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Risk of Interruption SMART Study
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SMART researchers plan follow-through
AIDS June 26, 2006 Vol 20, Issue 10
Enrollment in the Strategies for Management of Anti-HIV Therapy (SMART) clinical trial ended unexpectedly early, but the work of the study's investigators is by no means over. They continue, of course, to analyze the 'counter-intuitive' findings in hopes of explaining why the participants who took episodic antiretroviral therapy fared so poorly compared to those who stayed on medication. But they are also delving into the data of several substudies nested within the large international investigation.
And in April, members of SMART's executive committee met with representatives from the US National Institute of Allergy and Infectious Diseases (NIAID), the
component of the National Institutes of Health that funded the trial. It was the first of perhaps several meetings to hammer out an amended protocol to keep tabs on the 5472 people whowere already participating in SMART when enrollment was stopped on 11 January, 2006.
''We're getting together to review proposals on what to do with these patients, how to maximize the knowledge from this large study, and to try to understand from all the data we've been collecting what we should continue to collect,'' says Fred Gordin, director of the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) in Washington, DC, one of four regional centers overseeing SMART.
Begun in January 2002, the $20 million/year trial aimed to determine whether episodic use of antiretroviral drugs would slow disease progression while minimizing the short- and long-term toxicities, drug resistance, cost and quality-of-life issues associated with continuous antiretroviral therapy (ART). A total of 318 clinical sites in 33 countries had enrolled HIV-positive volunteers and randomly assigned them to either of two HIV treatment strategies. Half of the patients were treated following current HIV treatment guidelines, which call for
initiating antiretroviral drugs when CD4 cells drop to 350 cells/ml and maintaining therapy to keep HIV in the blood suppressed to low or undetectable levels.
The other half of the participants followed a drug conservation strategy that involved starting and stopping ART. These volunteers deferred taking antiretroviral drugs until their CD4 cell counts dropped below 250 cells/ml. They were taken off ART whenever their CD4 cells rose above 350 cells/ml. It was hypothesized that using less antiretroviral medication would reduce ART-related side effects such as cardiovascular disease.
But that proved wrong--at least for SMART's design parameters. On 18 January, NIAID announced that a review of the data collected up to 10 January 2006 (with an average 15 months of follow-up), had revealed that patients receiving episodic therapy were twice as likely to progress to clinical AIDS or death. In addition, people in the drug conservation arm of the study also experienced more major complications such as cardiovascular, kidney and liver diseases. In light of the findings, enrollment of new volunteers was stopped, and collaborators were urged to reinitiate ART in any participants who were currently off treatment.
More details were presented 3 weeks later at the Thirteenth Conference on Retroviruses and Opportunistic Infections in Denver, Colorado. SMART investigator Wafaa El-Sadr explained that there had been 164 'primary endpoints', defined as an AIDS-defining disease or death. Of these, 47 events occurred in the continuous treatment group while 117 occurred in the patients who went on and off therapy. Moreover, 1.7% of patients who had episodic
treatment died compared to 0.9% of patients on continuous ART. Progression to AIDS occurred in 0.9% of the drug conservation patients compared to 0.6% of the patients receiving continuous ART. As for serious complications, 2.1% of patients in the episodic treatment group developed them compared to 1.4% of the continuous treatment group.
No matter how the researchers sliced the data - by race, sex, baseline HIV RNA levels, baseline CD4 cell count, or a patient's lowest ever (nadir) CD4 cell count - people on continuous therapy did better. Interestingly, the risk of disease progression or death was threefold higher for people with baseline HIV RNA less than 400 copies/ml compared to those with baseline viral loads greater than 400 copies/ml.
Since the findings were made public, the SMART investigators have been working to explain them. They have embarked on more detailed analyses of existing data and are discussing the best use of stored blood samples to
further explain these outcomes. Analysis of inflammatory markers in blood could explore, for example, whether inflammation accounts for some of the heart disease. Exploring the possible role of drug resistance is also a priority.
The researchers are also starting to look at other questions that the study can answer. SMART gathered information for several substudies aimed at comparing differences in body composition and body fat distribution, quality of life and cost effectiveness, and HIV transmission risk, between the two study arms. Many of the findings will likely be presented at the International AIDS Conference in Toronto next August.
Meanwhile, the collaborators are deliberating SMART's future with NIH. They would like to amend the study's protocol to continue to track patients enrolled in the study. But deciding the scientific objectives of further follow up is ''a more contentious issue than what you may think,'' says Jens Lundgren, director of the Copenhagen HIV Program.
However, a big question that the investigators want to answer now is whether the harm can be reversed if people go back on therapy? In otherwords, do thosewho received episodic treatment suffer some sort of permanent change or harm, or do their rates of disease progression eventually revert to those of people on continuous therapy? ''We'd like to see those two lines converging,'' says Adrian Palfreeman a study investigator at the Peterborough and Stamford Hospitals NHS Foundation Trust in England.
SMART investigators hope to finalize an amended protocol this summer. ''This is the largest randomized trial ever been done in HIV/AIDS medicine,'' explains Gordin. ''We're really trying to understand it as much as possible. And we want to make an appropriate, rational decision about what science can we learn, what would it cost, and what is really the best thing to do next.''
Charlene Crabb
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