ABSTRACT
Background. Sotrovimab (VIR-7831) is an engineered human monoclonal antibody targeting a conserved region of the SARS-CoV-2 spike protein;it has been shown to have a favorable safety profile and be effective for early treatment of highrisk COVID-19 patients. The COMET-TAIL phase 3 study evaluated sotrovimab administered intravenously (IV) or intramuscularly (IM) for the treatment of participants with mild to moderate COVID-19 who are at high risk of disease progression. Methods. Between June to August 2021, 973 participants were randomized and received sotrovimab by 500 mg IV infusion or by 500 or 250 mg IM injection. Deep sequencing of the spike gene was performed on nasopharyngeal samples. Baseline (BL;Day 1 or Day 3), post-BL (Day 5 or later), treatment-emergent (TE) substitutions at sotrovimab epitope positions, and presence of variants of concern/interest (VOC/ VOI), were evaluated at a >=5% allelic frequency. Phenotypic analyses were conducted using a pseudotyped virus assay. Results. Sequences were available from 764 participants (500 mg IV: 314/393;500 mg IM: 302/387;250 mg IM: 148/193). Consistent with VOC circulation during enrollment, the Delta variant was detected in 88.2% (674/764) of participants. Alpha and Mu variants were also seen at >2% prevalence. Of the 764 participants, 26 met the primary endpoint for clinical progression to hospitalization >24 hours or death due to any cause through day 29 and were infected with Delta (500 mg IV: 4;500 mg IM: 9;250 mg IM: 11), Alpha (500 mg IM: 1), or Mu (500 mg IV: 1) variants. Substitutions at sotrovimab epitope positions were similar across arms and were detected in 82/764 (10.7%) participants at any visit (500 mg IV: 42/314;500 mg IM: 27/302;250 mg IM: 13/148). Of these, 2 participants experienced clinical progression: 1 participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution at BL;1 participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions detected at Day 3 and P337L was enriched at Day 8. The predominant TE epitope substitutions included P337L and E340A/K/V, which confer reduced susceptibility to sotrovimab in vitro. Conclusion. Overall, TE epitope substitutions were not associated with clinical progression.
ABSTRACT
Background: Sotrovimab is a pan-sarbecovirus neutralizing monoclonal antibody shown to be safe and effective for the treatment of early COVID-19 in high-risk patients and retains activity against variants of concern, including delta and omicron. To facilitate wider access to sotrovimab, it was formulated to allow for either intramuscular (IM) or intravenous (IV) administration. Methods: COMET-TAIL (NCT04913675) is a Phase III, randomized, multicenter, open-label, noninferiority (NI) study of IM vs IV sotrovimab for the treatment of mild/moderate COVID-19 in participants ≥12 years of age at high risk of disease progression. Participants were randomized to receive sotrovimab by single 500 mg IV infusion or IM injection (500 mg or 250 mg). The primary objective was to evaluate the efficacy of 500 mg IM vs 500 mg IV sotrovimab in preventing hospitalization for >24 hours for acute management of illness due to any cause or death. The 250 mg IM arm discontinued early due to a greater number of hospitalizations seen in that arm. A 3.5% NI margin on the risk difference scale was prespecified. Results: COMET-TAIL enrollment occurred from Jun-Aug 2021, coinciding with a surge in the SARS-CoV-2 delta variant in southern USA. The majority (∼85%) of participants were Hispanic or Latino and ∼25% were ≥65 years of age. In the 500 mg IM sotrovimab arm, 10/376 (2.7%) participants compared with 5/378 (1.3%) in the sotrovimab 500 mg IV arm met progression criteria for the primary endpoint (adjusted risk difference: 1.07% [95% CI:-1.25%, 3.39%]), meeting the NI margin of 3.5%. The overall rate of adverse events and injection/infusion-related reactions was low and similar between the 500 mg treatment arms. Most injection-site reactions were mild (grade 1), occurred shortly after dosing, and were limited in duration. Disease-related events (DREs) were balanced between the 500 mg IV and 500 mg IM arms. The most frequent DREs were COVID-19 pneumonia and pneumonia. There was a low percentage of participants (∼1%) with serious adverse events across all treatment arms, and none were considered related to treatment. Two participants (1 with BMI 69 mg/kg2 and an 82-year-old man) in the 500 mg IM arm died due to progression of COVID-19;no deaths occurred in the 500 mg IV arm. Conclusion: In the COMET-TAIL trial, sotrovimab given by 500 mg IM injection was found to be noninferior to IV infusion and was well tolerated. The option of IM administration will expand the potential for outpatient treatment with sotrovimab.
ABSTRACT
Background: Sotrovimab is a pan-sarbecovirus monoclonal antibody clinically evaluated for prevention of progression of COVID-19 in high-risk patients early in the course of infection. We investigated the rate of prevention of hospitalization or death by baseline anti-SARS-CoV-2 serostatus. Methods: COMET-ICE (NCT04545060) was a multicenter, double-blind, Phase III trial in nonhospitalized adults with symptomatic COVID-19 and ≥1 risk factor for disease progression. Participants were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was all-cause hospitalization >24 hours or death due to any cause within 29 days. Anti-nucleocapsid SARS-CoV-2 antibody was measured by the Abbott SARS-CoV-2 IgG assay run on the Architect i2000SR immunoassay analyzer. Results: In the final dataset (N=1057), the adjusted relative risk (RR) reduction in all-cause hospitalization or death due to any cause in the sotrovimab group compared to the placebo group was 79% (p<0.001) at Day 29. 70% and 19% of participants were seronegative and seropositive for anti-nucleocapsid protein at baseline, respectively. 11% of participants had unknown antibody status and were excluded. In the seronegative subgroup, 4/365 (1%) participants in the sotrovimab group met the primary endpoint compared to 26/375 (7%) in the placebo group (84% reduction in risk [RR: 0.16;95% CI: 0.06, 0.45]). Of the 4 seronegative participants who received sotrovimab and met the primary endpoint, 1 participant was hospitalized for small intestinal obstruction that was likely unrelated to COVID-19. Two of the 26 seronegative participants in the placebo arm who met the primary endpoint died compared to no deaths in the sotrovimab group. In the seropositive subgroup, conclusions are limited by small numbers. Numerically fewer participants in the sotrovimab group (2/105, 2%) were hospitalized compared to the placebo group (4/97, 4%). Importantly, both hospitalized seropositive participants in the sotrovimab group had an alternative reason for their hospitalization that was likely unrelated to COVID-19 (diabetic foot ulcer, non-small cell lung cancer). Progression rates in the sotrovimab arm were low and similar regardless of serostatus (1% seronegative, 2% seropositive). Safety profile by serostatus was consistent with that reported in the overall population. Conclusion: Sotrovimab appeared to consistently reduce the likelihood of a COVID-19-related hospitalization or death regardless of baseline serostatus.
ABSTRACT
Background: COVID-19 outcomes among people with HIV (PWH) remain inconclusive. We characterized all cases of COVID-19 identified in a long-term multi-site cohort of PWH, as well as factors associated with increasing severity of COVID-19 during the early months of the COVID-19 pandemic. Methods: We examined all PWH with SARS-CoV-2 infection and COVID-19 disease identified from laboratory testing data (RT-PCR, antigen test results) and ICD-10 codes March-July 2020 from seven sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort. Cases were verified by medical record review. We evaluated predictors of increased disease severity, indicated by hospitalization. Relative risks were estimated using Poisson regression, adjusted for clinical and demographic characteristics using disease risk scores. Results: Among 13,862 PWH in care (20% female, median age 52 (IQR 40-59), 58% Black or Hispanic race/ethnicity), 198 COVID-19 cases were detected during the study period. A higher proportion of PWH with COVID-19 were female (27%), Black or Hispanic (76%), and had BMI ≥30 (45%). No significant differences in CD4+ count (current or lowest) were seen between PWH with and without COVID-19. We found evidence suggesting more unstable housing among COVID-19 cases compared to non-cases (14% vs. 9%). Among PWH with COVID-19, 38 (19%) were hospitalized, 10 (5%) required intensive care, 8 (4%) received invasive mechanical ventilation, and 4 (2%) died. Hospitalization among PWH with COVID-19 was associated with: CD4+ count ≤350 (aRR 1.77;95% CI 1.05, 2.98);age ≥60 (aRR 2.0;95%CI 1.13, 3.54);pre-existing kidney disease with eGFR <60 (aRR 1.76;95% CI 0.99, 3.13);and BMI ≥30 (aRR 1.96;95% CI 1.02, 3.78) (Table). Conclusion: The population frequency of COVID-19 detected in PWH was 1.4%, likely an underestimate of the true frequency of SARS-CoV-2 infection and COVID-19 disease due to evolving testing availability and access over time. A higher proportion of PWH with COVID-19 were Black or Hispanic, in excess of the overrepresentation of people of color with HIV compared to the general population. PWH with decreased eGFR, low CD4+ count, and obesity had greater risk of more severe COVID-19 disease. Our results highlight disparities in risk of COVID-19 acquisition among PWH in the US and indicate additional vigilance in screening and monitoring of COVID-19 among PWH with these characteristics. The expected accrual of additional COVID-19 cases will allow more precise evaluation of the impact of comorbidities. (Figure Presented).