Fatal lamivudine‐induced exacerbation of peripheral neuropathy in a patient with HBV and HCV positivity: evidence for iatrogenic mitochondrial damage

Abstract

A 57‐year‐old man with diabetes, HBV and HCV positivity, cryoglobulinemia and mild neuropathy was treated by the nucleoside reverse transcriptase inhibitor (NRTI), Lamivudine (300 mg/daily). Three months later he presented dysphonia, progressive muscle weakness at lower limb with mild upper limb involvement. Three weeks later, he was unable to walk and developed acute tetraparesis followed by an acute respiratory failure and cardiac arrest that required assisted ventilation. Electrophysiological studies evidenced a worsening of a sensorimotor axonal neuropathy. Nerve biopsy showed complete lack of myelinated fibers with vasculitic features whereas muscle biopsy presented denervation and reinnervation with diffuse type grouping. Mitochondrial respiratory chain enzyme activities demonstrated a marked reduction of complex I and IV, whereas Southern and dot blot analyses evidenced a ∼60% depletion of mtDNA. Lamivudine administration was discontinued. One week later the patient was awake and able to move his fingertips and his respiratory drive resumed with partial mechanical support, but he died a few days later. Lamivudine is often administered in HBV treatment. In the last few years, it has been considered neurotoxic and capable of exacerbating a peripheral neuropathy. Its NRTI mechanism may cause mitochondrial toxicity and cellular polymerase inhibition. In our patient, polyneuropathy worsened after lamivudine treatment; biochemical and molecular results of our studies suggest possible diffuse iatrogenic mitochondrial damage.