ABSTRACT
Background: Omicron subvariants questioned the efficacy of the approved therapies for the early COVID-19. In vitro data show that remdesivir (RDV), molnupiravir (MLN), and nirmatrelvir/ritonavir (NMV/r) all retained activity against all sub-lineages, while poor neutralizing activity was observed for Sotrovimab (SOT) and Tixagevimab/cilgavimab (TIX/CIL). No data about the risk of clinical failure or even in vivo antiviral activity are available. Method(s): Single-center observational comparison study enrolling all consecutive patients (pts) seen for care with a confirmed SARS-CoV-2 Omicron diagnosis and who met the AIFA criteria for eligibility for treatment with RDV, MLN, NMV/r, TIX/CIL, or SOT. Treatment allocation was subject to drug availability, time from symptoms onset, and comorbidities. Nasopharyngeal swab (NPS) VL was measured on day 1 (D1) and D7 and was expressed by log2 cycle threshold (CT) scale. Comparisons between treatment groups were made by Chi-square, and Wilcoxon paired tests. Primary endpoint was D1-D7 VL variation. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Result(s): A total of 971 pts received treatments (SOT 321, MLN 231, NMV/r 211, TIX/CIL 70, and RDV 138): female 457 (47%), median age 67 yrs (IQR 56-78), 93% vaccinated;12% with negative baseline serology. At D1, median time from symptoms onset was 3 days (IQR 2,4). 379 (39%) pts were infected with BA.1, 215 (22%) with BA.2, 372 with BA.4/5 (38%), and 5 with BQ.1 (0,5%). D1 mean viral load was 4.02 log2. Adjusted analysis (ATE) showed that NMV/r significantly reduced VL compared to all the other drugs in pts infected with all sublineages, (Fig.1A-B) while less evidence for a difference vs. TIX/CIL was seen in those infected with BA.2 (p=0.05) (Fig.1 C-D). Conclusion(s): In this analysis of in vivo early VL reductions, NMV/r appears to be the drug showing the greatest antiviral activity, regardless of the underlying subvariant, perhaps with the exception of TIX/CIL in people infected with BA.2 for which there was less evidence for a difference. In the Omicron era, due to the high prevalence of vaccinated people and in absence of clinical events, VL is one of the possible alternative endpoints which guarantees adequate statistical power. Fig 1 SARS-CoV-2 RNA levels at D1 and D7 in patients treated with Nirmatrelvir/ ritonavir, Sotrovimab, Molnupiravir, Remdesivir, and Tixagevimab/cilgavimab. Dot-plots showing the comparison of viral loads detected at D1 and D7 and the variation of RNA levels observed between the two time-points by intervention in (A) all patients treated with Nirmatrelvir/ritonavir (n=211), Sotrovimab (n=321), or Molnupiravir (n=231), or Remdesivir (n=138), or Tixagevimab/ cilgavimab (n=136);(C) patients with Omicron BA.2 infection treated with Nirmatrelvir/ritonavir (n=58), Sotrovimab (n=81), or Molnupiravir (n=21), or Remdesivir (n=37), or Tixagevimab/cilgavimab (n=18);(D) patients with Omicron BA.4/5 infection treated with Nirmatrelvir/ritonavir (n=102), Sotrovimab (n=92), or Molnupiravir (n=110), or Remdesivir (n=16), or Tixagevimab/cilgavimab (n=52). Viral RNA levels are expressed as log2 CT values. The horizontal dashed line represents the limit of detection (CT: 40.0), values >=40 are considered negative. Mean of log2 CT values, and SD are shown in the graph. Statistical analysis of the differences in viral loads by intervention as compared to Nirmatrelvir/ritonavir was performed by Mann-Whitney test. Potential decrease in VL and average treatment effect (ATE) were calculated from fitting marginal linear regression models weighted for calendar month of drug initiation, duration of symptoms, and immunodeficiency using NMV/r as the comparator trial arm. Results are shown (B) for patients infected with all Omicron sublineages and (D) for those infected with Omicron BA.2 sublineage.
ABSTRACT
Background: Although a full course of vaccine against Sars- Cov-2 is effective in most patients with MS (PwMS), the duration of the protection and the efficacy of a booster dose remain poorly explored, especially across different disease modifying treatments (DMTs). Aim(s): To characterize humoral and T-cell immune response along time and following third dose of COVID-19 vaccination in PwMS. Method(s): From an established cohort evaluated at baseline (T0), PwMS were recruited after 24 weeks (T1) from the first cycle of mRNA vaccine and 4 weeks after third dose (T2). At each timepoint we evaluated the serological response by measuring the anti- Region-Binding-Domain (RBD). Cell-mediated response was analyzed by computing interferon (IFN)-gamma in response to spike peptides. Result(s): The baseline cohort consisted of 134 PwMS [mean age 46.6+/-10.8 years;F:92;mean disease duration 15.1+/-9.4 years;26.9% ocrelizumab (OCR) 30.6% fingolimod (FTY), 16.4% cladribine (CLA), 26.1%IFN-s-1a (IFNB)]. Of them, 109 were reassessed at T1, 78 at T2 and 64 completed all evaluations. In the whole cohort there was a significant reduction (p<0.0001) in anti- RBD rate from T0 [76% positive, median 52.8 BAU/ml Interquartile Range (IQR) 1150.9] to T1 (57.8% positive, median 13.2 BAU/ml IQR 95.98] and a significant 20- and 5-fold increase in median titer at T2 (75% positive, median 272.3 BAU/ml IQR 4212.3) from T1 and T0 respectively (p<0.0001). Median IFN-gamma level at T2 was significantly higher than those evaluated at T1 (p<0.0001) and T0 (p=0.009). These latter results were consistent across all DMTs. At T1 the highest detectable anti-RBD response was found in CLA (100%, median 87.7 BAU/ml IQR 22) and IFNB (93.5%;median 126.3 BAU/ml IQR 149.2) cohort, while PwMS treated with FTY and OCR showed 60% (median 8.25 BAU/ml IQR 34.3) and 21% (median 0.8 BAU/ml IQR 6) rate of anti-RBD response respectively. At T2 100% PwMS showed positive anti-RBD response except those treated with OCR (23.8% positive, median 0.6 BAU/ml IQR 4.1). IFN-gamma-S-specific T-cell response was reduced in FTY cohort at both T1 and T2 (3.3 % positive, median 0.8 pg/ml IQR 3.1 and 0.6 pg/ml IQR 2.4 respectively). Conclusion(s): A third dose of COVID-19 vaccine reinforces both humoral and cell-mediated immune response in PwMS on DMTs. Despite vaccination, PwMS treated with OCR and FTY show lower humoral and T-cell specific immune response respectively, suggesting the need of specific treatment to halt COVID-19 in case of infection.
ABSTRACT
COronaVIrus Disease-2019 (COVID-19) is a pandemic respiratory infection caused by a new betacoronavirus, the Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2). Few data are reported on the gut microbiota in COVID-19 patients. 16S rRNA gene sequencing was performed to reveal an altered composition of the gut microbiota in patients with COVID-19 pneumonia admitted in intensive care unit (ICU) (i-COVID19), or in infectious disease wards (w-COVID19) as compared to controls (CTRL). i-COVID19 patients showed a decrease of Chao1 index as compared to CTRL and w-COVID19 patients indicating that patients in ICU displayed a lower microbial richness while no change was observed as for Shannon Index. At the phylum level, an increase of Proteobacteria was detected in w-COVID19 patients as compared to CTRL. A decrease of Fusobacteria and Spirochetes has been found, with the latter decreased in i-COVID19 patients as compared to CTRL. Significant changes in gut microbial communities in patients with COVID-19 pneumonia with different disease severity compared to CTRL have been identified. Our preliminary data may provide valuable information and promising biomarkers for the diagnosis of the disease and, when validated in larger cohort, it could facilitate the stratification of patients based on the microbial signature.