The SMART STUDY IS HALTED WITH Treatment Questions left unanswered
by Chael Needle
LifeGuide [Treatment Horizons]
Most knowledge about treatment options have been based on short-term studies. And good short-term treatments do not necessarily translate into good long-term treatments. The SMART (Strategies for Management of Anti-Retroviral Therapy) trial—one of the largest ever conducted in HIV/AIDS research—set out a few years ago to examine several still-unanswered questions about long-term antiretroviral treatments. When and under what conditions should a patient start antiretrovirals? How long will the treatment effects last? What are the risks and benefits of long-term use?
These questions, and others, were framed within an investigation into the pros and cons of two ways of treating HIV over a period of six to nine years. The first is continuous antiretroviral treatment, no matter what a patient’s CD4 cell count is, in order to suppress viral loads to undetectable. A consensus within the HIV research community agree that antiretroviral treatment should be used in asymptomatic patients when a CD4 cell count falls below 200 cells per cubic millimeter. However, in the absence of definitive data, no broad consensus has been reached for when to start therapy for asymptomatic patients with counts above this level. While the benefits of antiretrovirals has been established, patients are also facing the challenges of drug resistance, side effects, and drug adherence—not to mention cost. Is it better to wait until the risk of HIV-related complications are greater to begin therapy? The second is an episodic approach, and addresses this question by placing a patient on antiretroviral medications whenever his or her CD4 cell count drops below 250 cells per cubic millimeter, when the risk of getting sick is supposed to be higher, and taking them off the medications when the count rises to 350 or higher.
Sponsored by the National Institute of Allergy and Infectious Diseases, the international randomized, long-term study is being conducted by the Community Programs for Clinical Research on AIDS (CPCRA), the Copenhagen HIV Programme (CHIP), the Medical Research Council (MRC), and the National Centre in HIV Epidemiology and Clinical Research (NCHECR). The trial has enrolled 5,472 patients across 318 clinical sites in thirty-three countries. Individual physicians designed antiretroviral-based regimens according to the specific needs of patients; no standard regimen was requisite.
As of January, the trial has been stopped because patients who have been receiving episodic therapy were found to have more than twice the risk of disease progression, as well as increased complications such as cardiovascular, kidney, and liver diseases, than those patients who have been receiving continuous therapy. The halt of the study was the result of a recommendation by an independent Data and Safety Monitoring Board; the SMART executive committee and NIAID agreed with the recommendation. Average follow-up at the time of the DSMB review had been fifteen months. Though enrollment has stopped, the study will continue with its follow-up visits with participants and consider plans for a longer follow-up. The SMART executive committee recommended to study investigators that patients who were antiretroviral-experienced and in the group receiving episodic therapy to begin continuous treatment.
Researchers had hoped that complications, such as cardiovascular disease and liver-related problems, would abate in those receiving episodic therapy, as antiretroviral treatment has long been associated with side effects such as these. Investigators will look into the reasons for the increased risk associated with this particular short-term episodic therapy and patient group. The question of long-term episodic therapy, as posed by the SMART study, has been deferred for now. Other researchers have not written off episodic therapy, noting that it may turn out to confer more benefit to those who initiate therapy with high CD4 counts than those whose counts have previously fallen. And of course the question of the benefits of long-term continuous therapy still remains unanswered.
In the January issue, Chael Needle wrote about residual effects of anti-HIV medications which have been interrupted and the possible benefits of resistant strains of HIV.
February 2005 |
