CD4+ Count–Guided Interruption of Antiretroviral Treatment

This study, known as the Strategies for Management of Antiretroviral Therapy (SMART) trial, investigated whether an episodic approach to HIV treatment—where antiretroviral therapy (ART) is interrupted and only resumed when CD4+ cell counts drop below a specific threshold—could reduce the long-term adverse effects of continuous medication without compromising patient health.

Researchers randomly assigned 5,472 HIV-infected participants with CD4+ counts above 350 cells/mm³ to one of two groups: a viral suppression group (continuous ART) or a drug conservation group (episodic ART). In the drug conservation group, therapy was deferred until CD4+ counts fell below 250 cells/mm³ and was stopped again once counts rose above 350 cells/mm³. The primary endpoint was the development of opportunistic disease or death from any cause, with secondary endpoints including major cardiovascular, renal, or hepatic disease.

The trial was stopped early after an average follow-up of 16 months because the drug conservation group showed significantly higher rates of adverse outcomes. Participants in the episodic group experienced a 2.6-fold higher risk of opportunistic disease or death compared to those on continuous therapy. Furthermore, the episodic strategy did not reduce the incidence of major cardiovascular, renal, or hepatic disease; in fact, these conditions were more frequent in the drug conservation group. The excess risk was largely attributed to the prolonged periods of lower CD4+ counts and higher viral loads in the episodic group.

These findings provide clear evidence that interrupting ART based on CD4+ count thresholds is deleterious. The study demonstrates that continuous viral suppression is essential for maintaining immune function and preventing both AIDS-related and non-AIDS-related complications, effectively debunking the hypothesis that treatment-sparing strategies would mitigate the risks of long-term drug exposure.