Findings from one of the largest HIV/AIDS therapy studies conducted to date show that a specific strategy of interrupting antiretroviral therapy more than doubles the risk of AIDS or death from any cause. Researchers affiliated with the Mailman School of Public Health and Harlem Hospital Hospital led a large multi-center international study, known as Strategies for Management of Anti-Retroviral Therapies, or SMART, comparing two treatment strategies for people with human immunodeficiency virus (HIV). Findings from the study, published in the November 30 New England Journal of Medicine, demonstrate the value of continuous antiretroviral therapy.
As HIV/AIDS has evolved into a chronic disease without a cure, lifelong antiretroviral therapy has become the norm. Lifelong therapy, however, can be difficult to adhere to as well as expensive. For these reasons, there has been a concerted research effort to test treatment interruption strategies that may enhance patients’ quality of life and limit adverse drug effects.
The strategies evaluated in the SMART Study compared the recommended continuous use of antiretroviral therapy (anti-HIV medicines) with use of antiretroviral therapy in an episodic (interrupted) manner. The study found that the use of episodic antiretroviral therapy was inferior to continuous therapy as episodic therapy significantly increased the risk of opportunistic diseases or death from any cause. Further, episodic antiretroviral therapy did not reduce the risk of serious complications, including those related to the heart, kidneys, and liver.
Antiretroviral therapy in people with HIV is associated with remarkable benefits including longer survival and less illness. However, life-long treatment is difficult and can be associated with both short- and long-term risks, such as major metabolic and cardiovascular complications and built-up resistance to treatment. According to Wafaa El-Sadr, MD, MPH, co-chair of the SMART Study and professor of clinical Medicine and Epidemiology, “Interruption of antiretroviral therapy has been generally advocated as a potential treatment strategy to enhance the quality of life, limit side effects, and allow for the emergence of the predominant wild-type virus in patients infected with multidrug-resistant HIV. However, our data clearly demonstrate that continuous use of anti-retroviral therapy is superior to its episodic use.”
In the SMART Study, researchers from more than 30 countries around the world randomly assigned 5,472 participants infected with HIV with a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy or to the episodic use of antiretroviral therapy. The participants—2,720 in the episodic therapy group and 2,752 in the continuous therapy group—were followed for an average of 16 months. Episodic therapy involved only using antiretroviral therapy when the CD4+ count decreased to less than 250 per cubic millimeter and then stopping therapy when the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease.
There were 120 participants in the episodic therapy group and 47 in the continuous therapy group who had an opportunistic disease or died from any cause. Analysis of study data showed that those on episodic therapy had more than twice the risk of developing these endpoints compared to those in the continuous therapy group. In addition, participants in the episodic group experienced significantly more cardiac, renal, and hepatic complications. Observes Dr. El Sadr, “The latter finding is surprising considering that cardiac complications have been associated in other studies with such events and liver and kidney complications have been linked to such treatment.”
According to Dr. El-Sadr, “Our findings provide clear and compelling evidence that the episodic antiretroviral strategy, guided by the CD4+ count, should not be recommended.” Dr. El-Sadr also stated that further research is needed to evaluate the effect of interrupting antiretroviral therapy on immune function, inflammation, and other markers.
The Strategies for Management of Antiretroviral Therapy (SMART) Study was designed and initiated by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and implemented in collaboration with regional coordinating centers in Copenhagen, London, and Sydney. The study is funded by the Division of AIDS of the National Institute of Allergy and Infectious Diseases (NIAID). The full study can be viewed at http://content.nejm.org/.