Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral therapy (ART) increased the risk of distal sensory polyneuropathy (DSPN) in patients with HIV infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in DRG sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in HAART.
We evaluated current and past exposure to PIs as a risk factor for DSPN in 1159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models.
In univariate analyses, both past and current PI exposure significantly increased the risk of DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naïve subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly non-significant in multivariate models, except for small effects of amprenavir and lopinavir.
Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ART regimens.