Effects of COVID-19 on Endothelium in HIV-Positive Patients in Sub-Saharan Africa (ENDOCOVID)

• ClinicalTrials.gov Identifier: NCT04709302
• Recruitment Status: Enrolling by invitation
• First Posted: January 14, 2021
• Last Update Posted: March 10, 2023
• Sponsor: Medical University of Graz
• Collaborators: University of Olso; Kristiania University College; Walter Sisulu University; Lagos State University; Management Sciences for Health
• Information provided by (Responsible Party): Medical University of Graz

Study Description

Brief Summary:

Background: Coronavirus disease 2019 (COVID-19) has affected almost every country in the world, especially in terms of health system capacity and economic burden. People from sub-Saharan Africa (SSA) often face interaction between human immunodeficiency virus (HIV) infection and non-communicable diseases such as cardiovascular disease. Role of HIV infection and anti-retroviral treatment (ART) in altered cardiovascular risk is questionable and there is still need to further carry out research in this field. However, thus far it is unclear, what impact the COVID-19 co-infection in people living with HIV (PLHIV), with or without therapy will have. The ENDOCOVID project aims to investigate whether and how HIV-infection in COVID-19 patients modulates the time course of the disease, alters cardiovascular risk, and changes vascular endothelial function and coagulation parameters/ thrombosis risk.

Methods: In this long-term study, cardiovascular research on PLHIV with or without ART with COVID-19 and HIV-negative with COVID-19 will be carried out via clinical and biochemical measurements for cardiovascular risk factors and biomarkers of cardiovascular disease (CVD). Vascular and endothelial function will be measured by brachial artery flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) assessments, and retinal blood vessel analyses, along with vascular endothelial biomarkers and coagualation markers. The correlation between HIV-infection in COVID-19 PLHIV with or without ART and its role in enhancement of cardiovascular risk and endothelial dysfunction will be assessed. Potential changes in these endpoints by COVID-19 will be followed for 4 weeks across the three groups (PLHIVwith or without ART and HIV negatives).

Impact of project: The ENDOCOVID project aims to evaluate in the long-term the cardiovascular risk and vascular endothelial function in PLHIV thus revealing an important transitional cardiovascular phenotype in COVID-19.

Condition or disease	Intervention/treatment
Covid19; Hiv; ART	Biological: COVID-19; Biological: HIV; Drug: ART

Detailed Description:

Background:

SARS-CoV-2 has affected almost every country worldwide with regard to health system capacities and economic burden, so far. The typical clinical presentations of COVID-19 are fever, sore through, cough, dyspnea, abdominal pain and diarrhea. Approximately 15% of patients with COVID-19 must be hospitalized and 5% are critically ill, and often develop acute respiratory distress syndrome and need to be admitted to intensive care units. Risk of severe disease increases with age, male sex, and with co-morbidities such as chronic lung disease, CVDs, and diabetes. COVID-19 can also affect the nervous systems and cause loss of smell or taste sensation.

Populations in SSA are increasingly facing a double burden of disease involving the interaction between HIV-AIDS and non-communicable diseases such as CVDs. In general, vascular endothelial function can be regarded as a marker of the net harmful effects of cardiovascular risk factors on the vascular wall. HIV- infected patients have premature atherosclerosis and increased risk of ischemic heart disease. The cardiovascular risk represented by HIV-infection is moreover affected by anti-retroviral treatment (ART). ART may, among other effects, prompt dyslipidaemic and metabolic changes in patients over to systemic immune activation, stimulation of endothelial inflammation and atherosclerosis. However, a recent meta-analysis showed that evidence for - and against - a role for ART in the development of CVDs remains unconvincing and that more research is necessary.

With the current COVID-19 pandemic, which has also spread across Africa, another burden is added. However, thus far it is unclear, what effect the additional COVID-19 co-infection in people with HIV (PLHIV) will have as there are no data yet on how HIV/AIDS a prevalent diseases SSA, will affect COVID-19 infection rates or outcomes. Currently, there is no proof for a higher COVID -19 infection rate in PLHIV compared to HIV-negatives. However, there is a possibility that HIV infection may have an influence on the course of infection. PLHIV who are on ART with a normal CD4 T-cell count and suppressed viral load should not be at an increased risk of severe disease. On the other hand, this theoretically positive situation could be counterbalanced by recent evidence that ART could also have effects on COVID-19. Furthermore, HIV-infected patients may additionally suffer from co-morbidities, which could pose a greater risk of COVID-19 infection. Currently, there is no data available about COVID-19 infection in PLHIV in SSA reflecting who in particular is at high risk for infections, complications and fatal outcomes. As COVID-19 associated multisystem inflammation, and the way organ damage caused by COVID-19 occurring in patients with COVID-19 is still incompletely understood, and current treatment options are limited. There is therefore an urgent need to better understand the risk of severe and fatal COVID-19 outcomes, especially in PLHIV (+/- ART).

A severe course of COVID-19 can cause the development of COVID-19-associated coagulopathy, with features of both disseminated intravascular coagulation and thrombotic microangiopathy, resulting in widespread microvascular thrombosis that may involve consumption of coagulation factors and the liver. There seems to be a causal relationship with the inflammatory and reparative processes involving diffuse alveolar damage (DAD), because thrombi are frequently detected in small pulmonary arteries, most presumed secondary to endothelial damage. The damage of endothelium could be due to the direct viral infection of the endothelial cells, which express ACE-2 receptors, or to a host response. Besides, the alveolar fibrin deposition in DAD may affect the local homeostasis between fibrinolysis and coagulation. Alveolar and endothelial damage of smaller vessels may be followed by microvascular pulmonary thrombosis, which could then extend to larger vessels. Additionally, elevated D-dimer has been observed in patients with COVID-19. It is known that inceased D-dimer is associated with acute pulmonary emboli (APE), deep venous thrombosis (DVT), cancer, peripheral vascular disease, inflammatory diseases and pregnancy. It has been found that patients with COVID-19, including those not on respirators but bedconfined, develop DVT and APE much earlier than expected. Even with usage of prophylactic anticoagulation, autopsy has shown that deaths in COVID-19 may be caused by the thrombosis in segmental and subsegmental pulmonary arterial vessels. ENDOCOVID project aims to evaluate the degree to which COVID-19 induced inflammation contributes to endothelial function and coagulation changes and cardiometabolic risk in PLHIV (+/-ART). Endothelial function will be evaluated non-invasively via FMD and blood asymmetric dimethyl arginine (ADMA).

Problem statement HIV infection is a burden for the cardiovascular system but coinfection of HIV and SARS-CoV-2 in SSA population could be a very big load and could lead to higher menace of cardiovascular health. However, the potential of risk in this population, including early vascular and endothelial changes, is yet unclear. Given the ongoing global pandemic, epidemiological studies to address this knowledge gap is necessary. The aim of this study is to evaluate cardiovascular risk in HIV and COVID-19 populations, which also would allow assessment of current - and future - cardiovascular risk, via vascular endothelial function measurements. The ENDOCOVID project has been designed to give an evaluation of cardiovascular risk in PLHIV and COVID-19 living in SAA. ENDOCOVID builds up on the EndoAfrica study, which is currently being carried out in SSA.

Aim and objectives The general aim of the ENDOCOVID project is to identify whether and how HIV-infection with or without ART in COVID-19 patients relates to the time course of the disease, alters cardiovascular risk, and changes vascular endothelial structure and function in adults living in the SSA.

Three groups of participants will take part in this project:

1. PLHIV without ART but with COVID-19
2. PLHIV with ART and COVID-19
3. HIV-negative patients with COVID-19, sex- /age matched

The following objectives will be investigated:

1. Evaluation of the prevalence of COVID-19 in PLHIV (with or without ART) admitted to clinics in South Africa and Nigeria because of COVID-19.
2. Assessment of the incidence of acute respiratory distress syndrome, admission to ICU, fatal course of disease (30-days mortality), and thromboembolic events in hospitalized patients included in the study.
3. Evaluation of the influence of ART on severity of COVID-19 in PLHIV (with or without ART) as well as clinical presentation, changes of endothelial/vascular function and biomarkers.
4. Evaluation of the effects of COVID-19 on endothelial/vascular function, thrombotic factors, and oro-naso sensory alterations over infection and after recovery.
5. Correlation of hospitalization and mortality of COVID-19 infected PLHIV(with or without ART) and HIV negatives with co-morbidity incidence;
6. Assessment of the incidence of obesity and insulin resistance in the 3 groups.

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 342 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 4 Weeks
• Official Title: COVID-19 and Its Effects on Endothelium in HIV-Positive Patients in Sub-Saharan Africa: Cardiometabolic Risk, Thrombosis and Vascular Function
• Actual Study Start Date: February 1, 2021
• Estimated Primary Completion Date: June 2024
• Estimated Study Completion Date: December 2025

Groups and Cohorts

Group/Cohort	Intervention/treatment
COVID-19 positive, HIV-positive with ART; Patients tested positive for SARS-CoV-2 Patients tested positive for HIV who are on ART	Biological: COVID-19; Patients diagnosed with a COVID-19 infection; Other Name: SARS-CoV-2 positive; Biological: HIV; Patients diagnosed HIV-positive; Drug: ART; Patients on ART
COVID-19 positive, HIV-positive without ART; Patients tested positive for SARS-CoV-2 Patients tested positive for HIV ART naive group	Biological: COVID-19; Patients diagnosed with a COVID-19 infection; Other Name: SARS-CoV-2 positive; Biological: HIV; Patients diagnosed HIV-positive
COVID-19 positive, HIV-negative; Patients tested positive for SARS-CoV-2 Patients tested positive for HIV ART naive group	Biological: COVID-19; Patients diagnosed with a COVID-19 infection; Other Name: SARS-CoV-2 positive

Outcome Measures

Primary Outcome Measures :

1. Number of patients developing Acute Respiratory Distress Syndrome [ Time Frame: through study completion, up to 3 months ]
   Comparison of all three groups, recorded for each patient
2. Number of ICU admissions [ Time Frame: through study completion, up to 3 months ]
   Comparison of all three groups, recorded for each patient
3. Number of Deaths [ Time Frame: through study completion, up to 3 months ]
   Comparison of all three groups

Secondary Outcome Measures :

1. Cardiometabolic Status: ADMA [ Time Frame: through study completion, an average of 3 months ]
   Asymmetric dimethylarginine (ADMA) as marker for endothelial function (from blood sample) measured via commercially available ELISA kits
2. Cardiometabolic Status: Cholesterol [ Time Frame: through study completion, an average of 3 months ]
   To assess the lipid profile, cholesterol levels will be assessed via blood samples in a routine laboratory
3. Cardiometabolic Status: Triglycerides [ Time Frame: through study completion, an average of 3 months ]
   To assess the lipid profile, triglyceride concentrations will be assessed via blood samples in a routine laboratory
4. Cardiometabolic Status: HDL cholesterol [ Time Frame: through study completion, an average of 3 months ]
   To assess the lipid profile, HDL cholesterol concentrations will be assessed via blood samples in a routine laboratory
5. Cardiometabolic Status: LDL cholesterol [ Time Frame: through study completion, an average of 3 months ]
   To assess the lipid profile, LDL cholesterol concentrations will be assessed via blood samples in a routine laboratory
6. Cardiometabolic Status: Glucose [ Time Frame: through study completion, an average of 3 months ]
   Assessed via blood samples in a routine laboratory
7. Cardiometabolic Status: Glycated Hemoglobin [ Time Frame: through study completion, an average of 3 months ]
   HbA1c as marker for diabetes, assessed via blood samples in a routine laboratory
8. Cardiometabolic Status: hs-CRP [ Time Frame: through study completion, an average of 3 months ]
   high sensitivity CRP as inflammatory marker, assessed via blood samples in a routine laboratory
9. Endothelial function and vascular changes: FMD [ Time Frame: through study completion, an average of 3 months ]
   Assessed non-invasively using ultrasound in the brachial artery (flow mediated dilatation)
10. Endothelial function and vascular changes: PWV [ Time Frame: through study completion, an average of 3 months ]
    PWV, a marker of aortic stiffness, is most commonly measured as the time it takes a pulse wave to travel from the carotid to the femoral arteries divided by the distance multiplied by 0.8. PWV can be measured by several devices. The non-invasive Vicorder device has been shown to have good reproducibility - even when the assessor has limited experience in its usage - and the results obtained reflect those obtained via invasive central blood pressure measurements and those of SphygmoCor device.
11. Endothelial function and vascular changes: Retinal microvasculature analysis [ Time Frame: through study completion, an average of 3 months ]
    A non-mydriatic, hand-held, portable digital retinal camera (Optomed Aurora, Optomed Oy, Oulu, Finland) will be used for collecting retinal images. Dimensions of vessels and microvascular state will be analyzed offline with the semi-automated MONA REVA software (VITO, Belgium).
12. Endothelial function and vascular changes: IMT [ Time Frame: through study completion, an average of 3 months ]
    Intima media thickness is assessed via ultrasound in the carotid artery
13. Coagulatory Parameters: D-dimer [ Time Frame: through study completion, an average of 3 months ]
    increased D-Dimer as marker for pulmonary embolism in a routine laboratory
14. Coagulatory Parameters: CAT [ Time Frame: through study completion, an average of 3 months ]
    Calibrated automated thrombography as thrombosis marker (Thrombinoscope BV)
15. Coagulatory Parameters: TF [ Time Frame: through study completion, an average of 3 months ]
    Tissue factor (TF) measured via triggered thromboelastometry (TEM) coagulation analyzer (ROTEM05)

Biospecimen Retention:   Samples With DNA

Blood

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Participants of the ENDOCOVID study population are patients with COVID-19, who at the same time are infected with HIV (with or without ART), or are HIV negative. Some may be admitted in the ICU. For inclusion into the study, participants must be positive for SARS-CoV-2 RNA and 18 years or older. Participants will be excluded from the study if they are less than 3 months post-partum and those with other co-infections than HIV such as tuberculosis Participants fulfilling the criteria will be invited into the study and asked to provide written informed consent.

Criteria

Inclusion criteria:

• PLHIV without antiretroviral therapy but with COVID-19 infection
• PLHIV with antiretroviral therapy and COVID-19 infection
• HIV-negative patients, sex- and age matched, infected with COVID-19;
• older than 18 years

Exclusion criteria:

• Those with known co-infections such as hepatitis B and C
• with a viral load of HIV RNA >1000 copies/ml under ART or with advanced symptoms of AIDS
• negative for SARS-CoV-2 RNA

Contacts and Locations

Locations

Nigeria

University of Ilorin Teaching Hospital

Ilorin, Kwara State, Nigeria

Lagos Stae University Teaching Hospital Ikeja

Lagos, Nigeria

South Africa

Walter Sisulu University

Mthatha, South Africa

Sponsors and Collaborators

Medical University of Graz

University of Olso

Kristiania University College

Walter Sisulu University

Lagos State University

Management Sciences for Health

Investigators

• Principal Investigator: Nandu Goswami, Dr PhD; Medical University of Graz

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Goswami N, Fredriksen PM, Lundin KEA, Agu C, Elias SO, Motaung KS, Brix B, Cvirn G, Sourij H, Stelzl E, Kessler HH, Salon A, Nkeh-Chungag B. COVID-19 and its effects on endothelium in HIV-positive patients in sub-Saharan Africa: Cardiometabolic risk, thrombosis and vascular function (ENDOCOVID STUDY). BMC Infect Dis. 2021 Jul 31;21(1):719. doi: 10.1186/s12879-021-06426-8.

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT04709302
• Other Study ID Numbers: ENDOCOVID
• First Posted: January 14, 2021
• Last Update Posted: March 10, 2023
• Last Verified: March 2023

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

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases