Background:  Because ART regimens containing dideoxynucleosides, such as stavudine (d4T) and didanosine (ddI) (d-drugs) are first-line therapy for HIV in the developing world, there is clinical concern about their long-term toxicities in settings where the ability to monitor complications is limited and other ART options are few. Previous studies show that treatment-limiting, painful neuropathies occur in some patients within weeks-to-months after starting d-drugs. However, long-term risks are not well-characterized. Our objective was to determine the adverse risk to peripheral nerve function of long-term maintenance on d-drugs.

Methods:  In a prospective, observational study, among 951 HIV⁺ individuals examined at 2 or more time points between 1990 and 2005, 252 were on d-drugs at the initial visit and remained on them at all subsequent evaluations (d-drug exposed, DDE), while 250 were on ART, but had never been exposed to d-drugs (non-d-drug exposed; NDDE). We excluded from consideration subjects (n = 449) who never took ART, or who took ART (including d-drugs) only transiently before or during the period of observation. Prospective clinical evaluations were performed to identify symptoms (pain, paresthesias, sensory loss) and signs (reduced distal vibratory or pin sensation; diminished or absent ankle reflexes) of distal, sensory-predominant polyneuropathy (DSPN). Prevalence rates and incidence rates for DSPN diagnoses, sensory symptoms, and signs were determined.

Results:  All 252 DDE subjects remained on d-drugs for the entire follow-up period, suggesting that symptoms, if any, were tolerable. As expected because prescribing physicians often stop d-drugs in patients complaining of neuropathic symptoms, DDE subjects at baseline were less likely to have symptomatic DSPN than NDDE subjects (17% vs 28%; p <0.01). During 359 person-years of follow-up in 194 DDE subjects who were initially DSPN-free, incident DSPN developed in 53 (0.148 cases/year). By comparison, during 311 person-years of follow-up among 177 DSPN-free NDDE subjects, incident DSPN developed in 49 (0.158 cases/year). Time-to-event analyses for worsening of neuropathic symptoms and signs revealed no significant differences.  

Conclusions:  These data suggest that among patients who tolerate an initial period of d-drug therapy without developing neuropathic signs or symptoms, the great majority can safely receive d-drugs for extended periods.