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Lipoatrophy, Lipodystrophy - Let's Not Forget their
Contribution to Heart Disease in HIV
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Lipoatrophy, Lipodystrophy - from Jules: a solution to this problem was never achieved desire millions in dollars devoted to research to try to understand the causes and for a solution for patients. Apparently although there are many potential causes that have been discussed - just below - mitochondrial toxicity by HIV 7 old thymidine nucleosides appear to be a major contributor. In a poster at CROI 2017 the study explored additional implications of the effects of mtDNA decreased levels - that it was associated with decreased adiponectin & HOMA2-IR & authors conclude: "These results suggest that decreased adipose mitochondrial function after ART initiation corresponds to adverse adiponectin and glucose metabolism changes, and (consistent with a prior analysis) the mtDNA 10398A>G mutation may influence this relationship. The clinical implications of these findings are not known and deserve further study." In their Introduction they say: "Some antiretroviral therapy (ART) and perhaps HIV infection itself carry a risk of adverse metabolic effects which may be related, in part, to alterations in mitochondrial function and adipokines. A prior AIDS Clinical Trials Group (ACTG) study (A5224s; a sub-study of A5202 [NCT00118898]) found that ART decreased adipose mitochondrial DNA (mtDNA) levels in HIV-infected individuals randomized to initiate two different NRTI regimens with efavirenz or ritonavir-boosted atazanavir, and decreased adipose mitochondrial electron transport chain complex I and complex IV activity in those randomized to TDF/FTC-containing regimens.1"
ADIPONECTIN - previous studies indicated decreased circulating adiponectin levels in lipodystrophic ART-naive and -experienced HIV patients (21, 22, 23)......adiponectin is an important correlate of adiposity in HIV and HCV infections.....our study shows that circulating total adiponectin levels are suppressed in HIV mono-infected anti-retroviral treatment-naive IDUs. Importantly, adiponectin levels are associated with anthropometric measures of adiposity indicating its utility in assessing and monitoring the nutritional profiles of HIV and HCV mono- and co-infected IDUs. This study underscores the complex nature of the interactions of HCV, HIV, ART and injection drug use on adipose tissue and the possible development of metabolic perturbations.....We found marked reduction in serum adiponectin in HIV mono-infected anti-retroviral-naive IDUs relative to healthy controls and uninfected IDUs, suggesting suppression of adiponectin production. Our results are, in part, consistent with previous studies showing decreased adiponectin protein and mRNA expression in HIV infected anti-retroviral treatment-naive patients (22, 31). Although the underlying mechanisms suppressing adiponectin release were not examined in the current study, opioid illicit drugs activate HIV receptor expression on human adipocytes promoting infectivity, replication and disease progression (5, 32). Therefore, HIV infection in IDUs suppresses adipose tissue function leading to reduced adiponectin release.....The relationship of adiponectin with anthropometric markers in the injection drug using study groups is shown in Table 2. Adiponectin levels correlated positively with body weight (ρ=0.687; P=0.003) and BMI (ρ=0.598; P=0.014) in HIV mono-infected ART-naive IDUs. In addition, adiponectin levels correlated inversely with waist (ρ=-0.626; P<0.0001) and hip (ρ=-0.561; P=0.001) circumferences, and positively with bust-to-waist ratio (ρ=0.561; P=0.001) in HIV mono-infected ART-experienced individuals. Furthermore, adiponectin levels were directly associated with waist girth (ρ=0.375; P=0.024) in HCV mono-infected individuals. Adiponectin levels were also indirectly associated with waist-to-hip ratio (ρ=-0.872; P=0.048) in HIV and HCV co-infected ART-naive individuals. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566843/
"....The incidence of cardiovascular death has been found to be higher in patients with renal failure who have decreased adiponectin levels (hypoadiponectinemia) (34). Decreased adiponectin levels were found to be closely related to the degree of insulin resistance and hyperinsulinemia in a study conducted on Pima Indians and Caucasians-individuals with a wide range of glucose tolerance (13) http://care.diabetesjournals.org/content/26/8/2442
Across the randomized class-sparing arms and for those who received a thymidine analog NRTI (stavudine or zidovudine), median 24-week adiponectin changes ranged from -5% to +6% in the m.10398A group, compared with -27% to -55% among the m.10398G group. Wilcoxon p-values ranged from 0.005 to 0.1 for these comparisons.....Adiponectin is an adipose tissue-derived peptide hormone that mediates energy balance and metabolism, and has antioxidant properties. In HIV-negative populations, low adiponectin is associated with cardiovascular risk factors32,33 and disease.34 Recent in vitro data suggest adiponectin synthesis is dependent on mitochondrial function.35 Adipokines are dysregulated in HIV-infected persons.36-38 Lean HIV-positive, ART-treated men had adiponectin levels similar to obese, insulin-resistant HIV-negative men, and those with extremity fat loss had even lower levels.36
In summary, these pilot data support a previously published association between an mtDNA SNP and adiponectin levels17 and suggest a potentially novel association with poorer FMD on ART. The m.10398G allele was associated with adverse adiponectin and FMD phenotypes in this population. These findings suggest a potential role for mtDNA variation in metabolic/cardiovascular complications in HIV-infected, ART-treated persons. Although not definitive, these data also suggest a possible mechanistic link between mtDNA variation and metabolic derangements through relatively short-term (24 week) effects on adiponectin.....Overall median (IQR) baseline FMD for 37 subjects was 3.3% (1.9, 4.7). After 4 and 24 weeks of ART, median FMD increased to 4.8% (3.0, 6.4) and 5.1% (3.0, 6.7), respectively (Table 2). This represented median percentage increases of 43% and 36%, respectively. No haplogroup demonstrated significant differences in FMD responses over 4 or 24 weeks of ART (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/aid), nor did combined mtDNA clades IWX or Uk (data not shown). However, in analyses that considered mtDNA variant (m.) 10398A>G (rs2853826) status, those with the m.10398G allele and paired FMD data (N=7) had significantly lower median week 24 FMD [3.6% (IQR 2.5, 4.7)] than those with the m.10398A allele [N=27; 5.4% (3.6, 7.0); p=0.04; Table 2], indicating impaired endothelial function. This association would not withstand correction for multiple comparisons, so should be interpreted cautiously. Median baseline and week 4 FMD and week 24 FMD change from baseline among persons with m.10398G were lower but not statistically different than those with m.10398A.

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