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Brief Report: Improvement in Metabolic Health Parameters at Week 48 After Switching From a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen to the 2-Drug Regimen of Dolutegravir/Lamivudine: The TANGO Study.
van Wyk, J, Ait-Khaled, M, Santos, J, Scholten, S, Wohlfeiler, M, Ajana, F, Jones, B, Nascimento, MC, Tenorio, AR, Smith, DE, et al
Journal of acquired immune deficiency syndromes (1999). 2021;(2):794-800
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Abstract
BACKGROUND In TANGO, switching to dolutegravir/lamivudine was noninferior at 48 weeks to continuing 3-/4-drug tenofovir alafenamide-based regimens in virologically suppressed individuals with HIV-1. Antiretroviral agents have been associated with weight gain and metabolic complications. SETTING One hundred thirty-four centers; 10 countries. METHODS We assessed weight; fasting lipids, glucose, and insulin; and prevalence of insulin resistance and metabolic syndrome at baseline and week 48 in TANGO participant subgroups by boosting agent use in baseline regimens (boosted and unboosted). RESULTS In each treatment group, 74% of participants used boosted regimens at baseline. In boosted and unboosted subgroups, weight and fasting glucose changes at week 48 were small and similar between treatment groups. Overall and in the boosted subgroup, greater decreases from baseline were observed with dolutegravir/lamivudine in fasting total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), total cholesterol/high-density lipoprotein cholesterol ratio (overall, P = 0.017; boosted, P = 0.007), and insulin (boosted, P = 0.005). Prevalence of HOMA-IR ≥2 was significantly lower at week 48 with dolutegravir/lamivudine overall [adjusted odds ratio (aOR), 0.59; 95% confidence interval (CI), 0.40 to 0.87; P = 0.008] and in the boosted subgroup [aOR, 0.56; 95% CI, 0.36 to 0.88; P = 0.012] but not in the unboosted subgroup [aOR, 0.70; 95% CI, 0.31 to 1.58; P = 0.396]. Prevalence of metabolic syndrome at week 48 was low and consistent between treatment groups overall, with differences trending to favor dolutegravir/lamivudine in the unboosted subgroup [aOR, 0.41; 95% CI, 0.15 to 1.09; P = 0.075]. CONCLUSION Generally, switching from 3-/4-drug tenofovir alafenamide-based regimens to dolutegravir/lamivudine improved metabolic parameters, particularly when switching from boosted regimens. Because of smaller sample size in the unboosted subgroup, results warrant further investigation.
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Metabolic effects of initiating lopinavir/ritonavir-based regimens among young children.
Patel, K, Lindsey, J, Angelidou, K, Aldrovandi, G, Palumbo, P, ,
AIDS (London, England). 2018;(16):2327-2336
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OBJECTIVE The aim of this study was to estimate the long-term metabolic effects of initiating a lopinavir/ritonavir (LPV/r)-based regimen as a first-line therapy for HIV-infected children less than 3 years of age in resource-limited settings. DESIGN A prospective cohort study after conclusion of the P1060 randomized clinical trials (ClinicalTrials.gov Identifier: NCT00307151), with an overall follow-up of 7 years. METHODS Longitudinal total cholesterol and triglyceride measures were compared between 222 and 227 children randomized to initiate LPV/r and nevirapine (NVP)-based regimens, respectively. Adipokines (adiponectin and leptin) and biomarkers of inflammation [C-reactive protein and interleukin (IL)-6], microbial translocation (lipopolysaccharide) and immune activation (sCD14), measured in 117 participants at a median of 45 weeks of follow-up, were also compared by a randomized arm. RESULTS Mean total cholesterol and the percentage of participants with borderline or high total cholesterol was higher in the LPV/r arm from years 3 to 7 of follow-up than in the NVP arm (adjusted relative differences ranging from 10.9 to 23.4 mg/dl and adjusted relative risks ranging from a 60% increased risk to a more than four-fold increased risk for cholesterol ≥170 mg/dl at 7 years of follow-up). Initiation of a LPV/r-based regimen was not associated with high triglycerides over follow-up or large differences in markers of metabolic syndrome, inflammation, microbial translocation or immune activation. CONCLUSION Given the virologic superiority of LPV/r-based regimens in young children and open questions regarding the roll-out of dolutegravir in resource-limited settings, children are currently being maintained on LPV/r-based regimens. Our results suggest continual assessment of total cholesterol among young children initiating a LPV/r-based regimen to monitor cardiometabolic health.
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HIV/AIDS and lipodystrophy: implications for clinical management in resource-limited settings.
Finkelstein, JL, Gala, P, Rochford, R, Glesby, MJ, Mehta, S
Journal of the International AIDS Society. 2015;(1):19033
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INTRODUCTION Lipodystrophy is a term used to describe a metabolic complication of fat loss, fat gain, or a combination of fat loss and gain, which is associated with some antiretroviral (ARV) therapies given to HIV-infected individuals. There is limited research on lipodystrophy in low- and middle-income countries, despite accounting for more than 95% of the burden of HIV/AIDS. The objective of this review was to evaluate the prevalence, pathogenesis and prognosis of HIV-related lipoatrophy, lipohypertrophy and mixed syndrome, to inform clinical management in resource-limited settings. METHODS We conducted a structured literature search using MEDLINE electronic databases. Relevant MeSH terms were used to identify published human studies on HIV and lipoatrophy, lipohypertrophy, or mixed syndrome in low-, low-middle- and upper-middle-income countries through 31 March 2014. The search resulted in 5296 articles; after 1599 studies were excluded (958 reviews, 641 non-human), 3697 studies were extracted for further review. After excluding studies conducted in high-income settings (n=2808), and studies that did not meet inclusion criteria (n = 799), 90 studies were included in this review. RESULTS AND DISCUSSION Of the 90 studies included in this review, only six were from low-income countries and eight were from lower middle-income economies. These studies focused on lipodystrophy prevalence, risk factors and side effects of antiretroviral therapy (ART). In most studies, lipodystrophy developed after the first six months of therapy, particularly with the use of stavudine. Lipodystrophy is associated with increased risk of cardiometabolic complications. This is disconcerting and anticipated to increase, given the rapid scale-up of ART worldwide, the increasing number and lifespan of HIV-infected patients on long-term therapy, and the emergence of obesity and non-communicable diseases in settings with extensive HIV burden. CONCLUSIONS Lipodystrophy is common in resource-limited settings, and has considerable implications for risk of metabolic diseases, quality of life and adherence. Comprehensive evidence-based interventions are urgently needed to reduce the burden of HIV and lipodystrophy, and inform clinical management in resource-limited settings.
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HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line antiretroviral therapy.
Martin, A, Moore, CL, Mallon, PW, Hoy, JF, Emery, S, Belloso, WH, Phanuphak, P, Ferret, S, Cooper, DA, Boyd, MA, et al
PloS one. 2013;(10):e77138
Abstract
OBJECTIVE To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy. METHODS Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status. RESULTS 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment. CONCLUSION In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks. TRIAL REGISTRATION This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.
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The HIV-1/HAART associated metabolic syndrome - novel adipokines, molecular associations and therapeutic implications.
Tsiodras, S, Perelas, A, Wanke, C, Mantzoros, CS
The Journal of infection. 2010;(2):101-13
Abstract
The use of highly active anti-retroviral therapy has been associated with effects on various metabolic and morphological parameters that are underlied by significant hormonal and cytokine changes. Novel adipokines may have a role in the pathogenesis of these changes. In fact, leptin deficiency and hypoadiponectinemia correlate with lipoatrophy and central fat accumulation respectively whereas hypoadiponectinemia also appears to be associated with insulin resistance and lipid disorders. Preliminary evidence from proof-of-concept studies suggests that administration of recombinant leptin in replacement doses and/or administration of medications that increase adiponectin levels may improve the HIV-1/HAART associated metabolic syndrome (HAMS). Immune effects of hypoleptinemia and hypoadiponectinemia might have a role in the evolution of the HAMS that need to be further elucidated. The role for resistin in relation to HAMS is controversial and further investigation is necessary. A potential role of other novel cytokines like visfatin, retinol-binding protein-4, apelin, acylation stimulating protein, omentin and vaspin needs to be further elucidated.
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HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients.
Kotler, DP
Journal of acquired immune deficiency syndromes (1999). 2008;:S79-85
Abstract
It has been demonstrated that patients on highly active antiretroviral therapy are at increased risk for developing metabolic abnormalities that include elevated levels of serum triglycerides and low-density lipoprotein cholesterol and reduced levels of high-density lipoprotein cholesterol. This dyslipidemia is similar to that seen in the metabolic syndrome, raising the concern that highly active antiretroviral therapy also potentially increases the risk for cardiovascular complications. This paper reviews the contribution of both HIV infection and the different components of highly active antiretroviral therapy to dyslipidemia and the role of these abnormalities toward increasing the risk of cardiovascular disease in HIV-infected patients; therapeutic strategies to manage these risks are also considered.
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[Changes in carbohydrate metabolism in the HIV/AIDS patient].
Gómez Candela, C, de Cos Blanco, AI, Mateo, R, Castro, E, Lorenzo, A, Polo, R
Nutricion hospitalaria. 2002;(3):147-53
Abstract
Over the last few years, there has been a considerable reduction in the mortality and morbidity associated with HIV patients, due to the use of protease inhibitors which have led to a true revolution in the treatment of this infection. A new problem has arisen with the increased life expectancy: the onset of a plurimetabolic syndrome characterized by hypertriglyceridaemia, hypercholesterolaemia and hyperglycaemia; in addition to anomalies in composition and distribution of body fat (central obesity and loss of peripheral fat) due to the associated lipodystrophy. As a result of the metabolic alterations, there is an increase in the risk of cardiovascular disease. Hyperglycaemia is the result of insulin resistance and is detected in between 13.6% and 46% of patients, possibly leading to type 2 diabetes (diagnosed in between 2.4% and 7% of the patients). These alterations have been documented as potentially related with the use of protease inhibitors and other drugs used in the handling of HIV patients. The appropriate treatment of altered metabolism of carbohydrate requires: 1) a customized dietary approach depending on individual BMI and lipid alterations; 2) a physical exercise programme; 3) the use of insulin sensitization drugs: metformin and thiazolidinediones and, where the therapeutic goals are not achieved or there is a contraindication for oral hypoglycaemic drugs; 4) insulin therapy with regimens similar to other diabetic patients.
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Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome.
Kosmiski, LA, Kuritzkes, DR, Lichtenstein, KA, Glueck, DH, Gourley, PJ, Stamm, ER, Scherzinger, AL, Eckel, RH
AIDS (London, England). 2001;(15):1993-2000
Abstract
OBJECTIVE To examine the relationships between protease inhibitor (PI) therapy, body fat distribution and metabolic disturbances in the HIV lipodystrophy syndrome. DESIGN Cross-sectional study. SETTING HIV primary care practices. PATIENTS PI-treated patients with lipodystrophy (n= 14) and PI-treated (n= 13) and PI-naive (n= 5) patients without lipodystrophy. MAIN OUTCOME MEASURES Body composition was assessed by physical examination, dual-energy X-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Lipid profiles, other metabolic parameters, duration of HIV infection, CD4 lymphocyte counts, HIV-1 RNA load and resting energy expenditure (REE) were also assessed. RESULTS PI-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution (SI(22) x 10(-4) (min(-1)/microU/ml) versus 3.2 x 10(-4) and 4.6 x 10(-4) (min(-1)/microU/ml), respectively; P < 0.001). Visceral adipose tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy (36.9 versus 31.5 and 29.4 kcal/kg lean body mass; P < 0.001), and SI was strongly correlated with and was an independent predictor of REE in this population. CONCLUSIONS Body fat distribution and metabolic disturbances are strongly correlated in the HIV lipodystrophy syndrome and REE is increased.