Retrovirus & Opportunistic Infections (cont.)
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.