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SMART Starts! (And Not a Moment Too Soon)

January 2002

The Community Programs for Clinical Research on AIDS (CPCRA) has opened a new clinical trial of a size and duration designed to finally provide high quality data about what happens to people who have been on antiretroviral therapy for more than a couple of years. The SMART study (Strategies for Management of Antiretroviral Therapy) plans to enroll 6,000 people and follow them for as long as seven years. The trial will be the first randomized comparison of two viable but competing strategies for how to treat HIV. The study is open to both treatment-naive and treatment-experienced HIV-positive people over the age of 13 who currently have CD4 counts over 350. The only other requirement is a willingness to admit an open mind (or just plain confusion) about the optimum way to use antiretroviral therapy for the best long-term outcome.

SMART participants will be randomly assigned to one of two camps. One group will follow the classic path of making every effort to keep their viral loads undetectable at all times. This is the VS (viral suppression) group. They will face off against the DC (drug conservation) group who will follow a strategy of avoiding treatment (despite detectable viral load numbers) as long as their CD4 counts stay above 250. People in this group will probably tend to go on and off drugs as needed, while the folks in the VC group will tend to go on drugs and stay on, switching parts of their regimens whenever viral load bounces back. The trial has been characterized as a comparison of continuous versus episodic therapy or the "hit hard" versus the "go slow" schools of thought.

Although recent versions of treatment guidelines recommend starting therapy later, there is little evidence other than some observational studies and expert opinion for either treatment strategy. Many clinicians reason that some drug toxicity is an acceptable price to pay compared to the risk of becoming resistant to antiviral drugs, losing immune competency and developing AIDS. Other HIV physicians increasingly worry that long-term toxicity from the drugs may eventually erase the life-extending benefits of HAART. Both of these views are reasonable given an individual's training and experience, but there is little objective data to convincingly support one over the other. This is what SMART will help provide.

Seven years ago when the promise of protease inhibitors was first coming into focus, the idea of launching a seven-year trial was unthinkable to many people. Most were thrilled to be given another six months of life; seeing the next century seemed like an impossible dream. But expectations have changed, although after many years we still lack answers to fundamental questions about the best way to treat the disease. With the realization that no truly dramatic therapeutic breakthrough is on the horizon, setting out on a seven-year long study doesn't seem as impractical these days.

The trial also incorporates several substudies within the main objective. One particularly overdue investigation will examine the effects of treatment on the heart. Another will examine how treatment causes changes to body fat distribution and bone density. Additional substudies will compare quality-of-life measures, cost-effectiveness, drug resistance and HIV transmission.

Dr. Wafaa El-Sadr, principal investigator at Harlem Hospital and Columbia University in New York and co-chair of the study commented, "A trial of this scope and length will be a challenge. [But] the SMART study will address questions that are uppermost in the minds of people with HIV and the clinicians who treat them. While significant advances have been made in the treatment of HIV, after two decades we still do not know for certain that the current method of treating HIV, with continuous therapy to maximally suppress viral load, is the best way to manage HIV in the long-run."

SMART is one of the most important research undertakings to come out of the government trials system since the early 1990s. It has the historic potential to produce a body of information with broad and lasting significance, not only for the health of the participants, but for the millions of HIV-positive people in the world who will eventually face the need to begin treatment.

For more information about the trial, visit the SMART Study Web site at Information about SMART and other AIDS clinical trials and how to enroll is available at the AIDS Clinical Trials Information Service (ACTIS) Web site or 1-800-874-2572 (1-800-TRIALS-A).

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