CTN 190: Strategies for management of ART (The SMART Study)

About The Study

The purpose of this study was to compare the long-term clinical consequences of two strategies of ART: The drug conservation (DC) strategy, aiming at conserving drugs through episodic use of ART for the minimum time to maintain CD4 cell count of at least 250 cells/mm3, versus the viral suppression (VS) strategy, aiming at suppressing viral load as much as possible, immediately following randomization and throughout follow-up, irrespective of CD4 cell count.

Study Approach

This study consists of a large, simple trial in which participants will be randomly assigned to one of two groups in order to determine th effectiveness of the strategies described above.

Study population

This is an international study with 318 sites in 33 countries. A total of 5472 participants were enrolled between January 8, 2002 and January 11, 2006. At baseline, the median and nadir (lowest ever) CD4+ counts were 597/mm3 and 250/mm3, respectively, and 71% of participants had plasma HIV RNA levels of 400 copies/mL or less. A majority of participants (95%) had some experience with ART (a median of six years of ART use prior to enrolment).

Results

Both study groups were followed for an average of 16 months before enrolment was closed early on January 11, 2006 since the Data Safety Monitoring Board was concerned with the high number of adverse events and deaths in the DC group. The protocol was amended, in July 2006, to encourage participants in the drug conservation group (2720 were in the DC group and 2452 were in the VS group) to re-start HAART therapy. Opportunistic disease or death from any cause occurred in 120 participants in the DC group and 47 participants in the VS group (people in the DC group had 2.6 times more risk to reach the primary endpoint than people in the VS group). For the secondary endpoint, major cardiovascular, renal, and hepatic disease, the risk was 1.7 more in the DC group. Regardless of the outcome measure, the DC group had higher event rates than the VS group. This was associated with lower CD4+ count during follow-up. The reason for the additional excess risk of events in the DC arm is still unknown. The study also showed that for some sub-groups or individuals with different baseline characteristics the poorer outcome in the DC arm was particularly marked. Additionally, participants in the VS group had better outcome than those in the DC group irrespective of baseline or nadir CD4+ cell count.

Conclusions

Episodic antiretroviral therapy guided by the CD4+ count, as used in this study, increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, possibly due to lowering the CD4+ cell count and increasing the viral load. Within the context of this protocol, episodic ART does not reduce the risk of adverse events that have been associated with ART.