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: It is unclear if chronic immune dysfunction in HIV might affect immune response in COVID19. Our aim was to analyze the inflammatory profile and the immune response to COVID19 of a cohort of patients (pts) with a previous AIDS diagnosis and SARS-CoV-2 infection in an assisted living facility in which an outbreak occurred, and to compare them to HIV-negative COVID-19 patients and advanced HIV-positive without COVID-19. Methods: Levels of the inflammatory markers (IL1, IL6, IL8 and TNFα) were analyzed in advanced HIV+ pts without COVID-19 (group 1), in advanced HIV+ pts infected by SARS-CoV-2 (group 2) along with SARS-CoV-2 specific T-cell response, and in HIV-pts with mild/moderate COVID-19 consecutively hospitalized during the first pandemic wave (group 3). Inflammatory cytokines were quantified by automatic ELISA assay (ELLA system);antibodies titer was evaluated by Elisa assay (Diesse) and SARS-CoV-2 specific T cell response was quantified by Elispot assay. Mann-Whitney was used for comparison between each couple of groups Results: The analysis included group 1 (n=76 pts), group 2 (n=30), group 3 (n=58). Pts of group 1 and 2 did not differ by age, gender and duration of HIV infection. Median CD4 and CD8 was higher in group 2 vs group 1 (348/mm3 vs 118/mmc3 and 756 vs 518;p<.001). HIVRNA was <50cps/ml in 96.7% of pts in group 2 and 70% in group 1. HIV+/COVID19 pts had lower prevalence of COVID19 symptoms than HIV-uninfected COVID19 comparators (p<.001). Pneumonia was diagnosed in 66% of pts in group 2 and 86% in group 3 (p=0.141), and here was no difference for SpO2 at COVID19 diagnosis (p=0.146). 10% of pts in group 2 and 15% in group 3 died during follow-up (p=0.475). Of note, we observed significant higher level of IL6, IL8 and TNFα in group 3 vs group 2 (p<0.05) and group 1 (p<0.0001) (Figure 1). The median time to SARS-CoV-2 clearance was 18 (IQR 16-25) days in group 2, and 12 (IQR 6-23) days in group 3 (p=0.002). Focusing on group 2, 90% of pts showed positive antibodies titers and 100% positive SARS-CoV-2 specific T cell response, suggesting the ability to induce an effective specific immunity. Conclusion: These preliminary results suggest that HIV infection, even in advanced stage, did not seem to negatively impact on COVID-19-related inflammatory state. Moreover, specific immune response in these patients did not differ than that observed in HIV-negative COVID-19 pts. Further investigations are needed to better define the interplay between HIV and SARS-CoV-2.
ABSTRACT
SARS-CoV-2 serum neutralization assay represents the gold standard for assessing antibody-mediated protection in naturally infected and vaccinated individuals. In the present study, 662 serum samples collected from February 2020 to January 2021 from acute and convalescent COVID-19 patients were tested to determine neutralizing antibody (NAb) titers using a microneutralization test (MNT) for live SARS-CoV-2. Moreover, anti-SARS-CoV-2 IgG, IgA, and IgM directed against different viral antigens were measured by high-throughput automated platforms. We observed higher levels of NAbs in elderly (>60 years old) individuals and in patients presenting acute respiratory distress syndrome. SARS-CoV-2 NAbs develop as soon as five days from symptom onset and, despite a decline after the second month, persist for over 11 months, showing variable dynamics. Through correlation and receiver operating characteristic (ROC) curve analysis, we set up a testing algorithm, suitable for the laboratory workload, by establishing an optimal cutoff value of anti-SARS-CoV-2 IgG for convalescent plasma donors to exclude from MNT samples foreseen to have low/negative NAb titers and ineligible for plasma donation. Overall, MNT, although cumbersome and not suitable for routine testing of large sample sizes, remains the reference tool for the assessment of antibody-mediated immunity after SARS-CoV-2 infection. Smart testing algorithms may optimize the laboratory workflow to monitor antibody-mediated protection in COVID-19 patients, plasma donors, and vaccinated individuals.