A 42-year-old man on stavudine and didanosine based ART presents with nausea, abdominal pain, and severe metabolic acidosis. CT shows hepatic steatosis and lactate is markedly elevated. Which mechanism best explains this presentation?
- A Inhibition of cytochrome oxidase by accumulated drug in hepatocytes
- B Direct hepatocyte membrane pore formation causing cell death
- C Inhibition of mitochondrial DNA polymerase gamma leading to impaired oxidative phosphorylation ✓
- D Autoimmune hepatitis triggered by the NRTI backbone
Correct answer: C. Inhibition of mitochondrial DNA polymerase gamma leading to impaired oxidative phosphorylation
Explanation
Stavudine and didanosine have strong affinity for human mitochondrial DNA polymerase gamma, depleting mitochondrial DNA in liver, muscle and fat. Impaired oxidative phosphorylation forces anaerobic metabolism, producing lactic acidosis with hepatic steatosis. This class effect underlies lipoatrophy and neuropathy too. Direct membrane injury is the mechanism of amphotericin C, not any antiretroviral, making option A the tempting but wrong distractor.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.