Episodic CD4-Guided Use of ART Is Inferior to Continuous Therapy: Results of the SMART Study

Wafaa El-Sadr* and J Neaton
for the SMART Study Investigators

Background: Use of ART is associated with known benefits and potential risks, eg, adverse events, metabolic and cardiovascular complications, waning adherence, and HIV resistance. The SMART trial was designed to identify an ART strategy that maximizes benefits while minimizing risks through use of ART to maintain CD4 above specific threshold.

Methods: Patients with CD4 >350 cells/mm3 were randomized to a CD4-guided drug conservation (DC) arm or to continuous ART aimed at viral suppression (VS arm). In the DC arm, ART was stopped until the CD4 count fell to <250 cells/mm3, when ART was initiated; ART was stopped again when CD4 >350 cells/mm3. The primary endpoint was HIV disease progression or death. To detect a 17% difference between arms, 6000 patients were required. On 10 January 2006, the DSMB notified the team of increased HIV progression risk in the DC arm. Enrollment was stopped on January 11.

Results: A total of 5472 patients were enrolled from 318 sites in 33 countries. The majority (95%) were ART experienced (median 6 years prior ART use). The mean age was 46 years; 26% were women and 31% black, 69% white or other. At baseline, median CD4 was 598 cells/mm3, nadir CD4 was 253 cells/mm3, 70% had HIV RNA <400 and 24% prior AIDS diagnosis. By December 10, 2005, median follow-up was 10 months (IQR 4 to 23), with 6139 person-years of follow-up; 2.1% of patients were lost to follow-up. In the DC and VS arms, ART was used 33% and 93% of the follow-up time and patients spent 938 (31.7%) and 236 (8.1%) patient-years at CD4 <350 cells/mm3, 276 (9.3%) and 59 (2.0%) patient-years at CD4 <250 cells/mm3, respectively. Confirmed clinical endpoints are shown in the table. The relative risk of disease progression or death (DC/VS) was greater in the first 2 years of follow-up (RR = 2.7, 95%CI 1.8 to 4.2) compared to afterward (RR = 1.1, 95%CI 0.6 to 2.2).

Conclusions: SMART, a large international trial, demonstrated that CD4-guided episodic ART use aimed at maintaining CD4 >250 cells/mm3 is associated with increased short-term risk of progression of HIV disease and death compared to continuous ART.