NIH NEWS
************************************************************
National Institute of Allergy and Infectious Diseases
National Institutes of Health

FOR IMMEDIATE RELEASE
Wednesday, Jan. 18, 2006

Media Contact: Laurie K. Doepel
(301) 402-1663
niaidnews@...



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 in Minneapolis.

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 treatment
question."

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 at
http://www3.niaid.nih.gov/news/newsreleases/2002/smart.htm.



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>.




NIH NEWS
************************************************************
National Institute of Allergy and Infectious Diseases
National Institutes of Health

FOR IMMEDIATE RELEASE
Wednesday, Jan. 18, 2006



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 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 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, and Uruguay.

4. What is the Data and Safety Monitoring Board, and how does it
monitor this study?

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,
niaidnews@....

News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at <http://www.niaid.nih.gov>.