By Liz Highleyman

In an effort to reduce the toxicity and cost of antiretroviral therapy, researchers have explored alternative strategies, including structured treatment interruption or intermittent therapy.

The CPCRA SMART (Strategies for Management of Anti-Retroviral Therapy) Study compared the safety and efficacy of 2 treatment strategies, CD4-guided intermittent therapy and continuous therapy. A total of 5472 participants were randomly assigned to the 2 arms. In the former arm, patients went (or stayed) off antiretroviral treatment while their CD4 cell counts remained above 350 cells/mm3, and resumed when their counts fell below 250 cells/mm3.

The study was terminated in January 2006 after an interim analysis showed that patients in the intermittent therapy arm were more likely to experience disease progression or death. Unexpectedly, patients in this arm not only had a higher rate of AIDS-related illnesses, but also were more likely to experience complications potentially related to antiretroviral toxicity, such as cardiovascular, liver, and kidney disease. Results were published in the November 30, 2006 New England Journal of Medicine.

At the 14th Conference on Retroviruses and Opportunistic Infections last week in Los Angeles, 2 research teams presented further data on metabolic complications in the SMART study.

Cardiovascular Risk Factors

Andrew Phillips and colleagues performed an exploratory analysis of risk factors for cardiovascular events in the 2 SMART strategy arms, and also looked at associations with different classes of antiretroviral drugs.

Results

• Of the 5472 total participants, 79 (1.4%) developed major cardiovascular events, including death, non-fatal heart attacks, silent myocardial infarctions, strokes, coronary artery disease, or related procedures.

• Of these events, 48 occurred in the intermittent therapy arm and 31 in the continuous therapy arm, for a hazard ratio (HR) of 1.57.

• In the intermittent therapy arm, rates of cardiovascular events differed based on type of antiretroviral regimen:

- Patients taking NRTI-only regimens had a somewhat higher risk of cardiovascular events compared with those taking protease inhibitor (PI)-based regimens (HR = 1.78).
- Those taking NNRTI-based regimens had approximately twice the risk compared with PI-based regimens (HR = 2.07).
- The highest risk was observed in patients taking nevirapine (Viramune) (HR = 9.29).

• In the continuous therapy arm, but not in the intermittent therapy arm, there was in small increase in the risk of cardiovascular events per additional year of exposure to PI-based regimens, but not NNRTI-based combinations.

• Cardiovascular risk was not significantly associated with:

- Current HIV viral load;
- Current CD4 cell count;
- Whether patients were currently on or off therapy.

• Total and low-density lipoprotein (LDL or "bad") cholesterol levels were lower among participants on intermittent therapy after the first year.

• Levels of high-density lipoprotein (HDL or "good") cholesterol were also reduced.

Conclusion

The researchers concluded that there was a "borderline significant excess risk of cardiovascular disease" among patients receiving intermittent antiretroviral therapy.

However, there was "no evidence that [treatment] interruption immediately increases risk of cardiovascular disease," leading the investigators to recommend that antiretroviral therapy "should not be stopped or avoided solely because of perceived cardiovascular risk."

University of Minnesota, Minneapolis; St Vincent's Hosp, University of New South Wales, Sydney, Australia; Baylor College of Medicine, Houston, TX; University of Wake Forest School of Medicine, Winston-Salem, NC; Denver Public Health, CO; Royal Free and University College London Medical School, UK; National Center for HIV Epidemiology and Clinical Research, Sydney, Australia; Hvidovre Hosp, Copenhagen, Denmark.

Link to study abstract

Lipoatrophy and Lipid Profiles

Fehmida Visnegarwala and colleagues presented a poster with data from a body composition sub-study of SMART. Body fat changes (both central fat accumulation and peripheral fat loss, or lipoatrophy) and blood lipid abnormalities are among the key metabolic complications researchers have hoped to mitigate with intermittent therapy.

The sub-study enrolled 275 participants from the U.S., Australia, and Spain, of whom 142 were assigned to intermittent therapy and 133 to continuous therapy. Subjects received annual DEXA scans and lipid and blood glucose measurements twice yearly.

After 12 months, mean limb fat increased in the intermittent therapy arm, while falling in the continuous therapy group. In addition, there were significant reductions in blood lipids in the intermittent compared with the continuous therapy arm starting at month 4.

These data suggest that, as hoped, treatment breaks may improve some of the metabolic parameters associated with cardiovascular disease, including blood lipid abnormalities. This leaves the reason(s) for the observed elevated risk of cardiovascular events uncertain, but an increasing number of experts believe inflammation related to HIV infection itself may play a role.

Baylor College of Med, Houston, TX; CPCRA University of Minnesota, Minneapolis; VAMC, Washington, DC; Denver CPCRA, Denver Public Health, University of Colorado Health Science Center; National Center for HIV Epidemiology and Clinical Research, University of New South Wales, Australia; Hosp Clin, University of Barcelona, Spain; Harlem Hosp, Columbia University, New York, NY; St Vincent's Hosp, University New South Wales, Sydney, Australia.

Link to study abstract and PDF of poster.

03/06/07

References

A Phillips, A Carr, J Neuhaus, and others. Interruption of ART and risk of cardiovascular disease: findings from SMART. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Los Angeles. February 25-28, 2007. Abstract 41 (oral).

F Visnegarwala, B Grund, A Thomas, and others. The effects of intermittent, CD4-guided ART on peripheral limb Fat and metabolic parameters: the SMART body composition substudy. 14th CROI. Los Angeles. February 25-28, 2007. Abstract 803 (poster).

W M El-Sadr, J D Lundgren, J Neaton, and other (the SMART Study Group). CD4+ Count-Guided Interruption of Antiretroviral Treatment. New England J Medicine 355(22): 2283-2296. November 30, 2006.