ACETYL-CARNITINE DEFICIENCY IN AIDS PATIENTS WITH NEUROTOXICITY ON TREATMENT WITH ANTIRETROVIRAL NUCLEOSIDE ANALOGS

Objective: A severe dose-limiting axonal peripheral neuropathy may dev elop in subjects on treatment with the nucleoside analogues didanosine (ddl), zalcitabine (ddC), and stavudine (d4T). The impairment of mitr ochondrial DNA synthesis is crucial to the pathogenesis of this disord er although other mechanisms have not been ruled out. The depletion of acetyl-carnitine, which regulates the metabolism and function of peri pheral nerves, could contribute to the neurotoxicity of these compound s. Design: Non-randomized, cross-sectional study of selected patients. Methods: We measured the serum levels of acetyl- and total carnitine in 12 subjects with axonal peripheral neuropathy developed on treatmen t with different regimens of neurotoxic nucleoside analogues (ddl, ddC , d4T). Subjects who did not develop peripheral neuropathy while stayi ng on treatment with ddl (n = 10) or zidovudine (n = 11) served as the control groups. HIV-negative subjects with axonal or demyelinating au toimmune neuropathies (n = 10) and healthy individuals (n = 13) were a dditional control groups. Results: Subjects experiencing axonal periph eral neuropathy on treatment with ddl, ddC and d4T had significantly r educed levels of acetyl-carnitine in comparison to the control groups. No difference was observed in the levels of total carnitine between s tudy subjects and the control groups. Conclusions: Our results demonst rate that subjects who developed peripheral neuropathy while staying o n treatment with ddl, ddC and d4T had acetyl-carnitine deficiency. The normal levels of total carnitine in the study group appear to indicat e the specificity of the defect and rule out coexisting relevant nutri tional problems. The critical role of acetyl-carnitine for the metabol ism and function of the peripheral nerves supports the view that the a cetyl-carnitine deficiency found in these subjects may contribute to t he neurotoxicity of ddl, ddC and d4T, even though the interference wit h mitochondrial DNA synthesis is regarded as the main cause of their t oxicity.