However, the impact attributable to HIV itself may still be important. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study found a lower CD4 cell count nadir to be a significant risk factor for neuropathy [15]. In the HIV Outpatient Study (HOPS) cohort, low nadir CD4 cell count and high plasma HIV RNA at first visit were a nearly equivalent or stronger predictor of developing neuropathy than use of ARV

medications, with the exception of higher dose d4T [16]. Our study results are consistent with pre-HAART data and demonstrate that peripheral nerve damage is seen at lower CD4 cell counts among individuals free of clinical neuropathy signs and/or symptoms. The findings of this study are also consistent with other reports that have identified age and height as significant predictors of neuropathy risk [15, 17, 18]. High ENFDs are seen in young people [19] and remodelling and ‘pruning’ of epidermal nerves may be part of BMS-354825 cost the aging process. The aetiology of HIV-SN even in the absence of ARV medications may include important contributions from

mitochondrial dysfunction. Recently, mtDNA damage was demonstrated to be more pronounced in the distal mitochondria of long axons from post mortem patients who CHIR-99021 cell line died with HIV-SN, consistent with the length-dependent nature of this neuropathy [20]. Furthermore, terminal nerve endings in skin from HIV-infected patients have demonstrated abnormal mitochondrial accumulations [21]. Depletion of PBMC mtDNA and OXPHOS enzyme activities has been observed in ARV-naïve subjects, suggesting that HIV in the absence of ARV medications causes mitochondrial dysfunction [22, 23]. Older potentially mitochondrial-toxic NRTIs [d4T and didanosine (ddI)] are still used as components of ARV regimens enough in developing countries. Pre-existing mitochondrial dysfunction related to HIV may increase the risk of neuropathy when such drugs are used. Adequate energy production is necessary for normal metabolism; thus, our initial expectation was that lower

ENFD, as a predictor of peripheral nerve damage, would be associated with lower OXPHOS enzyme activities. However, our study found that OXPHOS CI and CIV activity levels increased, rather than decreased, as ENFD decreased. We speculate that such increases in PBMC OXPHOS enzyme activities among ARV-naïve patients with lower ENFD may represent a general increase in cellular energy requirements secondary to increases in inflammatory tendencies mediated by HIV. In vitro, HIV infection has been reported to increase CIV activity in HIV-infected T cells [24]. In another tissue source, we have reported increases in ATP level within adipocytes from ARV-naïve subjects compared with HIV-seronegative controls [25]. Our study has several important limitations. Its applicability is limited to subjects of Thai descent and to those free of clinically defined neuropathy.