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Antiretroviral Treatment Interruption Is Associated with Evidence of Kidney Dysfunction in SMART Study

Evidence continues to accumulate showing that antiretroviral treatment interruption, as evaluated in the large SMART trial, is a potentially risky strategy. A new study, published in the January 2, 2009 issue of AIDS, sheds further light on kidney dysfunction in this setting.

As previously reported, SMART included more than 5000 mostly treatment-experienced participants with a baseline CD4 cell count above 350 cells/mm3. They were randomly assigned to either remain on continuous antiretroviral therapy (the "viral suppression" arm) or to interrupt treatment when their CD4 count was above 350 cells/mm3 and resume when it fell to 250 cells/mm3 (the "drug conservation" arm).

The study was halted in January 2006 after it became apparent that participants in the treatment interruption arm not only had a higher rate of AIDS-related opportunistic disease or death due to any cause, but also were more likely to develop serious cardiovascular, liver, and kidney disease.

In the present analysis, Amanda Mocroft and colleagues with the INSIGHT SMART study group looked at levels of cystatin C, a protein proposed as an alternative marker of renal (kidney) function. The investigators aimed to determine whether participants randomized to the treatment interruption group had altered cystatin C levels compared with patients in the continuous therapy group, and to identify factors associated with increased cystatin C.

The researchers measured cystatin C levels in plasma collected at randomization and 1, 2, 4, 8, and 12 months thereafter from a random sample of 249 participants in the treatment interruption arm and 250 patients in the continuous therapy arm.

Results

• At the time of randomization, mean cystatin C levels were 0.99 mg/dl in the treatment interruption arm and 1.01 mg/dl in the continuous therapy arm (P = 0.29, not a statistically significant difference).
• In the first month after randomization, 21.8% of patients in the treatment interruption and 10.6% in the continuous therapy arm had at least a 0.15 mg/dl increase in cystatin C (P = 0.0008).
•  The difference in cystatin C levels between the treatment interruption and continuous therapy arms was maintained through 12 months.
• After adjusting for other factors, participants in the continuous therapy arm had significantly lower risk of experiencing at least a 0.15 mg/dl increase in cystatin C during the first month (odds ratio 0.42; P = 0.0023).

In conclusion, the study authors wrote, "These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function."

University College London Medical School, London, UK; Mount Sinai School of Medicine, NY; Duke University Medical Center, Durham, NC; University of Minnesota School of Public Health, MN; Harlem Hospital Center and Columbia University, NY; University of Vermont College of Medicine, VT; University of Pittsburgh, Pittsburgh, PA; San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA; Nuffield Department of Medicine, University of Oxford, Oxford, UK; Medical Research Council, HIV Clinical trials Unit, London, UK; Klinikum der Universität, Würzburg, Germany.

1/27/09

Reference

A Mocroft, C Wyatt, L Szczech, and others (INSIGHT SMART study group). Interruption of antiretroviral therapy is associated with increased plasma cystatin C. AIDS 23(1): 71-82. January 2, 2009. (Abstract).