Among patients on long-term antiretroviral therapy, which drug class is the most common cause of lipodystrophy and metabolic syndrome?

Explanation

## Most Common Cause of Lipodystrophy in ART **Key Point:** Protease inhibitors (PIs) are the most common antiretroviral class associated with lipodystrophy, metabolic syndrome, dyslipidemia, and insulin resistance. ### Mechanism of PI-Induced Lipodystrophy 1. **Mitochondrial dysfunction**: PIs inhibit mitochondrial protease, impairing β-oxidation of fatty acids 2. **Adipocyte apoptosis**: Direct toxicity to subcutaneous fat cells → lipoatrophy (loss of facial, limb, and truncal fat) 3. **Lipogenesis**: Paradoxical fat redistribution to visceral and dorsocervical regions ("buffalo hump") 4. **Metabolic effects**: Hypertriglyceridemia, hypercholesterolemia, insulin resistance, diabetes ### Lipodystrophy Risk by Drug Class | Class | Lipodystrophy Risk | Metabolic Syndrome | Notes | |---|---|---|---| | **Protease Inhibitors** | **High (most common)** | **Yes** | Ritonavir-boosted regimens especially problematic | | NRTIs | Moderate (thymidine analogs: AZT, d4T) | Mild | Thymidine analogs now largely phased out | | NNRTIs | Low | Minimal | Generally metabolically favorable | | INSTIs | Very low | No | Dolutegravir, bictegravir preferred | **High-Yield:** The classic triad of PI-induced metabolic toxicity = **lipoatrophy (face/limbs) + lipohypertrophy (visceral/dorsocervical) + dyslipidemia**. **Mnemonic: LIPID** = **L**ipoatrophy, **I**nsulin resistance, **P**rotease inhibitors, **I**ncreased triglycerides, **D**ysmetabolism. **Clinical Pearl:** Modern PI-based regimens (e.g., darunavir/ritonavir) have lower metabolic toxicity than older PIs (indinavir, lopinavir), but still carry greater risk than NNRTI or INSTI-based regimens. Switching to integrase inhibitors (dolutegravir, bictegravir) is often recommended for patients with established lipodystrophy. **Warning:** ~~NRTIs are the most common cause~~ — while thymidine analogs (AZT, d4T) do cause lipodystrophy, they are rarely used now; PIs remain the primary culprit in current practice. [cite:Harrison 21e Ch 197]