Body Composition and Metabolic Changes in the SMART Treatment Interruption Trial

		SUMMARY: Intermittent antiretroviral therapy (ART) was associated with increased subcutaneous fat, but no changes in visceral abdominal fat, according to an analysis from the large SMART treatment interruption trial published in the January 2010 issue of AIDS. In addition, levels of both LDL (bad) and HDL (good) cholesterol decreased, while one measure of blood glucose increased.

By Liz Highleyman

Cycles of intermittent therapy have been proposed as a strategy for reducing side effects and toxicities associated with antiretroviral drugs, including lipodystrophy (body fat changes) and abnormal blood lipid levels associated with increased cardiovascular risk. But the SMART trial and other studies of CD4 cell-guided treatment interruption have shown that this is a potentially risky approach.

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 ART ("viral suppression" arm) or to interrupt therapy while their CD4 count was above 350 cells/mm3 and resume when it fell to 250 cells/mm3 ("drug conservation" arm).

The study was discontinued prematurely in January 2006 after data analysis showed that participants in the treatment interruption arm not only had a higher rate of AIDS-related opportunistic illness and death from any cause, but also were more likely to develop serious cardiovascular, liver, and kidney disease.

Members of the INSIGHT-SMART study group have performed numerous analyses looking at different aspects of the data. For example, they previously reported that patients taking intermittent therapy had higher levels of blood biomarkers associated with inflammation, coagulation, and cardiovascular disease.

In the present analysis, Esteban Martinez from the University of Barcelona and colleagues assess the effects of intermittent ART exposure on body fat and metabolic parameters.

Participants at 33 sites were co-enrolled in the SMART Body Composition sub-study. This analysis included a total of 275 patients, 142 randomly assigned to the treatment interruption arm and 133 assigned to the continuous therapy arm. Most (81%) were men, about three-quarters were on ART at study entry, and 58% had baseline HIV RNA < 400 copies/mL.

Participants were followed for a median of 2 years. Investigators assessed regional fat levels annually using whole-body dual-energy X-ray absorptiometry (DEXA) and abdominal computed tomography (CT) scans. Fasting metabolic parameters were assessed at months 4 and 8, and then annually.

Results

	At the 12-month analysis, patients in the treatment interruption group had been on ART for 2.7 months, or 22% of follow-up time.
	By month 12, limb fat increased by 9.0% in the intermittent therapy group and remained stable (-0.8%) in the continuous therapy group, for an estimated difference of 9.8% (P = 0.003).
	Subcutaneous (under the skin) abdominal fat increased in both groups, with a borderline significant difference of +14.3 cm2 in the intermittent therapy group (P = 0.05).
	Both groups gained visceral (internal) abdominal fat by 12 months, but the between-group difference was not statistically significant (-2.1% difference; P = 0.72).
	There were no significant differences in satisfaction with body image reported by participants.
	Blood lipids levels significantly decreased in the treatment interruption group by month 4, and between-group differences persisted throughout the follow-up period (P < 0.001).
	By 12 months, hemoglobin A1C (a measure of blood glucose over time) increased in the intermittent therapy group (+0.3%) while remaining stable in the continuous therapy group (P = 0.003).
	However, changes in other related measures including standard blood glucose, insulin level, and insulin resistance (HOMA) were not statistically significant.

Based on these findings, the study authors concluded, "After 12 months, intermittent antiretroviral therapy increased subcutaneous fat, had no effect on visceral abdominal fat, decreased plasma lipids, and increased hemoglobin A1C compared with continuous antiretroviral therapy."

"In the SMART Body Composition substudy, the strategy of intermittent ART in HIV-infected patients had significant effects on body fat and plasma lipids," they elaborated in their discussion. "For most endpoints, the treatment difference was fully evident at 12 months and did not increase with longer follow-up."

"All plasma lipids decreased significantly in the [intermittent therapy] group as compared with the [continuous therapy] group," they continued. "Our study showed rapid decrease in lipids after ART discontinuation, which mirrored the increase in lipids after starting ART reported in other studies.:

"The decrease in plasma lipids associated with ART interruption was initially considered to be a positive effect," they noted. "However, low HDL cholesterol would be expected to increase the risk of cardiovascular disease even if LDL cholesterol is low."

Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Absolute Care Medical Center, Atlanta, GA; University of Minnesota, Minneapolis, MN; Veterans Affairs Medical Center, Washington, DC; Denver Public Health, Denver, CO; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; AltaMed Health Services, Los Angeles, CA: Mortimer Market Centre, University College Hospital, London, UK; Center for Infection and Immunity (CINIMA), Academic Medical Center, Amsterdam, Netherlands; Harlem Hospital and Columbia University, New York, NY; St. Vincent's Hospital, University of New South Wales, Sydney, Australia.

2/16/10

Reference

E Martinez, F Visnegarwala, B Grund, and others (INSIGHT-SMART study group). The effects of intermittent, CD4-guided antiretroviral therapy on body composition and metabolic parameters. AIDS 24(3): 353-563 (Abstract). January 2010.