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

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.