The MISTRAL Study: Gut Microbiome Correlates of Serious AIDS and Non-AIDS Events

Inflammation Clinical Trial

— MISTRAL  

Official title:

Microbiome-based Stratification of Individuals at Risk of HIV-1 Acquisition, Chronic Clinical Complications, Antimicrobial Drug Resistance, and Unresponsiveness to Therapeutic HIV-1 Vaccination

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05421286
• Other study ID #: The MISTRAL Study
• Status: Not yet recruiting
• Start date: July 1, 2022
• Est. completion date: June 2025

Study information

• Verified date: June 2022
• Source: Rigshospitalet, Denmark
• Contact: Jakob Friis Larsen, Team Leader
• Phone: +45 35 45 57 71
• Email: jakob.friis.larsen[@]regionh.dk
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

MISTRAL (Microbiome-based stratification of individuals at risk of HIV-1 acquisition, chronic clinical complications, antimicrobial drug resistance, and unresponsiveness to therapeutic HIV-1 vaccination) is a 5-year EU Horizon 2020 project, running from 1/1/2020 - 31/12/2024.

The project is led by Fundacio Privada Institut de Recerca de la Sida-Caixa CAIXA in Barcelona and aims to explore the gut microbiota in relation to HIV-1, seeking microbiome biomarkers to support development of interventions that mitigate infection and enhance response to vaccines and therapies.

If successful, MISTRAL will benefit millions of human beings living with, or at risk of acquiring HIV-1 infection, and will produce novel concepts and technical innovations applicable to other human diseases. By doing that, MISTRAL will help to unlock the full clinical potential of the human microbiome to stratify patient outcomes and will irreversibly bring microbiome science closer to clinical practice

Description:

Background and Rationale: The HIV/AIDS pandemic continues to be one of the major health challenges ever faced by mankind. Far from being resolved, HIV is soaring in Eastern Europe (60% increase in new infections and 27% increase in deaths since 2010) and other regions of the world despite increasing access to antiretroviral treatment . There is emerging evidence that the human microbiome impacts some of the most important clinical aspects of HIV-1 infection, including immune disorders, chronic inflammation and accelerated aging . Work in other viral diseases and cancer immunotherapy suggest a critical role of the human microbiome also in the outcome of immune therapeutic interventions in HIV-1 infection .

MISTRAL (The Microbiome-based stratification of individuals at risk of HIV-1 acquisition, chronic clinical complications, antimicrobial drug resistance, and unresponsiveness to therapeutic HIV-1 vaccination) is a European Union (EU) Horizon 2020 funded project that aims to explore the impact of the human microbiome on clinical outcomes in people living with HIV (PLWH). The MISTRAL project brings together a team of world-class HIV and microbiome researchers with ideal complementary knowledge and expertise. This team will work to discover and validate novel gut microbiome biomarkers to inform rationally designed, mechanistically-driven interventions on the gut microbiome to mitigate HIV-1 acquisition, systemic inflammation, chronic clinical complications, antimicrobial drug resistance, and boost the efficacy of HIV cure immunotherapies.

Within the MISTRAL project, the MISTRAL study will explore the impact of the microbiome on clinical outcomes in a large clinical cohort of PLWH through the collection and analysis of stool, plasma and blood samples. The MISTRAL study will utilize the long-established network, clinical sites and expertise of the EuroSIDA study, a prospective, observational cohort study of PLWH that has been collecting observational data since 1994.

The stool samples collected in the MISTRAL study will configure a microbiome repository module. The microbiome data/test results will be combined with those of other biomarkers obtainable from testing plasma and blood samples, which could result in increased efficiency and the possibility to use other biomarkers to test the relevance of specific hypothesized pathways. Ultimately, the expected outcome of the MISTRAL study is to have a better basic understanding of the pathophysiological factors of the interplay of HIV infection and the human microbiome.

Study objectives: The primary objective of the MISTRAL study is to strengthen and evaluate the understanding of the association between the gut microbiome composition and the risk of developing serious AIDS and non-AIDS events, including cardiovascular events. The second objective is to evaluate the associations between the gut microbiome composition and function and pathologic increases in inflammation and coagulation mediators in PLWH. The third objective is to develop a risk score which makes use of information in the gut microbiome as well as other risk factors separately for the different endpoints.

Study Design: As the MISTRAL study is a non-interventional observational study, data is only collected during participant visits and treatment will not be influenced by the participation. Participants will provide a stool, plasma and whole blood sample at baseline and an additional follow-up sample up to two years after baseline. Participant information about their diet, time and frequency of defecation, medication history and usage and lifestyle data will also be collected at baseline and up to two years after baseline. Clinical data including demographic, laboratory, medical treatment and clinical event history will be collected at enrolment and during annual follow-up. The biological samples will be used to conduct pre-specified analyses into microbiome and immunological related factors, as well as form the basis of an ongoing research biobank for future exploration of the impact on microbiome on clinical outcomes in PLWH. For a subset of the cohort, analyses of host-genetic material will also be performed.

Data Collection: MISTRAL study enrolment, participant information and follow-up data are captured electronically in electronic case reports forms (e-CRFs) using the free secure online browser-based Research Electronic Data Capture tool (REDCap) or RESPOND Electronic Data Submission Tool (REST). Data are collected initially into EuroSIDA servers based at CHIP. At CHIP, the clinical data will undergo quality assurance procedures before being transferred to the MISTRAL data repository for storage. The MISTRAL data repository is contained within Amazon Web Services servers located within the EU and complies with EU data protection. All data is pseudonymised. A de-coding list is held in a safe location by the individual site.

Sample Repository/Research Biobank: Stool, plasma and blood samples will initially be shipped to the coordinating centre at CHIP, Rigshospitalet, Denmark, and stored in secure holding facilities at - 80° Celsius. These samples will then be transferred to the MISTRAL biobank at IrsiCaixa, Hospital Germans Trias I Pujol, Barcelona Spain. Analyses will be performed by members of the MISTRAL Consortium. Samples will not be sent outside the European Union without data transfer agreements. A proportion of the samples collected will be stored for future, yet unspecified research. Samples will be destroyed the latest on 31 December 2045 in accordance with current legal and ethical requirements.

Safety: Participation in the MISTRAL study does not include any risk for participants. The study does not test or investigate any treatments and participation in this study does not interfere with the treatment/care participants may receive at the clinic. There are no direct benefits to the participants. However, the benefit of conducting observational research that includes analysis of biological samples will advance scientific understanding of HIV infection and other co-infections and co-morbidities as well as their complications. This knowledge guides international and European treatment recommendations for the benefit of PLWH and national health systems.

Economy: Sites participating in the MISTRAL study will be reimbursed for enrolment and follow up data collection for each participant, event forms and sending samples.

The MISTRAL study has received funding from the European Commission Directorate-General for Research and Innovation Horizon 2020 Grant Agreement number 847943 (9,994,383.75€).

Participants in the study receive no financial compensation.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1000
• Est. completion date: June 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• HIV-1 positive persons

• Age =50 years old

• Prospectively followed in a EuroSIDA site

Exclusion Criteria:

• Creatine Clearance <50

• Child-Pugh C end-stage liver disease

• Any ongoing severe life-threatening disease

• Experiencing any of the following events prior to inclusion: myocardial infarction, stroke, an invasive cardiovascular procedure, AIDS (diagnosed within 5 years of MISTRAL enrolment), and non-AIDS cancers (not including non-melanoma skin cancers)

Related Conditions & MeSH terms

• AIDS
• HIV-1-infection
• Inflammation

Locations

Country	Name	City	State
Belgium	CHU Saint-Pierre Hospital	Brussels
Croatia	University Hospital of Infectious Diseases	Zagreb
Czechia	Faculty Hospital Bulovka	Prague
Denmark	Aarhus University Hospital	Aarhus
Denmark	Hvidovre Universitets Hospital	Hvidovre
Denmark	Odense Universitetshospital	Odense
France	Hôpital Necker-Enfants Malades	Paris
Germany	University Hospital Bonn, Klinisches StudieZentrum Immun.	Bonn
Germany	University Hospital Cologne	Cologne
Germany	University Clinic Hamburg Eppendorf	Eppendorf
Germany	J.W.Goethe University Hospital	Frankfurt am Main
Germany	ICH Study Center, Innere Medizin	Hamburg
Greece	Ippokration General Hospital	Athens
Hungary	Szent László Hospital	Budapest
Israel	Hadassah Hospital	Jerusalem
Italy	Ospedale San Paulo	Milano
Luxembourg	Centre Hospitalier de Luxembourg	Luxembourg
Poland	Wojewodzki Szpital Specjalistyczny im. WI. Bieganskiego	Lodz
Spain	Hosp. Universitari Germans Trias i Pujol, Hospital de dia VIH	Badalona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Clinic - IDIBAPS. University of Barcelona, C/Villarroel, 170	Madrid
Spain	Hospital Ramon y Cajal	Madrid
United Kingdom	Royal Sussex County Hospital, HIV/GUM Research	Brighton
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	University College London, Mortimer Market Centre	London

Sponsors (3)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Horizon 2020 - European Commission, IrsiCaixa

Countries where clinical trial is conducted

Belgium,  Croatia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Luxembourg,  Poland,  Spain,  United Kingdom, 

References & Publications (3)

Herrera S, Martínez-Sanz J, Serrano-Villar S. HIV, Cancer, and the Microbiota: Common Pathways Influencing Different Diseases. Front Immunol. 2019 Jun 27;10:1466. doi: 10.3389/fimmu.2019.01466. eCollection 2019. Review. — View Citation

Hsu DC, Sereti I, Ananworanich J. Serious Non-AIDS events: Immunopathogenesis and interventional strategies. AIDS Res Ther. 2013 Dec 13;10(1):29. doi: 10.1186/1742-6405-10-29. — View Citation

Li SX, Armstrong A, Neff CP, Shaffer M, Lozupone CA, Palmer BE. Complexities of Gut Microbiome Dysbiosis in the Context of HIV Infection and Antiretroviral Therapy. Clin Pharmacol Ther. 2016 Jun;99(6):600-11. doi: 10.1002/cpt.363. Epub 2016 Apr 16. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of serious AIDS and non-AIDS events, in particular cardiovascular events, across Europe; and multi-omics (in particular gut microbiome), demographic, dietary, clinical, therapeutic, immunological and viral factors associated with these outcomes		: From date of enrolment until lost to follow-up or death, whichever came first, assessed up to 5 years

External Links

•   Journal of the European Union, 2005
•   Journal of the European Union, 2016
•   UNAIDS announces nearly 21 million people living with HIV now on treatment." UNAIDS, 20 Nov. 2017, Press release.
•   World Medical Association, 2018