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The rapid occurrence of lipodystrophy and metabolic alterations in the late 1990s at the same time as antiretroviral treatments were able to control HIV infection led to defining a new field of HIV-related complications. Even if their pathophysiology is partly but incompletely understood, the different antiretroviral drugs play the leading role. In addition, Western countries' populations face a major metabolic risk due to high-fat diet and sedentary lifestyle.The mechanisms whereby antiretroviral drugs, including first-generation protease inhibitors and thymidine analogues, alter adipose function have been partly deciphered. Lipodystrophic adipose tissue presents an inflammatory state with insulin resistance which can impact on the liver and muscles, leading to metabolic alterations. In addition, some drugs are also responsible for direct effects on metabolic parameters. These abnormalities occur in the context of patients' aging, nutritional excess, sedentariness and smoking, leading to increased metabolic and cardiovascular risks.More research is required to find antiretroviral drugs devoid of adverse metabolic effects and to find and validate molecules able to reverse the lipodystrophic phenotype. At present, it is critical to optimize the patients' antiretroviral treatment by considering drugs with a friendly adipose and metabolic profile. The specific metabolic alterations require adapted treatment interventions to decrease the occurrence of cardiovascular and hepatic complications and of diabetes.