DOI: 10.31038/CST.2020531

Abstract

Cancer patients are more vulnerable to acquiring COVID 19 infection and may also experience higher morbidity and mortality. In the context of COVID-19, cancer patients may be affected through delayed diagnosis and have significant impact on management in resource strained settings. Cancer treatment typically involves a possible combination of surgical resection, chemotherapy and radiation therapy (RT). RT delivery requires often daily attendance to a cancer center, is complex and poses potentially additional risks for infection as well as treatment related complications. Optimization of infection control measures and RT treatment schedules is paramount to minimize the impact of the pandemic on patients and optimize outcomes. This review aims to summarize the existing limited literature surrounding RT administration and optimization in the context of COVID-19.

Introduction

Since the recognition of the COVID-19 pandemic, evidence has become available that a cancer diagnosis is considered one of the comorbid conditions that increase the risk of COVID 19 infection [1- 3]. Meanwhile COVID-19 infection in cancer patients is associated with higher morbidity and mortality [4]. Data is still preliminary, but it is likely that both the increased risk of acquiring COVID-19 and more severe consequences thereof in cancer patients are multifactorial in nature likely involving complex relationships between the type of cancer site and extent or location of the disease as well as more nuanced patient and treatment related factors. While a number of publications have delved into the presentation and management of COVID-19, and its relationship to comorbid conditions including malignancy, and yet others into the implications of systemic management (chemotherapy, targeted agents), fewer publications specifically discuss the implications for patients who undergo radiation therapy (RT) and the operational considerations of radiation therapy (RT) departments. RT is administered mostly on a daily basis in cancer centers or facilities with complex logistics, unique organizational demands, high possibility of interaction between vulnerable patients and risk of exposure to multiple patients and staff. The lack of evidence surrounding best practices has left radiation oncology providers and patients with many questions still unanswered.

These questions include the level of vulnerability of cancer patients, who for example may undergo radiation but may not be undergoing systemic management and may therefore not necessarily be immune- compromised, as well as the implication for daily attendance to a RT facility and the associated infection risk and how to best mitigate it. Other questions involve the ability to and safety of delaying or altering RT treatment schedules to minimize risk of infection. Important additional considerations abound in particular settings such a RT emergencies and treatment of the COVID-19 positive patient as well as the administration of radioactive isotopes such as radioactive iodine in thyroid patients who then need to self-isolate at home or as inpatients for several days. Since the COVID-19 pandemic has raised unprecedented challenges and questions, with ongoing lack of robust data, periodic review of the available evidence is important to help guide providers and patients in order to enable evidence-based care hence prompting this scoping review.

Materials and Methods

To carry out the scoping review, publications that specifically addressed the impact and management of cancer patients undergoing radiation therapy in the context of the COVID 19 pandemic were identified in PubMed using the following mesh terms: ((“risk”[MeSH Terms] OR “risk”[All Fields]) OR “risk of”[All Fields]) AND (((((((“covid 19”[All Fields] OR “covid 2019”[All Fields]) OR “severe acute respiratory syndrome coronavirus 2”[Supplementary Concept]) OR “severe acute respiratory syndrome coronavirus 2”[All Fields]) OR “2019 ncov”[All Fields]) OR “sars cov 2”[All Fields]) OR “2019ncov”[All Fields]) OR ((“wuhan”[All Fields] AND (“coronavirus”[MeSH Terms] OR “coronavirus”[All Fields])) AND (2019/12/1:2019/12/31[Date – Publication] OR 2020/1/1:2020/12/31[Date – Publication]))) AND ((((“patient s”[All Fields] OR “patients”[MeSH Terms]) OR “patients”[All Fields]) OR “patient”[All Fields]) OR “patients s”[All Fields]) AND (((((((((“cancer s”[All Fields] OR “cancerated”[All Fields]) OR “canceration”[All Fields]) OR “cancerization”[All Fields]) OR “cancerized”[All Fields]) OR “cancerous”[All Fields]) OR “neoplasms”[MeSH Terms]) OR “neoplasms”[All Fields]) OR “cancer”[All Fields]) OR “cancers”[All Fields]) AND ((((((((((((“radiate”[All Fields] OR “radiated”[All Fields]) OR “radiates”[All Fields]) OR “radiating”[All Fields]) OR “radiation”[MeSH Terms]) OR “radiation”[All Fields]) OR “electromagnetic radiation”[MeSH Terms]) OR (“electromagnetic”[All Fields] AND “radiation”[All Fields])) OR “electromagnetic radiation”[All Fields]) OR “radiations”[All Fields]) OR “radiation s”[All Fields]) OR “radiator”[All Fields]) OR “radiators”[All Fields]). 87 abstracts were identified.

Results

As of July 10, 2020: 1706 papers were published on the topic of COVID 19 and oncology in 2020 to date of which 457 (27%) of these discussed cancer as a risk factor for the development of the COVID 19 infection. The MeSH term was generated to capture papers specific to the context of the cancer patient undergoing radiation therapy during the COVID 19 pandemic. 87 papers were identified using the above MeSH term. Of these 5 (6%) were literature reviews or broad guideline recommendation papers, 12 (14%) dealt related to oncology but were not RT specific (eg. systemic management of hematological malignancies), 63 (72%) were oncology and RT specific and 7 (8%) were not directly relevant to either oncology or radiation but were relevant to COVID 19 more broadly. All of the abstracts were published between March and July, with 75% of the abstracts between the end of April and beginning of July 2020.

Types of Publications Identified

Four types of publications were broadly identified: 1) Literature reviews and operational/planning guidelines which did not contain patient data but rather represent institutional or expert opinion (Table 1); 2) consensus guidelines generated by governing bodies and site- specific groups for specific cancer histologies (Table 2); 3) retrospective single or multiple institution papers (Table 3) and 4) more context focused papers eg. management of the elderly with cancer during COVID-19 and palliative management (Table 4).

Literature reviews involving COVID-19 and oncology identified with ** were made available by Al-Shamsi et al., Shankar et al. and Anderson et al. (Table 1 ** denotes encompassing reviews), * smaller important reviews) [1-3]. These broader reviews (**) were not necessarily RT specific but contained some information regarding RT. Discussion of RT departmental planning, logistics and operational considerations were available in other reviews (Table 1). Site specific consensus guideline papers with recommendations (organ or histology specific) were also identified specifically for head and neck, lung, genitourinary and hematological malignancies and to a lesser extent in other sites (Table 2). Some papers dealt more generally with single center experiences which also provided some guidelines while others reported on testing for COVID 19 in cancer patients undergoing or about to undergo radiation therapy (Table 1). Finally, there were also papers that were more specifically targeting the elderly patient with cancer, palliative management and other smaller topics (Table 4).

Logistical and Operational Focused Publications

Logistics and Operational Considerations – Limit the Risk of Infection

From a practical day to day perspective the ability to effectively manage new logistical and operational challenges in order to mitigate risk of infection to patients and staff with need of frequent adaptation, poses one of the greatest challenges to RT in the context of COVID-19 [5-7]. In the absence of both data and homogenous higher-level guidelines, cancer therapy centers and individual radiation therapy departments have created their own guidelines and this is reflected in the publications uncovered in this review. Important insights originate in virus epicenters like Italy [8], New York in the US [9,10]. According to a survey by Opperman et al., who conducted an online survey among medical physicists in Germany, Austria and Switzerland from March 23rd to 26th 2020, 72.4% of the respondents stated that their processes were affected due to COVID-19, with longer processing times (54.2%), patient no-shows (42.5%) and staff reduction (36.7%). 75.8% expected further unavailability of their personnel in the upcoming weeks [11].

COVID-19 Testing in Cancer Patients Undergoing RT – Address Testing Practices

Another challenge is that of the selection, timing and actions taken with respect to patient and staff testing for COVID-19. As noted with respect to other aspects of the management of the pandemic, guidelines are lacking and complex standard of care practices had to be rapidly adapted to include patient (and staff) testing when appropriate [12]. This is particularly complex when patients may need to undergo brachytherapy or radioactive iodine and carry significant risk on infecting other staff if they themselves are infected and/or pose significant logistical challenges eg. Isolation as in or outpatient in the case of radioactive iodine administration. We now understand that testing negative for COVID carries a not in-insignificant possibility that the patient may have a false negative test and that the timing of the test is also impacting on its usefulness and accuracy. Testing itself is not readily available in many jurisdictions and may take some time to obtain results. Patients have to be pre-screened and directed to undergo testing, which may be difficult or impossible. However, data does support the notion that a positive result may render cancer patients more vulnerable to COVID-19 [4,13]. Bajaj et al. report on the salivary detection of SARS-CoV-2 (COVID-19) and implications for oral health-care providers summarizing guidelines for oral care specialists [14]. This literature review notes that salivary specimens have a higher than 90% concordance rate with nasopharyngeal specimens which while enabling PCR testing of salivary samples also reveals that saliva poses additional risk to health care providers. Since there is currently no data available to assess the risk of transmission of COVID-19 in dental practices, and since cancer patients in particular with head and neck primaries require dental interventions, this is an area where further data is required to optimize management and outcomes. Madriaga et al. reviewed the literature for COVID-19 testing in cancer patients and describe the approach to COVID-19 testing adopted in a large cancer center in Toronto [15].

Indications for/Modification of RT – Modify RT When Possible to Mitigate Risk

Parashar et al. from a tertiary cancer center in New York provides a general set of robust guidelines for curative RT in the context of the pandemic echoing other site-specific papers and setting some “ground rules” for this approach while summarizing alternative dose and fractionation options for each tumor site that may be employed in the context of COVID-19 to minimize risk to patients and staff [16]. They discuss the scenarios of RT as an alternative to surgery when immediate surgery is not possible, RT as a ‘bridge’ to surgery and radiation options as an alternative to chemotherapy given the risk of hospitalization with high-dose chemotherapy. It should be noted that while enrollment of patients on clinical trials is considered in this paper and would be preferable when fractionation schemes with lesser evidence are employed or patients are documented COVID-19 positive, in practical terms this is often curtailed as clinical trials are on hold in many centers due to the pandemic. Vordermark also provides a review of organ-specific cancer management [17]. In this publication the author searched for multidisciplinary and expert recommendations to guide potential shift in RT indications and found limited data as of April 2020 when it was published however provides a good summary of the available data at that point. Chen et al. and Franco et al. provide broader frameworks for prioritization of patients [6,18]. Franco et al. also provides guidelines for the management of patients with COVID-19 [18].

Brachytherapy

Williams et al. provide a thorough review of the impact of delaying or prolonging brachytherapy treatment courses in multiple disease sites including gynecological sites, prostate and breast [19]. While the timing and duration of brachytherapy is highly sensitive in sites like cervix and vaginal cancer, breast and in particular prostate may allow for some postponement of brachytherapy. Additional alternative fractionation schemes are also discussed for each cancer site. Aghili et al. review brachytherapy guidelines in the context of COVID-19 highlighting the need to consider the best regimens as opposed to discontinuation or postponement of brachytherapy [20].

Oncology Site Specific Publications and Consensus Guidelines

Head and Neck Cancers

Head and neck cancer patients are vulnerable to COVID-19 because in addition to the cancer diagnosis they may also share other risk factors (smoking, nutritional depletion, swallowing and/ or breathing dysfunction) [21,22]. In addition, many head and neck primaries are rapidly progressive causing significant clinical deterioration and often requiring hospital admission for nutritional support and refeeding syndrome. Delay in diagnosis is particularly detrimental [23] and in the case of nasopharyngeal cancer additional chemotherapy could be employed to counteract the delay in diagnosis [23]. Head and neck cancers also require significant PPE due to the diagnoses requiring examination under anesthesia or direct laryngoscopy with biopsy [24]. Thomson et al. provide the ASTRO-ESTRO consensus to risk adapted head and neck cancer RT [25]. Two pandemic scenarios: early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated and a panel of experts developed treatment recommendations for 5 HNC cases. They evaluated potential symptomatic benefit with the risk of active COVID-19 infection balancing potential for cure and risk of progression as well as patient fitness to recommended rational patient triage. With respect to interventions in the upper aerodigestive tract region (eg. rhinoscopy or flexible laryngoscopy in the outpatient setting and tracheostomy or rigid endoscopy under anesthesia), it is recommended that all health care personnel wear personal protective equipment such as N95, gown, cap, eye protection, and gloves [26]. Additional guidelines are provided by Werner et al. and Mehanna et al. [24,27].

Breast Cancer

Breast cancer patients make up a large proportion of the patients on treatment and follow-up in most cancer treatment centers and therefore a robust approach to risk stratification is crucial to ensure adequate access to care and diminish the risk of adverse outcomes while minimizing risk of COVID-19 infection. Curigliano et al. creates a framework on how to approach these using scenarios often encountered in clinical practice [28]. The use of primary systemic therapy is also discussed as an alternative to upfront surgery in the context of COVID-19. RT is prioritized according to the risk categorization of the cancer and whether the patient is already on treatment. Palliative treatments and acute spinal cord compression are considered urgent, followed by high risk patients while postoperative RT for low risk patients and post treatment visits are of lower priority. Additional recommendations include the omission of boost RT and accelerated partial breast RT for low risk patients. It is recognized that patients receiving chemotherapy regimens with intermediate/ high risk of immunosuppression, such as anthracyclines, 3-weekly docetaxel or 3 weekly platinum are at intermediate or high risk of immunosuppression. Vuagnat et al. set up a prospective registry for 15600 patients actively treated for early or metastatic breast cancer in the last 4 months [29]. They found that the COVID-19 mortality rate depended more on the comorbidities prior to RT that the treatment itself. Other recommendations are also provided by Chan et al. and Braunstein et al. but patient outcome data is still lacking [30,31].

Lung Cancer

Lung cancer patients pose a uniquely challenging scenario in the context of COVID-19 in part because they are already vulnerable to lung infections and in the context of RT because they are at risk for radiation pneumonitis which can be challenging to distinguish clinically and radiographically [32] but is also treated with high dose steroids which may worsen COVID-19 related lung injury. Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic are provided in an ESTRO-ASTRO consensus statement by Guckenberger et al. Singh et al. and Dingemans et al. also make recommendations on standardizing the care of lung cancer patients during COVID-19 while recommending that general standard principles of practice be followed [33-35]. Wu et al. provide guidelines for thoracic radiation therapy specifically while Kumar et al. discusses alternative management options [36,37].

Genito-Urinary

Delaying treatment in genito-urinary cancers is potentially of significant detriment [38]. In penile cancer, surgery should proceed when possible due to the aggressive nature of the disease, with RT as an organ preserving approach [39]. Zaorsky et al. provide RT recommendations for prostate cancer [40]. However, since prostate cancer is a more indolent malignancy in early stages, treatment can be avoided or delayed for very low, low, and favorable intermediate- risk disease For unfavorable intermediate-risk, high-risk, clinical node positive, recurrence post-surgery, oligometastatic, and low- volume M1 disease neoadjuvant hormone therapy for 4-6 months was recommended [40]. Ultrahypofractionation may be preferred for localized, oligometastatic, and low volume M1, and moderate hypofractionation may be preferred for post-prostatectomy and clinical node positive disease. Postoperatively, salvage RT is preferred to adjuvant radiation [40]. Short fractionation RT for early prostate cancer is at the forefront of the field and is discussed in the context of COVID-19 by Barra et al. [41].

Central Nervous System Cancers

In the context of central nervous system cancers, the unique aspects include the often older age of the patients and co-existing neurological symptoms requiring ongoing steroid use to decrease increased intracranial pressure. In addition to these, the prognosis is often guarded, and advanced care planning will be more important than ever to address upon diagnosis and initiation of management. Guidelines are provided by Mohile et al. [42]. These include mitigating risk through social distancing and discussions of goals of care (considering that ventilator use may unfortunately be denied to some of these patients considering that high grade glioma such as glioblastoma will be considered a terminal diagnosis particularly in the elderly). Nonetheless maximal safe resection is recommended both to decrease intracranial pressure but also to improve longevity and diminish steroid use. In lower grade glioma prognosis may be far superior and thus some interventions may be deferred. Tabrizi et al. extracted patient level data from 1321 elderly glioblastoma patients to provide a quantitative framework for modelling COVID-19 risk using published randomised trials in the elderly with glioblastoma [43]. They support hypofractionated RT and increased utilization of temozolomide alone in patients with MGMT methylation when the risk of COVID-19 infection is high. With respect to WHO grade III and IV gliomas Bernhardt et al. combined the opinion of 6 international experts in a consensus-based practice recommendation including neuro-oncologists, neurosurgeons, radiation -oncologists and a medical physicist [44]. Overall agreement was had that treatment cannot be significantly delayed and initiating therapy should not be outweighed by COVID-19.

Hematological  Cancers

Patients with hematological cancers are vulnerable to COVID-19 as they may suffer for cytopenias and may be immunosuppressed. Yahalom et al. offer guidelines to potentially omit RT in order to decrease the risk of exposure as a result of daily attendance to the cancer center [45]. They recommend possible omission of RT in: palliative settings where alternatives can be offered, for completely excised localized low-grade lymphomas and localized nodular lymphocyte- predominant Hodgkin lymphoma and for consolidation RT for diffuse large B-cell lymphoma/aggressive non-Hodgkin lymphoma (NHL) in patients who have completed a full chemotherapy course and achieved a complete remission [45]. Some lymphomas can safely delay RT (eg. asymptomatic localized low-grade lymphomas, localized nodular lymphocyte-predominant Hodgkin lymphoma, patients who develop COVID-19 infection prior to commencing RT), while others can benefit from shortened RT courses (eg. 20 Gy in 10 fractions or 30.6 Gy in 17 fractions). A consensus statement is available from Di Ciaccio et al. and Kirova et al. [46,47].

Other Cancer Subtypes

Guidelines have been published for pancreatic cancer [48], representing the UK consensus position. Endoscopy is recommended to continue for malignant biliary obstruction, however as it is an aerosol-generating procedure it is recommended that all elective and non-essential endoscopic procedures not be performed. Chemotherapy is suggested when surgery is not possible in the context of COVID-19 as are hypofractionated RT approaches (eg. 5-15 fraction regimens). Skin cancer management and triage was discussed by Baumann et al. and Tagliaferri et al. [49,50]. For patients with Merkel cell carcinoma, the authors recommend prioritizing treatment, unless favorable T1 disease. For patients with melanoma, the authors recommend delaying the treatment of patients with T0 to T1 disease for 3 months if there is no macroscopic residual disease at the time of biopsy. Treatment of tumors ≥T2 can be delayed for 3 months if the biopsy margins are negative. For squamous cell carcinoma, early disease can have treatment delayed for 2 to 3 months unless there is rapid growth, symptomatic lesions, or the patient is immunocompromised. The treatment of tumors ≥T2b should be prioritized, but a 1-month to 2-month delay is considered acceptable. For squamous cell carcinoma in situ and basal cell carcinoma, treatment can be deferred for 3 months unless symptomatic [49]. With respect to gynecological cancers Martinelli et al. carried out a survey showing that responders prioritized treatment of early stage high-risk uterine cancers (45%), newly diagnosed epithelial ovarian cancer (41%), and locally advanced cervical cancer (41%) [51]. 77% of respondents reported no changes in surgical treatment for early stage cervical cancer in COVID-19- negative patients, but treatment was postponed by 54% if the patient tested COVID-19-positive. Responders also considered neoadjuvant chemotherapy for advanced ovarian cancers and hypofractionation of RT for locally advanced cervical cancers. A similar survey was carried out by Nakayama et al. Rossi et al. report on their early experience in the management of sarcoma with priority given to bone and soft tissue sarcomas, metastases and aggressive benign tumors at risk of impending or pathologic fracture. For these and other sites further publications are as yet lacking [52,53].

Single Center Experiences

Single center experiences provide an “on the ground” perspective of the transformative experience COVID-19 has had on radiation oncology practice and health care resources and can provide an avenue for practical guidelines. Several papers exemplify this in particular in areas that were/are epicenters for the disease. Tey et al. provides a workflow for the COVID-19 positive patient on RT [54]. Chen et al. reports from a multicenter New York area institution with experience- based guidelines for disease sites that require concurrent chemo- irradiation and thus were more likely to result in patient presentation to the emergency room or in hospital admission [6]. The priority framework in this publication implemented as of April 13, 2020 is extremely practical in that it addresses efficiency from a systemic standpoint to optimize care for all patients within a RT department. Three priority levels are described; the first for cases where delay may result in loss of life, progression of disease or permanent loss of neurologic or other function (oncologic emergencies, advanced head and neck, gastrointestinal, gynecologic and lung cancers); priority 2 for cases that may be delayed for up to 4 weeks (early stage head and neck, lung and lymphoma, benign central nervous system cases) and priority 3 for cases that may be delayed for 30 days or more (early prostate, breast or prostate already on androgen deprivation therapy). This publication also presents patient data and addresses approaches to toxicity management in the context of COVID-19. Press et al. also described a single institution experience from a proton center in Manhattan quantifying the impact of treatment delays and interruptions [9]. Chhabra et al. also provide recommendations for prioritization of proton patient in the New York Proton Center [55]. Additional radiation oncology center experiences are published by Tan et al. (Singapore), Montesi et al. (Italy), Wu et al. (Wuhan), Handoko et al. (Indonesia), Mishra et al. (New York) [8,56-59].

Specific Considerations

The Elderly: Desideri et al. provides a very good summary of the data surrounding COVID-19 and the elderly [60]. Freedman et al. report specifically on managing older adults with breast cancer noting appropriately that considerations for management are highly relevant “within the new normal” considering that 30% of breast cancer patients are 70 years old or older [61]. They provide options for the most commonly encountered scenarios within the framework of existing evidence. Interestingly they also recommend deferral of routine follow-up and routine breast imaging and anticipate that this postponement will prompt discussion of the limited utility of these measures beyond the pandemic, as will no doubt be the case for other low value interventions. Asokan et al. provide a review of the impact of COVID-19 on the cardio-oncology population [62]. This is a population that also includes elderly patients with pre- existing cardiac comorbidities and possibly additional cardiotoxic insults such as chemotherapy and/or radiation or systemic treatment such as androgen deprivation therapy. Data surrounding the risk of COVID-19 infection and outcomes in this population is currently lacking.

Palliative RT: Yerramilli et al. provide a review of palliative RT for oncologic emergencies with emphasis on balancing risk and benefit [63]. Palliative treatments make up a large proportion of the workload of the RT department and the patients who require palliative RT often require it within days if not hours. This patient population is particularly vulnerable to the impact of the pandemic in a resource strained environment. Yerramilli et al. provides a framework for the triaging a patient with an oncologic emergency which is not dissimilar from frameworks already employed in resources strained environments [63]. Patients who are symptomatic and/or have an oncologic emergency and a more prolonged life expectancy are recommended to receive short course palliative RT, delay of RT or best supportive in the case of limited life expectancy is otherwise recommended. Thureau et al. in their GEMO (the European Study Group of Bone Metastases) position paper, astutely note that the indications and treatment modalities for palliative bone metastases must be re-discussed in the context of COVID-19 [64-67]. Palliative treatments often require the most clinical judgement and can benefit the most from available evidence surrounding reduction in the number of treatments and the complexity thereof in a resource strained setting. Their recommendations to carry out simulation planning and treatment at the same time as the consult, carry out tele- consults when appropriate, and use existing criteria to assess bone instability to allow for optimization of decision making enabling the least invasive technique. They also provide guidelines for retreatment of bone metastasis, spinal cord compression and SBRT (Stereotactic Body Radiation Therapy) for which they consider the level of evidence too low to be considered in the current situation.

Conclusions

Although multiple attempts at guideline and consensus generation have been made with respect to RT administration in the context of the COVID-19 pandemic in several tumor sites, evidence for the effectiveness or adequacy of these is lacking and some cancer sites have as yet very little or no guidelines. This is equally so the case with respect to the utilization of altered fractionation schemes being potentially proposed to diminish patient visits to cancer centers which should likely be approached with some caution and emphasis on following standard of care practice whenever possible. Several frameworks have been published for the optimization of logistics and operational planning that may be employed in radiation therapy centers and departments. Over time it is likely that more data will become available with respect to patient management and outcome, however as of July 2020, very few small retrospective data sets are available with respect to the outcomes of COVID-19 positive cancer patients undergoing RT. It is as yet unclear to what extent adverse outcomes in cancer patients may be related to preexisting comorbidities, the cancer diagnosis and its implications or the treatment of the cancer itself. Additional areas where evidence is lacking include:

1) The impact on of COVID-19 on older patients with cancer

2) The impact of treatment delay in patients currently considered intermediate or low risk for tumor progression

3) The impact of altered fractionation schedules

4) The long and short-term psychological impact of COVID-19 and altered cancer management on patients and staff.

Declarations

Ethics approval and consent to participate: This study is a literature review and does not report on data collected from humans and is exempt from ethics approval.

Consent for publication: Not applicable.

Availability of data and material: The data supporting the conclusions of this article are included within the article as references.

Competing Interests: The author declares that they have no competing interests.

Authors’ contributions: AVK conceived the idea for the review, reviewed the literature, created the accompanying material, and wrote the manuscript.

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DOI: 10.31038/CST.2020525

Abstract

The success of an antiviral drug depends on its potency to neutralize the virus in vitro and its ability after administration in vivo to reach the anatomic compartments that fuel viral dissemination in the body. For instance, remdesivir, a potent SARS-CoV-2 antiviral drug based on studies in vitro, if administered orally would be poorly effective because low drug levels would reach the lungs due to its high first pass destruction in the liver. This is the reason remdesivir can only be administered intravenously, a requirement that clearly limits its use as a prophylactic agent for COVID-19, although novel formulations for its easier administration are under development. Whether an antiviral prophylaxis could further control or even stop the COVID-19 epidemic in synergy with other non-pharmacological based mitigation strategies is today unknown. Since the mid-1960s, pharmacologists have investigated the use of lipid-based nanoparticles for efficient delivery of antivirals to tissues, for example by transforming the route of administration from intravenous to oral, subcutaneous or aerosol administrations. These novel encapsulation strategies have also the potential to maintain high levels of the antiviral drugs in tissues, with reduced dose frequency compared to the non-encapsulated drug. Several lipid-based nanoparticles are today approved by the US Food and Drug Administration or being tested in clinical studies with favorable toxicity profiles.

Nonhuman primate models of coronavirus infection offer unique platforms to accelerate the search for SARS-CoV-2 antiviral prophylaxis.Paradigms, to corroborate this claim, are borrowed from nonhuman primate research studies, some of which had a profound impact on global public health in the specific setting of the AIDS pandemic. Sharing information from nonhuman primate research programs, invoking principles of scientific transparency and bioethics similar to those universally agreed for human studies, would also likely significantly help our collective fight (as the human species) against this public health emergency.

What Makes an Antiviral Potent Against SARS-CoV-2?

Remdesivir, a nucleoside analogue specific for the RNA-dependent RNA polymerase of several coronaviruses, is a potent SARS-CoV-2 antiviral drug based on studies in vitro. Its half maximal effective concentration (EC50) leans consistently towards the lowest estimates when screened, using the same assay, with other antivirals tested against several coronaviruses [1-4] hence, a relatively lower concentration of the drug is needed to cut similar levels of viral replication in vitro, compared to other antiviral drugs less successfully repurposed, so far, as medical countermeasures against COVID-19. These include the HIV-1 protease inhibitor lopinavir/ritonavir (Kaletra) and the immunosuppressive and anti-parasitic drug hydroxychloroquine [5,6].

The success of an antiviral drug in fighting a virus depends, however, not only on how potent the drug is in inhibiting the virus in vitro but also on how well the drug penetrates the anatomic compartments in which the virus mostly replicates in vivo; the lungs for COVID-19. If administered orally, for instance, remdesivir would be ineffective because low drug levels would reach the lungs due to its high first pass destruction in the liver, resulting in poor oral bioavailability. This is the reason remdesivir can only be administered intravenously to exert its viral inhibitory function, a requirement that clearly limits its use as a prophylactic agent or as a test-and-treat pharmacologic-based mitigation strategy for COVID-19.

Delivering Potent Antivirals Straight to the Lungs, without Calling a Nurse

What can be done to transform the route of administration of an antiviral or to enhance its concentration into the lungs? Since the mid-1960s, pharmacologists have investigated the use of lipid-based nanoparticles for efficient delivery of antivirals and other drugs, for example by transforming the route of administration from intravenous to oral, subcutaneous or aerosol administrations [7,8], with potentially useful ramifications in the pharmacoeconomics of developing countries [9]. These novel encapsulation strategies are capable of maintaining high levels of the antiviral drugs in tissues, with reduced dose frequency. For instance, Kaletra in its oral formulation requires daily administration due to its rapid clearance, but data produced from nonhuman primates have demonstrated that the equivalent mass of one pill of Kaletra formulated as a lipid-nanoparticle for subcutaneous administration achieves approximately 10-fold higher concentrations in lymph nodes for about one week [10]. Similarly, the lipid-nanoparticle encapsulation of tenofovir, a nucleotide analogue used to treat HIV and hepatitis B infection that has some structural and functional similarities with remdesivir, has also been shown to enhance tissue concentrations and prolong retention of its active phosphorylated moieties in nonhuman primate studies [11]. The opportunity offered by nanoparticle technologies, not only to simplify the administration of a candidate antiviral drug, but also to enhance its concentrations in tissues, is relevant in the search for SARS-CoV-2 antiviral prophylaxes, especially given the limited data we have today for the penetration in the lungs or in the upper airways of most anti-SARS-CoV-2 repurposed antivirals [12], including lopinavir/ritonavir [13] and nelfinavir (another HIV-1 protease-inhibitor with a favorable EC50 against coronaviruses [14]). It is well known that lipophilic drugs preferentially penetrate the lungs and, in fact, this formed the rationale for encapsulating certain hydrophilic drugs in liposomes to promote delivery to the pulmonary compartment [15,16]. One example is amphotericin, an antifungal drug encapsulated in nanocochleates (soy-bean organic-based lipid particles) which can be formulated as an oral drink. Pharmacodynamic animal studies have advanced to phase-II clinical trials, in which patients are being administered the oral nanocochleate antifungal formulation, which appears to offer an overall effective oral formulation associated with low toxicity after prolonged (more than one year) continuous treatment [17]. Several lipid-based nanoparticles are today approved by the US Food and Drug Administration or being tested in clinical studies with favorable toxicity profiles [18]. Indeed these nanocarriers, by affecting the biodistribution in the body of the encapsulated antiviral compound, can substantially modify toxicological properties of the formulated drug. Of note, subcutaneous and aerosol formulations of remdesivir are now under development [19].

Consistent with the ranking by in vitro potency (the EC50), clinical trials in which these drugs have been administered to COVID-19 patients have thus far shown clear evidence of therapeutic potential only for remdesivir(intravenous formulation) [5,6]. Pharmacodynamic correlates of poor clinical responses could guide efforts in the search for an optimal prophylaxis. For instance, the antiviral drug Kaletra (available in pills) has been administered to COVID-19 patients with the same dose used to treat HIV-1 infected patients; however, its potency in vitro against SARS-CoV-2 is known to be significantly weaker than against HIV-1 [20].

Lessons Learned from the History of HIV-Prophylaxis Research

A successful antiviral prevention strategy is Truvada-PrEP for HIV, a combination of two nucleo(t)side analogues, that is lighter than the combination therapies (Highly Active Anti-Retroviral Therapy, HAART) used to treat HIV-1 infected patients, with important toxicological implications. Of note, dosing and administration strategies to conceive Truvada-PrEP (tenofovir+emtricitabine) were generated primarily from two monkey studies that produced, through invasive experimental designs not implementable in humans, precious data on the minimal drug levels needed in tissues to achieve protection from viral challenges [21,22]. These molecules attack the polymerase of HIV (or of lentiviruses that possess replication capacity in monkeys similar to HIV in humans, e.g. the simian-human immunodeficiency virus, SIV/SHIV) with a mechanism similar to the one adopted by remdesivir to attack the polymerase of several coronaviruses (including SARS-CoV-2), i.e. as chain terminators by mimicking the structure of a natural nucleoside [23].

Those studies demonstrated that the administration of two pills of Truvada (two hours prior to viral exposure) followed by two consecutive pills at 24 and 48 hours post-exposure provided sufficient drug levels in the rectal mucosa tissue to cut most viral transmissions. That prophylactic regimen (later called “On-Demand”) achieved in monkeys a protection similar to that achieved through daily drug administrations. This data prompted randomized clinical trials of “On-Demand-PrEP” prophylaxis, which confirmed an efficacy similar to the one estimated with the heavier “Daily-PrEP” regimen [24] and which later received endorsement in revised HIV treatment and prevention recommendations issued by the International Antiviral Society–USA [25]. Hence the former are two examples of nonhuman primate studies that have had a profound impact on public health worldwide.

Similarly, two decades earlier, the simian-human immunodeficiency virus (SIV/SHIV)-monkey model had been used to generate the HIV Post-Exposure Prophylaxis (PEP) guidelines we are using today for both occupational and non-occupational exposure to HIV, by demonstrating the effectiveness of a cocktail of HIV drugs (a combination of antiretrovirals similar to the one administered to HIV-1 infected patients, for four consecutive weeks), in preventing viral transmission if administered within 72 hours (but the sooner the better) from viral exposure [26,27]. The length of this window of opportunity for HIV PEP was identified, again, through nonhuman primate studies, in which lentiviruses replicate with dissemination capacity and antiviral drugs distribute in tissues with kinetics, much more similar to humans than any other animal model in our hands. In general, although animal models (including nonhuman primates) are known to be poor predictors (for obvious reasons) of the efficacy of specific HIV vaccines in humans [28], the monkey models proved to be valuable resources, during the past decades, in predicting the efficacy of antiviral HIV strategies not only as prophylaxis but also in the therapeutic arena.

The lessons learned from HIV and Truvada-PrEP studies include the following: 1) an antiviral may show a weak therapeutic effect, especially if administered late in the course of the viral induced disease, yet can effectively cut most viral transmissions if administered prophylactically. This observation holds true also for COVID-19. For instance, a recent study in a coronavirus rodent model showed that another nucleoside analogue with in vitro inhibitory activity similar to remdesivir can efficiently reduce viral replication in the lungs yet may fail to prevent disease progression if administered too late [29]; and 2) the higher the drug concentration in the anatomic compartments that fuel viral dissemination in the body, the higher the efficacy of the pharmacologic prevention strategy aimed at promptly eradicating the virus from the body [30]. The latter observation built the rationale for encapsulating HIV drugs in lipid-nanoparticles in research programs developed in the past decades [31], with the dual objective of simplifying (by reducing dosing frequency) and optimizing (by enhancing drug tissue levels) the delivery of antiretroviral drugs for both HIV-1 prevention and treatment, through proof-of-concept studies in nonhuman primate models of AIDS; an important experimental step for its effective translation into human studies.

The same experimental designs can be efficiently conceived to develop medical countermeasures to COVID-19 through the SARS-CoV-2 rhesus macaque model [32], which induces a respiratory disease milder than in COVID-19 patients, but that replicates at similar levels in the lungs [33,34]. In general, although non-invasive in vivo imaging technologies have also been used to study the biodistribution of antiviral drugs (including in the upper and lower respiratory tracts of humans [35,36]), our understanding of how an antiviral prophylaxis strategy succeeds or fails in protecting people from SARS-CoV-2 infection would inherently advance (as it did for HIV prophylaxis), by designing viral challenge experiments and producing measurements directly in tissues using these animal models. Sharing information from nonhuman primate research programs on what antiviral strategies are being tested on these animal models for COVID-19 throughout the world, invoking principles of scientific transparency and bioethics similar to those universally agreed for human studies (e.g. by registering studies in public databases) [37], would also likely significantly help our collective fight (as the human species) against this public health emergency [38].

These studies could also, in principle, be efficiently designed using other nonhuman-primate coronavirus animal models [39], especially if the antiviral target is the polymerase gene, given its high level of sequence conservation through evolution [29]. To date, remdesivir is the only antiviral drug tested in nonhuman primate models of SARS-CoV-2 with published observations [39,40]. Macaques infected with either the MERS-CoV [39] or the SARS-CoV-2 [40] rapidly cleared the virus following intravenous administration of remdesivir compared to untreated controls, consistent with the successful therapeutic effect of remdesivir observed in COVID-19 patients [6]. Data from both monkey studies also predict that remdesivir could prevent SARS-CoV-2 infection in humans, if used prophylactically. Prophylactic remdesivir (intravenous) treatment had been also successfully tested in nonhuman primates models of Ebola virus [41] and Nipah virus infection [42], two RNA viruses with an RNA-dependent RNA polymerase also highly sensitive to its inhibitory activity [43]. Indeed, both the cynomolgus [44] and the rhesus macaque models [45] of SARS-CoV-2 infection are being interrogated in these weeks to test the prophylactic efficacy of hydroxychloroquine.

These studies have been run in laboratories with the highest levels of biological safety (biosafety level-3 [39,40,44,45] and biosafety level-4 [41,42]) due to the high risk these pathogens pose to research personnel, which are very expensive to build and maintain, hence not readily available in most countries [46]. The modification of an antiviral, e.g. through lipid nanoparticle technology, as anticipated above, requires preliminary testing in vitro as well as in animal models. Specifically, there is need to demonstrate that the lipid structure does not impair the inhibitory activity of the encapsulated antiviral (e.g. does not increase its EC50 against the challenge virus). In healthy uninfected animals, biodistribution studies are subsequently needed to demonstrate that the encapsulated antiviral is capable of reaching the tissues in which the virus is expected to mostly replicate in vivo, and, in the case of a nucleoside analogue (like remdesivir), that its active phosphorylated moieties are produced at sufficient concentrations in those tissues. These preliminary pharmacokinetic studies will inform on the optimal dose of the encapsulated antiviral under scrutiny and on how frequently it will need to be administered in the pharmacodynamic studies. The latter studies can demonstrate the feasibility of the modified antiviral drug to exert its inhibitory activity in an infected host, hence an important step for the translation of the nanoparticle approach to human studies.

While alternative animal models could possibly serve the pharmacodynamic study objectives, the nonhuman primate model is likely the best model to accelerate this area of research. To my knowledge, coronaviruses less pathogenic to humans [47] but still sensitive to the inhibitory activity of remdesivir [48] (and possibly to other antiviral drugs [29]) have not been tested in nonhuman primates, although serologic studies suggest that these viruses may be able to replicate well in these hosts [49]. Indeed, a 229E coronavirus experimental infection study in normal volunteers failed to demonstrate efficacy of a nucleoside analogue for prophylaxis, as previously shown in rodent models, possibly due to the differential tissue pharmacokinetics of the specific drug under scrutiny in the two evolutionarily distant hosts [50].

In other words, “non-perfect” nonhuman primate models (i.e. those in which the SARS-CoV-2 or an older cousin does not cause disease yet replicates in tissues at levels similar to humans) can still generate useful data to screen prophylactic antiviral strategies, including, for instance, lipid nanoparticle formulations of “non-perfect” antiviral drugs (i.e. a putative antiviral drug failing to demonstrate a robust therapeutic effect in patients with advanced COVID-19 or if suboptimal drug levels in the lungs are confirmed from preclinical or post-mortem studies). Had we not discovered the rhesus-macaque model of HIV infection (in which the simian immunodeficiency virus [SIV] causes a disease similar to AIDS), we likely still would have generated pharmacodynamic data using the natural hosts of SIV infection (in which SIV does not cause disease, but still replicates in the body at levels similar to HIV in humans or SIV in the non-natural nonhuman-primate hosts [51]) equally useful for their inference to HIV-(post- and pre-exposure) prophylaxis (PEP and PrEP, respectively) in humans.

Had We the Equivalent of Truvada-Prep for SARS-CoV-2, How Would We Use it to Mitigate COVID-19?

Pharmacologic-based mitigation strategies to curb epidemics have been postulated [52], but their efficacy in synergy with social distancing and face mask wearing mitigation strategies (with or without digital contact-tracing technology [53]) for an epidemic with a doubling-time and dynamic features similar to COVID-19 [54,55] is today unknown. Consensus is growing among modelers, however, that mitigation strategies interventions (which primarily act on reducing the same variable of the viral transmission dynamic models adopted in their studies, i.e. the infectivity rate) work best in keeping the number of new cases at bay (or could even stop the epidemic [53]), if administered when the pool of infected people is small, i.e. during the early steps of a viral outbreak or when the R-naught (average number of people that one infected person will pass the virus to) has been sufficiently reduced, for instance following a period of effective lock-down [53,55]. The larger the initial pool of infected people, the more aggressive the interventions aimed to promptly control an epidemic may need to be (including voluntary centralized quarantine) [56].

Efforts in this area of mathematical modeling research are critically needed to serve this and any future viral outbreak. For bioethical reasons, similarly to what happened for PEP studies in the 1990s, once the effectiveness of the first available COVID-19 prophylaxes is demonstrated, it will be difficult to estimate the relative contribution of each mitigation strategy to the curve of new cases in a given region. Epidemiological models of COVID-19 for instance predict that a 50% reduction in within-population contact rates can already have a dramatic effect in slowing the course of the epidemic [54]. Massive data sharing among countries, which will likely adopt different combinations of those strategies at different times, will be of utmost importance to produce that knowledge.

The role of an antiviral prophylaxis goes beyond its ability to substantially impact the curve of cases. The high likelihood of SARS-CoV-2 transmission among individuals living in households with infected people [57] offers an important context in which a safe antiviral drug is highly desired to protect, first of all, those at high risk of severe disease, such as the elderly with chronic health conditions, as well as those at high risk of contracting the virus through occupational exposure. This would enhance the quality of life not only for uninfected adults living in the same household but also for the COVID-19 patients who could go through the quarantine period with less fear of infecting those who gravitate around their lives; a peace of mind that carries priceless benefits to patient welfare, somewhat similar (within the limitations of the proposed parallelism) to those experienced by HIV serodiscordant couples with the advent of Truvada-PrEP.

Acknowledgements

The author thanks Katelyn W. Le, from Frederick National Laboratory for Cancer Research/Leidos Biomedical Research, for providing medical writing editorial support during the preparation of this paper.

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