropped below 350 cells/uL, not 250 cells/uL as used in the SMART and Trivacan studies. In this particular study the week on / week off arm was prematurely terminated some time ago because of poor outcomes. In contrast, those in the CD4-guided therapy had similar outcomes to those with continuous treatment, only the latter group having had less total drug exposure.

There was a panel discussion of experts in the field that followed these presentations to discuss some of the differences and what the clinical implications were of these findings and what additional research might be pursued as a result of this work. The most obvious difference between the studies was that CD4 counts were allowed to go lower in the two studies that showed inferior outcomes. Therefore, it may very well be, that in people who are on treatment, many of whom may have had more advanced disease and low CD4 cells in the past- do need to stay on treatment or are at risk for clinical progression. There are likely to be other differences that will be defined as additional information emerges. In the interim, treatment interruption should be performed with great caution and with careful monitoring of CD4 cells while off therapy.



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