HIV-associated neurocognitive disorders (HAND) persist despite plasma HIV RNA suppression with antiretrovirals (ARV). Sequestered reservoirs in the central nervous system and circulating monocytes are theorized to contribute to persistent brain injury. We previously demonstrated that elevated intracellular HIV DNA from circulating cells was associated with HAND in ARV-treated and ARV-naive subjects. We now report that failure to suppress intra-monocyte HIV DNA 3.5 years after initiating ARV is linked to persistent HAND and subjects with dementia are least likely to suppress intra-monocyte HIV DNA at 3.5 years. These findings suggest that antiviral strategies may need to target intra-monocyte HIV DNA.

These authors equally contributed to this work.

Objective Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV. As pre-existing damage may increase risk of neuropathy following antiretroviral (ARV) therapy, particularly when the regimen contains stavudine (d4T), we assessed the relationship between ENFD and various parameters including mitochondrial factors in HIV-infected Thai individuals naïve to ARV therapy. Methods Distal leg and proximal thigh ENFDs were quantitated in HIV-infected Thai individuals without neuropathy prior to randomization to a HIV clinical trial that focused on mitochondrial toxicity issues. We assessed their association to various clinical and immuno-virologic parameters as well as to peripheral blood mononuclear cell (PBMC) mitochondrial (mt) DNA copies/cell, oxidative phosphorylation (OXPHOS) complex I (CI) and complex IV (CIV) enzyme activities, and mt 8-oxo-deoxyguanine (8-oxo-dG) break frequencies. Results In 132 subjects, the median [interquartile range] ENFD (fibers/mm) values were 21.0 [16.2–26.6] for the distal leg and 31.7 [26.2–40.0] for the proximal thigh. By linear regression, lower CD4 count (p<0.01), older age (p<0.01), increased body mass index (BMI) (p=0.04), increased height (p=0.02), and higher PBMC OXPHOS activity as measured by CIV activity (p=0.02) were associated with lower distal leg ENFD. Conclusions Older age, increased height, higher BMI, poorer immunologic status and higher PBMC OXPHOS activity are associated with lower distal leg ENFD in HIV-infected subjects free of neuropathy prior to initiation of first time ARV therapy.

Distal leg epidermal nerve fiber density (ENFD) is a validated predictor of HIV sensory neuropathy (SN) risk. We assessed how ENFD is impacted by initiation of first-time antiretroviral therapy (ART) in subjects free of neuropathy and how it is altered when mitochondrial toxic nucleoside medications are used as part of ART. Serial changes in proximal thigh and distal leg ENFD were examined over 72 weeks in 150 Thai subjects randomized to a regimen of stavudine (d4T) switching to zidovudine (ZDV) at 24 weeks vs ZDV vs tenofovir (TDF) for the entire duration of study, all given in combination with nevirapine. We found individual variations in ENFD change, with almost equal number of subjects who decreased or increased their distal leg ENFD over 72 weeks and no relationship to nucleoside backbone or to development of neuropathic signs or symptoms. Lower baseline distal leg ENFD and greater increases in mitochondrial oxidative phosphorylation complex I (CI) activity were associated with larger increases in distal leg ENFD over 72 weeks. Distal leg ENFD correlated with body composition parameters (body surface area, body mass index, height) as well as with blood pressure measurements. Assessed together with a companion cross-sectional study, we found that mean distal leg ENFD in all HIV+ subjects was lower than in HIV− subjects but similar among HIV+ groups whether ART-naïve or on d4T with/without neuropathy/neuropathic symptoms. The utility of ENFD as a useful predictor of small unmyelinated nerve fiber damage and neuropathy risk in HIV may be limited in certain populations.

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