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Virologic and Immunologic Characterization of COVID-19 Recrudescence after Nirmatrelvir/Ritonavir Treatment.

ABSTRACT: We isolated a SARS-CoV-2 BA.2 variant from a person with COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Antiviral sensitivity and neutralizing antibody testing were performed with both parental SARS-CoV-2 and multiple variants of concern. We found that neither NM resistance nor absence of neutralizing immunity were likely causes of the recrudescence.

SUBMITTER: Carlin AF

PROVIDER: S-EPMC9278181 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Virologic and Immunologic Characterization of Coronavirus Disease 2019 Recrudescence After Nirmatrelvir/Ritonavir Treatment.

Carlin Aaron F AF Clark Alex E AE Chaillon Antoine A Garretson Aaron F AF Bray William W Porrachia Magali M Santos AsherLev T AT Rana Tariq M TM Smith Davey M DM

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20230201 3

We isolated a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2 variant from a person with coronavirus disease 2019 recrudescence after nirmatrelvir/ritonavir treatment. Antiviral sensitivity and neutralizing antibody testing were performed with both parental SARS-CoV-2 and multiple variants of concern. We found that neither nirmatrelvir resistance nor absence of neutralizing immunity was a likely cause of the recrudescence. ...[more]

PMID: 35723411

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Project description:BackgroundNirmatrelvir/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.MethodsSix 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.ResultsHigh 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.ConclusionsNirmatrelvir/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 registrationNCT04401436.

Project description:Abstract Background Uptake of coronavirus disease 2019 (COVID-19) bivalent vaccines and the oral medication nirmatrelvir-ritonavir (Paxlovid) has remained low across the United States. Assessing the public health impact of increasing uptake of these interventions in key risk groups can guide further public health resources and policy and determine what proportion of severe COVID-19 is avertable with these interventions. Methods This modeling study used person-level data from the California Department of Public Health on COVID-19 cases, hospitalizations, deaths, and vaccine administration from 23 July 2022 to 23 January 2023. We used a quasi-Poisson regression model calibrated to recent historical data to predict future COVID-19 outcomes and modeled the impact of increasing uptake (up to 70% coverage) of bivalent COVID-19 vaccines and nirmatrelvir-ritonavir during acute illness in different risk groups. Risk groups were defined by age (≥50, ≥65, ≥75 years) and vaccination status (everyone, primary series only, previously vaccinated). We predicted the number of averted COVID-19 cases, hospitalizations, and deaths and number needed to treat (NNT). Results The model predicted that increased uptake of bivalent COVID-19 boosters and nirmatrelvir-ritonavir (up to 70% coverage) in all eligible persons could avert an estimated 15.7% (95% uncertainty interval [UI], 11.2%–20.7%; NNT: 17 310) and 23.5% (95% UI, 13.1%–30.0%; NNT: 67) of total COVID-19–related deaths, respectively. In the high-risk group of persons ≥65 years old alone, increased uptake of bivalent boosters and nirmatrelvir-ritonavir could avert an estimated 11.9% (95% UI, 8.4%–15.1%; NNT: 2757) and 22.8% (95% UI, 12.7%–29.2%; NNT: 50) of total COVID-19–related deaths, respectively. Conclusions These findings suggest that prioritizing uptake of bivalent boosters and nirmatrelvir-ritonavir among older age groups (≥65 years) would be most effective (based on NNT) but would not address the entire burden of severe COVID-19. This modeling study, in collaboration with the California Department of Public Health, found prioritizing additional uptake of bivalent vaccines and nirmatrelvir-ritonavir among older age-groups would effectively reduce the number of severe COVID-19 cases but would not address the entire burden.

Project description:BackgroundData are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR).ObjectiveTo compare the frequency of VR in patients with and without N-R treatment for acute COVID-19.DesignObservational cohort study.SettingMulticenter health care system in Boston, Massachusetts.ParticipantsAmbulatory adults with acute COVID-19 with and without use of N-R.InterventionReceipt of 5 days of N-R treatment versus no COVID-19 therapy.MeasurementsThe primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL.ResultsCompared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected.LimitationsObservational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission.ConclusionVirologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus.Primary funding sourceNational Institutes of Health.

Dataset Information

Virologic and Immunologic Characterization of COVID-19 Recrudescence after Nirmatrelvir/Ritonavir Treatment.

Publications

Virologic and Immunologic Characterization of Coronavirus Disease 2019 Recrudescence After Nirmatrelvir/Ritonavir Treatment.

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