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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
Secondary Objectives
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:
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
After 2 years follow-up
Full 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 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:
Blood will be drawn (90 ml):
Microbiome analysis will be performed on stool and saliva samples.
Urine sample will be collected for creatinine measurements and microbiome.
After 2 years follow-up
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:
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. 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.
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
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 biomaterial 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 latest guidelines of the The Netherlands Federation of University Medical Centers. 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. 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:
Inclusion date
Length and weight
Last known blood pressure (and date measured)
Seroconversion date (if known)
Date first HIV-positive test
Date start cART
HIV transmission risk behavior:
First CD4 count
CD4 nadir
CD4/CD8 ratio pre-cART
HIV stadium at start cART according to CDC criteria
Pre-cART HIV RNA zenith
Opportunistic conditions before start cART
Malignancies before start cART
Other known medical problems before start cART, which require long-term treatment
Response cART:
Period between start cART and viral load < 500 (months)
Viral loads:
IRIS, yes/no
Opportunistic conditions after start cART (if known)
Malignancies after start cART (if known)
Vascular diseases after start cART:
SOAs
None
HAV: yes/no, if yes: treatment and how often
HBV:
Infected: active infection (PCR+) or non-active infection
Vaccination: No/Yes
anti-HBs> 100
anti-HBs< 100
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
COVID-19 infection before or after start cART:
Was a COVID-19 test done and if so type of test if known (PCR or antigen test), date of test and result of laboratory test for COVID-19 (positive or negative)
COVID-19 Serology results
Register COVID-19-related hospital admissions
COVID-19 vaccination: type and date(s)
Side effects of COVID-19 vaccination:
cART regimes
Prescribed co-medication
Full current medication list
Physical examination
Cardiovascular risk profile:
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)
HPV diagnostics in females (PAP, PCR)
Urine diagnostics (if available): α1-microglobulin, protein, albumin, phosphate, creatinin
Baseline data collected from electronic patient files or the HIV Monitoring Foundation during 2-year follow-up visit:
Medical history last 2 years:
Date of 2 year follow-up visit
Weight
Last known blood pressure (and date measured)
Response cART last 2 years
Opportunistic conditions last 2 years
Malignancies in the last 2 years
Signs/symptoms of cardiovascular diseases in the last 2 years:
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
anti-HBs> 100
anti-HBs< 100
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
COVID-19 infection before or after start cART:
Was a COVID-19 test done and if so type of test if known (PCR or antigen test), date of test and result of laboratory test for COVID-19 (positive or negative)
COVID-19 Serology results
Register COVID-19-related hospital admissions
COVID-19 vaccination: type and date(s)
Side effects of COVID-19 vaccination:
cART regimes in the last 2 years
Prescribed co-medication
Full current medication list
Physical examination
Cardiovascular risk profile:
Laboratory results of date closest to follow-up visit date:
Full blood count
Liver enzymes (ALAT, AF, bilirubin)
Creatinine
HIV-RNA
CD4 and CD8 counts
Glucose
Lipid profile
TPHA/VDRL
HCV serology
o If positive, HCV PCR
HPV diagnostics in females (PAP, PCR)
Urine diagnostics
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Exclusion criteria
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Data sourced from clinicaltrials.gov
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