Which antiretroviral drug class is most strongly associated with HIV-associated lipodystrophy?

• A. Protease inhibitors
• B. Non-nucleoside reverse transcriptase inhibitors
• C. First-generation nucleoside reverse transcriptase inhibitors
• D. Integrase inhibitors

Answer: (C)

HIV-associated lipodystrophy largely stems from drug-induced mitochondrial toxicity in adipose tissue, which disrupts fat metabolism and storage. The class most strongly linked to this pattern is the first-generation nucleoside reverse transcriptase inhibitors, especially the thymidine analogs such as stavudine and zidovudine. These drugs inhibit mitochondrial DNA polymerase gamma, causing mitochondrial dysfunction in fat cells and leading to lipoatrophy—loss of subcutaneous fat in the face and limbs—and sometimes redistribution of fat. Protease inhibitors can contribute to fat redistribution as well, but they are more commonly associated with central fat gain and metabolic changes rather than the classic lipoatrophy seen with early NRTIs. Integrase inhibitors and non-nucleoside RT inhibitors have a lower association with lipodystrophy. Modern regimens minimize lipodystrophy risk by avoiding these older NRTIs.