Background:  HIV-associated neuropathy (HIV-SN) is the leading neurological complication of HIV disease and is associated with advanced infection and exposure to dideoxynucleoside (ddX) drugs. The possibility that HIV infection leads to a subclinical defect in nerve repair and regeneration has not been systematically explored. To investigate this possibility, we measured the human regenerative response to a validated epidermal nerve denervation model.

Methods:  We enrolled into an IRB-approved study 80 healthy volunteer subjects without signs, symptom, or risk factors of peripheral neuropathy and 22 people with HIV infection. Peripheral neuropathy status was based upon leg skin biopsies and subjects’ total neuropathy score. Topical capsaicin cream was applied to a demarcated normal area on the distal thigh in all subjects resulting in a superficial denervation of the epidermis and dermis. Skin biopsies were obtained at baseline, immediately after denervation and at subsequent time points. Samples were processed for visualization of epidermal nerve and quantified by a blinded technician. The regeneration rate was determined by the regression line of post capsaicin treatment derived epidermal nerve densities over time.

Results:  Control and HIV⁺ subjects were of similar age (37.5 ± 11.5 vs 42.2 ± 6.3) and gender distributions (68% vs 73% male). Regeneration was efficiently measured over the course of 100 days and the regeneration rate among controls was 0.177 ±.075 and 0.110 ± 0.067 epidermal nerve/mm/day (p < 0.001) for all HIV subjects. Of the HIV subjects, 14 were determined to have neuropathy and there was a significant difference in the regeneration rate comparing HIV subjects with and without neuropathy to healthy control subjects (p = 0.003 ANOVA). Among HIV subjects, the rate of regeneration did not correlate to CD4 count, ddX exposure, age, gender, or ApoE4 allele presence.

Conclusions:  Nerve regeneration occurs and can be rigorously measured over a period of several months in HIV⁺ subjects. Our results suggest that abnormalities in nerve regeneration precede the development of clinical neuropathy. Regeneration rates for HIV subjects are impaired compared to healthy control subjects and this difference persists even among HIV⁺ subjects without signs or symptoms of peripheral neuropathy. This is consistent with subclinical pathologic abnormalities being present in nearly all AIDS patients. This approach to nerve regeneration measurement is attractive as an efficient outcome measure for future regenerative HIV-SN peripheral neuropathy trials.

Keywords: peripheral nerve ; regeneration; outcome measure