Limitations on achieving complete HIV eradication render it necessary to maintain highly active antiretroviral treatment over long periods, which may lead to the development of antiretroviral-associated toxicities. The current standard-of-care HAART regimens include a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs). Many studies have demonstrated that NRTIs particularly thymidine analogue nucleosides are important contributors to the development of lipoatrophy. This antiretroviral family inhibits also the mitochondrial gamma-DNA polymerase, which leads to mitochondrial dysfunction and side effects such as peripheral neuropathy, pancreatitis and liver dysfunction.