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1
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Taylor GH, Pandit NS. Angiolipoma associated with antiretroviral switch therapy: a case report. AIDS Res Ther 2024; 21:30. [PMID: 38734689 PMCID: PMC11088114 DOI: 10.1186/s12981-024-00620-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Angiolipomas have been well described in patients with HIV exposed to protease inhibitors with possible resolution after switching to non-nucleoside reverse transcriptase inhibitor-based regimens. Resolution of symptoms have occurred with switches to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; however, little is known regarding the development of angiolipomas when switching from NNRTI- to modern, integrase strand transfer inhibitor-based regimens. We describe a patient who underwent switch therapy from tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) to tenofovir alafenamide/FTC/bictegravir (TAF/FTC/BIC) who later developed angiolipomas. CASE PRESENTATION A 55-year-old male had been on TDF/FTC/EFV for 8 years before switching to TAF/FTC/BIC. Nineteen months after antiretroviral switch, the patient presented with multiple lesions in the upper extremities and abdomen. Diagnostic biopsies revealed non-encapsulated angiolipomas and HHV-8 and non-alcoholic fatty liver disease was ruled out. New lesions continued to appear 29 months after ART switch, after which now lesions appeared and prior lesions remained stable with no increase in size noted. No surgical intervention or change in antiretroviral therapy was needed. CONCLUSIONS Angiogenesis may have been suppressed with TDF/FTC/EFV treatment, however when switched to TAF/FTC/BIC, promoted the growth of angiolipomas. Clinicians should be aware of the impact of switching to modern ART therapies resulting in possible adipogenesis.
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Affiliation(s)
- Gregory H Taylor
- University of Maryland Baltimore School of Medicine, 800 Linden Avenue, 7th Floor, Baltimore, MD, 21201, USA
| | - Neha Sheth Pandit
- University of Maryland Baltimore School of Pharmacy, 20 N. Pine Street, Baltimore, MD, 21201, USA.
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2
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van der Post J, Guerra TEJ, van den Hof M, Vaz FM, Pajkrt D, van Genderen JG. Plasma Lipidomic Profiles in cART-Treated Adolescents with Perinatally Acquired HIV Compared to Matched Controls. Viruses 2024; 16:580. [PMID: 38675922 PMCID: PMC11053976 DOI: 10.3390/v16040580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Children with perinatally acquired human immunodeficiency virus (PHIV) are growing into adulthood with HIV and treatment-associated comorbidities, such as dyslipidemia and insulin resistance. HIV is identified as independent risk factor for cardiovascular disease (CVD). The hypothesis behind increased CVD risk associated with HIV includes vascular inflammation, dyslipidemia and combination antiretroviral therapy (cART) metabolomic toxicity. To investigate differences in lipid profiles and pathophysiological mechanisms of CVD risk in adolescents with PHIV, we compared the plasma lipidome of PHIV adolescents and HIV-negative controls. We additionally investigated the influence of current cART regimens and increased lipoprotein(a) (Lp(a)) levels on the plasma lipidome. We included 20 PHIV-infected adolescents and 20 HIV-negative controls matched for age, sex, ethnic origin and socio-economic status. Plasma lipidome was measured using Thermo Scientific Ultimate 3000 binary high-performance liquid chromatography (HPLC)-mass spectrometry. We evaluated the plasma lipidome in PHIV adolescents using different cART regimens (including those known to be associated with lipid alterations). The median age was 17.5 years (15.5-20.7) and 16.5 years (15.7-19.8) for PHIV adolescents and controls, respectively. Of PHIV adolescents, 45% used a non-nucleotide reverse transcriptase inhibitor (NNRTI)-based (25%) or protease inhibitor (PI)-based (20%) cART regimen. In this pilot study, we observed no significant differences between lipidomic profiles between PHIV adolescents and controls. We observed no differences in the plasma lipidome in participants with increased versus normal Lp(a) levels. Different cART regimens appear to influence chain length differences in the plasma lipidome of PHIV adolescents; however, the significance and causality of this observation remains undetermined. Further research on the influence of cART on lipid composition could further identify these alterations.
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Affiliation(s)
- Julie van der Post
- Department of Pediatric Infectious Diseases, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
| | - Thiara E. J. Guerra
- Department of Pediatric Infectious Diseases, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
| | - Malon van den Hof
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
- Department of Epidemiology and Data Science, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Public Health, Ageing & Later Life, Health Behaviors and Chronic Diseases, Amsterdam, The Netherlands
| | - Frédéric M. Vaz
- Department of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children’s Hospital, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
- Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands
- Core Facility Metabolomics, Amsterdam UMC, Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Dasja Pajkrt
- Department of Pediatric Infectious Diseases, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
- Amsterdam Infectious Diseases and Immunology Research Institute, Amsterdam, The Netherlands
| | - Jason G. van Genderen
- Department of Pediatric Infectious Diseases, Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, 1100 DD Amsterdam, The Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands
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Yuen Jr JSK, Saad MK, Xiang N, Barrick BM, DiCindio H, Li C, Zhang SW, Rittenberg M, Lew ET, Zhang KL, Leung G, Pietropinto JA, Kaplan DL. Aggregating in vitro-grown adipocytes to produce macroscale cell-cultured fat tissue with tunable lipid compositions for food applications. eLife 2023; 12:e82120. [PMID: 37014056 PMCID: PMC10072877 DOI: 10.7554/elife.82120] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 03/06/2023] [Indexed: 04/05/2023] Open
Abstract
We present a method of producing bulk cell-cultured fat tissue for food applications. Mass transport limitations (nutrients, oxygen, waste diffusion) of macroscale 3D tissue culture are circumvented by initially culturing murine or porcine adipocytes in 2D, after which bulk fat tissue is produced by mechanically harvesting and aggregating the lipid-filled adipocytes into 3D constructs using alginate or transglutaminase binders. The 3D fat tissues were visually similar to fat tissue harvested from animals, with matching textures based on uniaxial compression tests. The mechanical properties of cultured fat tissues were based on binder choice and concentration, and changes in the fatty acid compositions of cellular triacylglyceride and phospholipids were observed after lipid supplementation (soybean oil) during in vitro culture. This approach of aggregating individual adipocytes into a bulk 3D tissue provides a scalable and versatile strategy to produce cultured fat tissue for food-related applications, thereby addressing a key obstacle in cultivated meat production.
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Affiliation(s)
- John Se Kit Yuen Jr
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Michael K Saad
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Ning Xiang
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Brigid M Barrick
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Hailey DiCindio
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Chunmei Li
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Sabrina W Zhang
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | | | - Emily T Lew
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Kevin Lin Zhang
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Glenn Leung
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - Jaymie A Pietropinto
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
| | - David L Kaplan
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts UniversityMedfordUnited States
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4
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Evaluation the food safety of cultured fat via detection of residues of adipogenic differentiation cocktail in cultured fat with high performance liquid chromatography and enzyme-linked immunosorbent assay. Food Res Int 2023; 165:112486. [PMID: 36869499 DOI: 10.1016/j.foodres.2023.112486] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/14/2022] [Accepted: 01/13/2023] [Indexed: 01/19/2023]
Abstract
Cultured fat is inducing adipose progenitor cells (APCs) to differentiate into mature adipocytes for consumption. The traditional adipogenic differentiation cocktail, including insulin, dexamethasone, indomethacin, isobutylmethylxanthine and rosiglitazone, has potential food safety problems in cultured fat. Therefore, the detection of these residues is necessary to ensure food safety. In this research, a method of high performance liquid chromatography (HPLC) was established to quantitatively analyze the potential residual content of dexamethasone, indomethacin, isobutylmethylxanthine and rosiglitazone in cultured fat and medium. Quantitative analysis showed that the content of four residues in cultured fat decreased to zero on Day 10. Subsequently, enzyme-linked immunosorbent assay (ELISA) was performed to detect the insulin content in the cultured fat and found that the insulin content in the cultured fat on Day 10 was 2.78 ± 0.21 μg/kg. After soaking with phosphate buffered saline (PBS), the insulin content decreased to 1.88 ± 0.54 μg/kg. In conclusion, this research provided an effective approach to clarify the content of potential residual components in cultured fat and it will provide reference for the safety of cultured fat in the future.
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5
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Yuen JSK, Stout AJ, Kawecki NS, Letcher SM, Theodossiou SK, Cohen JM, Barrick BM, Saad MK, Rubio NR, Pietropinto JA, DiCindio H, Zhang SW, Rowat AC, Kaplan DL. Perspectives on scaling production of adipose tissue for food applications. Biomaterials 2022; 280:121273. [PMID: 34933254 PMCID: PMC8725203 DOI: 10.1016/j.biomaterials.2021.121273] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 01/03/2023]
Abstract
With rising global demand for food proteins and significant environmental impact associated with conventional animal agriculture, it is important to develop sustainable alternatives to supplement existing meat production. Since fat is an important contributor to meat flavor, recapitulating this component in meat alternatives such as plant based and cell cultured meats is important. Here, we discuss the topic of cell cultured or tissue engineered fat, growing adipocytes in vitro that could imbue meat alternatives with the complex flavor and aromas of animal meat. We outline potential paths for the large scale production of in vitro cultured fat, including adipogenic precursors during cell proliferation, methods to adipogenically differentiate cells at scale, as well as strategies for converting differentiated adipocytes into 3D cultured fat tissues. We showcase the maturation of knowledge and technology behind cell sourcing and scaled proliferation, while also highlighting that adipogenic differentiation and 3D adipose tissue formation at scale need further research. We also provide some potential solutions for achieving adipose cell differentiation and tissue formation at scale based on contemporary research and the state of the field.
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Affiliation(s)
- John S K Yuen
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Andrew J Stout
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - N Stephanie Kawecki
- Department of Bioengineering, University of California Los Angeles, 410 Westwood Plaza, Los Angeles, CA, 90095, USA; Department of Integrative Biology & Physiology, University of California Los Angeles, Terasaki Life Sciences Building, 610 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
| | - Sophia M Letcher
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Sophia K Theodossiou
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Julian M Cohen
- W. M. Keck Science Department, Pitzer College, 925 N Mills Ave, Claremont, CA, 91711, USA
| | - Brigid M Barrick
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Michael K Saad
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Natalie R Rubio
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Jaymie A Pietropinto
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Hailey DiCindio
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Sabrina W Zhang
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA
| | - Amy C Rowat
- Department of Bioengineering, University of California Los Angeles, 410 Westwood Plaza, Los Angeles, CA, 90095, USA; Department of Integrative Biology & Physiology, University of California Los Angeles, Terasaki Life Sciences Building, 610 Charles E. Young Drive South, Los Angeles, CA, 90095, USA
| | - David L Kaplan
- Biomedical Engineering Department, Tissue Engineering Resource Center, Tufts University, 4 Colby St, Medford, MA, 02155, USA.
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Bourgeois C, Gorwood J, Olivo A, Le Pelletier L, Capeau J, Lambotte O, Béréziat V, Lagathu C. Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment. Front Immunol 2021; 12:670566. [PMID: 34220817 PMCID: PMC8250865 DOI: 10.3389/fimmu.2021.670566] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
White adipose tissue (AT) contributes significantly to inflammation – especially in the context of obesity. Several of AT’s intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.
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Affiliation(s)
- Christine Bourgeois
- CEA - Université Paris Saclay - INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
| | - Jennifer Gorwood
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France
| | - Anaelle Olivo
- CEA - Université Paris Saclay - INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France
| | - Laura Le Pelletier
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France
| | - Jacqueline Capeau
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France
| | - Olivier Lambotte
- CEA - Université Paris Saclay - INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, IDMIT Department, IBFJ, Fontenay-aux-Roses, France.,AP-HP, Groupe Hospitalier Universitaire Paris Saclay, Hôpital Bicêtre, Service de Médecine Interne et Immunologie Clinique, Le Kremlin-Bicêtre, France
| | - Véronique Béréziat
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France
| | - Claire Lagathu
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-métabolisme et Nutrition (ICAN), FRM EQU201903007868, Paris, France
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7
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Impact of Efavirenz Mid-dose Plasma Concentration on Long-Term Weight Change Among Virologically Suppressed People Living With HIV. J Acquir Immune Defic Syndr 2021; 87:834-841. [DOI: 10.1097/qai.0000000000002650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/18/2021] [Indexed: 01/11/2023]
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8
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Muche Belete A, Seifu D, Menon M, Amogne W, Shewa A, Adela Tefera A. Serum Lipid Profiles of Patients Taking Efavirenz-Based Antiretroviral Regimen Compared to Ritonavir-Boosted Atazanavir with an Optimized Background at Zewditu Memorial Hospital, Addis Ababa, Ethiopia. HIV AIDS (Auckl) 2021; 13:217-227. [PMID: 33642881 PMCID: PMC7903961 DOI: 10.2147/hiv.s296170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/11/2021] [Indexed: 01/11/2023] Open
Abstract
Background Dyslipidemia represents significant health care concerns in patients taking antiretroviral therapy due to their association with cardiovascular disease risk. There is limited data regarding the effects of boosted atazanavir (ATV/r) treatment in the lipid profiles of Ethiopian HIV patients. Thus, this study compares the mean values of lipid profile differences of HIV patients on ATV/r-based regimen compared to efavirenz (EFV)-based regimen, while the background is Tenofovir Disoproxil Fumarate/lamivudine. Materials and Methods A comparative hospital-based cross-sectional study was conducted among adult HIV-infected patients at Zewditu Memorial Hospital, Addis Ababa, Ethiopia, from July–September 2017. An equal number of EFV and ATV/r-treated patients (n=90 each) receiving for 1-year and over were included in the study. Serum total cholesterol (TC), triglyceride (TG), gigh-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were measured. Data comparison used chi-square test, Student’s t-test and Mann–Whitney U-test. Multivariate logistic regression analysis and p-value<0.05 were used to identify associated factors of serum lipid profiles. Results In the present study, the ATV/r-treated group results were significantly higher in the median values of TG [207 (56–1094) vs 145 (42–768) mg/dL; p=0.001] and the mean value of TG/HDL-c (6.6 vs 4.4; p=0.001) as compared to the EFV-treated group. The EFV-treated group showed significantly higher in the mean value of HDL-c (44.7 vs 38.7 mg/dL; p=0.001) as compared to the ATV/r-treated group. Body mass index was associate with LDL and HDL. CD4 was associated with TC. Current antiretroviral therapy was associated with TG. Duration of HIV since first diagnosis and duration of ART were associated with HDL. Conclusion ATV/r is associated with elevated in TG and TG/HDL-C, but low HDL as compared to EFV. Differences in LDL or HDL that were found were of unclear clinical significance. The long-term significance is unknown.
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Affiliation(s)
- Abebe Muche Belete
- Department of Biochemistry, Medical Faculty, Debre Berhan University, Debre Berhan, Ethiopia
- Correspondence: Abebe Muche Belete Department of Biochemistry, Medical Faculty, Debre Berhan University, P.O. Box 445, Debre Berhan, Ethiopia Email
| | - Daniel Seifu
- Department of Biochemistry, Division of Biomedical Sciences, University of Global Health Equity, Kigali, Rwanda
| | - Menakath Menon
- Department of Biochemistry, Medical Faculty, Addis Ababa University, Addis Ababa, Ethiopia
| | - Wondwossen Amogne
- Department of Internal Medicine, Medical Faculty, Addis Ababa University, Addis Ababa, Ethiopia
| | - Aster Shewa
- Department of Internal Medicine, Zewditu Memorial Hospital, Addis Ababa, Ethiopia
| | - Alemu Adela Tefera
- Department of Biochemistry, Medical Faculty, Debre Berhan University, Debre Berhan, Ethiopia
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Su J, Shiau S, Arpadi SM, Strehlau R, Burke M, Patel F, Kuhn L, Coovadia A, Yin MT. Switch to Efavirenz Attenuates Lipoatrophy in Girls With Perinatal HIV. J Pediatr Gastroenterol Nutr 2021; 72:e15-e20. [PMID: 32804904 PMCID: PMC8832869 DOI: 10.1097/mpg.0000000000002907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Children with HIV (CHIV) have lifetime exposure to antiretrovirals (ART); therefore, optimizing their regimens to have the least impact on fat redistribution is a priority. METHODS This is a cross-sectional study of 219 perinatally infected CHIV and 219 HIV-uninfected controls from similar socioeconomic backgrounds in Johannesburg, South Africa. We compared total body and regional fat distribution in CHIV on suppressive ART regimens with controls and, among CHIV, between ritonavir-boosted lopinavir (LPV/r)-based and efavirenz (EFV)-based regimens. RESULTS The mean age of the 219 uninfected children (45% girls) and the 219 CHIV (48% girls) was 7.0 and 6.4 years, respectively. CHIV had lower adjusted total body fat (P = 0.005) and lower percentage fat at the trunk (P = 0.020), arms (P = 0.001), and legs (P < 0.001) than uninfected children. CHIV on LPV/r had similar body composition as those on EFV, except for arm fat mass (P = 0.030). When stratified by sex, girls with HIV on LPV/r had lower adjusted total (P = 0.007), trunk (P = 0.002), arms (P = 0.008), legs (P = 0.048) fat mass; trunk-to-total body fat (P = 0.044); and higher legs-to-total body fat (P = 0.011) than those on EFV. CONCLUSIONS South African CHIV receiving ART had lower global and partial fat mass and percentage fat than healthy controls. In girls with HIV with sustained virologic suppression on ART, switching from LPV/r to EFV could attenuate fat mass loss, indicating that EFV-based regimen may be a better option in this group of individuals.
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Affiliation(s)
- Junwei Su
- The Department of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Stephanie Shiau
- Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ
| | - Stephen M Arpadi
- Gertrude H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
- Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Renate Strehlau
- Empilweni Services and Research Unit, Department of Pediatrics and Child Health, Faculty of Health Sciences, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Megan Burke
- Empilweni Services and Research Unit, Department of Pediatrics and Child Health, Faculty of Health Sciences, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Faeezah Patel
- Empilweni Services and Research Unit, Department of Pediatrics and Child Health, Faculty of Health Sciences, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Louise Kuhn
- Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY
- Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
| | - Ashraf Coovadia
- Empilweni Services and Research Unit, Department of Pediatrics and Child Health, Faculty of Health Sciences, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Michael T Yin
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY
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Abstract
Early in the HIV epidemic, lipodystrophy, characterized by subcutaneous fat loss (lipoatrophy), with or without central fat accumulation (lipohypertrophy), was recognized as a frequent condition among people living with HIV (PLWH) receiving combination antiretroviral therapy. The subsequent identification of thymidine analogue nucleoside reverse transcriptase inhibitors as the cause of lipoatrophy led to the development of newer antiretroviral agents; however, studies have demonstrated continued abnormalities in fat and/or lipid storage in PLWH treated with newer drugs (including integrase inhibitor-based regimens), with fat gain due to restoration to health in antiretroviral therapy-naive PLWH, which is compounded by the rising rates of obesity. The mechanisms of fat alterations in PLWH are complex, multifactorial and not fully understood, although they are known to result in part from the direct effects of HIV proteins and antiretroviral agents on adipocyte health, genetic factors, increased microbial translocation, changes in the adaptive immune milieu after infection, increased tissue inflammation and accelerated fibrosis. Management includes classical lifestyle alterations with a role for pharmacological therapies and surgery in some patients. Continued fat alterations in PLWH will have an important effect on lifespan, healthspan and quality of life as patients age worldwide, highlighting the need to investigate the critical uncertainties regarding pathophysiology, risk factors and management.
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11
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Bianconi V, Schiaroli E, Pirro M, Cardaci S, Busti C, Mannarino MR, Baldelli F, Francisci D. Effects of antiretroviral therapy on proprotein convertase subtilisin/kexin 9: focus on lipids, inflammation and immunovirological parameters. HIV Med 2020; 21:512-522. [PMID: 32496664 DOI: 10.1111/hiv.12884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2020] [Indexed: 11/28/2022]
Abstract
OBJECTIVES Plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol metabolism, have been reported to have an increasing trend in people living with HIV (PLWH) compared with controls. We assessed the impact of different antiretroviral (ARV) regimens on plasma PCSK9 levels as well as plasma lipids, systemic inflammation and immunovirological parameters. METHODS Eighty HIV-positive ARV therapy (ART)-naïve PLWH and 40 uninfected controls were retrospectively enrolled. At baseline and 3, 6 and 12 months after ART initiation, plasma PCSK9 levels, lipids, high-sensitivity C-reactive protein (hs-CRP), HIV-1 RNA levels and CD4 T-cell count were measured. RESULTS Baseline PCSK9 levels were significantly more elevated in PLWH and were associated with HIV-1 RNA levels (P < 0.001), CD4 T-cell counts (P < 0.001), triglycerides (P < 0.001) and high-density lipoprotein (HDL) cholesterol (P < 0.001), but not with total cholesterol, low-density lipoprotein (LDL) cholesterol and lipoprotein(a) levels. The prescription of ART was paralleled by significant decreases in plasma PCSK9 and hs-CRP levels, and increases in total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and lipoprotein(a), independent of regimen. CONCLUSIONS PCSK9 levels, along with systemic inflammation, were progressively reduced following the initiation of an effective ART. However, at the end of the study PCSK9 levels remained higher than in controls and did not correlate with any of the lipid variables.
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Affiliation(s)
- V Bianconi
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - E Schiaroli
- Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - M Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - S Cardaci
- Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - C Busti
- Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - M R Mannarino
- Unit of Internal Medicine, Department of Medicine, University of Perugia, Perugia, Italy
| | - F Baldelli
- Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - D Francisci
- Unit of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy
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12
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Trevillyan JM, Wong G, Puls R, Petoumenos K, Emery S, Mellett NA, Mundra PA, Meikle PJ, Hoy JF, for the ALTAIR Study Group. Changes in plasma lipidome following initiation of antiretroviral therapy. PLoS One 2018; 13:e0202944. [PMID: 30157268 PMCID: PMC6114786 DOI: 10.1371/journal.pone.0202944] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Accepted: 08/13/2018] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION HIV and antiretroviral therapy (ART) have been associated with increased cardiovascular disease and important changes in lipid metabolism. Advances in mass-spectrometry technology allow for the detailed assessment of individual lipid species which may illuminate the mechanisms underlying increased cardiovascular risk. We describe the change in plasma lipidome with initiation of antiretroviral therapy and compare these by regimen. METHODS Plasma lipid profiling (by electrospray isonisation-tandem mass spectrometry) was performed on ARV-naive HIV positive participants randomised to one of three regimens; tenofovir/emtricitabine with efavirenz, ritonavir-boosted atazanavir (atazanavir/r) or zidovudine/abacavir. Participants (n = 115) who remained on their randomised regimen with complete samples available at baseline, week 12 and 48 were included. 306 lipid species from 22 lipid classes were analysed. RESULTS Initiation of ART led to significant changes in lipidome which were partly dependent on the randomised regimen received. This led to significant differences in 72 lipid species and 7 classes (cholesterol ester, free cholesterol, phosphatidylcholine, GM3 ganglioside, trihexosylceramide, monohexosylceramide, and ceramides) by arm at week 48. Consistently higher lipid concentrations were seen with efavirenz compared with atazanavir/r or zidovudine/abacavir. Twelve of the lipid species and two lipid classes (cholesterol esters and ceramides) that were significantly increased in the efavirenz arm compared with the atazanavir/r or zidovudine/abacavir arms have previously been associated with future cardiovascular events in HIV positive patients. Change in HIV viral load was predictive of change in 3 lipid species. CONCLUSIONS Initiation of ART lead to significant changes in the plasma lipidome that were greatest in those receiving efavirenz.
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Affiliation(s)
- Janine M. Trevillyan
- Department of Infectious Diseases, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Australia
- * E-mail:
| | - Gerard Wong
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Rebekah Puls
- Faculty of Medicine, UNSW Sydney, Sydney, Australia
| | | | - Sean Emery
- The Kirby Institute, UNSW Sydney, Sydney, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Australia
| | | | | | | | - Jennifer F. Hoy
- Department of Infectious Diseases, Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Australia
- Department of Infectious Diseases, Alfred Hospital, Melbourne, Australia
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13
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Combination of Tenofovir and Emtricitabine with Efavirenz Does Not Moderate Inhibitory Effect of Efavirenz on Mitochondrial Function and Cholesterol Biosynthesis in Human T Lymphoblastoid Cell Line. Antimicrob Agents Chemother 2018; 62:AAC.00691-18. [PMID: 30012753 DOI: 10.1128/aac.00691-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 07/07/2018] [Indexed: 01/22/2023] Open
Abstract
Efavirenz (EFV), the most popular nonnucleoside reverse transcriptase inhibitor, has been associated with mitochondrial dysfunction in most in vitro studies. However, in real life the prevalence of EFV-induced mitochondrial toxicity is relatively low. We hypothesized that the agents given in combination with EFV moderate the effect of EFV on mitochondrial function. To test this hypothesis, we cultured a human T lymphoblastoid cell line (CEM cells) with EFV alone and in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) to investigate the effects on mitochondrial respiration and function and cholesterol biosynthesis. There was a statistically significant concentration- and time-dependent apoptosis, reduction in mitochondrial membrane potential, and increase in production of reactive oxygen species in cells treated with either EVF alone or in combination with TDF plus FTC. Compared to dimethyl sulfoxide-treated cells, EFV-treated cells had significant reduction in oxygen consumption rate contributed by basal mitochondrial respiration and decreased protein expression of electron transport chain complexes (CI, CII, and CIV). Treatment with EFV resulted in a decrease in mitochondrial DNA content and perturbation of more coding genes (n = 13); among these were 11 genes associated with lipid or cholesterol biosynthesis. Our findings support the growing body of knowledge on the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. Interestingly, combining TDF and FTC with EFV did not alter the effects of EFV on mitochondrial respiration and function and cholesterol biosynthesis. The gap between the prevalence of EFV-induced mitochondrial toxicity in in vitro and in vivo studies could be due to individual differences in the pharmacokinetics of EFV.
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14
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Tsai FJ, Cheng CF, Lai CH, Wu YC, Ho MW, Wang JH, Tien N, Liu X, Tsang H, Lin TH, Liao CC, Huang SM, Li JP, Lin JC, Lin CC, Chen JH, Liang WM, Lin YJ. Effect of antiretroviral therapy use and adherence on the risk of hyperlipidemia among HIV-infected patients, in the highly active antiretroviral therapy era. Oncotarget 2017; 8:106369-106381. [PMID: 29290955 PMCID: PMC5739740 DOI: 10.18632/oncotarget.22465] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 10/28/2017] [Indexed: 12/12/2022] Open
Abstract
HIV-infected patients exposed to antiretroviral therapy (ART) have an increased risk for hyperlipidemia and cardiovascular disease. We performed a longitudinal, comprehensive, and population-based study to investigate the cumulative effect of different types of ART regimens on hyperlipidemia risk in the Taiwanese HIV/ART cohort. A total of 13,370 HIV-infected patients (2,674 hyperlipidemia and 10,696 non-hyperlipidemia patients) were recruited after matching for age, gender, and the first diagnosis date of HIV infection by using the National Health Insurance Research Database in Taiwan. Hyperlipidemia risk associated with cumulative ART use, ART adherence, and their combination was assessed. The matched hyperlipidemia group had a larger number of patients using ART and a higher incidence of comorbidities, specifically, respiratory disease and diabetes. Patients with high ART dosage and dose-dependent manner adherence, respectively, demonstrated an increased risk of hyperlipidemia. For single ART regimens, patients receiving nucleoside reverse-transcriptase inhibitors (NRTI/NRTI)- containing regimen had the highest hyperlipidemia risk, followed by protease inhibitor (PI)- containing and non-NRTI- containing regimens. For combination ART regimens, patients receiving a NRTI/NRTI + PI regimen had the highest hyperlipidemia risk. An increased cumulative drug dose was observed in patients who received the PI, NRTI/NRTI, NRTI, and NNRTI regimens in the hyperlipidemia group, when compared to the non-hyperlipidemia group. In conclusion, ART cumulative use, adherence, and regimen may affect hyperlipidemia risk among HIV-infected patients in a dose-dependent manner.
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Affiliation(s)
- Fuu-Jen Tsai
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.,Asia University, Taichung, Taiwan
| | - Chi-Fung Cheng
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Chih-Ho Lai
- Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yang-Chang Wu
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Mao-Wang Ho
- Section of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jen-Hsien Wang
- Section of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ni Tien
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Xiang Liu
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Hsinyi Tsang
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Ting-Hsu Lin
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Chiu-Chu Liao
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Mei Huang
- Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Ju-Pi Li
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan
| | - Jung-Chun Lin
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Chih-Chien Lin
- Department of Cosmetic Science, Providence University, Taichung, Taiwan
| | - Jin-Hua Chen
- Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan.,School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan
| | - Wen-Miin Liang
- Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan
| | - Ying-Ju Lin
- School of Chinese Medicine, China Medical University, Taichung, Taiwan.,Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
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15
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Abstract
HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal-vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV-associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR-γ and other regulatory gene expression, and increased proinflammatory cytokine production. Newer-generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. © 2017 American Physiological Society. Compr Physiol 7:1339-1357, 2017.
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Affiliation(s)
- John R Koethe
- Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
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16
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Jones E, Mazirka P, McNurlan MA, Darras F, Gelato MC, Caso G. Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes. World J Virol 2017; 6:53-58. [PMID: 28868243 PMCID: PMC5561499 DOI: 10.5501/wjv.v6.i3.53] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/28/2017] [Accepted: 06/07/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome.
METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase (GP DH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher’s Least Significant Difference test.
RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI (14% at 48 h, P < 0.001) and PI + NRTI (19% at 48 h, P < 0.001) with additional suppression when ritonavir (RTV) was added (26% at 48 h). The drug combination of atazanavir (ATV) + RTV + emtricitabine (FTC) + tenofovir (TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity (64%) or lipid accumulation (39%), P < 0.001. Combining NRTIs with a PI (ATV + FTC + TDF) significantly suppressed differentiation (GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added (ATV + FTC + TDF + RTV, P < 0.001).
CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.
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17
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Apostolova N, Blas-Garcia A, Galindo MJ, Esplugues JV. Efavirenz: What is known about the cellular mechanisms responsible for its adverse effects. Eur J Pharmacol 2017; 812:163-173. [PMID: 28690189 DOI: 10.1016/j.ejphar.2017.07.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/04/2017] [Accepted: 07/05/2017] [Indexed: 02/08/2023]
Abstract
The HIV infection remains an important health problem worldwide. However, due to the efficacy of combined antiretroviral therapy (cART), it has ceased to be a mortal condition, becoming a chronic disease instead. Efavirenz, the most prescribed non-nucleoside analogue reverse transcriptase inhibitor (NNRTI), has been a key component of cART since its commercialization in 1998. Though still a drug of choice in many countries, its primacy has been challenged by the arrival of newer antiretroviral agents with better toxicity profiles and treatment adherence. The major side effects related to EFV have been widely described in clinical studies, however the mechanisms that participate in their pathogenesis remain largely ununderstood. This review provides an insight into the cellular and molecular mechanisms responsible for the development of the most significant undesired effects induced by efavirenz, both short- and long-term, revealed by in vitro and in vivo experimental pharmacological research. Growing evidence implicates the drug in energy metabolism, mitochondrial function, and other cellular processes involved in stress responses including oxidative stress, inflammation and autophagy.
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Affiliation(s)
- Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia-Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain.
| | - Ana Blas-Garcia
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia-Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
| | - Maria J Galindo
- Unidad de Enfermedades Infecciosas - Medicina Interna, Hospital Clínico Universitario de Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia-Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain; FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain
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18
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Unmasking efavirenz neurotoxicity: Time matters to the underlying mechanisms. Eur J Pharm Sci 2017; 105:47-54. [PMID: 28487145 DOI: 10.1016/j.ejps.2017.05.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 04/06/2017] [Accepted: 05/05/2017] [Indexed: 12/14/2022]
Abstract
Efavirenz is an anti-HIV drug that presents relevant short- and long-term central nervous system adverse reactions. Its main metabolite (8-hydroxy-efavirenz) was demonstrated to be a more potent neurotoxin than efavirenz itself. This work was aimed to understand how efavirenz biotransformation to 8-hydroxy-efavirenz is related to its short- and long-term neuro-adverse reactions. To access those mechanisms, the expression and activity of Cyp2b enzymes as well as the thiolomic signature (low molecular weight thiols plus S-thiolated proteins) were longitudinally evaluated in the hepatic and brain tissues of rats exposed to efavirenz during 10 and 36days. Efavirenz and 8-hydroxy-efavirenz plasma concentrations were monitored at the same time points. Cyp2b induction had a delayed onset in liver (p<0.001), translating into increases in Cyp2b activity in liver and 8-hydroxy-efavirenz plasma concentration (p<0.001). Moreover, an increase in S-cysteinyl-glycinylated proteins (p<0.001) and in free low molecular weight thiols was also observed in liver. A distinct scenario was observed in hippocampus, which showed an underexpression of Cyp2b as well as a decrease in S-cysteinylated and S-glutathionylated proteins. Additionally, the observed changes in tissues were associated with a marked increase of S-glutathionylation in plasma. Our data suggest that the time course of efavirenz biotransformation results from different mechanisms for its short- and long-term neurotoxicity. The difference in the redox profile between liver and hippocampus might explain why, despite being mostly metabolized by the liver, this drug is neurotoxic. If translated to clinical practice, this evidence will have important implications in efavirenz short- and long-term neurotoxicity prevention and management.
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19
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Moure R, Domingo P, Gallego-Escuredo JM, Villarroya J, Gutierrez MDM, Mateo MG, Domingo JC, Giralt M, Villarroya F. Impact of elvitegravir on human adipocytes: Alterations in differentiation, gene expression and release of adipokines and cytokines. Antiviral Res 2016; 132:59-65. [PMID: 27216995 DOI: 10.1016/j.antiviral.2016.05.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 04/19/2016] [Accepted: 05/17/2016] [Indexed: 11/28/2022]
Abstract
Elvitegravir is a recently developed integrase inhibitor used for antiretroviral treatment of HIV infection. Secondary effects, including disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function, are common concerns associated with antiretroviral treatments. Here, we provide the first study of the effects of elvitegravir (in comparison with efavirenz, a non-nucleoside analog inhibitor of reverse transcriptase; and raltegravir, another integrase inhibitor) on human adipocyte differentiation, gene expression and secretion of adipokines and cytokines. Elvitegravir impaired adipogenesis and adipocyte metabolism in human SGBS adipocytes in a concentration-dependent manner (delaying acquisition of adipocyte morphology and reducing the expression of adipogenesis marker genes such as PPARγ, glucose transporter GLUT4, lipoprotein lipase, and the adipokines adiponectin and leptin). Compared with efavirenz, the effects of elvitegravir were similar but tended to occur at higher concentrations than those elicited by efavirenz, or were somewhat less intense than those caused by efavirenz at similar concentration. Elvitegravir tended to cause a more moderate induction of pro-inflammatory cytokines than efavirenz. Efavirenz induced a marked concentration-dependent increase in interleukin-8 expression and release whereas elvitregravir had little effect. Raltegravir had totally neutral actions of adipogenesis, adipocyte metabolism-related gene expression and release of adipokines and cytokines. In conclusion, elvitegravir alters adipocyte differentiation and function and promotes induction of pro-inflammatory cytokines similarly to efavirenz, but several effects were less intense. Further assessment of lipid metabolism and adipose tissue function in patients administered elvitegravir-based regimes is advisable considering that totally neutral effects of elvitegravir on lipid homeostasis cannot be anticipated from the current study in vitro.
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Affiliation(s)
- Ricardo Moure
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Pere Domingo
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona and Red de Investigación en SIDA (RIS), Barcelona, Spain
| | - José M Gallego-Escuredo
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Joan Villarroya
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain; Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona and Red de Investigación en SIDA (RIS), Barcelona, Spain
| | - Maria Del Mar Gutierrez
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona and Red de Investigación en SIDA (RIS), Barcelona, Spain
| | - Maria G Mateo
- Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona and Red de Investigación en SIDA (RIS), Barcelona, Spain
| | - Joan C Domingo
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Marta Giralt
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain
| | - Francesc Villarroya
- Department of Biochemistry and Molecular Biology, Institut de Biomedicina (IBUB), University of Barcelona, CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
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20
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Karamchand S, Leisegang R, Schomaker M, Maartens G, Walters L, Hislop M, Dave JA, Levitt NS, Cohen K. Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy. Medicine (Baltimore) 2016; 95:e2844. [PMID: 26945366 PMCID: PMC4782850 DOI: 10.1097/md.0000000000002844] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged.
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Affiliation(s)
- Sumanth Karamchand
- From the Division of Clinical Pharmacology (SK, RL, GM, KC), Division of Endocrinology, Department of Medicine (JAD, NSL), Center for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town (MS), Aid for AIDS Management (Pty) Limited (MH), Health Intelligence Unit, Medscheme (Pty) Limited (LW), Chronic Disease Initiative for Africa, Cape Town (JAD, NSL), South Africa
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21
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Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-associated lipodystrophy. Metabolism 2015; 64:47-59. [PMID: 25267014 DOI: 10.1016/j.metabol.2014.07.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 02/07/2023]
Abstract
Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy.
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Affiliation(s)
- Michael A Tsoukas
- Section of Endocrinology, Boston VA Healthcare system and Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Olivia M Farr
- Section of Endocrinology, Boston VA Healthcare system and Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Section of Endocrinology, Boston VA Healthcare system and Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Svärd J, Blanco F, Nevin D, Fayne D, Mulcahy F, Hennessy M, Spiers JP. Differential interactions of antiretroviral agents with LXR, ER and GR nuclear receptors: potential contributing factors to adverse events. Br J Pharmacol 2014; 171:480-97. [PMID: 24372550 DOI: 10.1111/bph.12480] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 09/30/2013] [Accepted: 10/15/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND AND PURPOSE Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXRα/β), oestrogen receptors (ERα/β) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated. EXPERIMENTAL APPROACH The ability of an ARV drug library to activate LXRα/β, ERα/β and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression. KEY RESULTS Direct LBD interactions with LXRα and/or LXRβ were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/β in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir. CONCLUSIONS AND IMPLICATIONS There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through 'off-target' effects involving nuclear receptor activation.
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Affiliation(s)
- J Svärd
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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A 48-Week Study of Fat Molecular Alterations in HIV Naive Patients Starting Tenofovir/Emtricitabine With Lopinavir/Ritonavir or Efavirenz. J Acquir Immune Defic Syndr 2014; 66:457-65. [DOI: 10.1097/qai.0000000000000205] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet 2014; 383:1474-1482. [PMID: 24522178 DOI: 10.1016/s0140-6736(13)62187-x] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The optimum dose of key antiretroviral drugs is often overlooked during product development. The ENCORE1 study compared the efficacy and safety of reduced dose efavirenz with standard dose efavirenz in combination with tenofovir and emtricitabine as first-line treatment for HIV infection. An effective and safe reduced dose could yield meaningful cost savings. METHODS ENCORE1 is a continuing non-inferiority trial in HIV-1-infected antiretroviral-naive adults in 38 clinical sites in 13 countries. Participants (plasma HIV-RNA >1000 log10 copies per mL, CD4 T-cell count 50-500 cells per μL) were randomly assigned by a computer-generated sequence with a blocking factor of four (stratified by clinical site and by screening viral load) to receive tenofovir plus emtricitabine with either a reduced daily dose (400 mg) or a standard dose (600 mg) of efavirenz. Participants, physicians, and all other trial staff were masked to treatment group. The primary endpoint was the difference in proportions of participants with plasma HIV-RNA of less than 200 copies per mL at 48 weeks. Treatment groups were regarded as non-inferior if the lower limit of the 95% CI for the difference in viral load was less than -10% by modified intention-to-treat analysis. Adverse events were summarised by treatment. This trial is registered with ClinicalTrials.gov, number NCT01011413. FINDINGS The modified intention-to-treat analysis consisted of 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4·75 log10 copies per mL (IQR 0·88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94·1% for efavirenz 400 mg and 92·2% for 600 mg (difference 1·85%, 95% CI -2·1 to 5·79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per μL, 95% CI 6-44; p=0·01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400=89·1%, efavirenz 600=88·4%; difference 0·75%, 95% CI -4·19 to 5·69; p=0·77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference -10·5%, 95% CI -18·2 to -2·8; p=0·01) and significantly fewer patients with these events stopped treatment (400 mg=6 [2%], 600 mg=18 [6%], difference -3·96%, 95% CI -6·96 to -0·95; p=0·01). INTERPRETATION Our findings suggest that a reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with tenofovir and emtricitabine during 48 weeks in ART-naive adults with HIV-1 infection. Adverse events related to the study drug were more frequent with 600 mg efavirenz than with 400 mg. Lower dose efavirenz should be recommended as part of routine care. FUNDING Bill & Melinda Gates Foundation, University of New South Wales.
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Nolis T. Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies. J Hum Genet 2013; 59:16-23. [PMID: 24152769 DOI: 10.1038/jhg.2013.107] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 08/31/2013] [Accepted: 09/10/2013] [Indexed: 01/16/2023]
Abstract
Lipodystrophies are an immense group of genetic or acquired metabolic disorders that are characterized by varying degrees of body fat loss and in some instances localized accumulation of subcutaneous fat. Lipodystrophies are often tightly linked with profound metabolic complications; this strong bond emphasizes and reinforces the significance of adipose tissue as a dynamic endocrine organ. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis. The lipodystrophies can be divided into generalized, partial or local, depending on the degree and locality of the observable fat loss; moreover, the generalized and partial divisions can be partitioned further into inherited or acquired forms. The major genetic factors in the generalized forms of the lipodystrophies, particularly Congenital generalized lipodystrophy (CGL)-Berardinelli-Seip syndrome, are the AGPAT2, BSCL2, caveolin 1 (CAV1) and polymerase-I-and-transcriptrelease factor (PTRF) genes. In the acquired forms, genes such as LMNA, PPARG, CIDEC (cell-death-inducing DNA fragmentation factor a-like effector c) and PLIN1 are heavily involved in familial partial lipodystrophy (FPLD) type 2 (also known as the Dunnigan-Variety) and WRN along with RECQL5 in Werner Syndrome (WS). Autoimmune causes are particularly noted in acquired partial lipodystrophy (APL)-Barraquer-Simons syndrome and in AGL-Lawrence syndrome; panniculitis has been shown to have a substantial role in the former as well as in other forms of localized lipodystrophies. Patients with human immunodeficiency virus (HIV) exposed to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) (for example, zidovudine and stavudine) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) (for example, efavirenz) while undergoing Highly Active Antiretroviral Therapy (HAART) have led to the current most-prevalent form of the lipodystrophies: lipodystrophy in HIV-infected patients (LD-HIV) and HAART-associated lipodystrophy syndrome (HALS).
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Affiliation(s)
- Tom Nolis
- Graduate Entry Medical School, Richmond Hill, Ontario, Canada
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26
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Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation. Cytokine 2013; 61:808-15. [PMID: 23357304 DOI: 10.1016/j.cyto.2012.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Revised: 12/17/2012] [Accepted: 12/18/2012] [Indexed: 12/14/2022]
Abstract
Maraviroc (MVC) is a drug approved for use as part of HAART in treatment-experienced HIV-1 patients with CCR5-tropic virus. Despite the current concerns on the alterations in adipose tissue that frequently appear in HIV-infected patients under HAART, there is no information available on the effects of MVC on adipose tissue. Here we studied the effects of MVC during and after the differentiation of human adipocytes in culture, and compared the results with the effects of efavirenz (EFV). We measured the acquisition of adipocyte morphology; the gene expression levels of markers for mitochondrial toxicity, adipogenesis and inflammation; and the release of adipokines and cytokines to the medium. Additionally, we determined the effects of MVC on lipopolysaccharide (LPS)-induced pro-inflammatory cytokine expression in adipocytes. Unlike EFV-treated pre-adipocytes, MVC-treated pre-adipocytes showed no alterations in the capacity to differentiate into adipocytes and accumulated lipids normally. Consistent with this, there were no changes in the mRNA levels of PPARγ or SREBP-1c, two master regulators of adipogenesis. In addition, MVC caused a significant decrease in the gene expression and release of pro-inflammatory cytokines, whereas EFV had the opposite effect. Moreover, MVC lowered inflammation-related gene expression and inhibited the LPS-induced expression of pro-inflammatory genes in differentiated adipocytes. We conclude that MVC does not alter adipocyte differentiation but rather shows anti-inflammatory properties by inhibiting the expression and secretion of pro-inflammatory cytokines. Collectively, our results suggest that MVC may minimize adverse effects on adipose tissue development, metabolism, and inflammation, and thus could be a potentially beneficial component of antiretroviral therapy.
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Watanabe M, Uesugi M. Small-molecule inhibitors of SREBP activation – potential for new treatment of metabolic disorders. MEDCHEMCOMM 2013. [DOI: 10.1039/c3md00177f] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Fève B, Glorian M, Hadri KE. Pathophysiology of the HIV-Associated Lipodystrophy Syndrome. Metab Syndr Relat Disord 2012; 2:274-86. [PMID: 18370696 DOI: 10.1089/met.2004.2.274] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The widespread use of highly active antiretroviral therapy (HAART) has radically transformed the prognosis of HIV-infected patients in the developed countries. Unfortunately, a serious metabolic syndrome combining peripheral lipoatrohy, central adiposity, insulin resistance, and dyslipidemia has arisen in these individuals. The etiology of this heterogeneous syndrome named lipodystrophy syndrome (LDS) is multifactorial, but adipose tissue is very likely a key factor that contributes to several clinical or metabolic aspects of the syndrome. In peripheral adipose tissue, HAART may act on both preadipocytes and adipocytes to induce fat loss. Several components of the HAART regimen can inhibit preadipocyte differentiation, in particular through alterations in the expression and/or function of the transcription factor sterol responsive element binding protein-1c. In superficial mature adipocytes, HAART promotes insulin resistance and apoptosis. Insulin resistance of peripheral fat cells could be the consequence of increased lipolysis and adipocytokine dysregulation. In turn, the increased free fatty acid disposal and the disturbances in adipocytokine production may induce skeletal muscle and liver insulin resistance, dyslipidemia, and a fat redistribution toward deep depots, causing visceral lipohypertrophy. The metabolic profile observed in LDS is reminiscent of that observed in metabolic syndrome, raising potential implications for cardiovascular risk in these patients. The pathophysiological mechanisms at the basis of this syndrome represent a rational basis for the treatment or prevention of the metabolic complications.
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Affiliation(s)
- Bruno Fève
- UMR CNRS 7079-Université Paris VI, Centre de Recherches Biomédicale des Cordeliers, Paris, France
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Benhamed F, Denechaud PD, Lemoine M, Robichon C, Moldes M, Bertrand-Michel J, Ratziu V, Serfaty L, Housset C, Capeau J, Girard J, Guillou H, Postic C. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest 2012; 122:2176-94. [PMID: 22546860 DOI: 10.1172/jci41636] [Citation(s) in RCA: 315] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Accepted: 02/15/2012] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.
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Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antimicrob Agents Chemother 2012; 56:3369-75. [PMID: 22430974 DOI: 10.1128/aac.00104-12] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation in vitro. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.
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Abstract
The use of antiretroviral therapies has improved survival in people living with HIV to nearly normal rates. However, ongoing low-level HIV replication and incomplete immune recovery are associated with a chronic inflammatory stimulus. This increases several non-typically AIDS-related complications, including fat mass changes and metabolic conditions. Abdominal adiposity occurs as a result of complex interactions involving HIV itself, antiretroviral drug-associated factors, and several intermediary metabolic alterations and abnormal hormone levels. Abdominal adiposity in turn can further the metabolic derangements, and increase the risk of diabetes and cardiovascular disease. Abnormal growth hormone secretion plays a role in development of the fat depot changes. Effective long-term interventions to decrease central adiposity are limited but studies using growth hormone and especially growth hormone-releasing factor have shown encouraging results. Other emerging therapeutic options have been variably successful in the short term and the continuing clinical and therapeutic challenges will require ongoing investigation.
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Affiliation(s)
- Julian Falutz
- Immunodeficiency Treatment Center, McGill University Health Center, Montreal, Quebec, Canada.
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Lee MS, Kim IH, Kim CT, Kim Y. Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice. J Nutr 2011; 141:1947-53. [PMID: 21918057 DOI: 10.3945/jn.111.146050] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
This study investigated the antiobesity effect of garlic in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (45% fat) for 8 wk to induce obesity. Subsequently, they were fed a high-fat control diet, high-fat diets supplemented with 2%, or 5% garlic (wt:wt) for another 7 wk. Dietary garlic reduced body weight and the mass of various white adipose tissue deposits and also ameliorated the high-fat diet-induced abnormal plasma and liver lipid profiles. Garlic supplementation significantly decreased the mRNA levels of adipogenic genes in white adipose tissues (WAT). However, consumption of garlic increased the expression of mRNA for uncoupling proteins in brown adipose tissue (BAT), liver, WAT, and skeletal muscle. Mice treated with garlic maintained a significantly higher body temperature than untreated mice during a 6-h, 4°C cold challenge and, notably, AMP-activated protein kinase (AMPK) activity was stimulated in BAT, liver, WAT, and skeletal muscle. These results suggest that the antiobesity effects of garlic were at least partially mediated via activation of AMPK, increased thermogenesis, and decreased expression of multiple genes involved in adipogenesis.
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Affiliation(s)
- Mak-Soon Lee
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
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Apostolova N, Blas-García A, Esplugues JV. Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition. Trends Pharmacol Sci 2011; 32:715-25. [PMID: 21899897 DOI: 10.1016/j.tips.2011.07.007] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2011] [Revised: 07/27/2011] [Accepted: 07/29/2011] [Indexed: 02/06/2023]
Abstract
The combined pharmacological approach to the treatment of HIV infection, known as highly active antiretroviral therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, its use has been associated with serious adverse reactions, of which those resulting from mitochondrial dysfunction are particularly widespread. Nucleos(t)ide-reverse transcriptase inhibitors (NRTIs) have long been considered the main source of HAART-related mitochondrial toxicity due to their ability to inhibit Pol-γ, the DNA polymerase responsible for the synthesis of mitochondrial DNA. Nevertheless, accumulating evidence points to a more complex relationship between these organelles and NRTIs. Also, alternative pathways by which other groups of anti-HIV drugs (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) interfere with mitochondria have been suggested, although their implications, both pharmacological and clinical, are open to debate. This review aims to provide a comprehensive overview of the mechanisms and factors which influence the mitochondrial involvement in the toxicity of all three major classes of anti-HIV drugs.
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Affiliation(s)
- Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Avda Blasco Ibáñez n.15-17, 46010 Valencia, Spain
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Bedimo R. Growth hormone and tesamorelin in the management of HIV-associated lipodystrophy. HIV AIDS-RESEARCH AND PALLIATIVE CARE 2011; 3:69-79. [PMID: 22096409 PMCID: PMC3218714 DOI: 10.2147/hiv.s14561] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
HIV-infected patients on highly active antiretroviral therapy (HAART) develop a complex of body composition changes known, including peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). These changes may cause significant patient distress, which could in turn interfere with adherence to antiretroviral therapy. Treatment options - including antiretroviral switch, insulin sensitizers, and surgical approaches - have been associated with limited success and potential complications. The observation that low growth hormone levels are associated with central fat accumulation among HIV patients has led to the development of tesamorelin (a growth hormone releasing hormone analog) for the management of central fat accumulation. Randomized controlled trials have shown that administration of tesamorelin is safe and effective in reducing central fat accumulation among HIV-infected patients. This effect is transient, however, and its association with improved cardiovascular risk remains unclear.
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Affiliation(s)
- Roger Bedimo
- Infectious Disease section, VA North Texas Health Care System, TX, USA
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35
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Abstract
HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is an adipose tissue redistribution disorder characterized by subcutaneous adipose tissue lipoatrophy, sometimes including visceral adipose tissue hypertrophy and accumulation of dorsocervical fat ('buffalo hump'). The pathophysiology of HALS appears to be multifactorial and several key pathophysiological factors associated with HALS have been identified. These include mitochondrial dysfunction, adipocyte differentiation disturbances, high adipocyte lipolysis, and adipocyte apoptosis. These alterations in adipose tissue biology expand to involve systemic metabolism through alterations in endocrine functions of adipose tissue (via disturbed adipokine release), enhanced production of pro-inflammatory cytokines and excessive free fatty-acid release due to lipolysis. The deleterious action of some antiretroviral drugs is an important factor in eliciting these alterations in adipose tissue. However, HIV-1 infection-related events and HIV-1-encoded proteins also contribute directly to the complex development of HALS through effects on adipocyte biology, or indirectly through the promotion of local inflammation in adipose tissue.
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Affiliation(s)
- Marta Giralt
- Department of Biochemistry and Molecular Biology and Institut de Biomedicina (IBUB), University of Barcelona, Barcelona, Catalonia, Spain.
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Díaz-Delfín J, del Mar Gutiérrez M, Gallego-Escuredo JM, Domingo JC, Gracia Mateo M, Villarroya F, Domingo P, Giralt M. Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res 2011; 91:112-9. [PMID: 21619898 DOI: 10.1016/j.antiviral.2011.04.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 02/10/2011] [Accepted: 04/19/2011] [Indexed: 12/25/2022]
Abstract
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz are drugs of choice for initial antiretroviral treatment for HIV-1 infection. Although NNRTIs have not traditionally been associated with the appearance of adipose alterations, recent data suggest that efavirenz may contribute to adipose tissue alterations in antiretroviral-treated patients, consistent with its ability to impair differentiation of adipocytes in cell cultures. No such effects have been reported for nevirapine, the other most commonly used NNRTI. In this study, we determined the effects of nevirapine on differentiation, gene expression and release of regulatory proteins (adipokines and cytokines) in differentiating human adipocytes, and compared them with those of efavirenz. Efavirenz caused a dose-dependent repression of adipocyte differentiation that was associated with down-regulation of the master adipogenesis regulator genes SREBP-1, PPARγ and C/EBPα, and their target genes encoding lipoprotein lipase, leptin and adiponectin, which are key proteins in adipocyte function. In contrast, nevirapine does not affect adipogenesis and causes a modest but significant coordinate increase in the expression of SREBP-1, PPARγ and C/EBPα and their target genes only at a concentration of 20 μM. Whereas efavirenz caused a significant increase in the release of pro-inflammatory cytokines (interleukin [IL]-8, IL-6, monocyte chemoattractant protein-1), plasminogen activator inhibitor type-1 and hepatocyte growth factor (HGF), nevirapine either had no effect on these factors or decreased their release (IL-6 and HGF). Nevirapine significantly increased adiponectin release, whereas efavirenz strongly repressed it. Moreover, nevirapine inhibited preadipocyte endogenous reverse transcriptase activity, whereas efavirenz did not alter it. It is concluded that, in contrast with the profound anti-adipogenic and pro-inflammatory response elicited by efavirenz, nevirapine does not impair adipogenesis.
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Affiliation(s)
- Julieta Díaz-Delfín
- Department of Biochemistry and Molecular Biology and Institut de Biomedicina (IBUB), University of Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Spain
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Ikarashi N, Tajima M, Suzuki K, Toda T, Ito K, Ochiai W, Sugiyama K. Inhibition of Preadipocyte Differentiation and Lipid Accumulation by Orengedokuto Treatment of 3T3-L1 Cultures. Phytother Res 2011; 26:91-100. [DOI: 10.1002/ptr.3493] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 03/09/2011] [Accepted: 03/10/2011] [Indexed: 11/10/2022]
Affiliation(s)
- Nobutomo Ikarashi
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Masataka Tajima
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Kunihiro Suzuki
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Takahiro Toda
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Kiyomi Ito
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Wataru Ochiai
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
| | - Kiyoshi Sugiyama
- Department of Clinical Pharmacokinetics; Hoshi University; 2-4-41 Ebara, Shinagawa-ku Tokyo 142-8501 Japan
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Approach to dyslipidemia, lipodystrophy, and cardiovascular risk in patients with HIV infection. Curr Atheroscler Rep 2011; 13:51-6. [PMID: 21181310 PMCID: PMC3018260 DOI: 10.1007/s11883-010-0152-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There is a significant prevalence (20%–80% depending on the population and the study) of lipid disorders and other cardiovascular risk factors in people living with HIV infection. This review focuses on HIV and HIV treatment–associated metabolic and cardiovascular concerns, including dyslipidemias, lipodystrophy syndromes, endothelial dysfunctions, and associated metabolic events such as insulin resistance. Emerging hypotheses of the underlying pathophysiology of these issues, with impact on selection of specific antiretroviral treatment (ART) strategies, therapy, and preventive approaches to decreasing cardiovascular risk and other problems associated with these syndromes are discussed. Screening for cardiovascular risk as part of the decision of starting antiretroviral therapy, and during care of patients with HIV regardless of ART therapy status, is suggested with particular areas of focus. Statins, other hyperlipidemic therapies, treatment for specific problems arising due to lipodystrophy, and implications on ART selection to avoid drug interactions and adverse effects are also discussed.
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Abstract
Lipodystrophy is a medical condition characterized by complete or partial loss of adipose tissue. Not infrequently, lipodystrophy occurs in combination with pathological accumulation of adipose tissue at distinct anatomical sites. Patients with lipodystrophy exhibit numerous metabolic complications, which indicate the importance of adipose tissue as an active endocrine organ. Not only the total amount but also the appropriate distribution of adipose tissue depots contribute to the metabolic state. Genetic and molecular research has improved our understanding of the mechanisms underlying lipodystrophy. Circulating levels of hormones secreted by the adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subpopulations of patients with lipodystrophy. This finding rationalizes the use of these adipokines or of agents that increase their circulating levels, such as peroxisome proliferator-activated receptor γ (PPARγ) agonists, for therapeutic purposes. Other novel therapeutic approaches, including the use of growth hormone and growth-hormone-releasing factors, are also being studied as potential additions to the therapeutic armamentarium. New insights gained from research and clinical trials could potentially revolutionize the management of this difficult-to-treat condition.
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Affiliation(s)
- Christina G Fiorenza
- Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
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Abstract
OBJECTIVE antiretrovirals, especially thymidine-analogue nucleoside reverse transcriptase inhibitors (tNRTIs), may cause the mitochondrial damage in adipose tissue that has been associated with lipodystrophy development. HIV itself may damage blood cell mitochondria. However, the viral capacity to induce adipose tissue mitochondrial lesion is still a matter of doubt. We aimed to assess whether untreated HIV infection was associated with adipose tissue mitochondrial abnormalities. DESIGN : Single-site, cross-sectional, controlled observational and exploratory study without intervention. METHODS we included 24 uninfected controls and 18 HIV-infected patients with undetectable viral load and no clinical signs of lipodystrophy stratified as antiretroviral naive (n = 11) or at least 6-month antiviral-treated with a double NRTI combination, including lamivudine plus one tNRTI (n = 7). Subcutaneous adipose tissue was homogenated to determine mtDNA content by rtPCR and mitochondrial function per mitochondria through the spectrophotometric measurement of cytochrome c oxidase activity normalized by citrate synthase amount (COX/citrate synthase). Differences in mitochondrial parameters among groups were sought to determine the contribution of HIV and antiretrovirals to mitochondrial alterations. RESULTS compared with uninfected controls (arbitrarily assigned 100%), naive individuals presented a marked decrease in adipose tissue mtDNA content and COX/citrate synthase function (62 and 75% remaining content/activity, P < 0.001 and P < 0.05). Antiretrovirals did not increase this impairment (69 and 70% remaining content/activity, P < 0.05 compared to controls and P = not significant compared to naives). Additionally, molecular and functional mitochondrial parameters were positively correlated (P < 0.05). CONCLUSION in nonlipodystrophic HIV-infected naive patients, viral infection is associated with adipose tissue mtDNA decrease and mitochondrial dysfunction independently of antiretroviral treatment.
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McGee KC, Shahmanesh M, Boothby M, Nightingale P, Gathercole LL, Tripathi G, Harte AL, Shojaee-Moradie F, Umpleby AM, Das S, Al-Daghri NM, McTernan PG, Tomlinson JW. Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones. Antivir Ther 2011; 17:495-507. [DOI: 10.3851/imp2017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2011] [Indexed: 10/14/2022]
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Gazzola L, Tincati C, d’Arminio Monforte A. Noninfectious HIV-related comorbidities and HAART toxicities: choosing alternative antiretroviral strategies. ACTA ACUST UNITED AC 2010. [DOI: 10.2217/hiv.10.44] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In the HAART era, clinicians are faced with the challenge of treating an aging HIV-infected population increasingly affected by severe comorbidities, which may compromise the tolerability of antiretroviral regimens. In this special population, it is imperative for physicians to carefully tailor antiretroviral treatment in order not to worsen patients’ underlying clinical conditions and to achieve both tolerability and immune–virologic efficacy. This article aims to explore the impact of standard HAART regimens on the different noninfectious HIV-related comorbidities: metabolic, cardiovascular, bone and renal diseases, in order to provide tools to fit the most appropriate antiretroviral combination according to individual clinical conditions. Clinical experience with alternative antiretroviral strategies, avoiding nucleoside reverse transcriptase inhibitor toxicities and involving new antiretroviral classes, will be reviewed to obtain an overview on future perspectives.
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Affiliation(s)
- Lidia Gazzola
- Clinic of Infectious Diseases, Department of Medicine, Surgery & Dentistry, ‘San Paolo’ Hospital, University of Milan, Via A. Di Rudinì, 8, 20142 – Milan, Italy
| | - Camilla Tincati
- Clinic of Infectious Diseases, Department of Medicine, Surgery & Dentistry, ‘San Paolo’ Hospital, University of Milan, Via A. Di Rudinì, 8, 20142 – Milan, Italy
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Minami R, Yamamoto M, Takahama S, Ando H, Miyamura T, Suematsu E. Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: the minimal effect of raltegravir and atazanavir. J Infect Chemother 2010; 17:183-8. [PMID: 20706762 DOI: 10.1007/s10156-010-0101-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 07/12/2010] [Indexed: 02/06/2023]
Abstract
Antiretroviral therapy for HIV infection is associated with lipodystrophy. However, raltegravir (RAL), a new integrase inhibitor, and atazanavir (ATV), a new generation of protease inhibitor (PI), have not been reported to significantly induce metabolic abnormalities in some clinical studies. The aim of this study was to investigate the influence and molecular mechanisms of RAL and compared it with the other three classes of ARVs (nucleoside reverse-transcriptase inhibitors; NRTI, nonnucleoside reverse-transcriptase inhibitor; NNRTI, and PI) on adipogenesis using 3T3-L1 cells. RAL and ATV had minimal effects on the lipid metabolism of 3T3-L1 cells. NRTI induced a moderate change, and NNRTI and some PIs induced a severe reduction in cell lipid content. These ARVs induced a decrease in the expression of genes associated with lipogenic transcription factors (sterol regulatory-element-binding protein-1c, CAAT box enhancer-binding protein-α, and peroxisome proliferator-activated receptor-γ). The differentiated 3T3-L1 cells were less sensitive to ARV-induced metabolic disturbance than were predifferentiated cells. RAL and ATV did not significantly affect the lipid metabolism in our in vitro study. The other ARVs had a direct influence on adipocytes. Degree and underlying mechanisms of metabolic disturbance differed among different ARVs. These data suggest that the distinct metabolic side-effect profiles of ARVs are a consequences of their differential effects on the adipocyte physiology. A better understanding of the mechanism of ARV-induced metabolic abnormalities could lead to safer use of ARVs or selection of alternative agents for further clinical development.
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Affiliation(s)
- Rumi Minami
- Internal Medicine, Clinical Research Institute, National Hospital Organization, Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 810-8563, Japan.
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Blas-García A, Apostolova N, Ballesteros D, Monleón D, Morales JM, Rocha M, Victor VM, Esplugues JV. Inhibition of mitochondrial function by efavirenz increases lipid content in hepatic cells. Hepatology 2010; 52:115-25. [PMID: 20564379 DOI: 10.1002/hep.23647] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
UNLABELLED Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in human immunodeficiency virus (HIV) infection therapy. It has been associated with hepatotoxic effects and alterations in lipid and body fat composition. Given the importance of the liver in lipid regulation, we have evaluated the effects of clinically used concentrations of EFV on the mitochondria and lipid metabolism of human hepatic cells in vitro. Mitochondrial function was rapidly undermined by EFV to an extent that varied with the concentration employed; in particular, respiration and intracellular adenosine triphosphate (ATP) levels were reduced whereas reactive oxygen species (ROS) production increased. Results in isolated mitochondria suggest that the mechanism responsible for these actions was a specific inhibition of complex I of the respiratory chain. The reduction in energy production triggered a compensatory mechanism mediated by the enzyme adenosine monophosphate-activated protein kinase (AMPK), the master switch of cellular bioenergetics. Fluorescence and nuclear magnetic resonance demonstrated a rapid intracellular increase of neutral lipids, usually in the form of droplets. This was prevented by the AMPK inhibitor compound C and by removal of fatty acids from the culture medium. These effects were not reproduced by Nevirapine, another NNRTI. EFV is clinically coadministered with two nucleoside reverse transcriptase inhibitors. Evaluation of one of the most common combination, EFV/Lamivudine/Abacavir, revealed that the effects of EFV on ROS production were enhanced. CONCLUSION Clinical concentrations of EFV induce bioenergetic stress in hepatic cells by acutely inhibiting mitochondrial function. This new mechanism of mitochondrial interference leads to an accumulation of lipids in the cytoplasm that is mediated by activation of AMPK.
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Affiliation(s)
- Ana Blas-García
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia-CIBERehd, Valencia, Spain
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Lanostane triterpenes from Ganoderma lucidum suppress the adipogenesis in 3T3-L1 cells through down-regulation of SREBP-1c. Bioorg Med Chem Lett 2010; 20:5577-81. [PMID: 20702092 DOI: 10.1016/j.bmcl.2010.06.093] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2010] [Revised: 06/05/2010] [Accepted: 06/17/2010] [Indexed: 11/21/2022]
Abstract
Several lanostane triterpenes [butyl ganoderate A (1), butyl ganoderate B (2), butyl lucidenate N (3), and butyl lucidenate A (4)] bearing a butyl ester side chain from the fruiting bodies of Ganoderma lucidum exhibited considerable inhibitory effects on adipogenesis in 3T3-L1 cells. The inhibitory mechanism of 1 and 3 on adipogenesis in 3T3-L1 cells was investigated; we found that the mRNA and protein expression levels of SREBP-1c were reduced by treatment with 1 and 3 versus the untreated control. Furthermore, compounds 1 and 3 suppressed the mRNA expression levels of FAS and ACC. These results demonstrate that inhibition of adipogenesis in 3T3-L1 cells by treatment with 1 and 3 may be mediated in part through down-regulation of the adipogenic transcription factor SREBP-1c and its target genes, such as FAS and ACC.
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Hu Y, Fahmy H, Zjawiony JK, Davies GE. Inhibitory effect and transcriptional impact of berberine and evodiamine on human white preadipocyte differentiation. Fitoterapia 2010; 81:259-68. [DOI: 10.1016/j.fitote.2009.09.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 09/15/2009] [Accepted: 09/21/2009] [Indexed: 10/20/2022]
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Caron-Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV-associated lipodystrophy: from fat injury to premature aging. Trends Mol Med 2010; 16:218-29. [DOI: 10.1016/j.molmed.2010.03.002] [Citation(s) in RCA: 128] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Revised: 03/09/2010] [Accepted: 03/12/2010] [Indexed: 01/11/2023]
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Villarroya F, Domingo P, Giralt M. Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment. Biochim Biophys Acta Mol Cell Biol Lipids 2010; 1801:392-9. [DOI: 10.1016/j.bbalip.2009.09.018] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2009] [Revised: 09/09/2009] [Accepted: 09/17/2009] [Indexed: 12/24/2022]
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Adipocyte dysfunction in response to antiretroviral therapy: clinical, tissue and in-vitro studies. Curr Opin HIV AIDS 2009; 2:268-73. [PMID: 19372898 DOI: 10.1097/coh.0b013e32814b1638] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Lipodystrophy, a major complication of antiretroviral therapy, is an adipose tissue disease involving severe alterations of fat tissue distribution and metabolic functions. Protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are implicated to different extents. We review recent findings on the toxicity of HIV antiretroviral drugs at the fat cell and tissue levels and point out the underlying pathophysiological mechanisms. RECENT FINDINGS Peripheral fat loss and central accumulation are distinct phenomena. Lipoatrophy is the dominant feature after prolonged treatment. Protease inhibitors and NRTIs promote fat tissue disease by separate mechanisms that converge and worsen adipocyte dysfunctions. The pathogenesis involves the mitochondrial toxicity of NRTIs and the adverse effects of protease inhibitors and NRTIs on adipocyte differentiation status, insulin sensitivity, survival and adipokine secretion. Oxidative stress and local inflammation induced by these drugs may participate in the setup of lipodystrophy. Partial and slow reversion can be obtained by switch strategies or drug therapy. SUMMARY Patients using antiviral therapy develop severe fat tissue damage. The toxicity of protease inhibitors and NRTIs remains an important issue for patients and clinicians. Since fat tissue regeneration is difficult, it is important to understand the mechanisms by which these drugs alter fat tissue depots.
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Abstract
Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has been an important component of the treatment of HIV infection for 10 years and has contributed significantly to the evolution of highly active antiretroviral therapy (HAART). The efficacy of efavirenz has been established in numerous randomized trials and observational studies in HAART-naive patients, including those with advanced infection. In the ACTG A5142 study, efavirenz showed greater virological efficacy than the boosted protease inhibitor (PI), lopinavir. Efavirenz is more effective as a third agent than unboosted PIs or the nucleoside analogue abacavir. Some, but not all, studies have suggested that efavirenz (added to two nucleoside reverse transcriptase inhibitors) is more effective than nevirapine. Virological and immunological responses achieved with efavirenz-based HAART have been maintained for 7 years. Dosing convenience predicts adherence, and studies have demonstrated that patients can be switched from PI-based therapy to simplified, once-daily efavirenz-based regimens without losing virological control. The one-pill, once-daily formulation of efavirenz plus tenofovir and emtricitabine offers a particular advantage in this regard. Efavirenz also retains a role after failure of a first PI-based regimen. Efavirenz is generally well tolerated: rash and neuropsychiatric disturbances are the most notable adverse events. Neuropsychiatric disturbances generally develop early in treatment and they tend to resolve with continued administration, but they are persistent and troubling in a minority of patients. Efavirenz has less effect on plasma lipid profiles than some boosted PIs. Lipodystrophy can occur under treatment with efavirenz but it may be reduced if the concurrent use of thymidine analogues is avoided. Efavirenz resistance mutations (especially K103N) can be selected during long-term treatment, underscoring the importance of good adherence. Recent data have confirmed that efavirenz is a cost-effective option for first-line HAART. In light of these features, efavirenz retains a key role in HIV treatment strategies and is the first-line agent recommended in some guidelines.
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Affiliation(s)
- Franco Maggiolo
- Division of Infectious Diseases, Ospedali Riuniti, Largo Barozzi 1, Bergamo, Italy.
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