The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated Lipodystrophy: Cellular Mechanisms and Clinical Implications

Flint, Oliver; Noor, Mustafa A.; Hruz, Paul W.; Hylemon, Phillip B.; Yarasheski, Kevin E.; Kotler, Donald P.; Parker, Rex A.; Bellamine, Aouatef

doi:10.1177/0192623308327119

Cited by 87 publications

(58 citation statements)

References 121 publications

(189 reference statements)

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“…PIs may cause lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of toxic farnesylated prelamin A [128], increased oxidative stress and altered adipokine and cytokine production [89,127,129]. The adverse effect of PIs could also result from the induction of endoplasmic reticulum stress or the inhibition of the proteasome [130,131]. Different PIs might affect key intranuclear genes, causing reduction in levels of RNA encoding SREBP-1, which changes the expression of PPAR γ [28].…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

Freitas¹,

Carvalho²,

Souto³

et al. 2013

Current Perspectives in HIV Infection

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Section: Protease Inhibitorsmentioning

confidence: 99%

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

Freitas¹,

Carvalho²,

Souto³

et al. 2013

Current Perspectives in HIV Infection

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“…3 Specifically, some ritonavirboosted PIs have been associated with a worsening of lipid parameters and increases in inflammatory markers. [4][5][6][7] Additionally, some PIs have been associated with insulin resistance in HIV-negative healthy volunteers. [8][9][10][11] However, this association with insulin resistance seems to be ARV-specific, as opposed to class-specific, as studies evaluating other PIs have failed to demonstrate such an association.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks

Aberg

Tebas

Overton

et al. 2012

AIDS Research and Human Retroviruses

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We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/ 100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4 + cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, -0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.

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“…It has been suggested that PIs directly block glucose uptake though suppressing glucose transporter protein isoform 4 (GLUT4, SLC2A4) activity leading to reduced glucose uptake and hyperglycemia [10,22,23,29]. These effects appear to be caused by suppression of GLUT4 transport function and not translocation or interference with insulin signalling cascade [30].…”

Section: Pi-induced Glucose Intolerance and Insulin Resistancementioning

confidence: 99%

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

et al. 2017

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The use of highly active antiretroviral therapy (HAART) has extremely enhanced the clinical outcome of HIV disease with a decrease in mortality and morbidity. However, the inclusion of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (tNRTIs) has strongly been linked to the development of metabolic abnormalities and lipodystrophy. Lipodystrophy is defined by the loss of peripheral subcutaneous fat and central adiposity, mainly in the abdomen, breast and dorsocervical region. These disorders are reported to be cosmetically distressing and socially stigmatizing to many patients leading to decreased adherence to antiretroviral therapy. Metabolic syndrome precedes lipodystrophy leading to increased risk of diabetes and cardiovascular diseases. With a shifted trajectory of HIV/AIDS morbidity from immunodeficiency and opportunistic infections to metabolic complications, clinical management of these patients has therefore become more complex. Currently there are no evidence-based standard guidelines for the management of HIV-associated lipodystrophy. Several pharmacological interventions such as using anti-diabetic, anti-dyslipidemic drugs or hormone replacement therapy have been tried to effectively improve metabolic syndrome and lipodystrophy but have been hampered by low efficacy, drug interactions, or unwanted side-effects. Non-pharmacological interventions including surgical manipulations, dietary and lifestyle modifications have also been tried with limited success. This review focuses on the proposed mechanisms involved in the development of metabolic syndrome and lipodystrophy, and highlights suggested potential therapeutic interventions to prevent lipodystrophy associated with HAART.

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The Role of Protease Inhibitors in the Pathogenesis of HIV-Associated Lipodystrophy: Cellular Mechanisms and Clinical Implications

Cited by 87 publications

References 121 publications

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks

Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome and Lipodystrophy: Pathophysiology and Current Therapeutic Interventions

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