Background:  Sensory neuropathy affects 44% of HIV⁺ patients attending the Alfred Hospital HIV Clinic. Most cases are due to antiretroviral toxic neuropathy (ATN), with the main risk factor being exposure to stavudine (d4T) or didanosine (ddI):  both potentially neurotoxic nucleoside analogs (NRTI). An open-label study has suggested that L-acetyl carnitine (LAC) may improve ATN, but data to support the biological plausibility of this approach are lacking. 

We set out to examine the efficacy of LAC in preventing d4T and ddI neurotoxicity using cultured fetal rat dorsal root ganglia as an in vitro  model of ATN.

Methods: Fetal rat dorsal root ganglia were cultured on collagen-coated plates with nerve growth factor. NRTI or LAC were added to the collagen in clinically relevant concentrations. With each dose of drug, ≥16 dorsal root ganglia were cultured and monitored in terms of histology and length of neurite outgrowth using video imaging analysis.

Results:  Dorsal root ganglia exposed to ddI or d4T demonstrated dose-dependent toxicity that was effectively prevented by the co-administration of 50 mM LAC. No toxicity was seen with zidovudine (AZT), lamivudine (3TC), or abacavir—NRTI not associated with ATN clinically. Dorsal root ganglia cultured with high-dose (33 mM) ddI demonstrated reduced neurite growth relative to controls by day 2 (p = 0.02, unpaired t test), and were all dead by day 5. Dorsal root ganglia cultured with 33 mM ddI and 50 mM LAC remained healthy to at least day 10 and had neurite outgrowth similar to controls (p = 0.9). Dorsal root ganglia cultured with high dose (10.8 mM) d4T showed significant impairment of neurite growth by day 2 (60% reduced neurite length vs controls, p <0.0001). Dorsal root ganglia cultured with the same dose of d4T plus 50 mM LAC demonstrated similar neurite growth to controls to at least day 7 (p = 0.2).

Conclusions:  These results confirm fetal rat dorsal root ganglia as a useful model of ATN, with toxicity seen only from those NRTI associated with ATN clinically. LAC prevents ddI and d4T toxicity in this in vitro model, suggesting that LAC may be an effective means of preventing ATN in patients exposed to these agents. Controlled trials will be needed to confirm the efficacy of LAC in a clinical setting, and to determine whether it has a role in the treatment of established ATN.