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Issue: February 2007
February 01, 2007
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Episodic ART increases patient’s risk of death, AIDS and other diseases

The international SMART trial shows that interrupting ART more than doubles the risk of death and does not limit adverse events.

Issue: February 2007

A specific strategy of interrupting antiretroviral therapy more than doubles the risk of AIDS or death from any cause, according to results from a large HIV/AIDS treatment study published in The New England Journal of Medicine.

In the National Institute of Allergy and Infectious Diseases funded study, known as Strategies for Management of Anti-Retroviral Therapies (SMART), researchers used two predetermined levels of T-cells to guide them in respectively suspending or restarting participants with HIV on ART to determine what treatment method is best. Findings indicated that episodic ART does not reduce the risk of adverse events that are known to be associated with ART, according to the study.

“The SMART trial has provided important new data that will help physicians and their HIV-infected patients make treatment decisions,” said NIAID director Anthony S. Fauci, MD. “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.”

Wafaa El-Sadr, MD, MPH, MPA
Wafaa El-Sadr

As HIV/AIDS has evolved into a chronic disease without a cure, lifelong ART has become the norm. However, treatment for such a prolonged period can be difficult to adhere to as well as expensive. For these reasons, researchers have put forth a concerted effort to test treatment interruption strategies that may enhance patients’ quality of life and limit adverse events. The experimental strategies vary in their approach to when to interrupt therapy. Some, like the SMART trial, use a specific CD4 count as a guide; others schedule regular time periods during which treatment is stopped.

Evaluating treatment methods

The researchers designed the SMART trial to determine which of two different HIV treatment strategies would result in greater overall clinical benefit.

Four international centers coordinated the trial: the Medical Research Council Clinical Trials Unit in London; the Copenhagen HIV Program in Denmark; the National Center 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 in Washington, D.C. The statistical and data management center was based at the University of Minnesota in Minneapolis.

The SMART trial began in January 2002. The researchers conducted the study at 318 clinical sites in 33 countries. In the United States, the trial took place at locations in Arizona, California, Colorado, Connecticut, Delaware, Florida, Georgia, Illinois, Louisiana, Massachusetts, Michigan, Minnesota, Mississippi, New Jersey, New York, North Carolina, Oklahoma, Oregon, Pennsylvania, Texas, Virginia, Washington D.C. and Wisconsin.

The researchers recruited 5,472 volunteers with chronic HIV— nearly all of whom had taken ART — and randomly assigned them to one of two groups; the viral suppression group (2,752 participants) or the drug conservation group (2,720 participants).

In the viral suppression group, participants received ART on an ongoing basis throughout the study to suppress HIV viral load. Patients in the drug conservation group received episodic ART in an effort to reduce adverse events and preserve treatment options. In the latter group, the researchers suspended ART whenever CD4 counts were above 350 cells/mm3 and the participants started ART only when levels of CD4 cells dropped below 250 cells/mm3. The researchers chose the CD4 count thresholds for stopping and starting ART based on previously reported associations between CD4 counts and risks of opportunistic diseases and death.

They followed the participants for an average of 16 months. The primary end point was the development of an opportunistic disease or death from any cause and the secondary end point was major cardiovascular, renal, or hepatic disease, according to the study.

Findings to date

As reported in the February 2006 issue of Infectious Disease News, early last year NIAID made the decision to halt enrollment in the trial after an independent data and safety monitoring board reviewed interim results and found that those participants receiving episodic therapy had a significantly increased risk of disease progression. The researchers defined disease progression as the development of an opportunistic disease, specifically AIDS, or death from any cause.

The SMART trial’s executive committee recommended that ART be re-initiated in ART-experienced participants in the drug conservation group.

At the time that researchers stopped the trial, 120 participants in the drug conservation group developed disease progression or died compared with 47 on continuous ART in the viral suppression group. The difference represents a 2.6-fold increased risk for those receiving episodic treatment. Episodic ART guided by the CD4 count significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous ART, according to the study. Researchers said this is largely a result of lowering the CD4 cell count and increasing the viral load.

Notably, the drug conservation group had significantly more major adverse events, specifically, cardiovascular, kidney and liver disease, complications previously associated with ART. The researchers had hoped that these complications would be seen less frequently in those trial volunteers receiving fewer drugs.

“Quite unexpectedly, our results show that interrupting therapy increases the risk of serious non-AIDS-related events,” said Wafaa El-Sadr, MD, MPH, MPA, 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.”

James Neaton, PhD, of the University of Minnesota and the other co-chair and chief biostatistician for the trial, noted that this study demonstrated the advantages in conducting such a large trial among such a diversified group that can precisely access the benefits and risks of different treatment strategies.

“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,” he said. “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.”

Additional analyses

The NIH Office of AIDS Research held a workshop in July in London and assessed the current state of research on intermittent therapy strategies. Initial analyses of the findings in the SMART trial indicated that most but not all of the excess risk in the drug conservation group can be explained by CD4 count and viral load differences. The researchers said that continued patient follow-up and research will help to better understand the differences between the treatment groups and the best treatment for HIV patients.

“The prospect of lifelong treatment is difficult for people with HIV,” said David Cooper, MD, DSc, of the National Center in HIV Epidemiology and Clinical Research at the University of New South Wales. “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.”

Follow-up for the SMART trial is currently scheduled to continue through July 2007. – by Tara Grassia

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