Use of protease inhibitors does not independently contribute to distal polyneuropathy in HIV infection.

Type: Published Abstract
Title: Use of protease inhibitors does not independently contribute to distal polyneuropathy in HIV infection.
Authors: Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Ake C, Clifford D, McArthur JC, Simpson D, Collier A, Gelman BB, McCutchan JA, Morgello S, Grant I, and the CHARTER Group
Year: 2007
Publication: 8th International Symposium on NeuroVirology
Volume: Issue: Pages:
Abstract:Background. A recent analysis found that exposure to HIV protease inhibitors (PI), an important component of modern combination antiretroviral (ARV) therapy (ART), was associated with an increased likelihood of distal polyneuropathy (DPN) in patients with HIV infection. In dorsal root ganglion sensory neurons, PI exposure resulted in significant neurite retraction and process loss, suggesting neuronal toxicity. If confirmed, these findings could prove to be a substantial limiting factor in the long-term use of protease inhibitors in HIV-infected patients. Methods. We evaluated current and past exposure to PIs as a risk factor for sensory neuropathy in 1159 HIV-infected individuals enrolled in a large, NIH-funded, multicenter, cohort study. All subjects underwent a complete neurological exam to determine whether signs of DPN were present, including diminished ability to sense vibration on bilateral great toes, decreased ability to discriminate between sharp and dull, and absent or weakened ankle reflexes. Subjects were grouped into 5 categories according to past and current exposure to any ARV and to PIs into the following categories: (Group 1) past ARV use/no PIs, (Group 2) past ARV and PI use, (Group 3) currently on ARVs/never used PIs, (Group 4) currently on ARVs/past PI use, (Group 5) currently on ARVs and PIs. The odds of having DPN were calculated for each group relative to a sixth group of subjects who were ARV naïve. Concomitant risk factors were evaluated in multivariate models, including age, exposure to dideoxynucleoside reverse transcriptase inhibitors (d-drugs) and surrogate markers of HIV disease progression (CD4 nadir). Results. Relative to individuals never exposed to ARVs the odds for having DPN were significantly higher for all groups except group 1. Subjects currently on PIs or who had been exposed to PIs were more likely to have DPN relative to ARV naïve subjects (OR [95% CI] Group 1: 1.4 [0.8-2.5], Group 2: 2.2 [1.4-3.7], Group 3: 2.8 [1.8-4.4], Group 4: 3.8 [2.4-6.1], Group 5: 4.0 [2.8-5.9]). However, in a multivariate model accounting for other significant concomitant risks, no group was more likely to have DPN compared to ARV naïve subjects (adjusted OR [95% CI] Group 1: 0.9 [0.4-1.7], Group 2: 1.1 [0.6-2.1], Group 3: 1.4 [0.7-2.3], Group 4: 1.3 [0.7-2.3], Group 5: 1.6 [0.9-2.6]). Conclusions. Evaluation of confounding risk factors for neuropathy in HIV infection suggests that the independent risk attributable to PI exposure, if any, is small. This risk must be weighed against the important role of PIs in modern ART regimens.