In the news ... 2006 archive

SMART Study Stops Enrolling

January 12, 2006

The Executive Committee of the SMART (Strategies for Management of Anti-Retroviral Therapy) study has decided to halt further enrollment in the study. The decision was based on recommendations from the study’s Data Safety and Monitoring Board (DSMB)—an independent group charged with ensuring the safety and ethics of the trial. While little is known at this time, this article will review the study, the reason for the decision to stop enrollment, and what it means.

What is a DSMB?
When medical research is done on people, there are systems put in place to protect the rights and safety of the study volunteers. A Data Safety Monitoring Board is one of those systems. A DSMB is a group of experts who are not connected to the people doing the research or the companies that make the study drugs. They regularly review the information collected—the data—to ensure that any harm being done to the people in the study is caught as early as possible. The researchers conducting a study may see any harmful effects, but they are typically not allowed to know which medications each patient is on. Therefore, the role of the DSMB is critical to ensure patient safety.

What is SMART?
The SMART study was designed to compare two approaches to anti-HIV drug therapy: continual anti-HIV drug therapy vs. ”episodic” therapy guided by laboratory markers, where people go on and off anti-HIV drugs based on their CD4+ cell counts. The study was to enroll 6,000 people, who would be studied for 3.5 years.

There were two groups, or arms, in the study—one for each strategy. In the first approach, called the Virologic Suppression strategy, half of the people in the study would be put on anti-HIV drugs and stay on them as long as their viral load became and stayed undetectable. People would change anti-HIV drugs if either they couldn’t reduce their viral load to undetectable levels, or if their viral load became detectable later on. In the second approach, called the Drug Conservation strategy, people would only take anti-HIV drugs if their CD4+ count (T cell count) fell to 250 or below, and they would stop taking anti-HIV drugs once their CD4+ cell count rose above 350 on two successive tests.

Why SMART?
As experience and confidence in using anti-HIV drugs has grown, new questions have arisen, particularly on how best to use them. One question is once people start taking anti-HIV drugs: “Do they need to stay on them forever?” Three general observations have added weight to this question.

The first is the difficulty people have staying on, or adhering to, their anti-HIV drugs over the long term. A number of studies have shown that long-term adherence to anti-HIV drugs poses significant problems for many people living with HIV. For more information on adherence, read Project Inform’s publication, Adherence: Keeping Up with Your Meds.

The second observation is the very real and sometimes dangerous side effects and toxicities associated with anti-HIV drugs. Long-term use of anti-HIV drugs has been linked to changes in body shape (lipodystophy), increases in the risk of heart disease and diabetes, as well as liver and other organ system damage. In at least some of these examples the risk is directly linked to the amount of time people take anti-HIV drugs. For more information about side effects and lipodystrophy, read Project Inform’s publications, Dealing with Drug Side Effects and Lipodystrophy.

The last issue is the development of resistance to anti-HIV drugs. Numerous studies, as well as clinical experience have shown that the longer people take anti-HIV drugs the higher the risk of developing resistance.

The practice of taking people off of anti-HIV drugs for some period of time, under the guidance of their doctor is called a Structured Treatment Interruption. STIs have been studied in a variety of ways, with a number of different goals. For more information about STIs, read Project Inform’s publication, Strategies for Attempting an STI.

The SMART study was designed to compare one STI strategy—the Drug Conservation strategy—to the more accepted approach of uninterrupted anti-HIV drug treatment—the Virologic Suppression strategy.

What happened?
The DSMB recommended that enrollment in the study be halted when they reviewed data collected when they had an average of 15 months follow-up on the people enrolled. The study had not yet fully enrolled, but had reached 90% of its enrollment goal. At that time they found that people in the Drug Conservation group had approximately twice (1.7 times) the risk of disease progression than people in the Viral Suppression group. They determined that continuing the study as designed placed an unacceptably high risk of illness and death for the people in the Drug Conservation group.

As of this date, however, no actual numbers of the events of progression or death have yet been provided. A very surprising second finding was that the group receiving continuous therapy actually had a lower rate of the side effects commonly associated with long-term therapy use. This is a confusing finding since one of the hopes of reducing the time people spend on therapy was to reduce such side effects. Instead, people receiving more drugs for longer periods experience fewer such side effects.

In addition to halting further enrollment in the study, the letter made several recommendations. For people in the Viral Suppression group, no changes were advised. For people in the Drug Conservation group the recommendations depended on the person’s treatment history. If they had taken anti-HIV drugs before (treatment experienced) the study recommended that they restart anti-HIV drugs. If they had never taken anti-HIV drugs (treatment naïve), the study recommended that they base their decision whether to start anti-HIV drugs on ‘local guidelines.’

What didn’t happen?
The study was not stopped. The study will continue to follow all the people who were already enrolled in the study, under the same protocol as before. No new people will be able to start the study.

What does it all mean?
It is premature to draw many conclusions from this study’s enrollment being stopped. At this writing all we know is that the people in the Drug Conservation group were almost twice as likely to experience disease progression—defined as new AIDS-defining illness or death—as people in the Viral Suppression group. However, we don’t know the level of disease progression or death. It could be very small, in which case only a modest number of events might separate the two groups under study. Or the level of events could be higher, making it more important to avoid treatment interruptions. The data is simply not available to the public at this point. Clearly, much more data and analysis are needed to fully understand what this result means for people living with HIV in general and for STIs in particular.

Another issue which is impossible to determine is how broadly these conclusions can be applied. The Drug Conservation strategy in the study withheld therapy until a patient’s CD4+ cell count had fallen below 250, and they were taken off therapy again as soon as it reached above 350 cells. Withholding therapy until a patient has 250 CD4+ cells is generally considered a risky strategy. Federal guidelines recommend treatment when the CD4+ cell count falls below 350, the level at which this study instead too people off therapy. It is not clear whether the results of this study were affected by the use of this lower threshold for starting therapy, nor is it clear whether the harmful effects of interrupting treatment are as likely in people with higher CD4+ cell counts. Further details of this study will be presented at the Conference on Retroviruses and Opportunistic Infections in early February 2006 in Denver.

When we are able to evaluate more of the data that led to this decision, we will hopefully learn more. For now there are many unanswered questions. Here are some things we might learn from studying more of these data:

Did CD4+ cell nadir (the lowest point a person’s CD4+ cell count ever was) affect their risk of disease progression?

Did the use of a lower threshold for starting therapy (250 CD4+ cells) affect the risk of progression?

Did the choice on anti-HIV drugs have any affect on outcomes?

Was there a difference in quality of life measures between the groups?

It is almost always disappointing when a study is derailed before its work is done, especially when it was attempting to answer important questions. It is a particular disappointment that this study had to be stopped because of relatively short-term effects, when the goal of the study was to determine true long-term outcomes. We will not see meaningful long-term outcomes now from this study. While there is more to learn about this situation, it does appear that the systems in place to protect the people in the study worked as they are designed to.

Project Inform will continue to advocate for more quality research on STIs and other questions on how best to use anti-HIV drugs. While the problems with the SMART study are sobering, they should not detract us one bit from the vital work ahead of us—to better understand HIV disease and its treatment, and ultimately the cure.