The Drugs Maraviroc And Pravastatin Are Effective In Treating Long COVID

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A new American study involving researchers from the Californian biotech company incellDX and doctors from the Chronic COVID Treatment Center In U.S. (https://covidlonghaulers.com/), has found that the antiviral drug Maraviroc together with the cholesterol lowering medication Pravastatin, are effective in treating long COVID or PASC (Post-Acute Sequelae of COVID).

Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.
 
Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids.

Dr Bruce Patterson, CEO & Founder of incellDX and the Chronic COVID Treatment Center told , “Long COVID or Post-acute sequelae of COVID (PASC), is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness.”
 
Dr Patterson who was previously the Medical Director of Diagnostic Virology at Stanford University Hospitals and Clinics further added, “The pathophysiology behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection.

CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We believe targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC.”

The study findings were published on a preprint server (Research Square) and are currently being peer reviewed. https://www.researchsquare.com/article/rs-1344323/v1

Post-acute sequelae of COVID (PASC), commonly referred to as long COVID or chronic COVID, is an emerging public health syndrome that continues to devastate and debilitate adult and pediatric survivors of acute SARS-CoV-2 infection.

The World Health Organization (WHO)-led Delphi consensus defined PASC as a syndrome starting three months from onset of probable infection with symptoms lasting over two months and could not be explained by an alternative diagnosis (1).

Over 200 symptoms have been attributed to PASC (2,) thus posing an enormous challenge clinically. The multi-organ involvement causes cognitive impairment, debilitating neuropathy, chronic migraines, autonomic dysfunction, cardiac dysrhythmias, dyspnea at rest, severe fatigue, and myalgias (3).

Presently, minimal therapeutic options are available to treat PASC which can be attributed to the pathology not yet being fully described. However, we recently reported that the S1 protein subunit of SARS-CoV2 is retained in both nonclassical (CD14- CD16+) and intermediate (CD14+CD16+) monocytes several months after acute infection.

Typically, these monocytes persist only for a few days, but in PASC patients, the S1 containing monocytes can persist for months and years (4), which we propose contributes to the pathophysiology behind PASC. Nonclassical monocytes are involved in phagocytosis and vascular adhesion by patrolling the endothelium under homeostatic and inflammatory conditions through B2 integrin, lymphocyte function-associated antigen-1 (LFA-1) and high levels of fractalkine receptors (CX3CR1) (5, 6).

On the other hand, CD14+CD16+ monocytes express high levels of C-C chemokine receptor type 5 (CCR5) and fractalkine receptors and are involved in antigen presentation, cytokine secretion and apoptosis regulation (6, 7). Since CCR5 and fractalkine receptors have been studied for various chronic inflammatory pathologies, we hypothesized that these receptors may also be therapeutic targets for PASC.

CD16+ monocytes also produce high levels of various pro-inflammatory cytokines which could be an explanation for the heterogenous symptomatology in PASC. Specifically, elevations in C-C chemokine ligand 5 (CCL5) /RANTES (Regulated on Normal T-cell Expression and Secretion), IL-2, IL-6, IFN-gamma and Vascular Endothelial Growth Factor (VEGF), along with decrease in CCL4 have been observed in patients and are hypothesized to be contributing to the pathophysiology of PASC (8).

Here, we describe an 18 participant case series investigating the combination of the CCR5 receptor antagonist maraviroc, and pravastatin, which targets fractalkine, as a potential therapeutic approach in addressing and treating the potential pathology of PASC.

The CCR5 receptor is a seven-transmembrane G protein-coupled receptor (GPCR) that is found on macrophages and T-lymphocytes and functions to regulate trafficking and effector functions of these cells (9).

The role of CCR5 as a co-receptor for human immunodeficiency virus (HIV) entry was discovered in 1996. Maraviroc is the first and only US Food and Drug Administration (FDA) and European Medical Agency (EMA) approved CCR5 receptor antagonist available to date. Maraviroc is a negative allosteric modulator of the CCR5 receptor, and by binding to the CCR5 receptor, it induces receptor conformational changes that prevent the chemokine binding of RANTES (CCL5) and CCR5-mediated signaling (10).

While this mechanism has been researched and studied extensively in HIV infection, there is increasingly greater recognition and appreciation of the CCR5-CCL5 axis in many other conditions and pathologies such as cancer, autoimmune disorders and endothelial dysfunction.

This signaling is central to the pathophysiology of inflammation by directing immune cells through a process called chemotaxis. These actions are mediated through RANTES, which is produced by platelets, macrophages, eosinophils, fibroblasts, endothelial, epithelial and endometrial cells. (11).

The effects of RANTES have been implicated in respiratory tract infections, especially viruses possessing RNA genome (including coronavirus, influenza, RSV and adenovirus), asthma, neuroinflammation, and atherosclerosis (12, 13). Maraviroc has also been documented to restore the homeostasis of regulatory T-cells (Treg), increase CD4 and CD8 positive counts, and inhibit HIV-associated chronic inflammation and activation (14, 15).

Interestingly, CD4 and CD8 positive T-cells expressing PD-1 and T-regs have been observed to be significantly lower in PASC patients compared to healthy controls (8), thus suggesting maraviroc could restore the immune dysregulation seen in PASC. The commonly known mechanism of action of statins is inhibition of hydroxymethylglutaryl-CoA (HMG-CoA) reductase enzyme in lowering cholesterol.

However, statins have also been implicated in reducing inflammation, suppressing fractalkine, and lowering VEGF and IL-6 (16), and as such, may play a role in the pathophysiology of PASC. We targeted fractalkine using pravastatin since CD16+ monocytes express high levels of the fractalkine receptor believing this may address the elevations in vascular markers seen in PASC.

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