Objective: To investigate whether serially assessed epidermal nerve fiber (ENF) density and quantitative sensory thresholds (QSTs) are associated with the clinical transition from HIV infection with no neuropathy or asymptomatic neuropathy to symptomatic distal sensory neuropathy (SDSP). Background: Identifying predictors of transition to SDSP would enable identification of subjects at enhanced risk for development of HIV- SDSP and facilitate intervention studies with the ultimate goal of disease prevention. Asymptomatic signs of sensory dysfunction in the feet have been shown to be weakly predictive of SDSP; however, bedside evaluation of small sensory fibers is limited. Abnormality of these fibers may play an important role in the genesis of SDSP. Methods: Fifty- eight HIV- infected subjects underwent serial clinical, virologic, immunologic, skin biopsy, and QST assessments. Cox proportional hazards modeling was used to examine the associations of serial ENF density and QST assessments with the risk of development of SDSP among the subset of 26 subjects who had asymptomatic or no neuropathy at study entry. Results: Median follow- up was 2.9 years (range 6 months to 4.5 years) during which 19 of 26 subjects transitioned to SDSP. Using a model where ENF density and QST measures from the study visit before potential transition were examined, a lower leg ENF density, a higher cooling threshold, and a higher heat pain threshold for minimal pain (HP 0.5) were associated with a greater risk of SDSP in univariate analyses. In multiple regression analyses, leg ENF density but not QST measures were significantly associated with SDSP. A leg ENF density of 10 fibers/mm or less conferred a 14- fold greater risk of SDSP than a leg ENF density greater than 10 fibers/mm. Conclusions: Measures of small sensory fibers (leg epidermal nerve fiber density, cooling and heat pain thresholds) seem to be associated with transition to symptomatic HIV- associated distal sensory neuropathy 6 to 12 months later. Objective: To investigate whether serially assessed epidermal nerve fiber (ENF) density and quantitative sensory thresholds (QSTs) are associated with the clinical transition from HIV infection with no neuropathy or asymptomatic neuropathy to symptomatic distal sensory neuropathy (SDSP). Background: Identifying predictors of transition to SDSP would enable identification of subjects at enhanced risk for development of HIV-SDSP and facilitate intervention studies with the ultimate goal of disease prevention. Asymptomatic signs of sensory dysfunction in the feet have been shown to be weakly predictive of SDSP; however, bedside evaluation of small sensory fibers is limited. Abnormality of these fibers may play an important role in the genesis of SDSP. Methods: Fifty-eight HIV-infected subjects underwent serial clinical, virologic, immunologic, skin biopsy, and QST assessments. Cox proportional hazards modeling was used to examine the associations of serial ENF density and QST assessmen ts with the risk of development of SDSP among the subset of 26 subjects who had asymptomatic or no neuropathy at study entry. Results: Median follow- up was 2.9 years (range 6 months to 4.5 years) during which 19 of 26 subjects transitioned to SDSP . Using a model where ENF density and QST measures from the study visit potential potential transition were examined, a lower leg ENF density, a higher cooling threshold, and a higher heat pain threshold for minimal pain (HP 0.5) were associated with a greater risk of SDSP in univariate analyzes. In multiple regression analyzes, leg ENF density but not QST measures were significantly associated with SDSP. A leg ENF density of 10 fibers / mm or less conferred a 14-fold greater risk of SDSP than a leg ENF density greater than 10 fibers / mm. Conclusions: Measures of small sensory fibers (leg epidermal nerve fiber density, cooling and heat pain thresholds) seem to be associated with transition to symptomatic HIV-associated distal sensory neuropathy 6to 12 months later.