SMART & TAG

[Guest guest]

Important review from the Treatment Action Group re the SMART study.

M.

**

For immediate

release CONTACT:

Jefferys

18 January

2006

Treatment Action Group Statement on the

Termination of the SMART Study

New York NY, January 18, 2006 – The Treatment Action Group (TAAG) today

expressed disappointment that SMART – a large, international study

comparing CD4-guided, intermittent antiretroviral therapy to continuous

treatment – has had to be stopped due to a significantly higher

incidence of clinical events in the intermittent treatment arm. TAG

salutes the many researchers and participants involved in this large and

important trial of HIV treatment strategies. However, TAG also wishes to

stress that the conclusion being promulgated by the National Institutes

for Allergy & Infectious Diseases (NIAID), “International HIV/AIDS

Trial Finds Continuous Antiretroviral Therapy Superior to Episodic

Therapy†(see

http://www.nih.gov/news/pr/jan2006/niaid-18.htm), could be

over-interpreted. SMART has shown that, over the short term, continuous

therapy is superior to the specific strategy of episodic therapy employed

in the trial.

SMART evaluated a “drug conservation†approach that involved

interrupting therapy when CD4 counts crested 350 cells and restarting

when they fell below 250, and compared this to a standard “virological

suppression†strategy using continuous therapy. The primary endpoints

were progression to AIDS and death in the two arms, with secondary

endpoints including incidence of potentially drug-related toxicities such

as cardiovascular disease and liver problems. The study was addressing an

important question because, while it is known that continuous therapy is

beneficial in the short term, it remains unknown whether there is a point

at which long term toxicities become a greater risk than events related

to disease progression. It is also not known if intermittent CD4-guided

therapy might be a less costly and toxic strategy for preventing disease

progression. The study has reportedly been stopped by the Data Safety

Monitoring Board (DSMB) due to roughly twice as many clinical events

occurring in the drug conservation arm compared to the virological

suppression arm. The nature and seriousness of the clinical events in

question remain unknown at this time. Perhaps surprisingly, it is also

reported that there was a higher incidence of events relating to drug

toxicity in the drug conservation arm.

It is important to emphasize that the cessation of SMART does not

necessarily mean that all treatment strategies involving interruptions of

antiretroviral therapy are dangerous, just that the specific approach

employed by the SMART study design was less successful at preventing

clinical events than continuous treatment. There is a large body of data

suggesting that individuals who initiate therapy with relatively high CD4

counts (for whom therapy would no longer recommended based on recent

guidelines) can safely interrupt therapy.

Previous treatment interruption studies have also uniformly identified

the CD4 nadir (lowest ever CD4 count, usually experienced before any

antiretroviral therapy was initiated, or after virologic treatment

failure) as a predictor of clinical events during treatment interruption

and the SMART study accepted participants without regard to their CD4

nadir.

One of the key goals of the SMART study was to answer the question of

whether less exposure to antiretroviral therapy would reduce the

incidence of potentially life-threatening drug-associated toxicities.

Recent data has emphasized the importance of addressing this question,

suggesting that such toxicities can pose a greater risk for individuals

on therapy than clinical events related to disease progression (see

Reisler et al, JAIDS 34;4:379-386, 2003). In light of this fact, TAG

strongly believes that further studies of treatment interruption and

intermittent therapy strategies, addressing questions different from

those addressed by SMART, continue to be warranted. Data from the SMART

study should be used to design potentially safer approaches to CD4-guided

therapy, with particular attention paid to the impact of CD4 nadir and

the CD4 threshold for restarting therapy on the outcome of SMART. Ongoing

trials of treatment interruption strategies, such as the international

DART trial, should be reviewed in order to establish whether the data

from SMART impacts the study design, but it would be premature to cease

all investigation of intermittent treatment strategies because of the

results from SMART.

The early cessation of SMART also means that the long term incidence of

toxicity-related events among individuals on continuous antiretroviral

therapy in this study will not be quantified unless follow-up is

continued. TAG urges to the study sponsors to follow-up study

participants for long term outcomes.

The SMART study was designed and conducted by the Community Programs for

Clinical Research on AIDS (CPCRA), an international network of clinical

trial sites funded by the Division of AIDS (DAIDS) of the National

Institute of Allergy and Infectious Diseases (NIAID), one of the National

Institutes of Health (NIH). TAG has been a strong supporter of the SMART

study and believes that it asked and answered a question of paramount

importance in the search for optimal antiretroviral treatment strategies,

balancing the need to preserve immune function with that of avoiding

unnecessary toxicity and expense.

Well designed studies that ask and answer important questions in a

reliable, definitive way with adequate sample size, statistical power,

participant retention, and length of follow-up are all too rare in the

HIV field. The NIH should be commended for supporting, and the CPCRA for

designing and executing this important study, which adds to our

understanding of the optimal ART standard of care.

About TAG. The Treatment Action Group (TAG) fights to find a cure for

AIDS and to ensure that all people living with HIV receive the necessary

treatment, care, and information they need to save their lives. TAG

focuses on the AIDS research effort, both public and private, the drug

development process, and health care delivery systems. We meet with

researchers, pharmaceutical companies, and government officials to

encourage exploration of understudied areas in AIDS research and speed up

drug development, approval, and access. We work with the World Health

Organization and community organizations globally, and strive to develop

the scientific and political expertise needed to transform policy. TAG is

committed to working for and with all communities affected by HIV.

Jefferys is the Director of the Palm Basic Science,

Prevention, and Vaccines Project, which seeks to accelerate research on

HIV pathogenesis, immunology, immune-based therapies, vaccines, and

biomedical prevention interventions. The Project is funded by The

Palm Foundation. Palm was a philanthropist and an early and

consistent supporter of TAG.

For more information:

Treatment Action Group

611 Broadway, Suite 608

New York, NY 10012 USA

1. – tel.

1. – fax

www.treatmentactiongroup.org

tagnyc@...

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