The Risk of Developing Peripheral Neuropathy Induced by Nucleoside Reverse Transcriptase Inhibitors Decreases over Time: Evidence from the Delta Trial

Abstract

Background

Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI).

Methods

A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddI) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model.

Results

A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddI (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35–44 years compared with <30) and current CD4⁺ T-cell count (HR=2.27 for CD4⁺ T-cell counts <150 cell/mm³ compared with >350).

Conclusion

Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used.