Mitochondrial DNA Haplogroups Influence Lipoatrophy After Highly Active Antiretroviral Therapy

Abstract

Although highly active retroviral therapy (HAART) has been extremely effective in lowering AIDS incidence among patients infected with HIV, certain drugs included in HAART can cause serious mitochondrial toxicities. One of the most frequent adverse events is lipoatrophy, which is the loss of subcutaneous fat in the face, arms, buttocks and/or legs as an adverse reaction to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical symptoms of lipoatrophy resemble those of inherited mitochondrial diseases, which suggests that host mitochondrial genotype may play a role in susceptibility. We analyzed the association between mitochondrial haplogroup and severity of lipoatrophy in HIV-infected European American patients on HAART in the Multicenter AIDS cohort Study (MACS) and found that mitochondrial haplogroup H was strongly associated with increased atrophy (arms: p = 0.007, OR = 1.77, 95% CI = 1.17–2.69 legs: p = 0.037, OR = 1.54 95% CI = 1.03–2.31, and buttocks: p = 0.10, OR = 1.41 95% CI = 0.94–2.12). We also saw borderline significance for haplogroup T as protective against lipoatrophy (p = 0.05, OR = 0.52, 95% CI = 0.20–1.00). These data suggest that mitochondrial DNA haplogroup may influence the propensity for lipoatrophy in patients receiving NRTIs.

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

“…Given the importance of toxicity issues associated with NRTIs, including decreased BMD, 3 renal dysfunction, lipoatrophy, 4,5 dyslipidaemia, and mitochondrial toxicity, 4,5 we evaluated each of these parameters during this study. Compared with the BMS-986001 arms, the decrease in lumbar spine and hip BMD in the TDF arm was ~2·5-fold greater.…”

“…1,2 Despite the widespread use of NRTIs in first-line treatment regimens, they are associated with toxicities, which can lead to long-term complications. These can include decreased bone mineral density (BMD), 3 lipoatrophy, 4,5 anaemia, pancreatitis, 6,7 and hypersensitivity reaction. 8 Several NRTIs, including didanosine, stavudine (d4T), and zidovudine, are not used routinely due to toxicities associated with mitochondrial (mt) dysfunction, namely peripheral neuropathy, 9,10 lipoatrophy, 4,5 hepatic steatosis 11 , and metabolic acidosis 12,13 .…”

“…These can include decreased bone mineral density (BMD), 3 lipoatrophy, 4,5 anaemia, pancreatitis, 6,7 and hypersensitivity reaction. 8 Several NRTIs, including didanosine, stavudine (d4T), and zidovudine, are not used routinely due to toxicities associated with mitochondrial (mt) dysfunction, namely peripheral neuropathy, 9,10 lipoatrophy, 4,5 hepatic steatosis 11 , and metabolic acidosis 12,13 . Thus, there is a need for an NRTI with potent anti-HIV-1 activity, a tolerability profile better than currently available NRTI agents, a long-term safety profile that is favourable in terms of BMD and renal function, and limited cross-resistance to existing NRTIs.…”

Lipoatrofia facial associada ao HIV/AIDS: do advento aosconhecimentos atuais

“…32 Hendrickson and collaborators also agreed that lipoatrophy is one of the manifestations most commonly associated with the use of ARV and reported a variation on its frequency between 13% to 63%. 36 Viskovic and collaborators consider lipoatrophy the most common and disfigurating of all the body alterations associated with the syndrome. From a total of 151 HIV-positive patients evaluated 39% reported lipoatrophy is some area, while 45% of the doctors noted the presence of fat loss at clinical examination.…”

“…On the other hand the T halogroup showed marginal significance as a protective factor to the development of lipoatrophy on this same group of patients. 36 Some studies suggest that the fat redistribution and the metabolic abnormalities of the HIV infection are associated with alterations of the endocrine function of the adipose tissue. The adipose tissue, as well as acting on fat storage, is an active endocrine tissue and the biggest determinant of sensibility to insulin, modulating the glucose and lipidic metabolism through the secretion of adipocytokines.…”