Providing Access To Monoclonal Antibody Treatment Of Coronavirus (COVID-19) Patients In Rural And Underserved Areas

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In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
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Excerpt

This article is made available for historical review, monoclonal antibody use is not currently indicated for this condition.

Coronavirus disease 2019 (COVID-19) pandemic has impacted the world tremendously since the first cases were identified in 2019. COVID-19 was rapidly disseminated globally, with infections identified in most world societies within the first few months of 2020. COVID-19, the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had devastating effects on public health and the world economy. In the United States, the earliest and most well-documented areas impacted were large cities and urban communities. Initial efforts to curb the transmission of COVID-19 were largely successful in helping stem continued widespread transmission. As vaccinations for COVID-19 began rollout, authorities eased some of the initial transmission mitigation strategies, and coupled with the increased prominence of COVID-19 variant strains, transmission and infection rates saw an increase throughout the spring and summer of 2021.

Despite their lower population density, rural and underserved areas continue to be especially vulnerable to poor outcomes from SARS-CoV-2. The disparity in healthcare outcomes in these areas is multifactorial. In general, rural and underserved healthcare infrastructure is less developed than its urban counterparts. These residents often have significantly increased distances to travel to access advanced health care facilities. The travel gap often leads to residents not seeking care until the disease has reached advanced stages. Concerning rural and underserved patients, this distance affects all diseases, with cancer often being found after metastasis, diabetes after end-organ dysfunction, hypertension after a stroke or heart attack, and COVID-19 after pneumonia and subsequent hypoxia develop. Additionally, in rural and underserved areas, patient demographics (i.e., tobacco use, hypertension, diabetes, obesity, and older age) often fall in categories associated with a higher risk of mortality and morbidity from SARS-CoV-2 infection.

From a resource standpoint, rural areas have limited availability of intensive care unit (ICU) beds, ventilators, and access to novel medications through clinical trials. Furthermore, rural communities have always been especially vulnerable to supply chain disruptions, and the COVID-19 pandemic exposed some fragilities in our national supply chain. A nationwide shortage of personal protective equipment (PPE), testing devices (e.g., nasopharyngeal swabs, reagents, and test kits), and respiratory ventilators plagued initial efforts to combat COVID-19. The acute shortage of testing devices made it neither practical nor beneficial to promote universal screening for COVID-19 in rural areas. Perhaps even more disparate, as a country, the USA is experiencing a shortage of trained nurses, allied health providers, and physicians, and rural communities are often the most challenged in providing adequate numbers of health care professionals and, in particular, sub-specialist physicians to care for their residents.

SARS-CoV-2 primarily affects the respiratory system, with most transmission occurring from close contact with pre-symptomatic, asymptomatic, or symptomatic carriers. Since the declaration of COVID-19 as a global pandemic by the World Health Organization (WHO), considerable progress has been made in managing COVID-19 with the development of novel therapeutics and efficacious vaccines that have led to favorable patient outcomes and has helped limit the spread of the virus. A variety of therapeutic options are currently available in the management of COVID-19, including antiviral medications, monoclonal antibodies, and immunomodulatory agents. However, the therapeutic potential and clinical use of these drugs are limited and are specific to the stage of the illness. Further, rural areas have limited resources to provide access to monoclonal antibody therapy. Some strategies to provide options for rural healthcare systems will be discussed here.

The pathogenesis of COVID-19 illness occurs in two distinct phases, an early stage characterized by profound SARS-CoV-2 viral replication followed by a late phase characterized by a hyperinflammatory state induced by the release of cytokines such as tumor necrosis factor-α (TNF α), granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin-1 (IL-1), IL-6, interferon (IFN)-γ, and activation of the coagulation system resulting in a prothrombotic state. Antiviral therapy and antibody-based treatments are likely to be more effective if used during the early phase of the illness. Immunomodulating therapies, either alone or in combination with antiviral and antibody-based therapies, may be more effective when used in the later stage to combat the cytokine-mediated hyperinflammatory state that causes severe illness.

Individuals of all ages are at risk for infection and severe disease. However, as noted previously, high-risk individuals are those aged ≥60 years and with underlying medical comorbidities (obesity, cardiovascular disease, chronic kidney disease, diabetes, chronic lung disease, smoking, cancer, solid organ or hematopoietic stem cell transplant recipients) are at increased risk of developing severe COVID-19 infection. The percentage of COVID-19 patients requiring hospitalization was six times higher in those with preexisting medical conditions than those without medical conditions (45.4% vs. 7.6%) based on an analysis by Stokes et al. of confirmed cases reported to the CDC during January 22 to May 30, 2020.

An encouraging approach to address the COVID-19 associated mortality and preventing the increased utilization of healthcare resources is by terminating the progression of viral replication preventing the progression to the hyperinflammatory stage of COVID-19, which causes severe illness in high-risk non-hospitalized patients. Initially, the focus of treatment was directed mainly towards hospitalized patients with COVID-19 illness. However, the clinical focus over the course of the pandemic expanded towards combatting the illness early on by reducing the viral load in patients with early disease, thus attempting to halt the disease progression. Monoclonal antibodies targeting the spike protein of the SARS-CoV-2 have yielded positive in vitro results. They are considered a promising approach in managing non-hospitalized patients with mild to moderate COVID-19 who are at high risk of developing severe illness.

Monoclonal antibodies (mAbs) are immune system proteins developed from a single cell lineage that demonstrate a high affinity for their target cell. Monoclonal antibodies were first developed by Köhler and Milstein in 1975 using hybridoma technology. Since then, research has made significant progress in the molecular engineering world that has enabled the establishment of monoclonal antibodies as targeted therapies in various neoplastic conditions, autoimmune, post-transplant immunosuppression, and infectious diseases. When used as antiviral therapies, neutralizing antibodies play an indispensable part in achieving passive antiviral immunity and are also instrumental in preventing or regulating many viral illnesses.

Over the years, passive immunization against many viral diseases was achieved by administering polyclonal sera obtained from convalescent human donors or animals. However, polyclonal antibody preparations are increasingly being replaced by monoclonal antibodies by virtue of their favorable safety profile and target specificity when used in different viral diseases. Palivizumab was the first antiviral monoclonal antibody approved by the US Food and Drug Administration (FDA) for prophylaxis of respiratory syncytial virus (RSV) in high-risk infants.

Over the years, significant developments in antibody engineering, improved understanding of the biology of viruses, and the direct and indirect effect of monoclonal antibodies on viral infections have resulted in the development of many novel monoclonal antibodies. Like other antiviral drugs, monoclonal antibodies, when used as antiviral agents, are also susceptible to developing resistance as a result of alterations in the viral genome which can alter the pathogenic potential of the virus resulting in the emergence of viral escape mutants, which may render the virus-resistant to a specific monoclonal antibody.

To counter this viral escape phenomenon, some monoclonal antibodies were used in combination to complement each other and prevent neutralization escape by targeting multiple viral epitopes. However, as new variants emerged, resistance to multiple previously authorized monoclonal antibodies was noted. Several mAbs had their authorizations revoked in January 2022 by the FDA, with sotrovimab remaining as the only authorized monoclonal antibody that retains its efficacy as the dominant circulating variant of concern, Omicron.

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