Elevated TRG levels increased the risk of HIV-sensory neuropathy by nearly three-fold between those in the lowest (≤142) and the highest TRG tertile (≤244). After adjusting for concomitant clinical and demographic factors related to HIV-sensory neuropathy, the association of HIV-sensory neuropathy with TRG levels persisted. Medication use, specifically protease inhibitors, and statins was associated with both sensory neuropathy and triglyceride elevations. This was expected, as protease inhibitors have been associated with elevated TRG levels and HIV-sensory neuropathy [3
], whereas statins, known to lower levels of cholesterol and TRG [13
], are used to treat hypertriglyceridemia (hTRG) during CART therapy [14
]. D-drugs may cause both sensory neuropathy and elevated TRG levels [5
]. Despite this confounding, in multivariable models adjusting for these medications, elevated triglyceride levels remained associated with sensory neuropathy.
Lipodystrophy in HIV-infected patients (LDHIV) is associated with metabolic complications such as impaired glucose tolerance and hTRG [13
]. Elevated serum TRGs correlate with the development of neuropathy in prediabetic patients without HIV. Mice fed high-fat diets have increased TRG-containing oxidized LDLs and systemic and nerve oxidative stress and develop reduced nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance [16
]. Our study extends these observations found in animals to demonstrate that hTRG is a risk factor for neuropathy in HIV-infected humans.
We previously reported a positive association between elevated fasting TRG levels and HIV-sensory neuropathy in a HIV-positive cohort (CHARTER). The present study amplifies on this association in the following ways. First, whereas the previous studyexamined fasting TRG levels in a much smaller HIV-positive cohort (n=130), we now report similar risk relationship for nonfasting TRG which is more convenient to procure, in larger cohort of HIV-positive and HIV-negative participants (n=491 HNRC). Secondly the previous study cohort consisted of a very high percentage of d-drug users (70%), which could obscure other risk factors associated with HIV-sensory neuropathy, whereas d-drug use was only 30% in this current cohort.
Also, the present study used multivariable logistic regression models to adjust for concurrent HIV-sensory neuropathy risk factors, whereas the previous study applied univariable analyses. Finally, the present study included lipid-lowering statins among the variables modeled, whereas the previous study did not.
Other markers that correlated with HIV-sensory neuropathy in this study like age, height, nadir CD4, use of protease inhibitors were recognized in prior studies [2
]. However, several other risk factors identified in other studies were not found in our cohort. Exposure to d-drugs was not a risk factor for HIV-sensory neuropathy, possibly because only 30% of our cohort had a history of d-drug use. We also found no association of sensory neuropathy with type 2 diabetes in HIV-negative volunteers, which might be due to a very small number of diabetics in this cohort [10
Pathologically, HIV-sensory neuropathy is characterized by distal axonal degeneration of small myelinated and unmyelinated nerve fibers [19
]. Various mechanisms have been proposed in this regard. Mutations in mitochondrial DNA have been suggested as one of the primary mechanism for sensory neuropathy [20
]. High TRG levels might lead to alteration in mitochondrial energy metabolism and membrane permeability. Alteration of mitochondrial functions leads to release of hydrogen peroxide and peroxynitrites, resulting in degeneration of nerve fibers [21
]. A strong association between compromised microvascular blood flow with sensory neuropathy in type 2 diabetes has also been reported [22
Limitations of this study include first its observational cross-sectional design, which limits causal inference. Nevertheless, prior studies of non-HIV-infected individuals have shown high serum TRG to be a risk factor for progression of diabetic sensory neuropathy and animal studies, as noted previously, support a causal link [23
]. It is still possible that elevated TRG is a surrogate for another, underlying, unmeasured factor, such as mitochondrial dysfunction, oxidative stress or microvascular compromise, which serves as the causal link to neuropathy. An interventional study to reduce mitochondrial dysfunction and these other disturbances would provide a useful test of this hypothesis. Secondly the participants were enrolled at a single center. To address this limitation, future studies might assess a more broadly representative sample of HIV-positive patients. TRGs in most studies are measured in the fasting state because of its elevation after food intake [25
]. However, nonfasting TRG levels may be a better predictor of future cardiovascular events [25
The strengths of this study include the assessment of HIV-sensory neuropathy by trained personnel using standardized, quality-controlled methods and thorough accounting for potential confounding factors such as demographic variables, HIV and HCV infections, and alcohol and other drug exposures.
These findings illustrate the pathogenic complexity of HIV-sensory neuropathy to which not only HIV infection, but also its treatment, is a major contributor. Since increased TRG levels were identified as a major risk for HIV-sensory neuropathy, interventions leading to reduction of TRG levels [27
] could reduce incidence of HIV-sensory neuropathy, a possibility that should be explored in future studies.