Treatment interruption study stopped after excess number of AIDS events seen in people taking treatment breaks

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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:

Glossary

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

cardiovascular

Relating to the heart and blood vessels.

data safety monitoring board (DSMB)

An independent committee of clinical research experts that reviews data not available to the study team while a clinical trial is in progress to ensure that participants are not exposed to undue risks. A DSMB can recommend that the study be stopped if the intervention is not effective, is causing harm to participants or the study is not likely to serve its scientific purpose. Also known as an Independent Data Monitoring Committee (IDMC).

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 

cost-effective

Cost-effectiveness analyses compare the financial cost of providing health interventions with their health benefit in order to assess whether interventions provide value for money. As well as the cost of providing medical care now, analyses may take into account savings on future health spending (because a person’s health has improved) and the economic contribution a healthy person could make to society.

  • 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.