A major international study comparing two different methods of treating HIV has begun recruiting patients in the United States and Australia. The SMART study (Strategies for Management of Antiretroviral Therapy) will compare the strategies of beginning treatment after the CD4 cell count falls below 350 cells/mm3 (and staying on treatment) with the strategy of waiting until the CD4 cell count has fallen below 250 cells to begin treatment (and stopping treatment once the CD4 cell count has moved above 350 cells/mm3).
The study is designed to investigate a number of strategic issues:
- Whether continuous therapy results in better clinical outcomes after six to nine years of follow up when compared with a treatment sparing approach?
- Whether greater drug exposure is correlated with higher levels of body and metabolic changes?
- Whether the strategy of starting and stopping therapy at irregular intervals results in higher levels of drug resistance than continuous drug exposure?
- Whether it is easier to adhere to continuous therapy or intermittent therapy?
- Which approach is most cost effective in terms of drug costs and hospitalisation?
- Which approach leads to the best quality of life for patients?
SMART aims to enroll 6,000 patients, and people will be eligible to join the study even if they are already on HIV treatment, providing that they are willing to accept the possibility that they may be randomised to stop treatment. The study will run until 910 AIDS-defining events have been recorded; based on current data, the study investigators believe it will take at least six years for this number of events to be recorded, although faster recruitment could speed up the process.
In 2002, the aim is to recruit 1,000 patients in a pilot phase to prove that it is feasible to recruit patients to such a study and safe to manage HIV infection according to the protocol for stopping and starting therapy. If the pilot phase is successful, recruitment will be extended, with the possibility that the study will be extended to the United Kingdom and other countries.
Participants will be able to take any drugs they choose, and will be able to change therapy whenever necessary. As new drugs come along, participants will be able to use them, because the study is investigating strategic approaches to therapy that are unlikely to become out of date within the next ten years. In the view of the protocol committee, the problems of resistance, side effects and adherence to therapy are highly unlikely to be overcome in the next decade.
"The initiation of the SMART study marks an important turning point in HIV research," said James Neaton, Ph.D., principal investigator at the CPCRA Statistical Center at the University of Minnesota in Minneapolis and co-chair of the SMART study team. "Randomised evidence from large, long-term trials could substantially improve the management of HIV disease. Up until this point, we have relied heavily on the results of shorter-term, randomised trials that measured viral load and on observational studies to guide HIV management decisions. Because people with HIV are living longer and will potentially be on therapy for decades, longer-term trials comparing clinical outcomes are needed to fully understand the impact of HIV treatment decisions."
Researchers and treatment advocates have been arguing for long term strategic studies ever since the introduction of HAART in 1996. SMART is the largest strategic study yet attempted.
Further details of the study, including the full protocol, are available from the SMART website