November 29, 2006

The related SMART study news release can be found at http://www3.niaid.nih.gov/news/newsreleases/2006/nejmsmart.htm.

1.		What is the SMART trial?
		The Strategies for Management of Anti-Retroviral Therapy (SMART) trial is a large international trial designed to determine which of two distinct HIV treatment strategies yields a better clinical outcome over the long term. The trial enrolled HIV-positive participants with CD4+ cell counts of more than 350 cells per cubic millimeter (mm3) of blood. (CD4+ cells are a type of infection-fighting white blood cell and are a primary target of HIV.) Volunteers were randomized to receive one of two antiretroviral treatment (ART) strategies: continuous drug therapy, designed to suppress viral load as much as possible (the viral suppression, or VS, arm); or episodic ART (the drug conservation, or DC, arm). The use of ART in the DC arm was determined by the participant’s CD4+ cell count: trial participants in the DC arm began ART when CD4+ cell counts fell below 250 cells/mm3, with the aim of suppressing viral load and increasing the CD4+ cell count, and discontinued ART when counts were above 350 cells/mm3. Enrollment in SMART began in January 2002 (http://www3.niaid.nih.gov/news/newsreleases/2002/smart.htm). Full enrollment of 6,000 participants was expected to take three to five years. When enrollment was stopped on January 11, 2006, 5472 subjects had been enrolled.
2.		What were the rationale and primary objectives of the SMART trial?
		Widespread use of ART in economically developed countries has resulted in a significant decline in HIV-related illness and death. However, ART effectiveness may wane over time as the virus becomes resistant to drugs. There are also short- and long-term toxicities, as well as cost and quality-of-life issues, associated with lifelong ART. Therefore, a randomized clinical trial was implemented comparing the use of CD4+ cell-guided episodic ART (DC strategy) with continuous ART (VS strategy). The SMART trial was designed to compare the DC strategy with the VS strategy for progression to AIDS or death over a minimum follow-up period of six years for each patient. It was hypothesized that the DC strategy would result in lower rates of disease progression and serious toxicities as compared with the VS strategy in the planned follow-up period ranging from six to nine years.
3.		Who is conducting this study and where?
		The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA, http://www.cpcra.org) was funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to conduct the study. Since June 29, 2006, when NIAID announced the newly restructured HIV/AIDS clinical trials networks, the INSIGHT (International Network for Strategic Initiatives in Global HIV Trials, http://www.insight-trials.org/index.php) network has been conducting the study in continued collaboration with the Copenhagen HIV Programme in Denmark (CHIP, http://www.cphiv.dk); the Medical Research Council Clinical Trials Unit in London (MRC, http://www.ctu.mrc.ac.uk); the National Centre in HIV Epidemiology and Clinical Research at the University of New South Wales in Sydney, Australia (NCHECR, http://web.med.unsw.edu.au/nchecr); and the CPCRA. The 5,472 volunteers were enrolled at 318 sites in 33 countries. Sites are located in Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Denmark, Estonia, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Lithuania, Luxembourg, Morocco, New Zealand, Norway, Peru, Poland, Portugal, Russia, South Africa, Spain, Switzerland, Thailand, United Kingdom, United States and Uruguay.
4.		What did the study find?
		The article published in The New England Journal of Medicine [NEJM 355(22): 2283-96 (2006)] expands on the initial presentations of the trial data first announced by NIAID in January 2006 (www3.niaid.nih.gov/news/newsreleases/2006/smart06.htm) and subsequently presented by the principal investigators in February 2006 at the 13th Annual Conference on Retrovirology and Opportunistic Infections (see www.retroconference.org/2006/Abstracts/28085.HTM ) and in August 2006 at the XVI International AIDS Conference (http://www.iasociety.org/abstract/show.asp?abstract_id=2195953 and http://www.iasociety.org/abstract/show.asp?abstract_id=2194760). The main conclusion of the SMART study is as follows: Continuous use of ART is superior to episodic CD4+ count-guided ART in which ART is deferred until the CD4+ count falls to below 250 cells/mm3. The NEJM article clearly shows that the risks of death, opportunistic diseases and major cardiovascular, kidney and liver disease events were higher in the DC group than in the VS treatment group.  The higher risk of these events in the DC group was mostly due to their lower CD4+ cell count during follow-up. Not all of the increased risk in the DC group, however, was explained by their lower CD4+ counts and higher viral loads during follow-up. The reason for the additional excess risk of events in the DC arm is still unknown. The SMART study also found that diseases not typically associated with immunodeficiency or traditionally defined as AIDS-related (such as cardiovascular, kidney or liver disease) occurred at a significantly higher rate in the DC group compared with the VS group.  The article shows that regardless of the outcome measured—opportunistic disease or death from any cause; major cardiovascular, kidney or liver disease; or potentially life-threatening symptomatic events requiring medical intervention—the DC group had higher event rates than the VS group. The study also shows that the findings for a number of subgroups defined by baseline characteristics were consistent with the overall results. No subgroup had a better outcome in the DC group compared with the VS group. However, for some subgroups or individuals with different baseline characteristics the poorer outcome in the DC compared with the VS group was particularly marked. For instance, among individuals on ART with an HIV viral load of <400 copies/mL at entry, the relative risk (DC/VS) for opportunistic disease or death was much higher compared to individuals on ART with an HIV viral load >400 copies/mL at baseline. Additionally, participants in the VS group had better outcomes than those in the DC group irrespective of baseline or nadir (lowest ever) CD4+ cell count.
5.		How might these new findings affect the management of HIV disease?
		The current U.S. Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (Oct. 10, 2006) state: “Several clinical trials have been designed to determine the safety of such interruptions, in which re-initiation is triggered by pre-determined CD4+ T cell count thresholds.” Both the SMART and TRIVACAN studies showed that interruption was an inferior strategy, and the Guidelines go on to say, “… the interventions in both trials were stopped early because of these findings. Two small randomized studies with no reported safety concerns have been published. Other trials continue to collect data using other designs, including using higher CD4+ T cell count levels for reinitiation of therapy (e.g., CD4 >350/mm3), and have not been stopped because of safety concerns. These trials may yield additional data regarding the safety and efficacy of differing designs for intentional interruptions. However, until further data from randomized controlled trials are available, treatment discontinuation in clinical practice should be avoided outside of a clinical trial setting [italics added].”
6.		What is happening to the participants in the SMART Trial?
		Individuals enrolled in the VS arm of the study will continue to receive care from their primary care physician and will continue with the VS strategy, that is, continuous ART, as defined in the study. Participants in the DC arm who were on ART at the time the study was stopped were advised to stay on treatment. Those participants in the DC arm who were currently off ART but who had taken ART in the past were advised to review with their physicians the option to re-start ART. While the long-term risks and benefits of the DC arm remain uncertain, the short-term information indicated that it would be prudent to re-start ART. All study participants were invited to remain in study follow-up through July 11, 2007. Additional data are being obtained to determine whether the increased risk of opportunistic disease, death and other events in the DC group compared with the VS group is reduced when ART is reinitiated among DC participants.
7.		What are some of the key baseline characteristics of the trial participants?
		The overwhelming majority (95 percent) of SMART participants have had some experience with ART (a median of six years of ART use prior to enrollment). Median baseline and nadir CD4+ cell counts of study participants were 597 and 250 cells/mm3, respectively. Seventy-two percent of the participants had an HIV viral load < 400 copies/mL at baseline. The median age of enrollees at study entry was 43 years. Twenty-seven percent of the participants are women. Twenty-nine percent of participants are black, and 71 are white or of another race or ethnicity. Fifty-seven percent of participants were enrolled by sites in North America, 26 percent by sites in Europe, and the remainder from the other countries.

Media inquires can be directed to the NIAID OCPL media group at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID is a component of the National Institutes of Health. 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 basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

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 http://www.nih.gov

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