Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

Les traitements antirétroviraux de l’infection par le VIH sont responsables d’effets secondaires parfois sévères qui touchent en priorité le tissu adipeux, modifiant sa localisation (lipodystrophie avec lipoatrophie périphérique et hypertrophie centrale) et les paramètres du métabolisme glucido-lipidique (dyslipidémie, diabète). Les deux principales classes thérapeutiques, inhibiteurs de protéase et analogues nucléosidiques, sont délétères sur ces paramètres par des mécanismes différents mais qui convergent sur le tissu adipeux. Certaines des molécules de ces deux classes modifient profondément sa différenciation, son métabolisme, sa fonction mitochondriale et l’équilibre des hormones (leptine, adiponectine) et cytokines (TNFα, IL-6) qu’il sécrète. Ce syndrome de lipodystrophie induit un risque cardiovasculaire et de stéatohépatite grevant le pronostic vital. Le traitement reste difficile chez les patients atteints et privilégie le remplacement des molécules les plus délétères par des molécules antirétrovirales plus récentes et moins agressives sur le tissu adipeux.HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFα, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue

HIV-associated lipodystrophy: from fat injury to premature aging

Combination antiretroviral therapy (cART) against HIV infection dramatically reduces AIDS-related morbidity. However, many patients under cART display HIV-associated lipodystrophy. Moreover, some develop early agerelated comorbidities. Thymidine analog reverse transcriptase inhibitors (tRNTIs) are mainly responsible for peripheral lipoatrophy, and protease inhibitors (PIs) for fat hypertrophy and metabolic complications. Longterm HIV infection probably also causes fat alterations. Severe mitochondrial toxicity and oxidative stress cause lipoatrophy, whereas the hypertrophy of upper body fat depots could result from mild oxidative stress, cortisol activation and inflammation. The metabolic complications associated with lipodystrophy are responsible for increased cardiovascular and hepatic risks and could also participate in premature aging. We propose that adipose tissue injury by HIV and cART induces fat hypertrophy or atrophy and contributes to premature aging

Rôles des cytokines et de l'inflammation du tissu adipeux dans la résistance à l'insuline et dans les lipodystrophies liées au traitement antirétroviral de l'infection par le VIH

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Recent data on adipose tissue, insulin resistance, diabetes and dyslipidaemia in antiretroviral therapy controlled HIV-infected persons

International audiencePurpose of review Increased total body fat with truncal redistribution is common in antiretroviral therapy (ART)-controlled persons living with HIV(PLWH), leading to insulin resistance, prediabetes/diabetes and dyslipidaemia. We address these topics here.Recent findings Most antiretrovirals are associated with gain in trunk fat, including visceral adipose tissue (VAT). Protease-inhibitors could inhibit white fat ability to dissipate energy (i.e. beiging) favouring fat gain. Expansion of VAT is associated with a pro-inflammatory profile linked to the tryptophan-kynurenine pathway and CD4+ subtypes. ART-associated increased adipose tissue (AT) quantity leads to decreased AT density, insulin resistance and dyslipidaemia that could be improved by lifestyle modifications.PLWH present high level of insulin resistance, regardless of their treatment, and a higher prevalence of prediabetes, but not diabetes, than noninfected persons. Otherwise, HbA1c values appear inaccurate to diagnose prediabetes/diabetes in PLWH.ART-related-dyslipidaemia is characterized by elevated LDL-C and/or high triglycerides and reduced HDL-C. Whereas treatment with protease inhibitors generally results in worsened lipid values, treatment with integrase-strand-transfer-inhibitors is associated with a better profile. Tenofovir-alafenamide is associated with higher lipid levels than tenofovir-disoproxil-fumarate. Treatment of LDL-C-dyslipidaemia could benefit, in statin-insufficiently controlled patients, from the class of proprotein-convertase-subtilsin-kenin-type-9 (PCSK-9) inhibitors.Summary Lifestyle modifications are mandatory to reduce fat and improve dysglycaemia/dyslipidaemia. New drugs can efficiently control diabetes and LDL-C-dyslipidaemia

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Del llibre 'L'ombra de l'atzavara', Premi Sant Jordi: 196

The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation

International audienceTo maintain bone mass turnover and bone mineral density (BMD), bone marrow (BM) mesenchymal stem cells (MSCs) are constantly recruited and subsequently differentiated into osteo-blasts. HIV-infected patients present lower BMD than non-HIV infected individuals and a higher prevalence of osteopenia/ osteoporosis. In antiretroviral treatment (ART)-naive patients, encoded HIV proteins represent pathogenic candidates. They are released by infected cells within BM and can impact on neighbouring cells. In this study, we tested whether HIV proteins Tat and/or Nef could induce senescence of human BM-MSCs and reduce their capacity to differentiate into osteoblasts. When compared to nontreated cells, MSCs chronically treated with Tat and/or Nef up to 30 days reduced their proliferative activity and underwent early senescence, associated with increased oxidative stress and mitochondrial dysfunction. The antioxidant molecule N-acetyl-cysteine had no or minimal effects on Tat-or Nef-induced senescence. Tat but not Nef induced an early increase in NF-jB activity and cytokine/chemokine secretion. Tat-induced effects were prevented by the NF-jB inhibitor parthenolide, indicating that Tat triggered senescence via NF-jB activation leading to oxidative stress. Otherwise, Nef-but not Tat-treated cells displayed early inhibition of autophagy. Rapamycin, an autophagy inducer, reversed Nef-induced senescence and oxida-tive stress. Moreover, Tat+Nef had cumulative effects. Finally, Tat and/or Nef decreased the MSC potential of osteoblastic differentiation. In conclusion, our in vitro data show that Tat and Nef could reduce the number of available precursors by inducing MSC senescence, through either enhanced inflammation or reduced autophagy. These results offer new insights into the pathophys-iological mechanisms of decreased BMD in HIV-infected patients

Performances of NeuMoDx™, a random-access system for hepatitis B virus DNA and hepatitis C virus RNA quantification

International audienceOBJECTIVE: Monitoring of viral loads (VL) for hepatitis B and C viruses (HBV; HCV) is essential to evaluate disease progression and treatment response. Automated, random-access rapid systems are becoming standard to provide clinicians with reliable VL. The aim of this study was to evaluate the analytical performances of the recently launched NeuMoDx™ for HBV-DNA and HCV-RNA quantification. METHODS: Clinical samples routinely quantified on the Beckman-Veris system were either retrospectively (frozen samples; HBV n = 178, HCV n = 249), or in parallel (fresh primary tubes; HBV n = 103, HCV n = 117) tested using NeuMoDx™. Linearity range was assessed on serial dilutions of high-titre plasmas containing different genotypes for HBV (A-E, n = 9) and HCV (1a,1b,2-5, n = 12). RESULTS: Overall test failure, mostly internal control amplification failure, was 2.3% and was not influenced by matrix types (fresh or frozen). For HBV VL, κ agreement was 74%, with 27 (12.6%) discrepancies. Correlation between HBV assays on 72 quantified samples by both methods was excellent (r = 0.963) with a mean bias (NeuMoDx™-Veris) of 0.21 log IU/mL. For HCV VL, κ agreement reached 94%, with 9 (2.8%) discrepancies. The r correlation factor between assays on 104 samples was 0.960 with a mean bias of -0.14 log IU/mL (NeuMoDx™-Veris). Serial dilutions confirmed the claimed linear ranges for all analysed HBV and HCV genotypes. The mean turnaround time was 72 minutes (range 55-101 minutes) for HBV and 96 minutes (range 78-133 minutes) for HCV. CONCLUSION: Results obtained on the NeuMoDx™ confirmed the overall good functionality of the system with a short turn-around-time, full traceability and easy handling. These results on HBV and HCV VL look promising and should be challenged with further comparisons

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

International audienceIntroduction: Efficient antiretroviral-treatment (ART) generally allows control of HIV infection. However, persons-living-with-HIV (PLWH), when aging, present a high prevalence of metabolic diseases.Area covered: Altered adiposity, dyslipidemias, insulin resistance, diabetes, and their consequences are prevalent in PLWH and could be partly related to ART.Expert opinion: At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors (NRTIs) (stavudine zidovudine) and some protease inhibitors (PIs). Recently, use of some integrase-inhibitors (INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation. Lipid parameters were affected by some first-generation NRTIs, non-NRTIs (efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides. Insulin resistance is common associated with abdominal obesity. Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population. Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk