Treatment of COVID-19 in Immunocompromised Patients With Hematologic Conditions

Do moderately or severely immunocompromised individuals have a higher risk of severe illness?

To generate optimal immune responses following either SARS-CoV-2 infection or vaccination, functional host immunity is needed, particularly with respect to antigen presentation, B- and T-cell activation, and antibody generation. Therefore, hosts lacking functional adaptive immune cells may be unable to control SARS-CoV-2 infection or to generate a protective immune response to SARS-CoV-2 vaccines.

Individuals who are immunocompromised have been reported to be more likely to develop moderate or severe illness once infected with SARS-CoV-2 and may continue to shed virus and remain symptomatic for a longer period.^1-4 Individuals who have the following types of conditions and treatments may be at higher risk:

1. Active treatment for solid tumors or hematologic malignancies
2. Receipt of solid-organ transplants and on immunosuppressive therapy
3. Receipt of chimeric antigen receptor T-cell (CAR-T) therapies or hematopoietic cell transplantation (HCT) within two years of transplantation, or still requiring immunosuppressive therapy
4. Moderate or severe primary immunodeficiency disorders (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, severe combined immunodeficiencies, etc.)
5. Advanced or untreated HIV infection (most significantly, CD4 cell counts < 200/mm3, history of an AIDS-defining illness without immune reconstitution, or other clinical manifestations of HIV)
6. Active treatment with high-dose corticosteroids (i.e., > 20 mg of prednisone or equivalent per day administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory

Are there specialized therapies for patients with immunocompromise who contract COVID-19?

No therapies have been specifically approved for patients who are immunocompromised. There are, however, guidelines issued by the Centers for Disease Control and Prevention (CDC) that have addressed this category of patient.

What therapies should be considered in immunocompromised patients with COVID-19 disease?

For nonhospitalized immunocompromised patients with mild to moderate COVID-19 disease, the CDC calls for prompt treatment with antivirals or anti–SARS-CoV-2 monoclonal antibodies. For hospitalized immunocompromised patients with moderate to severe COVID-19 disease, the CDC recommends antivirals, monoclonal antibodies, as well as immunomodulatory therapies (i.e., steroids) in patients with worsening disease balancing risk and benefits of steroids in immunocompromised patients. The guidelines specifically indicated that combined therapies with both antivirals and monoclonal antibodies have not been studied and cannot be commented on; however, there is no inherent reason combined treatment cannot be given in high-risk and seriously ill patients per institutional policies. Breakthrough infection despite prior administration of prophylactic monoclonal antibodies would merit institution of an antiviral.

In the United States, two oral antiviral therapies are currently available under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for individuals at risk for serious COVID-19 and who have tested positive within the previous five days: ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir. Remdesvir is available for intravenous (IV) administration.

Paxlovid can be given to individuals 12 years or older and weighing at least 40 kg. Data from the randomized controlled trial (RCT) of more than 2,200 unvaccinated individuals supporting the EUA demonstrated relative risk reduction of 89 percent for hospitalization; however, no large trials in immunocompromised patients have been published.⁵

There are numerous drug interactions that can make administration of Paxlovid complex in the setting of anticancer therapies, immunosuppressive calcineurin inhibitors or mTOR inhibitors, anticoagulants, and/or prophylactic antimicrobial medications, as detailed on the National Institutes of Health (NIH) website or in the drug’s package insert. Notably, significant adverse reactions can include greater exposure to Paxlovid, loss of therapeutic effect of Paxlovid, or increased exposure to concomitant medications. Paxlovid is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions. Rivaroxaban and apixaban have significant drug interaction with ritonavir, a component of Paxlovid. Co-administration will increase the concentration of apixaban or rivaroxaban and may increase the risk of bleeding. As Paxlovid treatment lasts only five days, the clinical significance of the interaction with direct oral anticoagulants (DOACs) remains unclear. All patients receiving Paxlovid need to have a full review of concomitant medications prior to the administration of Paxlovid. A risk-benefit analysis is required in each patient to determine whether any interacting medications can be discontinued or dose-adjusted during Paxlovid therapy versus use of an alternative but less active antiviral, or reliance instead on a monoclonal antibody.

Current antiviral alternatives to Paxlovid include molnupiravir or remdesivir. Molnupiravir is the second oral antiviral available under an EUA. The RCT that led to EUA approval⁶ showed a reduction in the rate of hospitalization or death of 50 percent of individuals in an interim analysis; however, at trial completion, the decrease was only 30 percent over placebo. The study included very few participants who were immunocompromised. Drug interactions are much less problematic than for Paxlovid.

Remdesivir is the antiviral available for the longest time, with some conflicting data regarding efficacy in hospitalized patients with severe or critical COVID-19. However, a recent study documented an 87 percent reduction in hospitalization or death in outpatients treated for seven days with a three-day course of IV remdesivir. Remdesivir is not thought to have effects on drug metabolism of DOACs or other hematology-relevant medications. If outpatient IV treatment can be arranged, this can be an option for immunocompromised patients with mild to moderate disease who are unable to take Paxlovid.

Multiple engineered monoclonal antibodies directed against the SARS-CoV-2 spike protein have been developed. Initial clinical trials of monoclonal antibody therapies in hospitalized patients with severe COVID-19 disease were stopped due to futility, with no evidence of benefit in preventing intensive care unit admission or death, or composite critical disease end points. This lack of benefit is not surprising given that passive antibody administration is unlikely to improve clinical status in most patients already making their own anti-COVID antibodies a week or more after infection. In contrast, administration of these antibodies to nonhospitalized outpatients has shown promise in preventing hospitalization or progression to severe disease. Additionally, administration of a monoclonal antibody to nursing home residents and staff soon after a high-risk exposure was effective in decreasing the incidence of infection and death. These trials have recently been reviewed.

The FDA has issued EUAs for antibody treatment of high-risk nonhospitalized individuals with COVID-19 disease (or those hospitalized for an indication other than COVID-19), including immunocompromised patients, with products consisting of one or two monoclonal antibodies. Several products also received an EUA for postexposure prophylaxis or pre-exposure prevention in high-risk individuals.

However, with the evolution of viral spike protein mutant strains, particularly Omicron, the majority of available single or even double monoclonal antibody preparations have shown reduced neutralizing activity in the laboratory and are presumed to be less effective for prevention or protection against disease progression, though clinical studies documenting breakthrough infections or loss of efficacy are lacking. An NIH database updated daily contains information provided by manufacturers, regulators, and academics on the activity of both vaccines and antibody therapies against variants, and should be consulted before prescribing. Currently, sotrovimab is available in regions where less than 50 percent of cases are the Omicron B.2 variant, and bebtelovimab is available for all patients including those with Omicron B.2.

It is important for hematologists and other providers to discuss the potential benefits of antivirals and/or monoclonal antibodies for COVID-19 with their patients as soon as they meet high-risk criteria or undertake vaccination and/or prophylactic monoclonals as indicated, and to stress the importance of patients reporting symptoms, a positive SARS-CoV-2 test and/or a high-risk exposure to their health care providers immediately. All currently available treatments are much more effective and often only available for EUA use early after viral infection. During surges in infection rates, availability of drugs may be limited, and administration can be logistically challenging, requiring time and effort for procurement. All patients should be counseled to receive all recommended vaccinations, wear masks, and avoid high-risk activities as much as possible, even following antibody infusions.

What is the current status of COVID-19 convalescent plasma (CCP) for prevention or treatment of COVID-19 disease?

Particularly before monoclonal antibodies were available, multiple studies focused on the use of CCP to deliver antibodies to patients with COVID-19 without unexpected or serious adverse events. While many patients improved clinically, the specific role of CCP was unclear, given treatment with other therapies, including antivirals and/or corticosteroids. Multiple RCTs enrolling severely ill hospitalized patients failed to show benefit, which is not surprising based on theoretical considerations and experience with convalescent plasma for other infections.

The data regarding administration of CCP prior to hospitalization and/or early after symptom onset are less clear. While at least one small RCT reported that infusion of high-titer CCP within three days of symptom onset in at-risk patients yielded less progression to severe respiratory disease, NIH halted accrual to the C3PO trial for futility, after enrolling 511 of 900 planned patients presenting to the emergency department within one week of onset. A large double-blinded RCT of high-titer CCP in outpatients was recently published and showed a relative risk reduction of 54 percent in the CCP group. Of note, the enrollees were not selected to be high risk; thus, applicability to the immunocompromised is unclear. It is also important to stress that all these trials were carried out pre-Omicron.

The World Health Organization, Infectious Diseases Society of America, and NIH do not currently recommend use of CCP in COVID-19 infected or exposed patients, including immunocompromised patients, outside of clinical trials. On the current EUA, CCP cannot be administered to outpatients, but given the more promising recent results for outpatient administration of high-titer CCP, a request to modify the EUA is being considered.

The evolution of mutant strains such as Omicron, which is resistant to many available anti-spike monoclonal antibodies (see above), and the lack of availability of monoclonal antibodies in many countries worldwide have the potential to rekindle interest in using CCP. Evidence that patients who were previously infected with earlier strains of SARS-CoV-2 can develop disease from new strains such as Omicron suggests that CCP units collected following recovery from strains prevalent earlier in the pandemic may have little activity. Conversely, polyclonal antibody responses theoretically have advantages over monoclonal antibodies in terms of retaining activity against evolving mutants. Units of CCP collected from fully vaccinated individuals who have had a recent infection with Omicron or other variant likely contain extremely high titers of antibodies and deserve further study.

References

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5. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. N Engl J Med. 2022;386(15):1397-1408. doi: 10.1056/NEJMoa2118542.
6. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. doi: 10.1056/NEJMoa2116044.