A major HIV treatment strategy study has been stopped early on the grounds of futility. The SMART study (Strategies for Management of Antiretroviral Therapy) was designed to compare episodic use of anti-HIV treatment based on CD4 cell count against continuous therapy.
The trial was stopped after an excess of AIDS-defining events was observed amongst patients taking a break from treatment. No further recruitment to the trial will be allowed and individuals who have taken a treatment break are to be advised to restart therapy immediately.
SMART was supposed to last for up to nine years and answer a number of important questions about HIV treatment strategy, including:
- Whether continuous therapy results in better clinical outcome after six to nine years of follow-up compared to a treatment sparing approach?
- Whether greater drug exposure is correlated with lower levels of body fat and metabolic changes?
- Whether the strategy of starting and stopping therapy at irregular intervals results in higher levels of drug resistance than continuous drug use?
- Whether it is easier to adhere to continuous or intermittent therapy?
- Which approach is most cost effective in terms of drug costs and hospitalisations?
- Which approach leads to the best quality of life for patients?
Only two years' data have been collected, and analysis of this will continue. The study was designed to allow for an excess of AIDS in the interruption arm, but it was thought that this would be balanced by more cardiovascular events amongst individuals taking continuous treatment. The halting of the study on grounds of futility rather than safety suggests that these assumptions were incorrect and that AIDS-defining illnesses occurred with greater frequency than cardiovascular events.
The Data and Safety Monitoring Board (DSMB) for the study met in November of 2005 and concluded that it was safe to continue. However, a more recent review of the data lead the DSMB to conclude that the trial should stop recruiting new patients immediately and that patients who were in the treatment interruption arm should take continuous therapy.
Treatment interruptions as a strategy for the management of HIV do not now appear to have a viable future. Earlier studies have already shown that taking treatment breaks guided by viral load increases the risk of drug-resistant HIV emerging. Many clinicians were doubtful of the wisdom of structured treatment interruptions as an HIV treatment strategy – Dr Joep Lange, Professor of Medicine at the Centre for Poverty-Related Communicable Diseases, University of Amsterdam described them as “stupid treatment interruptions” whilst president of the International AIDS Society.