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Discouraging News on Structured Treatment Interruption

Structured treatment interruptions that allow CD4 counts to drop below 350 cells/mm³ are unsafe and should not be recommended.

Despite the intuitive appeal of structured treatment interruption (STI), the strategy failed miserably in 2006, with several large trials yielding negative results. Most notable were the SMART (Strategies for Management of Antiretroviral Therapy) study and the Trivacan ANRS 1269 study, both of which used a CD4 count <250 cells/mm³ as the threshold for restarting therapy. Enrollment in the SMART study was halted when clinical progression was noted to be significantly more common with STI than with continuous therapy. The causes of morbidity and mortality were widely dispersed but included many conditions not traditionally thought of as AIDS-related (e.g., renal, hepatic, and cardiac disease) (ACC Nov 29 2006). Similar findings were reported in the Trivacan study, where the STI arm was halted because of an increased rate of severe morbidity, mostly from serious bacterial infections (Lancet 2006; 367:1981). Together, these results indicate that the health consequences of unrestrained HIV replication probably reach well beyond the standard AIDS-defining endpoints.

Disappointing results were also reported from the DART (Development of Antiretroviral Therapy in Africa) trial, which compared continuous treatment with a 12-weeks-on/12-weeks-off approach. This study too was halted because of significantly worse clinical outcomes in the STI arm (see ACC’s IAS meeting report). The only study that yielded a positive result for STI this year was the Staccato trial, which used a higher CD4-count threshold for restarting therapy (<350 cells/mm³) than the other trials did — and also relied on boosted-PI regimens, which might be less likely than other regimens to lead to clinically significant drug resistance (ACC Aug 21 2006). Whether this higher CD4-count threshold is safe remains unknown, but one thing is clear from the cumulative evidence: STI strategies that allow CD4 counts to drop below 350 cells/mm³ are unsafe and should not be recommended.

Even with all this bad news, STI is still valuable in the research setting for evaluating the potential efficacy of immune-based therapies. In ACTG A5102, my colleagues and I examined whether administering interleukin-2 (IL-2) prior to treatment interruption would delay CD4-cell decay and thereby prolong the time that patients could spend off antiretroviral therapy. Although study participants did well clinically, there was no evidence for a beneficial effect of IL-2 (ACC Jul 11 2006). In ACTG 5068, researchers evaluated the effect of an exogenous HIV vaccine (ALVAC-HIV vCP1452) on viral rebound characteristics after a treatment interruption (J Infect Dis 2006; 194: 623). Although the vaccine had no demonstrable effect, intermittent treatment interruptions did modestly enhance immunologic control of HIV replication. Together, these findings illustrate that immune-based therapies can be evaluated safely in the context of careful STI-based studies.

— Keith Henry, MD

Published in AIDS Clinical Care December 29, 2006