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Convalescent Plasma Has No Effect on Survival or Disease Course With Severe COVID-19
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CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021
Mark Mascolini
Convalescent plasma from people with COVID-19 did not prolong survival, improve disease course, or affect virologic or immunologic markers of people receiving the plasma during severe disease [1]. Results of this 87-person open-label randomized trial in the Netherlands suggested to the researchers that this therapy "should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response."
Researchers from Erasmus University and colleagues at other centers noted that convalescent plasma (ConvP) could be a cheap and widely available therapy for COVID-19. In April 2020 this open-label randomized trial began enrolling participants at 14 secondary and academic hospitals across the Netherlands [2]. Participants had to be at least 18 years old and admitted to the hospital with PCR-documented SARS-CoV-2 infection within 96 hours. The trial excluded people with documented IgA deficiency, participating in other trials, or on mechanical ventilation for more than 96 hours. Participants could not have reached the terminal stage of their disease or recovered enough to be near discharge.
ConvP donors had to have PCR-confirmed SARS-CoV-2 infection but no symptoms for at least the past 14 days. Researchers selected donors with the highest SARS-CoV-2 plaque-reduction neutralization test (PRNT50) results. The trial's primary outcome was 60-day mortality, while secondary outcomes included disease severity and inflammatory and virologic markers.
The investigators randomized 44 eligible people to standard care and 43 to ConvP. Almost three quarters of participants (72%) were men, and median age stood at 63 interquartile range [IQR] 56 to 74). The group had COVID-19-related symptoms for a median of 10 days (IQR 6 to 15) and had been admitted to the hospital for a median of 2 days (IQR 1 to 3).
Multivariable logistic regression analysis saw no mortality difference between the ConvP and control groups (adjusted odds ratio 0.98, 95% confidence interval [CI] 0.20 to 4.67, P = 0.95) and no difference in time to hospital discharge (adjusted hazard ratio 0.88, 95% CI 0.49 to 1.60, P = 0.68). Compared with standard treatment, ConvP had no impact on viral clearance, SARS-CoV-2 antibody development, or changes in serum proinflammatory cytokine levels.
The researchers found pretreatment neutralizing antibodies in 44 of 56 participants analyzed (79%) at a median PRNT50 level of 160 (IQR 20 to 1280). These trial participants with pretreatment neutralizing antibodies had titers comparable to those measured in ConvP donors.
After reviewing results of these participants, the Data Safety Monitoring Board recommended stopping the trial for futility. The researchers believe the failure to see any clinical or lab benefit with ConvP reflects already-high neutralizing antibody titers when people entered the trial.
A new multicenter study in the Netherlands, CoV-Early, will assess the feasibility, efficacy, and safety of ConvP for COVID-19 outpatients at high risk for severe illness within 7 days of their first symptoms [3].
Around the time of CROI, researchers from the New York State Department of Health published findings on 981 ConvP samples from 196 repeat donors [4]. The proportion of ConvP samples that met a high-titer cutoff of 1:80 with the PRNT50 assay fell from an initial 79.5% to 48.4% at or beyond 85 days after the first donation. In other words, the authors conclude, "a significant proportion of repeat [convalescent plasma] donors experience declines in their neutralizing antibody titers."
References
1. Jordans C, Gharbharan A, Geurts van Kessel CH, et al. Potent neutralizing antibodies for severe COVID-19: a randomized clinical trial. CROI 2021, Conference on Retroviruses and Opportunistic Infections, March 6-10, 2021. Abstract 124.
2. ClinicalTrials.gov. Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease (CONCOVID Study) (ConCoVid-19). ClinicalTrials.gov identifier NCT04342182. https://clinicaltrials.gov/ct2/show/NCT04342182
3. ClinicalTrials.gov. Early Convalescent Plasma Therapy for High-risk Patients With COVID-19 in Primary Care (the CoV-Early Study) (CoV-Early). ClinicalTrials.gov identifier NCT04589949. https://clinicaltrials.gov/ct2/show/NCT04589949
4. Girardin RC, Dupuis II AP, Payne AF, et al. Temporal analysis of serial donations reveals decrease in neutralizing capacity and justifies revised qualifying criteria for coronavirus disease 2019 convalescent plasma. J Infect Dis. 2021;223:743-751. https://doi.org/10.1093/infdis/jiaa803
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