Long-term effects on subclinical cardiovascular disease of switching from boosted protease inhibitors to dolutegravir
Ana González-CordónLambert AssoumouGraeme MoyleLaura WatersMargaret JohnsonPeré DomingoJulie FoxHans‐Jürgen StellbrinkGiovanni GuaraldiMar MasiáMark GompelsChristoph StephanÉric FlorenceStefan EßerFrançois RaffiGeorg M. N. BehrensAnton PozniakJosé M. GatellEstebán MartínezLinos VandekerckhoveEls CaluwéChristoph StephanCoca NecsoiÉric FlorenceMaartje Van FrankenhuijsenFrançois RaffiClotilde AllavenaVéronique ReliquetD. BoutoilleMorane CavellecElisabeth André‐GarnierAudrey RodallecThierry Le TourneauJ. ConnaultJean‐Michel MolinaSamuel FerretMiresta PrévilonYazdan YazdanpanahRoland LandmanVéronique JolyAdriana PintoChristine KatlamaFabienne CabyNadine KtorzaLuminita SchneiderChristoph StephanTimo WolfGundolf SchüttfortJuergen RockstrohJan‐Christian WasmuthCarolynne Schwarze‐ZanderChristoph BoeseckeHans‐Jürgen StellbrinkChristian HoffmannMichael SabranskiChristoph StephanRobert JablonkaHeidi WiehlerGeorg M. N. BehrensMatthias StollGerrit AhrenstorfGiovanni GuaraldiGiulia NardiniBarbara BeghettoAntonella D’Arminio MontforteTeresa BiniViola CogliandroMassimo Di PietroFrancesco Maria FuscoMassimo GalliStefano RusconiAndrea GiacomelliPaola MeravigliaEstebán MartínezAna González-CordónJosé María GatellBerta TorresPeré DomingoGràcia MateoMaría Luisa Navarro GómezJoaquín PortillaEsperanza MerinoSergio ReusVicente BoixMar MasiáFélix GutiérrezSergio PadillaBonaventura ClotetEugènia NegredoAnna BonjochJosé L. CasadoSara Bañón-EscandellJosé SabánAfrica DuqueDaniel PodzamczerMaría SaumoyLaura AcereteJuan González‐GarcíaJosé I. BernardinoJosé Ramón ArribasVíctor HontañónGraeme MoyleNicole PaganiMargherita BracchiJaime H. VeraAmanda ClarkeTanya AdamsCelia RichardsonAlan WinstonBorja Mora-PerisScott MullaneyLaura WatersNahum de EstebanAna MilinkovicSarah PettJulie FoxJuan TiraboschiMargaret JohnsonMike YouleChloe OrkinSimon RackstrawJames HandMark GompelsLouise JenningsJane NichollsSarah Johnston
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Abstract Background In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. Methods PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. Results Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. Discussion After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.Keywords:
Dolutegravir
Intima-media thickness
Dolutegravir
Efavirenz
Tolerability
Emtricitabine
Integrase inhibitor
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To identify the proportion of low adiponectin level and to evaluate the role of low adiponectin level, age, body mass index, and waist circumference on the occurrence of metabolic syndrome in women with insulin resistance.The study was done by a cross-sectional survey on adult women aged 30-60 years. The study was conducted at Fatmawati Hospital-Jakarta from January to March 2008 with a total sample of 33. The sample was selected consecutively based on the presence of metabolic syndrome according to the IDF 2005 criteria. The examination of plasma adiponectin level was done by ELISA method. Insulin resistance was defined if HOMA IR > or = 2 (calculated by fasting insulin (microU/mL) x Fasting blood sugar (mmol/L) divided by 22.5). Association of low adiponectin level with insulin resistance was evaluated by calculating the Odds Ratio.Seventeen of 33 subjects with metabolic syndrome have insulin resistance, in which 7 of them (41.18%) show low adiponectin level. While in 16 subjects without insulin resistance, only one subject (6.25%) has low adiponectin level. From 8 subjects with low adiponectin level, 7 of them (87.5%) have insulin resistance. In other words, low adiponectin level is associated with increased risk of insulin resistance (Odds Ratio 10.5, P = 0.040 (CI 95% : 1.12-98.91).Low adiponectin concentration increases the risk of developing insulin resistance much more than normal adiponectin level.
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Introduction: Adiponectin has been known to play an important role in the glucose and lipid metabolism, and thereby may be considered as a potential treatment target for diabetes mellitus or atherosclerotic diseases. Recently, some basic studies showed that adiponectin might not function in an insulin-resistant condition, a concept called “adiponectin resistance.” However, this concept has not been confirmed in human. Therefore, we assessed the hypothesis that the well-known inverse association between adiponectin and insulin resistance is weakened in the insulin-resistant state. Methods: We studied 2,316 middle-aged Japanese men without a medical history of cancer, cardiovascular disease, diabetes, hypertension, or dyslipidemia to determine whether or not the association between serum adiponectin levels and the insulin resistance index (HOMA-IR) differed according to insulin resistant states. Results: Mean age and body mass index of study subjects were 48±7 and 23±3, respectively. A multiple linear regression analysis revealed that log-adiponectin was inversely associated with log-HOMA-IR independently of covariates (β= − 0.235, P <0.001). Subsequently, we re-analyzed after dividing study subjects according to the tertile of HOMA-IR. As shown in the Table , the inverse association between adiponectin and HOMA-IR was considerably weakened with the escalation of insulin resistance. Specifically, adiponectin was almost positively associated with HOMA-IR in insulin-resistant subjects (β= 0.114, P =0.059). Interestingly, statistically significant associations of adiponectin with triglyceride and HDL-C were uniformly observed in all tertiles. Conclusion: The inverse association of adiponectin with insulin resistance weakened with the escalation of insulin resistance, suggesting the existence of “adiponectin resistance” in insulin-resistant individuals. This adiponectin resistance may be restricted in glucose metabolism. Table. Coefficients of adiponectin in multiple linear regression analyses with independent variables
Dyslipidemia
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Dolutegravir, an integrase strand-transfer inhibitor (STI), shows a high genetic barrier to resistance. Dolutegravir is reported to be effective against viruses resistant to raltegravir and elvitegravir. In this study, we report the case of a patient treated with dolutegravir monotherapy. Failure of dolutegravir treatment was observed concomitant with the appearance of N155H-K211R-E212T mutations in the integrase (IN) gene in addition to the polymorphic K156N mutation that was present at baseline in this patient. The impact of N155H-K156N-K211R-E212T mutations was studied in cell-free, culture-based assays and by molecular modelling. Cell-free and culture-based assays confirm that selected mutations in the patient, in the context of the polymorphic mutation K156N present at the baseline, lead to high resistance to dolutegravir requiring that the analysis be done at timepoints longer than usual to properly reveal the results. Interestingly, the association of only N155H and K156N is sufficient for significant resistance to dolutegravir. Modelling studies showed that dolutegravir is less stable in IN/DNA complexes with respect to the WT sequence. Our results indicate that the stability of STI IN/DNA complexes is an important parameter that must be taken into account when evaluating dolutegravir resistance. This study confirms that a pathway including N155H can be selected in patients treated with dolutegravir with the help of the polymorphic K156N that acts as a secondary mutation that enhances the resistance to dolutegravir.
Dolutegravir
Elvitegravir
Raltegravir
Integrase inhibitor
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Background: Since 2019, the World Health Organization has recommended dolutegravir-based antiretroviral therapy (ART) as the preferred regimen for all people with HIV. Large-scale programmatic transitioning to dolutegravir-based ART was subsequently implemented across Africa, often in the absence of recent viral load testing and without access to genotypic resistance testing (GRT) in case of viraemia. Methods: This study aims to assess emerging acquired dolutegravir resistance in the Viral Load Cohort North-East Lesotho (VICONEL). We included participants who changed from non-nucleoside transcriptase inhibitor- (NNRTI-) to dolutegravir-based ART and had at least one viral load assessment before and after the change. We sequenced available samples of participants fulfilling the additional virological criteria of having two viraemic episodes while taking dolutegravir, thereof at least one viral load ≥500 copies/mL taken ≥18 months after changing to dolutegravir. Findings: Out of 15'299 participants, 151 (1·0%) met the virological criteria and for 78 (0·5%) GRT was successful. Among those 78, eight (10·3%) had dolutegravir resistance, with two (2·6%) and six (7·7%) predicted to have intermediate and high-level dolutegravir resistance, respectively. One had two, two had one, and five had zero active drugs in their current regimen. Prior to the change to dolutegravir, GRT was available for five out of these eight participants: four had zero and one had one active drug in their NNRTI-based regimen. Interpretation: To maintain the progress made through the roll-out of dolutegravir across Africa, detection and management of emerging dolutegravir drug resistance must be addressed.Funding: Swiss National Science Foundation, Research Fund of the University of Basel.Declaration of Interest: This study was funded by the Swiss National Science Foundation (Eccellenza grant number PCEFP3_181355 and R4D grant number IZ07Z0_160876/1 to NDL), and the Research Fund of the University of Basel (grant number 3ZX1404 to NT). JAB receives her salary through grants from Fondation Botnar (grant number REG-19-008 to JAB and NDL) and the Research Fund of the University of Basel (grant 3ZX1422 to JAB).Ethical Approval: The VICONEL cohort, within which this study was conducted, has been approved by the National Health Research Ethics Committee in Lesotho (ID134-2016, last renewal 16·05·2023, version ID134-2016-Renew 02). Written informed consent for the further use of biobanked samples was provided by all adult participants (≥18 years) and caregivers of minor participants for whom resistance data are reported.
Dolutegravir
Regimen
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Objective To explore the relationships between Serum levels of tumor necrosis factor-alpha TNFα,1L-6,adiponectin and insulin resistance in type 2 diabetes.Methods 80 T2DM patients and 40 healthy controls were recruited.Levels of serum TNF-α,IL-6,adiponectin,plasma glucose,insulin and BMI were measured.Insulin resistance was evaluated by HOMA-IR.Results The levels of TNF-α and IL-6 in T2DM group were significantly higher than that in control group(all P＜0.05);The levels of adiponeetin in T2DM group was significantly lower than that in control group(P＜0.05).The levels of TNF-α and IL-6 were positively correlated with HOMA-IR(P＜0.05),adiponeetin was egatively correlated nwith HOMA-IR(P＜0.01).Conclusion TNF-α,IL-6 and adiponectin were closely related with insulin resistance,and should take parts in development of T2DM.
Key words:
Diabetes mellitus,type 2; Insulin resistance; Cytokines; Adiponectin
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To assess insulin resistance and adiponectin profile in patients with chronic hepatitis C (CHC), according to the presence or absence of metabolic syndrome (MS).One hundred and fifty-two patients with histologically proven CHC, genotype I were prospectively studied. Parameters of MS according to the IDF criteria were evaluated. Insulin resistance was established by homeostasis model assessment (HOMA-IR]. An index > or = 2.0 was designated as IR and > or = 4 as prediabetic state. Serum adiponectin levels were measured by ELISA:MS was found in 61.48% of cases. HOMA-IR was significantly higher in patients with CHC and MS vs those without MS (7.88 +/- 1.11 vs 4.29 +/- 0.5, p=0.023]. Adiponectin levels had an inverse behaviour (9,946.1 +/- 5,811 ng/ml vs 13,215.5 +/- 815.5 ng/ml, p< 0.001]. By multiple linear regression analysis the independent predictors associated with HOMA-IR > or = 4 in patients with CHC and MS were visceral obesity, adiponectin levels, activity and degree of steatosis. Only visceral obesity and HOMA-IR were independently associated with adiponectin. A significant negative correlation was established between adiponectin and insulin (r = -0.169, p=0.003] and between adiponectin and HOMA-IR (r = -0.188, p=0.02].CHC with MS was associated with a higher insulin resistance and lower adiponectin level. Adiponectin level and insulin resistance were significantly correlated.
Steatosis
Homeostatic model assessment
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Adiponectin is one of the novel adipocytokines participates in the development of insulin resistance which is the common pathological basis of Type 2 Diabetes Mellitus and Metabolic Syndrome.Numerous studies have demonstrated that adiponectin is significantly correlated with the development of insulin resistance.It can ameliorate insulin sensitivity,improves glucose and lipid metabolism in vivo.The levels of adiponectin in vivo could predict the development of insulin resistance.Simultaneously,various of methods could ameliorate insulin resistance by increasing the levels of adiponectin in vivo in Traditional Chinese Medicine.Discovery of adiponectin provides a new idea for the theoretical studies and clinical preventions to insulin resistance.
Carbohydrate Metabolism
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Objective To investigate serum adiponectin levels in metabolic syndrome patients without diabetes and to analyse the relationship between serum adiponectin levels,and Insulin resistance(IR).Methods 92 metabolic syndrome patients without diabetes and 30 health persons were investigated. Serum adiponectin levels of all subjects were determined by using enzyme linked immunosorbent assay(ELISA).Homeostasis insulin resistance index (Homa-IR) and insulin sensitivity index(ISI) were calculated.And then,the relationship between serum adiponectin levels and Insulin resistance(IR) wil be analysed.Results 1.The serum level of adiponectin was significantly lower in metabolic syndrome without diabetes group than in normal control group (1.15±0.81mg/l,4.81±1.20 mg/1,P0.01 =).2.The serum adiponectin level was negatively correlated with Homa-IR(P0.01).and positively correlated with ISI through linear correlation analysis(P0.01).However,the serum adiponectin level was only negatively correlated with Homa-IR through multiple linear regression analysis.Conclusions The level of serum adiponectin in metabolic syndrome cases without diabetes was significantly decreased.The serum adiponectin level was negatively correlated with Homa-IR.This shows that level of serum adiponectin was correlated with metabolic syndrome and insulin resistance.
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Abstract Background Since 2019, the World Health Organization has recommended dolutegravir-based antiretroviral therapy (ART) as the preferred regimen for human immunodeficiency virus management. Large-scale programmatic transitioning to dolutegravir-based ART was subsequently implemented across Africa, often in the absence of recent viral load testing and without access to genotypic resistance testing (GRT) in case of viremia. Methods This study assessed emerging dolutegravir resistance in the routine care of the Viral Load Cohort North-East Lesotho. We included pediatric and adult participants who changed from nonnucleoside reverse transcriptase inhibitor– to dolutegravir-based ART and had at least 1 viral load assessment before and after the change. We sequenced available samples of participants fulfilling the additional virological criteria of having 2 viremic episodes while taking dolutegravir, with at least 1 viral load ≥500 copies/mL taken ≥18 months after changing to dolutegravir. Results Among 15 349 participants, 157 (1.0%) met the virological criteria, and GRT was successful for 85 (0.6%). Among these 85, 8 (9.4%) had dolutegravir resistance, with 2 (2.4%) and 6 (7.1%) predicted to have intermediate- and high-level dolutegravir resistance, respectively. One participant had 2, 2 had 1, and 5 had 0 active drugs in their regimen. A GRT from before the change to dolutegravir was available for 5 of these 8 participants: 4 had 0 and 1 had 1 active drug in their nonnucleoside transcriptase inhibitor–based regimen. Conclusions Nine percent of people with persistent or recurring human immunodeficiency virus viremia ≥18 months after changing to dolutegravir-based ART had dolutegravir resistance. Detection and management of emerging dolutegravir resistance must be addressed across Africa.
Dolutegravir
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