February 25, 2005
Over the past several years there have been many ongoing studies exploring how treatment interruptions can be safely undertaken. Indeed, one of the largest studies looking at this in the field of international HIV medicine is called the Strategies for Management of Anti-Retroviral Therapies, or SMART, trial -- it compares continuous antiviral treatment to periodic treatment interruptions.
Among the questions to be explored are ways to increase the length of time someone can be off of all antivirals. In general, antivirals are restarted in someone when his or her CD4+ cell count approaches some "restart" trigger -- in most studies this is often about 250 to 350 CD4+ cells/mm3.
The question asked in this study by Keith Henry et al is: Is there a way to maintain a CD4+ cell count above this target in order to prolong the time someone can be off all antivirals? This study explored a strategy of administering interleukin-2 (IL-2) to people with viral suppression (less than 200 copies/mL) when on a standard antiviral regimen with a CD4+ cell count of greater than 500 cells/mm3.
Participants were randomized to maintain either just antivirals or to add IL-2 at the standard cycle dose (4.5 million units twice daily for 5 days in a row every 8 weeks). After 18 weeks, if the CD4+ cell counts were still more than 500 cells/mm3, all patients underwent a treatment interruption until the counts fell below 350 cells/mm3. The comparison of those who did or did not add IL-2 were presented.
After a median follow-up time of about 78 weeks, the CD4+ cell counts were found to be higher in those who received IL-2 for the first 72 weeks. Prior to week 72, the benefit of IL-2 appeared to prolong the success of this strategy (i.e., time off antivirals) by about 20 weeks. However, after week 72, the groups appeared to have similar outcomes in terms of counts going below 350 cells/mm3. Overall, about 70% remained off antivirals as of week 72.
In terms of predictive factors of the ability to remain off antivirals with a CD4+ cell count above 350 cells/mm3, this study did confirm that someone's lowest ever CD4+ cell count (known as the CD4+ nadir) was predictive of the time someone could remain off antivirals -- a lower nadir results in a shorter time off antivirals.
In addition, this study did find that the viral load "peak" when stopping antivirals was also predictive of how long someone could remain off treatment, something that has not been reported in other studies. IL-2 had no "unexpected toxicities," though it is reasonable to note that there are considerable "expected toxicities" that have been well documented for years.
The implications of this study are not clear at this point. While there were some who did benefit from the additional CD4+ cell "boost" provided by IL-2, the majority of people in this study had no obvious benefit reported at this timepoint, at least from the perspective of maintaining a CD4+ cell count above 350 cells/mm3 when off antivirals. It may be that a subset of people considering treatment interruption who are at higher risk for a more rapid decline in counts would be able to prolong the time off by pretreating with IL-2. As this is a relatively small study of 47 people, further work will be needed to help define what role IL-2 can play in this setting.
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