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IMPORTANCEMonoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19. However, no studies have evaluated adverse events and effectiveness of mAbs in pregnant persons compared to no mAb treatment. OBJECTIVETo determine the frequency of drug-related adverse events and obstetric-associated safety outcomes after treatment with mAb compared to no mAb treatment, and the association between mAb treatment and a composite of 28-day COVID-19-related hospital admission or emergency department visit, COVID-19-associated delivery, or mortality. DESIGN, SETTING, PARTICIPANTSPropensity-score matched cohort study of persons aged 12 years of age or older with a pregnancy episode and any documented positive SARS-CoV-2 test (polymerase chain reaction or antigen test) in the UPMC health system from April 30, 2021 to January 21, 2022. EXPOSURESBamalanivmab and etesevimab, casirivimab and imdevimab, or sotrovimab treatment compared to no mAb treatment. MAIN OUTCOMES AND MEASURESDrug-related adverse events, obstetric-associated safety outcomes among persons who delivered, and a risk-adjusted composite of 28-day COVID-19-related hospital admission or ED visit, COVID-19-associated delivery, or mortality. RESULTSAmong 944 pregnant persons (median [IQR] age 30 [26, 33] years, White (79.5%, N=750), median [IQR] Charlson Comorbidity Index Score 0 (0,0)), 552 persons received mAb treatment (58%). Median gestational age at COVID-19 diagnosis or treatment was 179 days (IQR: 123, 227), and most persons received sotrovimab (69%, N=382). Of those with known vaccination status, 178 (62%) were fully vaccinated. Drug-related adverse events were uncommon (N=8, 1.4%), and there were no differences in any obstetric-associated outcome among 276 persons who delivered. After propensity score matching, the frequency of the composite 28-day COVID-19-associated outcome was 4.0 per 100 persons (95% CI 1.9, 6.2) in mAb-treated compared to 3.7 per 100 persons (95% CI 1.7, 5.8) in non-treated controls (risk difference = 0.31 per 100 persons [95% CI -2.6, 3.3). There were no deaths among mAb-treated patients compared to 1 death in the non-treated controls (p = 0.24). There were more non-COVID-19-related hospital admissions in the mAb-treated persons (risk difference 2.8 per 100 persons (95% CI 1.1, 4.5)). CONCLUSIONS AND RELEVANCEIn pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were mild and rare. There was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment among persons who delivered. MAb treatment was associated with similar 28-day COVID-19-associated outcomes and more non-COVID-19-related hospital admissions compared to no mAb treatment. Key PointsO_ST_ABSQUESTIONC_ST_ABSAmong pregnant persons with COVID-19, is monoclonal antibody (mAb) treatment associated with drug-related adverse events, similar frequency of obstetric-associated safety outcomes, and improved COVID-19-related clinical outcomes compared to no mAb treatment? FINDINGSIn 944 pregnant persons with COVID-19, drug-related adverse events were mild and infrequent. Obstetric-associated safety outcomes were similar between mAb treatment and no treatment. There was no evidence of difference in risk of COVID-19-related hospital admission, COVID-19-associated delivery, or mortality between mAb treatment and no mAb treatment. MEANINGIn pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were uncommon, and there was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment. MAb treatment was associated with similar 28-day risk of a COVID-19-associated outcome and more non-COVID-19-related hospital admissions compared to no mAb treatment.
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IMPORTANCEThe effectiveness of monoclonal antibodies (mAbs), casirivimab and imdevimab, and sotrovimab, for patients with mild to moderate COVID-19 from the Delta variant is unknown. OBJECTIVETo evaluate the effectiveness of mAbs for the Delta variant compared to no treatment, and the comparative effectiveness between mAbs. DESIGN, SETTING, AND PARTICIPANTSTwo parallel studies among patients who met Emergency Use Authorization criteria for mAbs from July 14, 2021 to September 29, 2021: i.) prospective observational cohort study comparing mAb treatment to no mAb treatment and, ii.) Bayesian adaptive randomized trial comparing the effectiveness of casirivimab-imdevimab versus sotrovimab. In the observational study, we compared eligible patients who received mAb at an outpatient infusion center at UPMC, to nontreated patients with a positive SARS-CoV-2 test. In the comparative effectiveness trial, we randomly allocated casirivimab-imdevimab or sotrovimab to patients presenting to infusion centers and emergency departments, per system therapeutic interchange policy. EXPOSUREIntravenous mAb per their EUA criteria. MAIN OUTCOMES AND MEASURESFor the observational study, risk ratio estimates for hospitalization or death by 28 days were compared between mAb treatment to no mAb treatment using propensity matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day) in a Bayesian cumulative logistic model, adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio <1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound. RESULTSAmong 3,558 patients receiving mAb, the mean age was 54 (SD 18 years), 1,511 (43%) were treated in an infusion center, and 450 (13%) were hospitalized or died by day 28. In propensity matched models, mAb treatment was associated with reduced risk of hospitalization or death compared to no treatment (risk ratio (RR)=0.40, 95% CI: 0.28-0.57). Both casirivimab and imdevimab (RR=0.31, 95% CI: 0.20-0.50), and sotrovimab (RR=0.60, 95% CI: 0.37-1.00) reduced hospitalization or death compared to no mAb treatment. Among patients allocated randomly to casirivimab and imdevimab (n=2,454) or sotrovimab (n=1,104), the median hospital-free days were 28 (IQR 28-28) for both groups, 28-day mortality was 0.5% (n=12) and 0.6% (n=7), and hospitalization by day 28 was 12% (n=291) and 12% (n=140), respectively. Compared to casirivimab and imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70-1.11) for sotrovimab. This odds ratio yielded 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence. CONCLUSIONS AND RELEVANCEIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were both associated with a reduced risk of hospitalization or death. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met. TRIAL REGISTRATIONClinicalTrials.gov: NCT04790786 Key PointsO_ST_ABSQuestionC_ST_ABSIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, what is the effectiveness of monoclonal antibodies (mAb) compared to no treatment, and what is the comparative effectiveness between mAb? FindingsAmong 3,069 patients, mAb treatment (casirivimab and imdevimab or sotrovimab) was associated with reduced risk of hospitalization or death by 28 days compared to no treatment (risk ratio=0.40, 95% CI: 0.28-0.57). In a Bayesian randomized comparative effectiveness trial of casirivimab and imdevimab vs. sotrovimab in 3,558 patients, the median hospital-free days were 28 days for both groups. Compared to casirivimab-imdevimab, the median adjusted odds ratio for hospital-free days was 0.88 (95% credible interval, 0.70-1.11) for sotrovimab, an 86% probability of inferiority of sotrovimab versus casirivimab and imdevimab, and 79% probability of equivalence. MeaningIn non-hospitalized patients with mild to moderate COVID-19 due to the Delta variant, casirivimab and imdevimab and sotrovimab were associated with reduced risk of hospitalization or death compared to no treatment. The comparative effectiveness of mAbs appeared similar, though prespecified criteria for statistical inferiority or equivalence were not met.
ABSTRACT
ImportanceMonoclonal antibody (mAb) treatment decreases hospitalization and death in outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but association with patient outcomes is understudied. ObjectiveTo evaluate whether or not, i.) subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization/death than non-treatment among mAb-eligible patients, and ii.) subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment. Design, Setting, and ParticipantsProspective cohort study of outpatients in a learning health system in the United States with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021 who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also selected. InterventionSubcutaneous injection or intravenous administration of the combined single dose of casirivimab 600mg and imdevimab 600mg. Main Outcomes and MeasuresThe primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios/differences of hospitalization, death, composite endpoint of ED admission and hospitalization, and rates of adverse events. ResultsAmong 1,956 matched adults with mild to moderate COVID-19, patients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization/death of 3.4% (n=652) compared to 7.8% (n=1,304) in nontreated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 patients treated with subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences (subcutaneous - intravenous) for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide. Conclusions and RelevanceSubcutaneously administered casirivimab-imdevimab is associated with reduced risk-adjusted hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment and indicates low adjusted risk difference compared to patients treated intravenously. Key PointsO_ST_ABSQuestionC_ST_ABSAmong outpatients with mild to moderate COVID-19, is subcutaneously administered casirivimab and imdevimab associated with improved risk-adjusted 28-day clinical outcomes compared to non-treatment with monoclonal antibodies, and clinically similar association compared to intravenously administered casirivimab and imdevimab? FindingsAmong 1,956 propensity-matched adults, outpatients who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (n=652) compared to 7.8% (n=1,304) in non-treated controls [risk ratio 0.44 (95% confidence interval: 0.28 to 0.68, p < .001)]. Among 2,185 outpatients who received subcutaneous (n=969) or intravenous (n=1,216) casirivimab and imdevimab, the 28-day rate of hospitalization/death was 2.8% vs. 1.7%, respectively, which resulted in an adjusted risk difference of 1.5% (95% confidence interval: -0.5% to 3.5%, p=.14). The 28-day adjusted risk differences comparing subcutaneous to intravenous route for death, ICU admission, and mechanical ventilation were 0.3% or less, although the 95% confidence intervals were wide. MeaningSubcutaneously administered casirivimab and imdevimab is associated with reduced hospitalization or death amongst outpatients with mild to moderate COVID-19 compared to no treatment, and has a small, adjusted risk difference compared to patients treated intravenously.
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BackgroundNeutralizing monoclonal antibodies (mAb) targeting SARS-CoV-2 decrease hospitalization and death in patients with mild to moderate Covid-19. Yet, their clinical use is limited, and comparative effectiveness is unknown. MethodsWe present the first results of an ongoing, learning health system adaptive platform trial to expand mAb treatment to all eligible patients and evaluate the comparative effectiveness of available mAbs. The trial launched March 10, 2021. Results are reported as of June 25, 2021 due to the U.S. federal decision to pause distribution of bamlanivimab-etesevimab; patient follow-up concluded on July 23, 2021. Patients referred for mAb who met Emergency Use Authorization criteria were provided a random mAb allocation of bamlanivimab, bamlanivimab-etesevimab, or casirivimab-imdevimab with a therapeutic interchange policy. The primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day. The primary analysis was a Bayesian cumulative logistic model of all patients treated at an infusion center or emergency department, adjusting for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio < 1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound. ResultsPrior to trial launch, 3.1% (502) of 16,345 patients who were potentially eligible by an automated electronic health record (EHR) screen received mAb. During the trial period, 23.2% (1,201) of 5,173 EHR-screen eligible patients were treated, a 7.5-fold increase. After including additional referred patients from outside the health system, a total of 1,935 study patients received mAb therapy (128 bamlanivimab, 885 bamlanivimab-etesevimab, 922 casirivimab-imdevimab). Mean age ranged from 55 to 57 years, half were female (range, 53% to 54%), and 17% were Black (range, 12% to 19%). Median hospital-free days were 28 (IQR, 28 to 28) for each mAb group. Hospitalization varied between groups (bamlanivimab, 12.5%; bamlanivimab-etesevimab, 14.7%, casirivimab-imdevimab, 14.3%). Relative to casirivimab-imdevimab, the median adjusted odds ratios were 0.58 (95% credible interval (CI), 0.30 to 1.16) and 0.94 (95% CI, 0.72 to 1.24) for the bamlanivimab and bamlanivimab-etesevimab groups, respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab respectively, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab, at the prespecified odds ratio bound of 0.25. Twenty-one infusion-related adverse events occurred in 0% (0/128), 1.4% (12/885), and 1.0% (9/922) of patients treated with bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. ConclusionIn non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to bamlanivimab-etesevimab and casirivimab-imdevimab, resulted in 91% and 94% probabilities of inferiority with regards to odds of improvement in hospital-free days within 28 days. There was an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early due to federal distribution decisions, and no mAb met prespecified criteria for statistical inferiority or equivalence. (ClinicalTrials.gov, NCT04790786).
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ObjectivesImmunocompromised patients were excluded from COVID-19 vaccine clinical trials. The objectives of the study were to measure antibody responses, levels, and neutralization capability after COVID-19 vaccination among immunocompromised patients and compare these variables to those of immunocompetent healthcare workers. MethodsThis is an interim analysis of an ongoing observational, prospective cohort study which launched on April 14, 2021 across Western Pennsylvania. Participants were healthy healthcare workers (HCW) and immunocompromised patients who had completed their COVID-19 vaccination series. Individuals with a history of COVID-19 were not eligible. Serum was collected to measure for the presence of IgG against the SARS-CoV-2 Spike protein using a semi-quantitative assay; antibody levels were available for comparisons. A quasi-random subset of patients was selected for pseudovirus neutralization assays. Seropositivity with 95% Clopper-Pearson exact confidence intervals and distribution of antibody levels were measured. To identify risk factors for seronegativity, clinical characteristics were univariately compared between antibody reactive and non-reactive individuals within the immunocompromised group. Results107 HCW and 489 immunocompromised patients were enrolled. Compared to HCWs, seropositivity was significantly lower (p<.001) among immunocompromised patients with Solid organ transplant (SOT), autoimmune, hematological malignancies, and solid tumors (HCW=98.1%; SOT=37.2%; autoimmune=83.8%; hematological malignancies=54.7%; and solid tumor=82.4%, p < 0.05). Over 94% of patients with Human Immunodeficiency Virus were seropositive. Among seropositive patients, antibody levels were much lower among SOT (4.5 [2.1,13.1], p=.020). Neutralization titers tightly correlated with antibody levels (Spearman r = 0.91, p < 0.0001). ConclusionOur findings demonstrate the heterogeneity of the humoral immune response to COVID-19 vaccines based on underlying immunosuppressive condition and highlight an urgent need to optimize and individualize COVID-19 prevention in these patients. These findings also have implications on public health guidance, particularly given revised Centers for Disease Control and Prevention recommendations permitting vaccinated individuals to abandon masking and social distancing in most settings. Future studies are warranted to determine assessment of cellular immunity, longitudinal measurement of immune responses, and the safety and efficacy of revaccination.
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ObjectiveCOVID-19 disproportionately impacts older adults residing at long-term care facilities. Data regarding antibody response to COVID-19 vaccines in this population is limited. Our objective was to quantify the presence and magnitude of antibody response in older, vaccinated residents at assisted living, personal care, and independent living facilities. DesignA cross-sectional quality improvement study was conducted March 15 - April 1, 2021 in the Pittsburgh region. Setting and PopulationParticipants were volunteers at assisted living, personal care, and independent living facilities, who received mRNA COVID-19 vaccine. Conditions that obviate immune responses were exclusionary criteria. MethodsSera were collected to measure IgG anti-SARS-CoV-2 antibody level with reflex to total anti-SARS-CoV-2 immunoglobulin levels. Descriptive statistics, Pearson correlation coefficients, and multiple linear regression analysis were performed to evaluate relationships between factors potentially associated with antibody levels. ResultsAll participants (N=70) had received two rounds of vaccination for COVID-19 and were found to have antibodies to SARS-CoV-2. There was wide variation in relative levels of antibodies as determined by extinction coefficients. Antibody levels trended lower in male sex, advanced age, steroid medications, and longer length of time from vaccination. Conclusions and ImplicationsHigher functioning long-term care residents mounted detectable antibody responses when vaccinated with COVID-19 mRNA-based vaccines. This study provides preliminary information on level of population risk of assisted living, personal care, and independent living residents which can inform reopening strategies. Data suggests some degree of immunity is present during the immediate period following vaccination. However, protective effects of such vaccination programs remain to be determined in larger studies. Clinical protection is afforded not just by pre-formed antibody levels, but by ongoing adaptive immunity, which is known to be decreased in older individuals. Thus, the implications of these levels of antibodies in preventing COVID-19 disease must be determined by clinical follow-up.
