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2000 HIV Human Functional Genomics Partnership Program (2000HIV)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03994835
Recruitment Status : Not yet recruiting
First Posted : June 21, 2019
Last Update Posted : June 21, 2019
Sponsor:
Collaborators:
ViiV Healthcare
Elisabeth-TweeSteden Ziekenhuis
Erasmus Medical Center
Onze Lieve Vrouwe Gasthuis
Information provided by (Responsible Party):
Radboud University

Brief Summary:

Background:

Chronic HIV infection leads to a dysregulated immune system, even when full viral suppression is achieved by combination AntiRetroviral Therapy (cART). On the one hand, HIV causes persistent immune activation, which is related 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 aging/depletion (senescence) 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. Restoring this balance has proven to be challenging and therapeutic targets for effectively restoring it are lacking. Inclusion of a larger cohort of HIV-infected patients in the discovery cohort, with higher numbers of the extreme clinical phenotypes, allows for a more precise assessment of the factors underlying the immune dysregulation.

Objectives:

Primary Objectives

  • Identify a set of candidate biomarkers (BM) in circulation and/or pathways & mechanisms that correlate with particular non-AIDS-related comorbidities ( NAFLD, CVD) in HIV-infected individuals relative to existing healthy and non-HIV chronic disease cohorts. Candidate BMs may be single or an algorithm-based multiparameter BM profile.
  • Unravel biological processes associated with extreme HIV clinical phenotypes, such as elite controllers, post-treatment controllers, immunological non-responders and rapid progressors.
  • Find therapeutic targets of interest either to identify novel assets or for repurposing of clinical phase assets from other disease areas for HIV.

Secondary Objectives

  • Evaluate potential relationship of host/immune profiles on efficacy, safety, and tolerability of different standard care regimens.
  • Evaluate the contribution of aging, female gender, and genetic background in host-immune profiles that are:

    • distinct to HIV infection relative to controls in other cohorts;
    • associated with non-AIDS-related comorbidities in HIV infection relative to non-HIV chronic disease.

Study design:

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 centres: Radboudumc (Nijmegen), Erasmus MC (Rotterdam), Onze Lieve Vrouwe Gasthuis (Amsterdam), Elisabeth Twee-Steden Ziekenhuis (Tilburg).

Several approaches will be utilized to characterize our study population:

At inclusion

  1. The investigators will collect metadata from all the participants 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.
  2. Co-pathology will be assesed:

    • Cardiovascular risk scores (D:A:D risk score and Framingham CVD score) will be collected as well as ECG and intima-media thickness (IMT) measurements.
    • Non-Alcoholic Fatty Liver Disease (NAFLD) assessment through liver ultrasound and FibroScan.
  3. Blood will be drawn (90 ml):

    • DNA will be isolated for genetic analysis.
    • The function of the immune system will be analyzed at several levels using circulating white blood cells from venous blood.
    • Metabolism will be analyzed by metabolome analysis.
    • Virological analysis, characterizing the HIV reservoir, HIV resistance and viral sequences in circulating DNA and RNA.
  4. Microbiome analysis will be performed on stool and saliva samples.
  5. Urine sample will be collected for creatinine measurements and microbiome.

After 2 years (20-26 months) follow-up

  1. The investigators will collect metadata from all the participants 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.
  2. Co-pathology will be assesed:

    • Cardiovascular risk scores (D:A:D risk score and Framingham CVD score) will be collected as well as ECG.
    • Non-Alcoholic Fatty Liver Disease (NAFLD) assessment through liver ultrasound and FibroScan.
  3. Blood samples (10ml) will be collected for biomarker and infection/inflammation parameter analysis.

Condition or disease
HIV Infections

Show Show detailed description

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 2000 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 2 Years
Official Title: 2000 HIV Human Functional Genomics Partnership Program
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS




Primary Outcome Measures :
  1. Change in liver fibrosis [ Time Frame: Change: 2-year value - baseline value ]
    Change in liver fibrosis measurement by FibroScan (method by Echosens)

  2. Change in liver steatosis [ Time Frame: Change: 2-year value - baseline value ]
    Change in liver steatosis measurement by FibroScan (method by Echosens) and liver ultrasound (method developed by Radboudumc)

  3. Change in cardiovascular risk score (Framingham score) [ Time Frame: Change: 2-year value - baseline value ]
    Framingham score

  4. Change in cardiovascular risk score (D:A:D score) [ Time Frame: Change: 2-year value - baseline value ]
    D:A:D score

  5. Number and type of cardiovascular events [ Time Frame: 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 …

  6. Genetic data [ Time Frame: At baseline only ]
    Genome-wide genotype data including >8 million SNPs per individual

  7. Colonizing microbiome profile [ Time Frame: At baseline only ]
    Colonizing microbiome profile will be generated from stool and saliva samples

  8. Transcriptomics [ Time Frame: At baseline only ]
    RNA-sequencing will be performed in PBMCs

  9. Quantification of a wide range of metabolites [ Time Frame: At baseline only ]
    Metabolomics analysis by multiplex immunoassays will be performed in plasma or serum

  10. Cytokine production of PBMCs in ex vivo stimulation experiments [ Time Frame: At baseline only ]
    Ex vivo cytokine responses of isolated PBMCs to a range of stimuli (TLR ligands, killed pathogens and viral antigen stimuli)

  11. Immune phenotyping [ Time Frame: At baseline only ]
    Extensive phenotyping of circulating immune cells by flow cytometry analysis

  12. Change in ECG [ Time Frame: Changes in ECG between baseline and 2-year time point ]
    Note changes in ECG performed at baseline and two years

  13. Intima-media thickness [ Time Frame: At baseline only ]
    Ultrasound measurement of intima-media thickness in the carotid artery as a measure for atherosclerosis and cardiovasculr disease risk.


Biospecimen Retention:   Samples With DNA
Blood for DNA isolation (no sequencing, only SNP array) Stool for microbiome analysis Saliva for microbiome analysis Plasma and serum for metabolomics Urine for creatinine analysis


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
HIV-infected patients (n=2000) will be recruited from the following Dutch HIV Treatment Centres: Radboudumc (Nijmegen), ErasmusMC (Rotterdam), Onze Lieve Vrouwe Gasthuis (Amsterdam), Elisabeth-TweeSteden Ziekenhuis (Tilburg). Our aim is to include approximately 20% females, 20% of Sub-Sahara African origin, elite controllers (~2-3%), immunologic non-responders (~3%), and rapid progressors (~4-5%) The total number of adult HIV patients under care in these treatment centers is 7000, of which 80% is male and 70% is of Caucasian origin. There is wide age distribution among the adult HIV population.
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • No informed consent
  • Insufficient communication because of language or other problems
  • Active hepatitis B/C or signs of acute infections
  • Pregnancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03994835


Contacts
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Contact: Maartje Jacobs-Cleophas, MSc. +31 (0)24 3666202 maartje.jacobs-cleophas@radboudumc.nl
Contact: André van der Ven, Prof. +31 (0)24 3686791 andre.vanderven@radboudumc.nl

Locations
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Netherlands
Onze Lieve Vrouwe Gasthuis
Amsterdam, Netherlands, 1091AC
Contact: Willem Blok, Dr.         
Sub-Investigator: Willem Vos, Drs.         
Principal Investigator: Willem Blok, Dr.         
Radboudumc
Nijmegen, Netherlands, 6525GA
Contact: Maartje Jacobs-Cleophas, MSc    +31 (0)24 3666202    maartje.jacobs-cleophas@radboudumc.nl   
Contact: André van der Ven, Prof.    +31 (0)24 3686791    andre.vanderven@radboudumc.nl   
Principal Investigator: Quirijn de Mast, Dr.         
Sub-Investigator: Louise van Eekeren, Drs.         
Erasmus MC
Rotterdam, Netherlands, 3015GD
Contact: Annelies Verbon, Prof.         
Principal Investigator: Annelies Verbon, Prof.         
Sub-Investigator: Albert Groenendijk, Drs.         
Elisabeth Twee-Steden ziekenhuis
Tilburg, Netherlands, 5042AD
Contact: Marvin Berrevoets, Drs.         
Principal Investigator: Marvin Berrevoets, Drs.         
Sub-Investigator: Marc Blaauw, Drs.         
Sponsors and Collaborators
Radboud University
ViiV Healthcare
Elisabeth-TweeSteden Ziekenhuis
Erasmus Medical Center
Onze Lieve Vrouwe Gasthuis
Investigators
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Principal Investigator: Quirijn de Mast, Dr. Radboud University
Principal Investigator: Annelies Verbon, Prof. Erasmus MC
Principal Investigator: Willem Blok, Dr. Onze Lieve Vrouwe Gasthuis
Principal Investigator: Marvin Berrevoets, Drs. Elisabeth Twee-Steden ziekenhuis

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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03994835    
Other Study ID Numbers: NL.68056.091.18
First Posted: June 21, 2019    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Radboud University:
HIV
Non-alcoholic fatty liver disease
Cardiovascular disease
Omics data
Inflammation
Additional relevant MeSH terms:
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HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases