2000 HIV Human Functional Genomics Partnership Program (2000HIV)

• ClinicalTrials.gov Identifier: NCT03994835
• Recruitment Status: Not yet recruiting
• First Posted: June 21, 2019
• Last Update Posted: June 21, 2019
• Sponsor: Radboud University
• Collaborators: ViiV Healthcare; Elisabeth-TweeSteden Ziekenhuis; Erasmus Medical Center; Onze Lieve Vrouwe Gasthuis
• Information provided by (Responsible Party): Radboud University

Study Description

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

Detailed Description:

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 Centres: Radboudumc (Nijmegen), Erasmus MC (Rotterdam), Onze Lieve Vrouwe Gasthuis (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 (SNP frequency, variable prevalence of specific microbial genera and species, etc.), 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

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.

Patient informed consent procedure:

Patients will always be approached first by a treating physician or specialized nurse. They will be provided with information and will be asked if a physician-researcher may contact the patient in one week. If there is oral consent for this, the researcher contacts the patient in one week to ask if they are interested in participating in the study. the physician-researcher will answer any questions the patient may have and plan the first visit. The informed consent procedure will be conducted during the patient's first visit to the physician-researcher.

Patient registry procedures:

All patient data will be recorded only in coded form in a secure database with audit and edit trail (CASTOR EDC). During the informed consent procedure, the patient is given a study code. The identifying patient data and study code is kept in a password-protected key file, only accessible to the local research team. No patient-identifying data will leave the local medical center.

In the questionnaires and eCRFs in CASTOR, the investigators will enter as many data checks as possible (e.g. specified ranges for laboratory results, and questions popping up dependent on certain answers).

Biomaterials:

All biomaterial (blood, stool, urine, saliva) will be transported to and processed in the laboratory of Experimental Internal Medicine of the Radboudumc in Nijmegen. Here, all the biometarial will also be stored collectively. All materials will be handled and stored only under the patient's study code.

Monitoring:

Monitoring will be performed by an independent monitor according to the lastest guidelines of the The Netherlands Federation of University Medical Centres (NFU, April 2019). An initiation and close-out visit will be planned in plenary form with all the centers in Radboudumc. There will be one extra visit per center. This will be an on-site visit in Radboudumc, and a teleconference monitoring visit in the other centers. During these visits informed consents will be checked, as well as inclusion and exclusion criteria and source data verification in a small subset of total participants.

Data collection for patient registry:

Baseline data collected from electronic patient files or the HIV Monitoring Foundation during inclusion visit:

Medical history

1. Inclusion date
2. Length and weight
3. Last known blood pressure (and date measured)
4. Seroconversion date (if known)
5. Date first HIV-postive test
6. Date start cART

7. HIV transmission risk behavior:

   • MSM
   • Heterosexual
   • Injecting drug use
   • Contaminated blood products
   • Unknown
8. First CD4 count
9. CD4 nadir
10. CD4/CD8 ratio pre-cART
11. HIV stadium at start cART according to CDC criteria
12. Pre-cART HIV RNA zenith (Note the mean if multiple HIV-RNA known pre-CART)

13. Opportunistic conditions before start cART (if known)

    • None
    • MTB If yes, specify when and treatment
    • Fungal infections If yes, specify what kind, when and treatment
    • Parasitic infections, If yes, specify what kind, when and treatment
    • Bacterial infections If yes, specify what kind, when and treatment

14. Malignancies before start cART (if known)

    • None
    • If yes, specify what kind, when and treatment

15. Other known medical problems before start cART, which require long-term treatment (such as asthma, IBD, gout, etc).

    • None
    • If yes, specify what kind, when and treatment

16. Response cART:

    • Period between start cART and viral load < 500 (months)

    • Viral loads:

      • Undetectable after 24 weeks: yes/no
      • Number/frequency of residual viremia (positive test with signal <50 copies): last year and last 5 years
      • Number of viral blips (50-200): last year and last 5 years
      • Number of viremia: 200-1000: last year and last 5 years
      • Number of failing cART (>1000): last year and last 5 years
      • Resistance associated mutations pre-cART and following failure
      • CD4 reconstitution
      • CD4/CD8 ratio and normalization >1 yes/no after cART initiation
17. IRIS, yes/no

According to Up-to-date criteria, most or all of the following features should be present in order to make the diagnosis:

• The presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/microL). One important exception to this general rule is tuberculosis. IRIS secondary to preexisting M. tuberculosis infection may occur in individuals with CD4 counts >200 cells/microL.
• A positive virologic and immunological response to antiretroviral therapy (ART).
• The absence of evidence of drug-resistant infection, bacterial superinfection, drug allergy or other adverse drug reactions, patient noncompliance, or reduced drug levels due to drug-drug interactions or malabsorption after appropriate evaluation for the clinical presentation.
• The presence of clinical manifestations consistent with an inflammatory condition

• A temporal association between ART initiation and the onset of clinical features of illness

  18. Opportunistic conditions after start cART (if known)

  • None
  • MTB If yes, specify when and treatment
  • Fungal infections If yes, specify what kind, when and treatment
  • Parasitic infections, If yes, specify what kind, when and treatment
  • Bacterial infections If yes, specify what kind, when and treatment 19. Malignancies after start cART (if known)
  • None
  • If yes, specify what kind, when and treatment 20. Vascular diseases after start cART:
  • None
  • Stroke/ TIA
  • Angina pectoris
  • Myocardial infarction
  • Claudicatio intermittens
  • Venous thrombo-embolism
  • Other … 21. STDs
  • None
  • HAV: yes/no, if yes: treatment and how often
  • HBV:
• Infected: active infection (PCR+) or non-active infection
• Vaccination: No/Yes
• Once with anti-HBs> 100

• Two times vaccination leading to

  • anti-HBs> 100
  • anti-HBs< 100

• No infection

  • HCV: yes/no, if yes: treatment and how often
  • Lues: yes/ no: if yes: treatment and how often
  • Chlamydia/Go: yes/ no: if yes: treatment and how often
  • HPV 22. cART regimes
  • Reasons for switching available from 'Stichting HIV Monitoring' 23. Prescribed co-medication
  • Full current medication list

Physical examination

• Signs of Kaposi sarcoma
• Lymphadenopathy
• For determination of medication levels: when was the last date and time HIV-medication was taken?
• Other abnormalities: …

Cardiovascular risk profile:

• D:A:D (R) and Framingham scores
• ECG

Laboratory results of date closest to inclusion date (standard care at least once a year according to Dutch guidelines):

• Full blood count
• Liver enzymes (ALAT, AF, bilirubin)
• Creatinine
• HIV-RNA
• CD4 and CD8 counts
• Glucose
• Lipid profile
• TPHA/VDRL

• HCV serology (for all at risk, such as MSM and i.v. drug users)

  o If positive, HCV PCR

• HPV diagnostics in females (PAP, PCR)
• Urine diagnostics (if available): α1-microglobulin, protein, albumin, phosphate, creatinine.

Data to be collected after 2 years from electronic patient files or HIV Monitoring Foundation (20-26 months)

Medical history last 2 years:

1. Date of 2 year follow-up visit
2. Last known weight
3. Last known blood pressure (and date measured)

4. Response cART last 2 years

   • Number of residual viremia (positive test with signal <50 copies*): last 2 years. *lowest level of detection
   • Number of viral blips (20-200): last 2 years
   • Number of viremia (200-1000): last 2 years
   • Number of failing cART (>1000): last 2 years
   • CD4 count
   • CD4/CD8 ratio (if known)

5. Opportunistic conditions last 2 years

   • None
   • MTB If yes, specify when and treatment
   • Fungal infections If yes, specify what kind, when and treatment
   • Parasitic infections, If yes, specify what kind, when and treatment
   • Bacterial infections If yes, specify what kind, when and treatment

6. Malignancies in the last 2 years

   • None
   • If yes, specify what kind, when and treatment

7. Signs/symptoms of cardiovascular diseases in the last 2 years:

   • None
   • Stroke/ TIA
   • Angina pectoris
   • Myocardial infarction
   • Claudicatio intermittens
   • Venous thrombo-embolism
   • Other …

8. New SOAs in the last 2 years

   • HAV: yes/no, if yes: treatment and how often

   • HBV:

     • Infected: active infection (PCR+), non-active infection,
     • Vaccination: No/Yes
     • Once with anti-HBs> 100
     • Two times vaccination leading to
   • anti-HBs> 100

   • anti-HBs< 100

     • No infection

   • HCV: yes/no, if yes: treatment and how often
   • Lues: yes/ no: if yes: treatment and how often
   • Chlamydia/Go: yes/ no: if yes: treatment and how often

9. cART regimes in the last 2 years

   o Reasons for switching available from 'Stichting HIV Monitoring'

10. Prescribed co-medication o Full current medication list

Physical examination

• Signs of Kaposi sarcoma
• Lymphadenopathy
• For determination of medication levels: when was the last date and time HIV-medication was taken?
• Other abnormalities: …

Cardiovascular risk profile:

• D:A:D (R) and Framingham scores
• ECG

Laboratory results of date closest to follow-up visit date (standard care at least once a year according to Dutch guidelines):

• Full blood count
• Liver enzymes (ALAT, AF, bilirubin)
• Creatinine
• HIV-RNA
• CD4 and CD8 counts
• Glucose
• Lipid profile
• TPHA/VDRL

• HCV serology (for all at risk, such as MSM and i.v. drug users)

  o If positive, HCV PCR

• HPV diagnostics in females (PAP, PCR)
• Urine diagnostics (if available): α1-microglobulin, protein, albumin, phosphate, creatinine

Study Design

• 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

Groups and Cohorts

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Contacts

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

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

• 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

More Information

• Responsible Party: Radboud University
• ClinicalTrials.gov Identifier: NCT03994835
• Other Study ID Numbers: NL.68056.091.18
• First Posted: June 21, 2019
• Last Update Posted: June 21, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

HIV Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases