The 2000HIV study: Design, multi-omics methods and participant characteristics

Vos, W. A.; Groenendijk, Albert L.; Blaauw, Marc; Eekeren, Louise E. van; Navas, Adriana; Cleophas, Maartje C. P.; Vadaq, Nadira; Matzaraki, Vasiliki; Santos, Jéssica Cristina dos; Meeder, Elise M. G.; Fröberg, Janeri; Weijers, Gert; Zhang, Yue; Fu, Jingyuan; Horst, Rob ter; Bock, Christoph; Knoll, Rainer; Aschenbrenner, Anna C.; Schultze, Joachim L.; Vanderkerckhove, L; Hwandih, Talent; Wonderlich, Elizabeth R.; Vemula, Sai V.; Kolk, M. van der; Vet, Sterre C P de; Blok, W. L.; Brinkman, Kees; Rokx, Casper; Schellekens, Arnt; Mast, Quirijn de; Joosten, Leo A. B.; Berrevoets, Marvin A.H.; Stalenhoef, Janneke E.; Verbon, Annelies; Lunzen, Jan van; Netea, Mihai G.; Ven, Andre J. A. M. van der

doi:10.3389/fimmu.2022.982746

Cited by 6 publications

(14 citation statements)

References 45 publications

(49 reference statements)

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“…Baseline characteristics and data collection procedures have been described in detail elsewhere ( 14 ). In brief, inclusion criteria were HIV-1 positivity, ≥18 years of age, ≥6 months on cART and latest viral load <200 copies/ml.…”

Section: Methodsmentioning

confidence: 99%

“…Hemocytometric procedures have been published previously ( 14 ). We analyzed whole blood using the Sysmex XN series hematology analyzer (Sysmex, Kobe, Japan) for absolute and relative immune cell counts ( 15 ).…”

Section: Methodsmentioning

confidence: 99%

“…Ex-vivo PBMC cytokine production capacity was measured by stimulating PBMCs with a variety of stimuli as described previously ( 14 ). To measure monocyte production capacity, PBMCs were stimulated using Poly I:C (a toll-like receptor (TLR) 3 agonist), lipopolysaccharide (LPS), imiquimod (a TLR 7 agonist), IL-1α, HIV-Envelope protein (HIV-Env), cytomegalovirus (CMV) protein, and Streptococcus pneumoniae ( S. pneumoniae ).…”

Section: Methodsmentioning

confidence: 99%

“…After stimulation, supernatant was collected and stored at -20°C until measurement of cytokines with enzyme-linked immunosorbent assay (ELISA). Concentrations, manufacturer and catalogue numbers of stimuli can be found elsewhere ( 14 ).…”

Section: Methodsmentioning

confidence: 99%

“…This structure reduces the chances of untrue coincidental findings. An extensive description of the discovery and validation cohort has been published previously ( 14 ). Discovery cohort participants were recruited at the HIV outpatient clinic of Radboudumc Nijmegen, OLVG Amsterdam and Erasmus MC Rotterdam, while participants in the validation cohort were recruited at HIV outpatient clinic of a separate large general hospital (Elisabeth-TweeSteden Ziekenhuis Tilburg).…”

Section: Methodsmentioning

confidence: 99%

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HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity

Vos,

Navas,

Meeder

et al. 2024

Front. Immunol.

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IntroductionImmunological non-responders (INR) are people living with HIV (PLHIV) who fail to fully restore CD4+ T-cell counts despite complete viral suppression with antiretroviral therapy (ART). INR are at higher risk for non-HIV related morbidity and mortality. Previous research suggest persistent qualitative defects.MethodsThe 2000HIV study (clinical trials NTC03994835) enrolled 1895 PLHIV, divided in a discovery and validation cohort. PLHIV with CD4 T-cell count <350 cells/mm3 after ≥2 years of suppressive ART were defined as INR and were compared to immunological responders (IR) with CD4 T-cell count >500 cells/mm3. Logistic and rank based regression were used to analyze clinical data, extensive innate and adaptive immunophenotyping, and ex vivo monocyte and lymphocyte cytokine production after stimulation with various stimuli.ResultsThe discovery cohort consisted of 62 INR and 1224 IR, the validation cohort of 26 INR and 243 IR. INR were older, had more advanced HIV disease before starting ART and had more frequently a history of non-AIDS related malignancy. INR had lower absolute CD4+ T-cell numbers in all subsets. Activated (HLA-DR+, CD38+) and exhausted (PD1+) subpopulations were proportionally increased in CD4 T-cells. Monocyte and granulocyte immunophenotypes were comparable. INR lymphocytes produced less IL-22, IFN-γ, IL-10 and IL-17 to stimuli. In contrast, monocyte cytokine production did not differ. The proportions of CD4+CD38+HLA-DR+ and CD4+PD1+ subpopulations showed an inversed correlation to lymphocyte cytokine production.ConclusionsINR compared to IR have hyperactivated and exhausted CD4+ T-cells in combination with lymphocyte functional impairment, while innate immune responses were comparable. Our data provide a rationale to consider the use of anti-PD1 therapy in INR.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity

Vos,

Navas,

Meeder

et al. 2024

Front. Immunol.

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Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment—A Cross-sectional Study

van Eekeren,

Vadaq,

Vos

et al. 2024

Open Forum Infectious Diseases

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Background Steatotic liver disease is suggested to have a higher prevalence and severity in people living with HIV (PLHIV), including in those with a normal BMI. In this study, we used data from the 2000HIV cohort to (i) assess the prevalence of liver steatosis and fibrosis in lean versus overweight/obese PLHIV, and (ii) assess associations in these subgroups between steatosis and fibrosis with traditional risk factors and HIV-specific characteristics. Methods The 2000HIV study cohort comprises 1895 virally suppressed PLHIV that were included between 2019 and 2021 in four HIV treatment centers in the Netherlands. The majority (58.5%) underwent vibration-controlled transient elastography for the assessment of liver steatosis and fibrosis. The prevalence of steatosis (controlled attenuation parameter [CAP] ≥ 263 dB/m) and fibrosis (liver stiffness measurement [LSM] ≥ 7.0 kPa) was estimated. Multiple factors including HIV-characteristics and antiretroviral drugs were tested in a logistic regression model for association with steatosis and fibrosis. Analyses were performed separately for lean (Asian descent: BMI < 23 kg/m2, other descent: BMI < 25 kg/m2) and overweight/obese (other BMI) participants. Results Of 1050 PLHIV including 505 lean and 545 overweight/obese PLHIV, liver steatosis was observed in 37.7% of the overall study population, 19.7% of lean and 54% of overweight/obese PLHIV, while fibrosis was observed in 9.0% of the overall study population, 5.9% of lean and 12.0% of overweight/obese PLHIV. All associations with fibrosis and most associations with steatosis concerned metabolic factors such as T2DM (overall population: adjusted odds ratio [aOR] for steatosis: 2.3 [1.21–4.4], p-value = 0.011; aOR for fibrosis: 3.7 [1.82–7.53], p-value < 0.001). Furthermore, in lean PLHIV, liver steatosis was associated with CD4 and CD8 counts at enrollment, dual therapy, and history of treatment with raltegravir (aOR: 3.6 [1.53-8.47], p-value = 0.003), stavudine (aOR: 3.73 [1.69-8.2], p-value = 0.001), and indinavir (aOR: 3.86 [1.59-9.37], p-value = 0.003). These associations were not observed in overweight/obese PLHIV. Conclusion Liver steatosis was highly prevalent, affecting approximately one-fifth of lean PLHIV and half of overweight/obese PLHIV. Fibrosis was observed in a minority. Both steatosis and fibrosis were associated with traditional metabolic risk factors. In addition, (prior) exposure to specific antiretroviral drugs was associated liver steatosis in lean, but not in overweight/obese PLHIV. Implementing increased screening protocols could enhance the identification of steatotic liver disease in lean PLHIV.

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Traditional Cardiovascular Risk Factors Are Stronger Related to Carotid Intima‐Media Thickness Than to Presence of Carotid Plaques in People Living With HIV

Blaauw,

Berrevoets,

Vos

et al. 2023

JAHA

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Background Cardiovascular disease is a major cause of morbidity and mortality in people living with HIV, who are at higher risk than the general population. We assessed, in a large cohort of people living with HIV, which cardiovascular, HIV‐specific, and lipoproteomic markers were associated with carotid intima‐media thickness (cIMT) and carotid plaque presence. We also studied guideline adherence on lipid‐lowering medication in individuals with high and very high risk for cardiovascular disease. Methods and Results In 1814 individuals with a median (interquartile range) age of 53 (44–60) years, we found a carotid plaque in 909 (50.1%) and a median (interquartile range) intima‐media thickness of 0.66 (0.57–0.76) mm. Ultrasonography was used for the assessment of cIMT and plaque presence. Univariable and multivariable regression models were used for associations with cIMT and presence of plaques. Age, Black race, body mass index, type 2 diabetes, and smoking (pack years) were all positively associated with higher cIMT. Levels of high‐density lipoprotein cholesterol, specifically medium and large high‐density lipoprotein subclasses, were negatively associated with higher cIMT. Only age and prior myocardial infarction were positively related to the presence of a carotid plaque. Lipid‐lowering treatment was prescribed in one‐third of people living with HIV, who are at high and very high risk for cardiovascular disease. Conclusions Traditional cardiovascular risk factors were significantly associated with higher cIMT but not with carotid plaques, except for age. HIV‐specific factors were not associated with both ultrasound measurements. Future studies are needed to elucidate which factors contribute to plaque formation. Improvement of guideline adherence on prescription of lipid‐lowering treatment in high‐ and very high‐risk patients for cardiovascular disease is recommended. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03994835.

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The 2000HIV study: Design, multi-omics methods and participant characteristics

Cited by 6 publications

References 45 publications

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity

HIV immunological non-responders are characterized by extensive immunosenescence and impaired lymphocyte cytokine production capacity

Liver Steatosis is Prevalent in Lean People With HIV and Associated With Exposure to Antiretroviral Treatment—A Cross-sectional Study

Traditional Cardiovascular Risk Factors Are Stronger Related to Carotid Intima‐Media Thickness Than to Presence of Carotid Plaques in People Living With HIV

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