tetano
Editor, Senior Moderator
Clin Infect Dis
. 2022 Oct 6;ciac663.
doi: 10.1093/cid/ciac663. Online ahead of print.
Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment
Brian P Epling[SUP] 1 [/SUP], Joseph M Rocco[SUP] 1 [/SUP], Kristin L Boswell[SUP] 2 [/SUP], Elizabeth Laidlaw[SUP] 1 [/SUP], Frances Galindo[SUP] 1 [/SUP], Anela Kellogg[SUP] 3 [/SUP], Sanchita Das[SUP] 4 [/SUP], Allison Roder[SUP] 5 [/SUP], Elodie Ghedin[SUP] 5 [/SUP], Allie Kreitman[SUP] 5 [/SUP], Robin L Dewar[SUP] 6 [/SUP], Sophie E M Kelly[SUP] 7 [/SUP], Heather Kalish[SUP] 7 [/SUP], Tauseef Rehman[SUP] 6 [/SUP], Jeroen Highbarger[SUP] 6 [/SUP], Adam Rupert[SUP] 8 [/SUP], Gregory Kocher[SUP] 9 [/SUP], Michael R Holbrook[SUP] 9 [/SUP], Andrea Lisco[SUP] 1 [/SUP], Maura Manion[SUP] 1 [/SUP], Richard A Koup[SUP] 2 [/SUP], Irini Sereti[SUP] 1 [/SUP]
Affiliations
Abstract
Background: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.
Methods: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.
Results: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.
Conclusions: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. Clinical trials registration. NCT04401436.
Keywords: COVID-19; COVID-19 rebound; COVID-19 transmission; antiviral therapy; nirmatrelvir/ritonavir.
. 2022 Oct 6;ciac663.
doi: 10.1093/cid/ciac663. Online ahead of print.
Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment
Brian P Epling[SUP] 1 [/SUP], Joseph M Rocco[SUP] 1 [/SUP], Kristin L Boswell[SUP] 2 [/SUP], Elizabeth Laidlaw[SUP] 1 [/SUP], Frances Galindo[SUP] 1 [/SUP], Anela Kellogg[SUP] 3 [/SUP], Sanchita Das[SUP] 4 [/SUP], Allison Roder[SUP] 5 [/SUP], Elodie Ghedin[SUP] 5 [/SUP], Allie Kreitman[SUP] 5 [/SUP], Robin L Dewar[SUP] 6 [/SUP], Sophie E M Kelly[SUP] 7 [/SUP], Heather Kalish[SUP] 7 [/SUP], Tauseef Rehman[SUP] 6 [/SUP], Jeroen Highbarger[SUP] 6 [/SUP], Adam Rupert[SUP] 8 [/SUP], Gregory Kocher[SUP] 9 [/SUP], Michael R Holbrook[SUP] 9 [/SUP], Andrea Lisco[SUP] 1 [/SUP], Maura Manion[SUP] 1 [/SUP], Richard A Koup[SUP] 2 [/SUP], Irini Sereti[SUP] 1 [/SUP]
Affiliations
- PMID: 36200701
- DOI: 10.1093/cid/ciac663
Abstract
Background: Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.
Methods: Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.
Results: High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.
Conclusions: Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. Clinical trials registration. NCT04401436.
Keywords: COVID-19; COVID-19 rebound; COVID-19 transmission; antiviral therapy; nirmatrelvir/ritonavir.