Antiretroviral Agent-induced Adipose Tissue Pathology and Metabolic Consequences
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is on the speaker's bureau for GSK and Cubist Pharmaceuticals, and is a consultant for Siemens Diagnostics.
Synopsis: Adipose tissue pathology and lipoatrophy frequently occur among patients receiving stavudine (d4T) and zidovudine (ZDV). Elevated ratios of total cholesterol to HDL correlated with lipoatrophy severity.
Source: Hammond E, et al. Human immunodeficiency virus treatment-induced adipose tissue pathology and lipoatrophy: prevalence and metabolic consequences. Clin Infect Dis. 2010; 51:591-599.
Two-hundred eleven adipose biopsies were obtained from 59 patients participating in the Western Australia HIV cohort study. Tissue was examined for adipocyte DNA content, adipocytokine expression, and adipose macrophage content. Whole-body, dual-energy X-ray absorptiometry (DEXA) scans were used to assess body composition.
Compared with 78 treatment-naïve control subjects, 98 ZDV-treated patients (48%) and 49 d4T-treated patients (67%) had leg fat measures < 10% threshold value. Adipose samples from patients currently receiving either ZDV or d4T demonstrated adipocyte mitochondrial DNA depletion, macrophage infiltration, and elevated pro-inflammatory cytokine levels, compared with samples obtained from control subjects and those receiving non-thymidine analogue nucleoside reverse transcriptase inhibitors. Improvements in adipose tissue pathology after NRTI switching (21 patients underwent longitudinal sampling) were demonstrated. Elevated levels of total/HDL cholesterol levels correlated with lipoatrophy severity and increased body mass index in thymidine analogue-treated patients.
Commentary
While ZDV and the dideoxynucleoside analogue reverse transcriptase inhibitors are no longer considered to be components of "first-line" antiretroviral regimens in the developed world, due to their low cost they are still used extensively in the developing world. Giving these drugs their due, many patients would not be alive today if ZDV, d4T, and ddI had not been available in the early 1990s and served as a "bridge" until modern HAART became available in the mid-late 1990s. Unfortunately, the prominent lipoatrophy, which resulted from the use of these agents, provides a visual reminder to the patients themselves (and the world) of their HIV-positive status.
This paper nicely characterizes the adipose tissue pathology associated with nucleoside-analogue induced lipoatrophy. One interesting aspect of the results is the correlation between adipose tissue mitochondrial toxicity and whole-body lipid metabolism. While the mechanism of this is not entirely certain, the authors postulate that mitochondrial adipocyte DNA depletion associated with thymidine analogue NRTI treatment not only induces cell death and fat loss, but also causes persistent defects in adipose tissue function that increase exposure of the liver and skeletal muscle to fatty acids. The loss of "fatty acid trapping" contributes to both dyslipidemia and insulin resistance.
While the beneficial metabolic effects of switching from thymidine analogues to "safer" NRTIs (tenofovir, abacavir, 3TC, FTC) were not rigorously addressed in this study, the authors cite earlier work suggesting that this benefit is likely to be greatest in those who have evidence of adipose tissue inflammation but have not yet progressed to more severe fat loss.1
Reference
- Cinti S, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46:2347-2355.
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