These data suggest excess RAAS activation in relationship to visceral adiposity in HIV-infected patients that may independently contribute to insulin resistance. Mineralocorticoid blockade may have therapeutic potential to reduce metabolic complications in HIV-infected patients with increased visceral adiposity.
In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50 years, and in that regard, the use of ART has transformed HIV into a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear but may be related to a complex interaction between long-term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors (PIs) and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer PIs, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.
Metabolic complications relating to complex effects of viral and immune-mediated mechanisms are now a focus of clinical care among persons living with human immunodeficiency virus (PLHIV), and obesity is emerging as a critical problem. To address knowledge gaps, the US National Institutes of Health sponsored a symposium in May 2018 entitled “Obesity and Fat Metabolism in HIV-infected Individuals.” Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among PLHIV. Fibrotic subcutaneous adipose tissue is metabolically dysfunctional and loses its capacity to expand, leading to fat redistribution, including visceral obesity and ectopic fat accumulation, promoting insulin resistance. Viral proteins, including viral protein R and negative regulatory factor, have effects on adipogenic pathways and cellular metabolism in resident macrophages and T cells. HIV also affects immune cell trafficking into the adipose compartments, with effects on adipogenesis, lipolysis, and ectopic fat accumulation. Key cellular metabolic functions are likely to be affected in PLHIV by gut-derived cytokines and altered microbiota. There are limited strategies to reduce obesity specifically in PLHIV. Enhancing our understanding of critical pathogenic mechanisms will enable the development of novel therapeutics that may normalize adipose tissue function and distribution, reduce inflammation, and improve insulin sensitivity in PLHIV.
Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.
Objective(s) To investigate differences in subclinical coronary atherosclerotic plaque and markers of immune activation among HIV-infected and non-HIV-infected women categorized by degree of ovarian reserve and menopause status. Design Cross-sectional evaluation. Methods Seventy-four women (49 HIV-infected, 25 non-HIV-infected) without known CVD were classified as premenopausal, premenopausal with reduced ovarian reserve, or postmenopausal based on menstrual history and antimullerian hormone (AMH) levels. Participants underwent contrast enhanced coronary computed tomography angiography (CCTA) and immune phenotyping. Comparisons in coronary atherosclerotic plaque burden and immune markers were made between the HIV-infected and non-HIV-infected women overall and within the HIV-infected and non-HIV-infected women by reproductive classification group. Results Among the overall group of HIV-infected women, the women with reduced ovarian reserve (undetectable AMH) had a higher prevalence of coronary atherosclerotic plaque (52% versus 6%, p=0.0007) and noncalcified plaque (48% versus 6%, p=0.002), as well as higher levels of log sCD163 (p=0.0004) and log MCP-1 (p=0.006), compared with the premenopausal women with measurable AMH. Furthermore, reduced ovarian reserve in the HIV-infected group related to noncalcified plaque, controlling for traditional CVD risk factors (p=0.04) and sCD163 (p=0.03). Conclusions HIV-infected women with reduced ovarian reserve have increased subclinical coronary atherosclerotic plaque compared with premenopausal women in whom AMH is measurable. This relationship holds when controlling for CVD risk factors (including age) and immune activation. Our findings demonstrate that reduced ovarian reserve may contribute to CVD burden in HIV-infected women and support a comprehensive assessment of CVD risk prior to completion of menopause in this population.
Objective Some intestinal microbiota-generated metabolites of phosphatidylcholine are recognized to be pro-atherogenic. As the HIV population is vulnerable to cardiovascular disease (CVD) and can develop intestinal dysbiosis associated with systemic inflammation, we investigated the novel relationship between microbiota-derived metabolites of phosphatidylcholine and coronary atherosclerosis in HIV. Design/Methods 155 HIV-infected and 67 non-HIV-infected subjects without known history of CVD were previously recruited to assess coronary plaque by CT angiography. In the current study, we evaluate whether serum choline, trimethylamine (TMA), or trimethylamine N-oxide(TMAO) levels are associated with plaque features. Results Young, asymptomatic HIV-infected subjects (age 47±7 years) demonstrated significantly higher prevalence of plaque (53 vs. 35%, P=0.01) and number of total plaque segments (1.8±2.5 vs. 1.2±2.2, P=0.03) when compared to well-matched non-infected subjects with similar co-morbidities. TMA was significantly associated with calcium score (r=0.22, P=0.006), number of total (r=0.20, P=0.02) and calcified (r=0.18, P=0.03) plaque segments, and calcium plaque volume (r=0.19, P=0.02) and mass (r=0.22, P=0.009) in the HIV cohort only. In multivariate modeling among HIV-infected subjects, TMA remained significantly associated with calcium score (P=0.008), number of total (P=0.005) and calcified (P=0.02) plaque segments, and calcium plaque volume (P=0.01) and mass (P=0.007), independent of Framingham Risk Score. In contrast, there was no association of TMAO to coronary plaque features in either cohort. Conclusion A link between TMA and atherosclerosis has not previously been established. The current study suggests that TMA may be a non-traditional risk factor related to the number of plaque segments and severity of calcified plaque burden in HIV.
Summary Objective Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate ‘beiging’ in HIV-infected patients. Design Fifty HIV-infected subjects with the metabolic syndrome were previously recruited and randomized to receive lifestyle modification (LSM) and/or metformin over 12 months. In the current study, we assessed FGF21 and irisin at baseline and after intervention. In addition, we assessed circulating FGF21 and irisin in relationship to brown adipose tissue (BAT) gene expression in dorsocervical subcutaneous fat biopsies from 13 HIV-infected subjects. Results At baseline, prior to intervention, HIV-infected subjects demonstrated increased log FGF21 (2·13 ± 0·06 vs 1·98 ± 0·05 pg/ml, P = 0·05) and log irisin (0·33 ± 0·02 vs 0·17 ± 0·04 μg/ml, P = 0·003) compared with healthy controls well matched based on waist circumference. After 12 months, HIV-infected subjects randomized to LSM demonstrated a relative reduction in FGF21 compared with those not randomized to LSM (−10 [−35,22] vs 40 [0,94] %change, P = 0·01). Changes in FGF21 were inversely associated with improved parameters of energy homoeostasis, including increased REE (ρ = −0·34, P = 0·046) and max VO2 (ρ = −0·38, P = 0·02), and reduced RQ (ρ = 0·40, P = 0·02) among all HIV-infected subjects. Increased UCP-1 (r = 0·75, P = 0·003), DIO2 (r = 0·58, P = 0·04) and CideA (r = 0·73, P = 0·01) gene expression in dorsocervical fat was significantly associated with FGF21 in HIV-infected subjects. Conclusion HIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression. Relative reductions in FGF21 in those receiving long-term LSM relate to overall improvements in energy expenditure parameters. In contrast, irisin levels are elevated in HIV-infected subjects, but are not influenced by LSM nor associated with BAT gene expression.
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