The Data Continue to Support Early ART . . . and Now the Guidelines Do, Too

For the past several years, the results of several large cohort studies have hinted that starting antiretroviral therapy (ART) at CD4 counts of 350 cells/mm³ or even higher would protect against a variety of adverse outcomes (JW AIDS Clin Care Dec 29 2008). This year, the evidence became harder to ignore, and on December 1, both the WHO and the U.S. Department of Health and Human Services (DHHS) adjusted their guidelines accordingly: The DHHS now suggests starting treatment when CD4 counts fall below 500 cells/mm³, while the WHO chose 350 cells/mm³ as the threshold.

The most compelling evidence for starting ART this early came from two studies that used sophisticated statistical methods to analyze pooled outcomes data from clinical cohorts (JW AIDS Clin Care Apr 17 2009). In the NA-ACCORD study of 22 North American cohorts, patients with CD4 counts between 351 and 500 cells/mm³ who deferred therapy were 69% more likely to die during follow-up than patients with similar CD4 counts who started ART immediately; among patients with CD4 counts >500 cells/mm³, deferring treatment was associated with a 94% increased risk for death. Both differences were significant, even after adjustment for multiple comorbidities. Similarly, in a pooled analysis of data from more than 24,000 patients in Europe and North America, deferring ART until CD4 counts were between 251 and 350 cells/mm³ was associated with a 28% increased risk for AIDS or death (no increase was seen for death alone).

Smaller studies suggested possible explanations for these observations. Among 366 patients with complete virologic suppression, the chances that CD4-cell counts would rise into the normal range were far higher among those who started ART with CD4 counts >300 cells/mm³ than among those who started it with lower counts (JW AIDS Clin Care Mar 2 2009). Among children with vertically acquired infection, B-cell number and function were significantly better among those who started ART in the first year of life than among those who started it later (JW AIDS Clin Care Jun 22 2009). Among 243 patients who experienced virologic rebound after initial virologic suppression, major resistance mutations were seen in fewer patients who started ART at CD4 counts >350 cells/mm³ than in those who started it at lower counts (JW AIDS Clin Care Jul 13 2009).

Meanwhile, in the developing world, treatment is seldom initiated until CD4 counts drop below 200 cells/mm³ or clinical AIDS develops, but this year a randomized controlled trial of early versus late treatment in Haiti had to be stopped after the Data and Safety Monitoring Board found a significant survival benefit from starting ART at CD4 counts between 200 and 350 cells/mm³ (JW AIDS Clin Care Aug 31 2009).

Of course, these findings tell only part of the story. Studies of the cumulative, long-term, treatment-related side effects associated with early versus late ART will supply some of the rest, while each patient's personal risk-benefit calculation will continue to weigh heavily in all treatment decisions.