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Episodic HIV Treatment: Not a SMART Idea

An episodic CD4-count–guided treatment strategy was associated with higher morbidity and mortality than was continuous antiretroviral therapy in HIV-infected patients.

Continuous antiretroviral therapy (ART) markedly reduces morbidity and mortality in HIV-infected patients, but it has potential adverse effects, is expensive, and poses difficulties with long-term adherence. Does episodic CD4-count–guided treatment offer a solution to these problems?

In the Strategies for Management of Antiretroviral Therapy (SMART) study, researchers randomized more than 5400 HIV-infected subjects with CD4 counts >350 cells/mm³ to receive either continuous ART or episodic ART guided by CD4-cell count (therapy was given when the CD4 count fell to <250 cells/mm³ and was stopped when the CD4 count increased to >350 cells/mm³). Although the median baseline CD4 count was >500 cells/mm³, the median CD4 nadir at baseline was only 250 cells/mm³, and about one quarter of subjects had histories of AIDS-defining illness.

The rate of opportunistic disease or all-cause mortality was significantly higher with episodic treatment than with continuous treatment (hazard ratio, 2.6). Surprisingly, episodic treatment was also associated with an increased rate of major cardiovascular, hepatic, and renal disease (HR, 1.7). Only 8% of all deaths in the study were due to opportunistic conditions, and more than a quarter of deaths in the episodic-treatment group were of unknown cause. Although the higher rate of death or opportunistic disease was seen even among subjects with nadir CD4 counts >300 cells/mm³, adjustment for the latest CD4-cell count and HIV RNA level reduced the hazard ratio for these events to 1.5 (95% confidence interval, 1.0–2.1).

Comment: Episodic CD4-count–guided therapy is associated with a greater risk for death and opportunistic disease than is continuous ART. This excess risk is largely related to the rapid loss of CD4 cells and increase in HIV RNA that occurs in subjects who interrupt therapy. Whether episodic treatment is safe when restarted at a higher CD4-cell–count threshold than that used in this trial (250 cells/mm³) remains unclear. In addition to an increased risk for opportunistic conditions, subjects receiving episodic treatment had a slightly higher rate of complications, such as cardiovascular events, that were not previously considered to be related to immune deficiency. This finding suggests that elucidating the effect of uncontrolled viremia on cytokine expression, inflammation, and immune activation may also have implications for infected individuals not yet on ART.

— Rajesh T. Gandhi, MD

Published in Journal Watch Infectious Diseases November 29, 2006

Citation(s):

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count–guided interruption of antiretroviral treatment. N Engl J Med 2006 Nov 30; 355:2283-96.

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• Medline abstract (Free)

Currier JS and Baden LR. Getting smarter — The toxicity of undertreated HIV infection. N Engl J Med 2006 Nov 30; 355:2359-61.

• Original article (Subscription may be required)
• Medline abstract (Free)