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Department of Medicine
Harvard Medical School
Director, Viral Hepatitis Clinic
Division of Infectious Diseases
Massachusetts General Hospital
Arthur Kim, MD, has no relevant conflicts of interest to report.
Approaches to treating COVID-19 should be based on what is known about the pathogenesis of the illness, and thanks to the work of countless research groups, we have a greater and more detailed understanding than we did even a year ago. Of note, studies of severely ill patients showed that by Day 10 or so of illness, anti–SARS-CoV-2 antibodies appear, correlating with a decline of viral titer and lack of infectious virus. For hospitalized patients, studies observed that surrogates for the burden of virus, such as cycle threshold value as measured in the nasopharynx or plasma viral load, helped to prognosticate in-hospital outcomes, whereas other studies showed for antibodies that a decrement in their potency and/or a minor delay in their arrival was associated with disease progression. For inpatients with higher viral burden and delayed antibody responses, a key question was whether we should deploy therapies beneficial in the outpatient sphere, such as antispike monoclonal antibodies (mAb). In a previous commentary for this program, Dr. Sharon Lewin described recent studies on the use of bamlanivimab for prevention of COVID-19 outbreaks in residential facilities, and sotrovimab in nonhospitalized patients with COVID-19 at risk for disease progression. Here, I’ll focus on new data on the use of casirivimab plus indevimab in patients hospitalized for COVID-19.
RECOVERY Trial—The Monoclonal Antibodies Strike Back
In mid-June 2021, a year after their landmark results for dexamethasone were announced, the RECOVERY trial reported results from their trial of mAb therapy. Between September 2020 and May 2021, 9785 participants hospitalized with COVID-19 were randomly allocated to receive either a cocktail of 2 mAb—casirivimab and imdevimab—plus usual care or usual care alone. Usual care often involved dexamethasone; more than 90% of patients also received corticosteroids. Of note, their analysis showed overall no mortality benefit to the antibody cocktail, unless one focuses on the 3153 patients who were seronegative at baseline. In the seronegative subgroup, mortality at 28 days was significantly lower in those receiving usual care plus casirivimab and imdevimab (24%) vs usual care alone (30%). Other reported outcomes support a clinical benefit in this subgroup, including a reduction in hospitalization length (13 days in the mAb arm vs 17 days usual care alone), and for those not yet on mechanical ventilation, lower rates of progression to a need for ventilatory support.
For the overall population enrolled on RECOVERY, there was no benefit of this mAb cocktail. The corollary to a benefit of this mAb cocktail for the subgroup of seronegative inpatients is that there may be harm associated with administration after development of seropositivity. Neutral effects on the overall population may help explain why at least 2 smaller studies of other mAb for inpatients were suspended for futility, and why it has been difficult to show benefits of high-titer convalescent plasma, another therapy that provides passive immunity. Of note, in RECOVERY, the median time from symptoms to administration was 7 days in the seronegative group and 9 days in the overall population. Based on what we know about the pathogenesis of disease, it is imperative to apply passive immunity such as mAb as early as possible and, based on these new clinical data, to target those testing seronegative as they enter hospitals.
The Rise of Variants and Vaccines
Of note, this period of enrollment (September 2020 - May 2021) largely preceded 2 major events in the United Kingdom: the emergence of the delta variant and the rollout of vaccines. Fortunately, thus far, casirivimab plus imdevimab retains significant activity against current major variants with mutations in the receptor-binding domain. Going forward, escape from antibodies bears watching, and a topic for debate will be whether benefit is specific to this cocktail or whether one can extrapolate these data to other mAb that target conserved epitopes.
In a postvaccine rollout setting, the patients we are seeing are now either unvaccinated or vaccine “failures” associated either exogenous or endogenous immunosuppression. Suboptimal vaccine responses may result in decrements in antispike antibody production and cell-mediated immune responses. This is a challenging group of patients to manage as they may have prolonged courses with recrudescent viral replication, and RECOVERY provides us, first, a rationale for administering passive immunity and, second, a preference for casirivimab plus imdevimab over convalescent plasma.
Considerations as of June/July 2021
To implement casirivimab plus imdevimab for inpatients more widely in the United States, we must overcome several logistical hurdles: (1) expansion of the Emergency Use Authorization by the FDA that currently limits administration to patients not hospitalized for COVID-19; (2) ensuring availability of standardized serologic assays with rapid turnaround for clinical decisions, especially as administration to already seropositive patients may be harmful; (3) assurance of supply and distribution of mAb wherever a sick patient may appear. The recent FDA amendment to the Emergency Use Authorization reduces the dosage of casirivimab plus imdevimab by one half, which will immediately double the supply. The logistical challenges of implementing rapid testing and administration should not be understated, especially as the areas with lower vaccine coverage and greater expected hospitalizations are often further away from major urban centers. Finally, it is critical to acknowledge that the high cost and limited supply of engineered mAb inhibits distribution to parts of the world currently suffering from low vaccine coverage and high hospitalization burdens.
How do we integrate these results into clinical care? This trial—like others before it—emphasizes the importance of finding the “sweet spot” for applying a particular therapy, as patients pass through the dynamic phases of COVID-19. With mAb, that sweet spot may be inpatients who are seronegative. Only approximately one quarter of patients in this report were also receiving remdesivir, so it remains unknown whether these mAb should also be accompanied by a second antiviral therapy. Nevertheless, we are also moving into a phase of COVID-19 treatment in which we can more smartly choose from the expanding toolbox of proven therapies while targeting them to the right patient at the right time, based on the pathogenesis of disease.
Do the results from RECOVERY regarding casirivimab plus imdevimab change the standard of care for seronegative patients hospitalized with COVID-19? Would you also administer remdesivir if both therapies were available to you? What logistical challenges to you foresee in implementing this therapy? Answer the polling question and join the conversation by posting in the discussion section. Then, see more from this ongoing series spotlighting exciting new and clinically significant data on COVID-19.