ABSTRACT
Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged SARS-CoV-2 infection, but the immune defects that predispose to persistent COVID- 19 remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median time to nasal viral RNA and culture clearance in the severe hematologic malignancy/transplant group (S-HT) were 72 and 21 days, respectively, which were significantly longer than clearance rates in the severe autoimmune/B-cell deficient (S-A), non-severe, and non-immunocompromised groups (P<0.001). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral, while only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.
Subject(s)
COVID-19 , Hematologic Diseases , Hematologic NeoplasmsABSTRACT
Abstract Objective: To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound. Design: Observational cohort study. Setting: Multicenter healthcare system in Boston, Massachusetts. Participants: We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir. Exposures: Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy. Main Outcome and Measures: The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads [≥]4.0 log10 copies/milliliter after a prior reduction in viral load to <4.0 log10 copies/milliliter. Results: Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and [≥]2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene. Conclusions and Relevance: Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
Subject(s)
COVID-19ABSTRACT
Background: Since August 2021, multiple vaccines have been approved to prevent infection with SARS-CoV-2; however, 20-40 % of immunocompromised people fail to develop SARS-CoV-2 spike antibodies after COVID-19 vaccination and remain at an exceptionally high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is an engineered monoclonal antibody that targets a highly conserved epitope on the SARS-CoV-2 spike glycoprotein. It is neither renally excreted nor metabolized by P450 (CYP) enzymes; therefore, interactions with concomitant medications are unlikely, which is an important consideration for patients receiving multiple immunosuppressive medications. In this Phase II open-label safety and tolerability study protocol, we propose to evaluate the safety and tolerability of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals.Methods: We will enroll a total of 93 eligible immunocompromised adults with a negative or low-positive (<50 U/mL) SARS-CoV-2 spike antibody. In Phase 1, the first 10 patients will participate in a lead-in pharmacokinetics (PK) cohort study to determine the optimal dosing interval between two sequential doses of sotrovimab. Phase 2 will expand this population to 50 participants to examine rates of infusion-related reactions (IRR) with a 30-minute 500mg sotrovimab IV infusion. Phase 3 will be an expansion cohort for further assessment of the safety and tolerability of sotrovimab in this patient population. In Phase 4, the first 10 patients receiving 2000mg IV of sotrovimab on the second sotrovimab infusion day (Treatment Day 2) will comprise a lead-in safety cohort that will inform the duration of observation following administration of the drug, with the observation period being reduced from two hours to one hour for the remaining study population if none of these patients have a grade 3-4 infusion-related reaction. The patients will be followed for safety and COVID-19 events for an additional 36 weeks after the second dose.Discussion: In a previous Phase III randomized, placebo-controlled pivotal trial, there were no significant differences in the prevalence of adverse events in patients receiving sotrovimab vs. placebo. Thus, we propose to study the safety and tolerability of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection and evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures over the course of the study.Trial registration: ClinicalTrials.gov Identifier: NCT05210101