Which reverse transcriptase inhibitor class is most likely to cause mitochondrial toxicity and lactic acidosis?

Explanation

## Mitochondrial Toxicity in Antiretroviral Therapy ### NRTIs and Mitochondrial Dysfunction **Key Point:** Nucleoside reverse transcriptase inhibitors (NRTIs) are incorporated into mitochondrial DNA by mitochondrial DNA polymerase, causing chain termination and energy depletion. ### Mechanism of NRTI-Induced Lactic Acidosis 1. **Mitochondrial DNA polymerase inhibition** — NRTIs are non-selective and inhibit both viral reverse transcriptase AND mitochondrial DNA polymerase 2. **Impaired oxidative phosphorylation** — Disruption of mitochondrial DNA replication leads to decreased ATP production 3. **Lactate accumulation** — Cells shift to anaerobic metabolism, producing lactate and causing lactic acidosis 4. **Hepatic steatosis** — Mitochondrial dysfunction in hepatocytes leads to fat accumulation ### High-Risk NRTIs | NRTI | Risk Level | Notes | | --- | --- | --- | | Didanosine (ddI) | **Very High** | Highest risk; now rarely used | | Stavudine (d4T) | **Very High** | Withdrawn from many regimens | | Zidovudine (AZT) | **High** | Risk increases with prolonged use | | Lamivudine (3TC) | **Low** | Minimal mitochondrial toxicity | | Tenofovir (TDF) | **Low** | Minimal mitochondrial toxicity | **High-Yield:** Lactic acidosis is a rare but life-threatening complication of NRTI therapy, presenting with malaise, nausea, dyspnea, and elevated serum lactate (>5 mmol/L). Risk increases with prolonged use and concurrent hepatic disease. **Mnemonic: "NRTI Mitochondrial Toxicity"** — **N**ucleoside analogs → **R**everse transcriptase in **M**itochondria → **T**ermination of **D**NA → **D**epletion of **E**nergy → **L**actic **A**cidosis.