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Preprint in English | MEDLINE | ID: ppcovidwho-326686


Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

Topics in Antiviral Medicine ; 29(1):304-305, 2021.
Article in English | EMBASE | ID: covidwho-1250563


Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.

Topics in Antiviral Medicine ; 29(1):210-211, 2021.
Article in English | EMBASE | ID: covidwho-1250023


Background: The relationship between nasopharyngeal (NP) SARS-CoV-2 RNA, demographics and symptom characteristics in non-hospitalized persons with COVID-19 is not well described. Methods: ACTIV-2 is a phase 2/3 adaptive platform trial testing antivirals for SARS-CoV-2 in symptomatic non-hospitalized adults. We analyzed associations between NP quantitative SARS-CoV-2 RNA (Abbott m2000sp/rt) and COVID-19 symptomatology in 284 participants with both a NP swab and symptom diary prior to study intervention. The diary included 13 targeted symptoms and questions about overall severity of COVID-19 symptoms, each scored as none, mild, moderate, or severe (and very severe for overall severity) and general physical health (scored as poor, fair, good, very good, excellent). Wilcoxon tests were used to compare NP RNA levels between pre-defined groups. Spearman correlations, Jonchkeere-Terpstra trend tests, and linear regressions evaluated associations between symptom measures and NP RNA. Results: Participants were 49% female, 82% white, 9% black, and 27% Latinx. Median age was 46 years and 50% met the protocol definition of higher risk for COVID-19 progression (age ≥55 years and/or protocol-defined comorbidities);32% reported moderate and 5% severe symptoms. Median (Q1, Q3) time from onset of symptoms to NP swab/symptom assessment was 6 (4, 8) days. NP RNA was above the lower limit of quantification in 85%;median (Q1, Q3) was 5.4 (3.5, 6.8) log10 copies/mL. Higher RNA levels were associated with shorter symptom duration (median 6.5 vs 4.7 log10 copies/mL for ≤5 vs >5 days) but not total symptom score (Figure). Controlling for symptom duration, higher NP RNA levels were associated with better general physical health (p=0.02) and more severe body/muscle pain (p=0.04). No associations were observed with symptom severity (sum of scores or overall severity) or any other symptoms. There was no association between NP RNA and age or risk category for COVID-19 progression. Conclusion: In symptomatic outpatients, NP SARS-CoV-2 RNA levels were higher in persons with more recent symptom onset, but were not associated with symptom severity or risk for disease progression. The range of viral RNA shedding was remarkably similar across the range of symptom severity, suggesting symptom severity may not correlate with transmission risk or the potential to respond to antiviral therapy. Outpatient trials aimed at evaluating antiviral activity of new agents should focus enrollment on participants with recent onset of symptoms. (Figure Presented).