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Pooled SMART, START trial data reaffirm benefits of early, continuous ART
A recent analysis of pooled data from the landmark SMART and START trials showed that interrupting or deferring ART had a similar impact on CD4 levels and viral suppression and also increased the risks for adverse events and mortality among patients with HIV.
“The present study is the best randomized evidence that a strategy of deferred/intermittent ART leads to an increased risk of AIDS-defining and serious non-AIDS-defining conditions,” Álvaro H. Borges, MD, MSc, PhD, of the Center of Excellence for Health, Infections and Immunity at the University of Copenhagen, and colleagues wrote in The Journal of Infectious Diseases.
SMART and START are international randomized controlled trials that assessed the impact of different ART treatment strategies on both AIDS- and non-AIDS-defining events. The SMART trial investigated the effects of continuous vs. delayed ART, whereas the START trial assessed early vs. delayed ART.
Findings from the studies established immediate and continuous ART as the standard of care for HIV, according to Borges and colleagues. However, safety monitoring boards terminated both trials prematurely before the target numbers of primary endpoints were met. As a result, each trial has limited evidence of some patient outcomes, including cardiovascular disease (CVD) and cancer, the researchers reported. To address this, Borges and colleagues analyzed pooled data from the studies to compare the effects of deferred and intermittent ART strategies vs. early and continuous ART strategies.
“We hypothesized that treatment hazard ratios would be similar in each study and that the pooled analysis would better quantify the relative difference between interrupted/deferred ART and continuous/immediate ART on risk of AIDS- and non-AIDS-defining events,” they wrote.
The pooled analysis included data from 10,156 participants with HIV (median baselined CD4 cell count, 634 cells/L). Among them, 124 developed AIDS-defining conditions, 247 developed serious non-AIDS-defining conditions, 117 developed cancer, 103 developed CVD and 120 died.
The median follow-up period was 1 year in the SMART trial and 3 years in the START trial. During follow-up, the average CD4 cell count in both trials was 194 cells/L higher in the immediate/continuous ART group than in the deferred/intermittent ART group. Differences in CD4 counts between the ART groups became apparent approximately 8 months after randomization and remained so throughout the follow-up period, according to the researchers.
Differences in viral load were also similar between SMART and START. Overall, 84.2% of participants in the immediate/continuous group had an HIV viral load of less than 400 copies/mL vs. 33.3% of participants in the deferred/intermittent group.
The similar differences in mean CD4 cell count and viral suppression led to parallel relative risk estimates for adverse events in SMART and START, Borges and colleagues reported. Compared with the immediate/continuous ART group, the risks were greater for AIDS-defining conditions (HR = 3.63; 95% CI, 2.37-5.56), serious non-AIDS-defining conditions (HR = 1.62; 95% CI, 1.25-2.09), CVD (HR = 1.59; 95% CI, 1.07-2.37), cancer (HR = 1.93; 95% CI, 1.32-2.83), and mortality (HR = 1.80; 95% CI, 1.24-2.61) among participants in the deferred/intermittent ART group. These findings were consistent across a range of subgroups, including age, gender, baseline CD4 count and income strata.
In a related editorial, Mark J. Siedner, MD, associate professor of medicine, and Virginia Triant, MD, assistant professor of medicine — both at Harvard Medical School and Massachusetts General Hospital — said it was “somewhat unexpected” that the benefits of ART were similar among patients with higher vs. lower levels of pretreatment inflammatory markers.
“On face value, this appears to contradict prior data from the SMART study, and others, that demonstrate how pretreatment levels of inflammation impact cardiovascular disease events and mortality,” they wrote. “However, more recently, other studies have suggested that time updated levels of disease control and inflammatory markers after ART initiation, as opposed to pretreatment levels, are more predictive of preclinical atherosclerosis and CVD events and that, particularly for non-AIDS events, inflammatory markers might not rise until just prior to events.”
The authors noted that the study results “offer a compelling reinforcement” of the benefits of early and continuous ART on individual health for people with HIV.
“Whereas many clinicians who treat HIV infection were likely aware of these effects before this study was published, there are accruing data that such protective individual benefits of ART are not always known among people with HIV,” they concluded. “Reaffirming these data in the public sphere will be a critical step towards improving ART uptake and improving health both for people with HIV and their partners and children.” – by Stephanie Viguers
Disclosures: The authors report no relevant financial disclosures.