Results from one of the largest HIV/AIDS treatment trials ever conducted show that a specific strategy of interrupting antiretroviral therapy more than doubles the risk of AIDS or death from any cause. In the study, the investigators used two predetermined levels of CD4+ T cells, the primary immune cell targeted by HIV, to guide them in respectively suspending or restarting the study participants on antiretroviral therapy.

A report describing this research — which involved 318 clinical sites in 33 countries — appears in this week’s issue of The New England Journal of Medicine. The trial, known as Strategies for Management of Anti-Retroviral Therapies, or SMART, was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

“The SMART trial has provided important new data that will help physicians and their HIV-infected patients make treatment decisions," says NIAID Director Anthony S. Fauci, M.D. "The study reflects an extraordinary global collaboration among hundreds of dedicated AIDS clinicians and thousands of their patients, all of whom should be commended for their contributions to this pivotal HIV/AIDS treatment study.”

As HIV/AIDS has evolved into a chronic disease without a cure, lifelong antiretroviral therapy has become the norm. Lifelong therapy, however, can be difficult to adhere to as well as expensive. For these reasons, there has been a concerted research effort to test treatment interruption strategies that may enhance patients’ quality of life and limit adverse drug effects. The experimental strategies vary in their approach to when to interrupt therapy. Some, like SMART, use a specific CD4+ count as a guide; others schedule regular time periods during which treatment is stopped (for example, alternating one month off and three months on).

SMART was designed to determine which of two different HIV treatment strategies would result in greater overall clinical benefit. Volunteers with chronic HIV infection — nearly all of whom had taken antiretroviral therapy (ART) — were assigned at random to one of two groups. In the “viral suppression” group, ART was taken on an ongoing basis to suppress HIV viral load; in the “drug conservation” group, participants received episodic ART in an effort to reduce drug side effects and preserve treatment options. In the latter group, ART was suspended whenever CD4+ counts were above 350 cells per cubic millimeter (mm3) and ART was started only when levels of CD4+ cells dropped below 250 cells/mm3. (For more details see http://www.smart-trial.org.) The CD4+ count thresholds for stopping and starting ART were chosen based on previously reported associations between CD4+ counts and risks of opportunistic diseases and death.

Beginning in January 2002, the trial recruited 5,472 volunteers: 2,720 were assigned at random to the drug conservation group and 2,752 to the viral suppression group. The participants were followed for an average of 16 months.

In early 2006, NIAID announced that enrollment into the trial had been halted after review of the interim data by an independent data and safety monitoring board (DSMB) found that those participants receiving episodic therapy had a significantly increased risk of disease progression. “Disease progression” was defined as the development of an opportunistic disease (AIDS) or death from any cause. The Executive Committee of SMART recommended that ART be re-initiated in ART-experienced participants in the drug conservation group. Follow-up is currently scheduled to continue through July 2007.

At the time the trial was stopped, 120 participants in the drug conservation group compared with 47 on continuous antiretroviral therapy had developed disease progression. The difference represents a 2.6-fold increased risk for those receiving episodic treatment. Notably, the drug conservation group had significantly more major adverse events, specifically, cardiovascular, kidney and liver disease, complications previously associated with ART. The study investigators had hoped that these complications would be seen less frequently in those trial volunteers receiving less drug.

“Quite unexpectedly, our results show that interrupting therapy increases the risk of serious non-AIDS-related events,” says Wafaa El-Sadr, M.D., M.P.H., M.P.A., of the Harlem Hospital Center and Columbia University in New York City, one of the co-chairs of the trial. “This is a major lesson learned for designing any HIV/AIDS treatment trial: It is important to evaluate all causes of death, not just death from AIDS, and to also evaluate other major non-fatal clinical diseases, not just those considered AIDS-related opportunistic diseases.”

The University of Minnesota’s James Neaton, Ph.D., the other co-chair and chief biostatistician for the trial, notes, “The SMART study demonstrates the tremendous advantages inherent in conducting large enough trials to precisely assess risks and benefits of any treatment strategy in a diverse population. First, the study ended much earlier than we expected. Second, we could analyze the data according to many variables — age, race, sex, HIV risk behavior, and baseline CD4+ count, among other factors. Importantly, among every subgroup we looked at, the conclusion remained consistent: CD4+ count-guided episodic antiretroviral therapy as implemented in the SMART study carries increased health risks compared with continuous therapy.”

The SMART study was coordinated by four international centers: the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia; and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) in Washington, DC. The statistical and data management center was based at the University of Minnesota in Minneapolis.

Fred Gordin, M.D., of the VA Medical Center in Washington, DC, the CPCRA director, says, “The study participants understood that our goal was to test a strategy that we hoped might simplify their treatment and prevent some adverse side effects. SMART has better focused the discussion of what questions we can and should be addressing in this important area of HIV/AIDS treatment research.” A workshop held by the NIH Office of AIDS Research in July in London assessed the current state of research on intermittent therapy strategies (http://www.oar.nih.gov/public/NIH_OAR_STI_IT_Report_Final.pdf).

Initial analyses indicate that most but not all of the excess risk in the drug conservation group can be explained by CD4+ count and viral load differences. Jens Lundgren, M.D., Director of the Copenhagen HIV Programme and the Copenhagen international coordinating center, says, “The continued follow-up of patients and planned research on patient specimens will help us better understand the differences between the treatment groups that we observed.”

David Cooper, M.D., D.Sc., of the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales, the Sydney international coordinating center director, notes, “The prospect of lifelong treatment is difficult for people with HIV. We are gratified that the SMART study has so clearly delineated the risk and benefits of these two strategies, and we are committed to continuing to try to find ways to improve treatment strategies for those with chronic HIV disease.”

Janet Darbyshire, M.Sc., FRCP and Director of the MRC Clinical Trials Unit and the London international coordinating center comments, “This question could not have been answered so quickly without the collaboration and active participation of the 318 clinical sites and thousands of patients worldwide which contributed to SMART. Such collaborations are essential if we are to answer some of the key strategic questions about how to best manage HIV disease.”

Further information concerning the SMART study findings can be found in a Questions and Answers document (http://www3.niaid.nih.gov/news/QA/NEJMsmart_QA.htm). Earlier NIAID news releases describing the initiation of the SMART trial and the stopping of enrollment into the trial can be viewed at http://www3.niaid.nih.gov/news/newsreleases/2002/smart.htm and http://www3.niaid.nih.gov/news/newsreleases/2006/smart06.htm, respectively.

NIAID is a component of the National Institutes of Health, an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.