|International HIV/AIDS Trial Finds Continuous Antiretroviral Therapy Superior to Episodic Therapy
The National Institute of Allergy and Infectious Diseases (NIAID), part
of the National Institutes of Health (NIH), today announced that enrollment
into a large international HIV/AIDS trial comparing continuous antiretroviral
therapy with episodic drug treatment guided by levels of CD4+ cells has
been stopped. Enrollment was stopped because those patients receiving episodic
therapy had twice the risk of disease progression (the development of clinical
AIDS or death), the major outcome of the study.
NIAID made the decision to halt enrollment in collaboration with
the study’s Executive Committee and following a recommendation
received from an independent Data and Safety Monitoring Board (DSMB).
The DSMB, charged with regularly evaluating data and safety issues
during the multi-year trial, conducted a review of the interim
study data in early January.
The trial, known as Strategies for Management of Anti-Retroviral
Therapy, or SMART, was designed to determine which of two different
HIV treatment strategies would result in greater overall clinical
benefit. HIV-positive volunteers were assigned at random to either
a viral suppression strategy, in which antiretroviral therapy (ART)
was taken on an ongoing basis to suppress HIV viral load; or a
drug conservation strategy, in which ART was started only when
the levels of key immune cells, called CD4+ cells, dropped below
250 cells per cubic millimeter (mm3). Volunteers in the drug conservation
group were taken off ART—with the aims of reducing drug side
effects and preserving treatment options—whenever their CD4+
cells were above 350 cells/mm3. (For more details see http://www.smart-trial.org).
The trial involved an international collaboration of 318 clinical
sites in 33 countries. It began enrollment in January 2002 and
had successfully recruited more than 90 percent of its target of
6,000 participants: as of January 11, 2006, when enrollment was
stopped, 5,472 volunteers had joined the study.
At the time of the DSMB review, the average follow-up was approximately
15 months. The analysis revealed that participants on CD4+ cell-guided
episodic treatment faced more than twice the risk of disease progression
relative to participants on continuous ART. Furthermore, there
was an increase in major complications such as cardiovascular,
kidney and liver diseases in the participants on the drug conservation
arm. These complications have been associated with ART, and it
was hoped that they would be seen less frequently in those patients
receiving less drug.
Although the risk-to-benefit ratio of drug conservation over the
longer term remains uncertain, the DSMB recommended that enrollment
into the trial be halted in light of the findings to date, and
the SMART Executive Committee and NIAID agreed with the recommendation.
Upon reviewing the results, the Executive Committee also conveyed
to local study investigators its recommendation that it would be
prudent to re-initiate therapy in ART-experienced patients in the
drug conservation arm. All study physicians and participants are
being notified of the findings and recommendations.
Follow-up visits will continue for all participants in the SMART
trial while the study team considers plans for longer follow-up.
The investigators will analyze the SMART study data in detail
to gain insights into the reasons for the increased risk.
“SMART is one of the largest HIV/AIDS treatment trials ever
conducted,” notes 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 exceptional achievement in
contributing to this pivotal HIV/AIDS treatment study.”
“This trial was designed to help physicians and their HIV-positive
patients identify the best approach to treatment management,” adds
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 principal
investigators for the trial. “We were surprised to learn
that in the short term, episodic antiretroviral therapy carries
such an increased risk without evidence of sparing patients the
known side effects associated with ART.”
The University of Minnesota’s James Neaton, Ph.D., another
principal investigator and chief biostatistician for the trial,
notes, “The SMART trial reached a conclusion much earlier
than we expected. That is the significant value and potential power
of conducting such a large trial.”
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
Fred Gordin, M.D., of the VA Medical Center in Washington, DC,
the CPCRA director, says, “It is gratifying when the fruits
of such hard work by so many individuals and the faith put in the
investigators by the volunteers results in important data concerning
the use of ART.”
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, “SMART
is an example of how a large group of investigators around the
world can work together to obtain an answer to an important HIV
Further information concerning the study findings can be found
in a Questions and Answers document below. An earlier NIAID news
release describing the initiation of the SMART trial can be viewed
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agency of the U.S. Department of Health and Human Services. NIAID
supports basic and applied research to prevent, diagnose and treat
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agents of bioterrorism. NIAID also supports research on transplantation
and immune-related illnesses, including autoimmune disorders, asthma
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Questions and Answers:
A Large International HIV/AIDS Study Comparing Two Strategies
for Management of Anti-Retroviral Therapy (The SMART Study)
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
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 3
to 5 years. As of January 11, 2006, when enrollment was stopped,
more than 90 percent of the volunteers 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 6 years for each patient. It was hypothesized that the DC
strategy would result in lower rates of disease progression and
serious toxicities as compared to the VS strategy in the planned
follow-up period ranging from 6 to 9 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. The CPCRA is conducting this study, known
as CPCRA 065, in 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);
and 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). As of January 11, 2006, 5,472
volunteers had been 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,
4. What is the Data and Safety Monitoring Board, and how does it monitor this
The Data and Safety Monitoring Board (DSMB) is an independent committee composed
of clinical research experts, statisticians, ethicists, and community
representatives. The DSMB reviews data while a clinical trial
is in progress to ensure the safety of participants. The DSMB
may recommend that a trial, or part of a trial, be stopped if
there are safety concerns or if the trial objectives have either
been achieved or are unlikely to be achieved. The DSMB looks
at analyses that are not available to the investigators or to
anyone else. The SMART study was monitored at a minimum annually
by an NIAID DSMB.
5. What were the results of the most recent DSMB review?
The DSMB for the SMART trial reviewed interim data from this study in early November
2005 and in early January 2006. At the time of their January
review, the average follow-up was approximately 15 months; some
patients had been followed for approximately 3.5 years. The data
at the last review indicated that volunteers in the DC arm of
the trial had more than twice the risk of progression to AIDS
or death compared with individuals in the VS arm.
6. What actions were taken by the DSMB and the SMART Executive Committee?
On January 10, 2006, the DSMB informed the Executive Committee that there was
an increased risk of disease progression in the DC group, and
that it appeared very unlikely that the DC arm would be found
to be superior to the VS strategy in the planned follow-up period
of the trial. The DSMB recommended that enrollment into the trial
be stopped and that steps be taken to minimize risks to patients.
The SMART Executive Committee decided to recommend to site investigators
that treatment-experienced patients in the DC arm who were not
taking ART be re-started on therapy.
On January 11, 2006, the Executive Committee informed the SMART trial investigators
of 1) the increased risk of disease progression and other clinical
events in the DC arm; 2) treatment recommendations for patients
in the DC arm; and 3) the decision to stop enrollment.
Study participants are currently being notified of the findings and recommendations.
7. What does the SMART Executive Committee recommend for study participants?
Individuals currently 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 as defined in the study.
Participants in the DC arm who are currently on ART will be advised to stay on
treatment. Those participants in the DC arm who are currently
off ART, but who have taken ART in the past, are being 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 indicates that it would be prudent
to re-start ART.
Because the study findings do not address the question of when to start ART,
it is advised that the decision to initiate ART for those participants
in the DC arm who have never been on ART should be based on local
treatment guidelines on when to initiate ART.
Follow-up visits will continue for all participants in the SMART trial while
the study team considers plans for longer follow-up. Data collection
(such as case report forms and laboratory reports) will continue
for all enrollees as specified by the trial protocol.
8. 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. 6, 2005) state: “Several clinical trials have
been conducted to better understand the role of treatment interruption in these patients,
yielding conflicting results. The Panel [the Panel on Clinical Practices for Treatment of
HIV Infection convened by DHHS] notes that partial virologic suppression from combination therapy
has been associated with clinical benefits, thus interruption is generally not recommended unless it
is done in a clinical trial setting.”
The data from the SMART trial provide evidence that episodic use of ART based on CD4+ cell
levels as used in the study is inferior to use of continuous therapy for treatment-experienced
patients and thus should not be routinely recommended.
9. What were 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 598 and 253 cells/mm3, respectively.
- Seventy percent of the participants had an HIV viral load < 400 copies/milliliter at baseline.
- The average age of enrollees at study entry was 46 years.
- Twenty six percent of the participants are women.
- Thirty-one percent of participants are black, and 69 are white or of another race or ethnicity.
- Fifty-five percent of participants were enrolled by sites in the United States,
26 percent by sites in Europe, and the remainder from the other countries.
Media inquiries can be directed to Laurie K. Doepel at 301-402-1663, firstname.lastname@example.org.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.