Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.

PURPOSE: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER: NCT04575597.

Rotavirus meningitis in an adult with transient aphasia.

We identified an additional case of documented Rotavirus meningitis in an adult with full medical history. A previously healthy 37-year-old patient presented herself for transient aphasia associated with fever and headaches at the end of a one-week history of gastroenteritis. Cerebrospinal fluid (CSF) analysis revealed lymphocytic meningitis, and treatment with aciclovir was initiated. Rotavirus A reverse transcription-polymerase chain reaction (RT-PCR) was positive in CSF and the patient's stools in favor of Rotavirus meningitis. Testing for other viruses was negative. Magnetic resonance imaging (MRI) showed no signs of encephalitis. Aphasia was resolutive in less than 12 hours, and no neurological symptoms relapsed. All symptoms evolved favorably despite aciclovir discontinuation. Viral sequencing methods have recently identified unexpected viruses as potential causative agents in meningitis, including Rotavirus. We confirm the detectability of Rotavirus in the analysis of CSF in the context of Rotavirus gastroenteritis in an adult. This case suggests postviral headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome may be linked to previously undetected direct viral infection of the central nervous system. Therefore, clinicians should consider Rotavirus meningitis in diagnosing meningitis associated with gastroenteritis in adults.

Impact of Casirivimab-Imdevimab on Severe Acute Respiratory Syndrome Coronavirus 2 Delta Variant Nasopharyngeal Virus Load and Spike Quasispecies.

Background: The increasing use of monoclonal antibodies (mAbs) to treat coronavirus disease 2019 raises questions about their impact on the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mAb-resistant variants. We assessed the impact of Casirivimab-Imdevimab on SARS-CoV-2 mutations associated with reduced mAb activity in treated patients. Methods: We measured the nasopharyngeal (NP) viral load and sequenced the haplotypes of spike gene of 50 patients infected with the SARS-CoV-2 delta variant and treated with Casirivimab-Imdevimab using single-molecule real-time sequencing. Results: The NP SARS-CoV-2 viral load of patients treated with Casirivimab-Imdevimab decreased from 8.13 (interquartile range [IQR], 7.06-8.59) log10 copies/mL pretreatment to 3.67 (IQR, 3.07-5.15) log10 copies/mL 7 days later (P < .001). Of the 36 patients for whom follow-up timepoints Spike sequencing were available, none of the Spike mutations that reduced mAb activity were detected. Conclusions: Casirivimab-Imdevimab is an effective treatment for patients infected with the SARS-CoV-2 delta variant. Despite selective pressure on SARS-CoV-2 Spike quasispecies, we detected no key mutations that reduced mAb activity in our patients.

Impact of Casirivimab-Imdevimab on SARS-CoV-2 delta variant nasopharyngeal virus load and Spike quasispecies

Objectives The increasing use of monoclonal antibodies (mAbs) to treat COVID-19 raises questions about their impact on the emergence of SARS-CoV-2 mAb-resistant variants. We assessed the impact of Casirivimab-Imdevimab on SARS-CoV-2 mutations associated with reduced mAb activity in treated patients. Patients and methods We measured the nasopharyngeal (NP) viral load and sequenced the haplotypes of spike gene of 50 patients infected with the SARS-CoV-2 delta variant and treated with Casirivimab-Imdevimab using single-molecule real-time sequencing (SMRT). Results The NP SARS-CoV-2 viral load of patients treated with Casirivimab-Imdevimab decreased from 8.13 [IQR, 7.06-8.59] log10 copies/ml pre-treatment to 3.67 [IQR, 3.07-5.15] log10 copies/ml seven days later (p<0.001). Of the 36 patients for whom follow-up time-points Spike sequencing were available, none of the Spike mutations that reduced mAb activity were detected. Conclusion Casirivimab-Imdevimab is an effective treatment for patients infected with the SARS-CoV-2 delta variant. Despite selective pressure on SARS-CoV-2 Spike quasispecies, we detected no key mutations that reduced mAb activity in our patients.

Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies.

OBJECTIVES: To evaluate the impact of neutralizing monoclonal antibody (mAb) treatment and to determine whether the selective pressure of mAbs could facilitate the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with spike protein mutations that might attenuate mAb effectiveness. PATIENTS AND METHODS: We evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single-molecule real-time sequencing. The mAbs used were: Bamlanivimab alone (four patients), Bamlanivimab/Etesevimab (23 patients) and Casirivimab/Imdevimab (five patients). RESULTS: The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 copies/mL before administration to 4.3 log10 copies/mL 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAb activity-reducing spike mutations. Two patients harboured SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harboured a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in three of five patients. CONCLUSION: Two-mAb therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread should be reinforced.

Impact of previous exposure to systemic corticosteroids on unfavorable outcome in patients hospitalized for COVID-19.

BACKGROUND: The impact of prior exposure to systemic corticosteroids on COVID-19 severity in patients hospitalized for a SARS-CoV-2 pneumonia is not known. The present study was designed to answer to this question. METHODS: The population study was the Covid-Clinic-Toul cohort which records data about all hospitalized patients with a positive reverse transcriptase polymerase chain reaction for a SARS-CoV-2 infection at Toulouse University hospital, France. Exposure to systemic corticosteroids was assessed at hospital admission. A propensity score (PS) according to corticosteroid exposure was calculated including comorbidities, clinical, radiological and biological variables that impact COVID-19 severity. The primary outcome was composite, including admission to intensive care unit, need of mechanical ventilation and death occurring during the 14 days after hospital admission. Logistic regression models adjusted for the PS (overlap weighting) provided odds ratios (ORs) and their 95% confidence intervals (95% CIs). RESULTS: Overall, 253 patients were included in the study. Median age was 64 years, 140 patients (59.6%) were men and 218 (86.2%) had at least one comorbidity. Seventeen patients (6.7%) were exposed to corticosteroids before hospital admission. Chronic inflammatory disease (n = 8) was the most frequent indication. One hundred and twenty patients (47.4%) met the composite outcome. In the crude model, the OR of previous exposure to systemic corticosteroids was 1.64; 95% CI: 0.60-4.44. In the adjusted model, it was 1.09 (95% CI: 0.65-1.83). CONCLUSION: Overall, this study provide some evidences for an absence of an increased risk of unfavorable outcome with previous exposure to corticosteroids in the general setting of patients hospitalized for COVID-19.

Hydroxychloroquine in Coronavirus Disease 2019 Patients: What Still Needs to Be Known About the Kinetics.

Different dosage regimens of hydroxychloroquine are used to manage coronavirus disease 2019 (COVID-19) patients, without information on the pharmacokinetics in this population. Blood samples (n = 101) were collected from 57 COVID-19 patients for 7 days, and concentrations were compared with simulated kinetic profiles. Hydroxychloroquine exposure is low and cannot be predicted by other populations.

Outcome of patients hospitalized for COVID-19 and exposure to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in France: results of the ACE-CoV study.

Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID-19 with hypertension/cardiovascular disease, particularly in Europe. The ACE-CoV study was designed to assess this question. The study was conducted in the Covid-Clinic-Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS-CoV-2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid-Clinic-Toul included 263 patients. Among them, 111 were included in the ACE-CoV study population. In OW-PS-adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73-3.33). It was 0.99 (95% CI: 0.68-1.45) for ACEIs and 1.64 (95% CI: 0.77-3.50) for ARBs. Analyses with weighting by the IPTW-PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE-CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID-19 with a history of cardiovascular disease/arterial hypertension.