Which nucleoside reverse transcriptase inhibitor is most commonly associated with mitochondrial toxicity and lactic acidosis?

Explanation

## Mitochondrial Toxicity in NRTIs **Key Point:** Didanosine is the NRTI with the highest risk of mitochondrial toxicity, manifesting as lactic acidosis, hepatic steatosis, and pancreatitis. ### Mechanism of Toxicity Didanosine's active metabolite (dideoxyadenosine triphosphate) accumulates in mitochondria and: 1. Inhibits mitochondrial DNA polymerase γ (pol-γ) 2. Depletes mitochondrial ATP production 3. Triggers oxidative stress and apoptosis ### Clinical Manifestations | Toxicity | Presentation | Incidence | |----------|--------------|----------| | **Lactic acidosis** | Nausea, dyspnea, altered mental status | 1–5 per 1000 | | **Pancreatitis** | Epigastric pain, elevated lipase | 1–3% | | **Hepatic steatosis** | Hepatomegaly, elevated transaminases | Variable | | **Peripheral neuropathy** | Distal paresthesias | 15–30% | **High-Yield:** Didanosine is now rarely used in modern regimens due to superior alternatives (TDF, TAF, ABC) with better tolerability. ### Comparison with Other NRTIs - **Lamivudine & Emtricitabine:** Excellent safety profile; minimal mitochondrial toxicity - **Abacavir:** Risk of hypersensitivity reaction (HLA-B*5701 screening required) but NOT mitochondrial toxicity - **Stavudine (d4T):** Historically high mitochondrial toxicity; phased out globally **Clinical Pearl:** If lactic acidosis is suspected in an HIV patient on didanosine, immediate discontinuation and supportive care (IV fluids, bicarbonate) are essential.