Background: Sensory neuropathies (SN) are the commonest neurological complications of HIV and are associated with significant morbidity.  Both distal sensory polyneuropathy (DSP, due to HIV) and antiretroviral toxic neuropathy (ATN, attributed to mitochondrial dysfunction from NRTI) are described. We hypothesize that appropriate monitoring of patients for peripheral nervous system (PNS) damage would allow early detection of SN, when they might respond to the introduction or manipulation of HAART regimens

Methods: HIV⁺ subjects were assessed 6 monthly for up to 2 years in an ongoing clinical study.  Assessments included clinical examination, quantitative sensory threshold (QST) testing, lower limb epidermal nerve fiber density (IENFD) measurement, and collection of PBMCs and subcutaneous fat for quantification of mitochondrial DNA (mtDNA).  Statistical analyses were performed using StatView 5.0.

Results: Data was available on 83 subjects (313 assessments). The adverse effects of advancing HIV disease on the PNS were seen in the 7 treatment naïve subjects.  Higher viral loads were associated with lower IENFD (Spearman correlation  r= 0.9, p = 0.04), and elevated warming thresholds ( r = 0.8,  p = 0.05). A treatment-naïve individual with early DSP commenced HAART on study.  Symptoms resolved and QST and IENFD results normalized. As previously reported, rapid mtDNA depletion follows exposure to d4T (fat) and ddI (PBMC), with no ongoing depletion over time. One subject developed ATN on study.  This was preceded by a large fall in tissue mtDNA (44% in PBMC, 61% and 89% in thigh and ankle fat).  Symptoms resolved and QSTs normalized with dose reduction of ddI/d4T. 18 subjects were on stable HAART regimens throughout study, including 8 subjects on d4T and/or ddI since a mean of 40 (14 to 102) months prior to study entry.  QST results remained stable over time in these individuals.

Conclusions: Advancing HIV disease causes significant PNS dysfunction and pathology that may reverse with viral suppression.  Acute ATN may also reverse with dose reduction of the causative drug.  No ongoing deterioration in QST or tissue mtDNA levels was seen with chronic exposure to ddI or d4T.  These results support monitoring for SN among individuals recently commenced on therapy with ddI or d4T, as well as among those with more advanced HIV disease.  Significant morbidity may be preventable through timely treatment adjustments in patients affected by HIV associated SN.

Keywords: sensory neuropathy; HAART; mitochondrial DNA