2000 HIV Human Functional Genomics Partnership Program
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 1,910
- 试验地点
- 4
- 主要终点
- Genetic data
研究概览
简要总结
Background Chronic HIV infection leads to a dysregulated immune system, even when full viral suppression is achieved. HIV causes persistent immune activation, relating to an array of common non-AIDS-related diseases such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). On the other hand, accelerated ageing of the immune system hinders effective immunity against infectious diseases and cancer. Likewise, this derailed inflammatory balance creates a niche for persistent viral replication and reservoir, and prevents cure or functional cure. Mechanisms behind this phenomenon are poorly understood. Inclusion of a larger cohort of HIV-infected patients allows for a more precise assessment of the factors underlying the immune dysregulation.
Primary Objectives
- Identify a set of candidate biomarkers that correlate with particular non-AIDS-related comorbidities
- Unravel biological processes associated with extreme HIV clinical phenotypes.
- Find therapeutic targets to identify novel assets or for repurposing of clinical phase assets from other disease areas for HIV.
Secondary Objectives
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Evaluate potential relationship of host/immune profiles on efficacy, safety, and tolerability of standard care regimens.
-
Evaluate the contribution of age, sex, and genetics in host-immune profiles that are:
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distinct to HIV infection relative to controls in other cohorts;
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associated with non-AIDS-related comorbidities in HIV infection relative to non-HIV chronic disease.
Study design 2000 HIV patients will be included in the cohort. The investigators estimate a 2-year inclusion and 2-year follow-up period and will strive for the inclusion of several clinical phenotypes and classical risk group patients. Patients will be recruited from four Dutch HIV treatment centers.
At inclusion
- Collection of metadata using questionnaires and patient medical records
- Asses co-pathology (CVD and NAFLD)
- Blood will be drawn for genetic, epigenetic, proteomic, metabolomic, microbiome, immunological, and virological analyses
After 2 years follow-up
- Collection of metadata using questionnaires and patient medical records
- Asses co-pathology (CVD and NAFLD)
- Blood samples will be collected for biomarker and infection/inflammation parameter analysis
详细描述
Study population A cohort with a total of 2000 HIV patients will be built, consisting of a discovery cohort (n=1200) and confirmation cohort (n=800). The investigators estimate a 2-year inclusion and 2-year follow-up period and will strive for the inclusion of several clinical phenotypes such as long-term non-progressors (~2-3%), immunologic non-responders (~3%), and rapid progressors (~4-5%) and classical risk group patients such as men who have sex with men (MSM), females, and subjects from Sub-Sahara Africa. Patients will be recruited from the following Dutch HIV Treatment Centers: Radboudumc (Nijmegen), Erasmus MC (Rotterdam), OLVG (Amsterdam), Elisabeth Twee-Steden Ziekenhuis (Tilburg).
A sample size calculation cannot be provided due to the variable frequencies of the various traits in genome-microbiome interaction, and their effect on cytokine production. Because of the explorative nature of this study, the size calculation will be variable depending on the type of polymorphism analyzed. The frequencies of the various microorganism classes in the colonizing microbiome is not known in our study population, and therefore power calculations are impossible to be performed.
Earlier studies in the Human Functional Genomics Project have assessed microbiome traits in 250-500 individuals. An earlier HFGP study included a uniform cohort of 200 HIV-infected individuals (all MSM). The present study will also include HIV-infected patients with a more extreme phenotype, females and subjects originating from Sub-Sahara Africa. Because of this, the investigators decided to increase the number of individuals tested to 2000, consisting of a discovery cohort of 1200 subjects, and a confirmation cohort of 800 participants.
Study visits and procedures At inclusion
- The investigators will collect metadata using questionnaires on lifestyle, health and clinical symptoms, including neuropsychiatric symptoms. Relevant data will also be collected from the patients records in the medical centers and the HIV Monitoring Foundation.
- Co-pathology will be assesed:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-infected,
- •aged ≥18 years,
- •on cART ≥6 months with an HIV-RNA load <200 copies/mL, *Apart from the above-mentioned subjects, elite controllers that are not on cART, are also eligible.
排除标准
- •No informed consent
- •Insufficient communication because of language or other problems
- •Active hepatitis B/C or signs of acute infections
- •Pregnancy
结局指标
主要结局
Genetic data
时间窗: At baseline only
Genome-wide genotype data including \>8 million SNPs per individual
Transcriptomics
时间窗: At baseline only
RNA-sequencing will be performed in PBMCs
Number and type of cardiovascular events
时间窗: Number of events over 2 years between baseline and 2-year time point
Recoring of cadiovascular diseases from patient file: * Stroke/ TIA * Angina pectoris * Myocardial infarction * Claudicatio intermittens * Venous thrombo-embolism * Other ...
Quantification of a wide range of metabolites
时间窗: At baseline only
Metabolomics analysis by multiplex immunoassays will be performed in plasma or serum
Change in liver fibrosis
时间窗: Change: 2-year value - baseline value
Change in liver fibrosis measurement by FibroScan (method by Echosens)
Change in ECG
时间窗: ECG paramater changes between baseline and 2-year time visit
Standardized signs of myocardial infarction with MEANS ECG software, as extensively described elsewehere. In addition, we will look at the full list of ECG output measurements as described elsewhere\*: in brief, MEANS reliably provides output on interpretation of the ECG rhythm and morphology. The morphological interpretation consists of separate analyses of the P wave, QRS complex, and ST-T segment. Reference: Van den Berg ME, Rijnbeek PR, Niemeijer MN, et al. Normal values of corrected heart-rate variability in 10-second electrocardiograms for all ages. Front Physiol. 2018;9:424
Change in cardiovascular risk score (D:A:D score)
时间窗: Change: 2-year value - baseline value
D:A:D score
Immune phenotyping
时间窗: At baseline only
Extensive phenotyping of circulating immune cells by flow cytometry analysis
Intima-media thickness
时间窗: At baseline only
Ultrasound measurement of intima-media thickness in the carotid artery as a measure for atherosclerosis and cardiovasculr disease risk.
Change in liver steatosis
时间窗: Change: 2-year value - baseline value
Change in liver steatosis measurement by FibroScan (method by Echosens) and liver ultrasound (method developed by Radboudumc)
Change in cardiovascular risk score (Framingham score)
时间窗: Change: 2-year value - baseline value
Framingham score
Colonizing microbiome profile
时间窗: At baseline only
Colonizing microbiome profile will be generated from stool and saliva samples
Cytokine production of PBMCs in ex vivo stimulation experiments
时间窗: At baseline only
Ex vivo cytokine responses of isolated PBMCs to a range of stimuli (TLR ligands, killed pathogens and viral antigen stimuli)
次要结局
未报告次要终点