Real world use of Tixagevimab/Cilgavimab pre-exposure prophylaxis of COVID-19 in immunocompromised individuals: data from the OCTOPUS study. (preprint)

We report real world use over time in immunocompromised subjects receiving tixagevimab/cilgavimab (T/C) pre-exposure prophylaxis (PrEP). Observational study on participants receiving T/C PrEP stratified: never had COVID-19 (NoC), hybrids (H) and breakthrough infections (BTIs) if COVID-19 before or after PrEP, respectively. Anti-RBD IgG and BA.5 neutralizing antibodies (nAbs), mucosal IgG, T-cell immunity at the administration of T/C (T0), 3 (T1), 6 (T2), and 9 (T3) months after, were measured. Comparison of markers in each group across timepoints, Poisson regression model for BTIs incidence rate ratios were performed. N=231 participants: median age 63 years (IQR 54.0-73.0), 84% hematological disease, median vaccine dose of three. N=72 NoC, 103 H and 56 (24%) BTIs, mostly mild/moderate, IR 4.2 (95%CI 3.2-5.4) BTIs/100 patients-months, no factors associated with. A significant increase of anti-RBD IgG at T1 was observed in all the groups, with a decline at T2. GMTs of anti-BA.5 nAbs were low at T1 for all the groups and around/below the cut off. No changes of IFN-γ. Overall, a mucosal response was observed at T1. An incidence of 24% of mild/moderate BTIs was observed. Anti-RBD IgG levels persistence was ensured, BA.5 nAbs were low/undetectable, cellular T immunity remained stable.

Limited BA.5 neutralization by pre-exposure prophylaxis with tixagevimab/cilgavimab in CAR-T treated people (preprint)

CAR T-cell recipients experience profound B-cell aplasia and hypogammaglobulinemia, being unable to mount any humoral response and at higher risk for severe COVID-19. Tixagevimab/cilgavimab has been approved for COVID-19 pre-exposure prophylaxis (PrEP) in immunocompromised people. 150/150 mg of tixagevimab/cilgavimab does not adequately neutralize against Omicron BA.5 and these results support recommendations on dose increase to 300/300 mg for prophylaxis in order to enhance effectiveness probability, until the European regulatory agency makes a decision on the usability of this compound as the FDA has already done

Prolonged SARS-CoV-2 infection successfully treated with a consecutive combined scheme therapy in an HIV- positive patient with AIDS (preprint)

Purpose Cases of persistent infection have already been widely described with some proposals for combination or extended course therapies in immunocompromised subjects, but nothing has been addressed in AIDS patients. We present a case of prolonged, mild SARS-CoV-2 infection that was successfully treated with a consecutive combined scheme of therapy. Methods/Results A prolonged shedding of SARS-CoV-2 was observed up to 92 days and the COVID-19 clinical manifestation was mild without evidence of pneumonia and/or acute respiratory insufficiency. The infection was not cleared after the first treatment with remdesivir IV as early treatment (for 3 days) suggesting a limited effect on SARS-CoV-2 in an immunocompromised individual. Several weeks later, a second therapeutic attempt was made with tixagevimab/cilgavimab 300/300 IM but SARS-CoV-2 RNA was still detected for further 5 weeks. A third attempt with nirmatrelvir/ritonavir determined the definitive viral clearance of SARS-CoV-2 after 92 days since the first detection. Conclusion Our data indicate that certain immunocompromised individuals may shed infectious virus longer and need a tailored and valuable therapeutics approach. Additional data from clinical trials are required to support a feasible approach to managing this vulnerable group of patients.

What is the impact of post-COVID-19 syndrome on health-related quality of life and associated factors: a cross-sectional analysis (preprint)

Background. After the acute phase, symptoms or sequelae related to post-COVID-19 syndrome may persist for months. We aim to measure their impact on health-related quality of life (HRQoL) and to investigate influencing factors, among patients, previously hospitalized and not, followed up to 12 months.Methods. We present the cross-sectional analysis of a prospective study, including patients referred to the post-COVID-19 service. Questionnaires and scales administered at 3, 6, 12 months were: Short-Form 36-item questionnaire (SF-36); Visual Analogue Scale of the EQ5D (EQ-VAS); in a subgroup, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II) and Pittsburgh Sleep Quality Index (PSQI). Linear regression was used to assess for the presence of a trend over time by month of evaluation after the acute infection (continuous measure in month); two different linear regression models were fitted to identify factors associated with HRQoL.Results. We considered the first assessment of each participant (n = 572): 235 (41%), 175 (31%) and 118 (21%) patients were evaluated 3 months [median 3.5 (IQR 2.9-3-9)], 6 months [5.6 (5.0-6.5)], and more than 6 months [9.6 (8.3–14.7)], after the acute infection, respectively. The mean scores in SF-36 and in EQ-VAS were significantly lower than the Italian normative values and remained stable over time, except the mental components score (MCS) of the SF-36 and EQ-VAS which resulted in lower ratings at the last observations. Female gender, presence of comorbidities, and corticosteroids treatment during acute COVID-19, were associated with lower scores in SF-36 and EQ-VAS; patients previously hospitalized (54%) reported higher MCS. Alterations in BAI, BDI-II, and PSQI, evaluated in a subgroup of 265 participants, were associated with lower ratings in SF-36 and EQ-VAS.Conclusions. This study provides evidence of a significantly bad perception of health status among persons with post-COVID-19 syndrome, associated with female gender and, indirectly, with disease severity. In case of anxious-depressive symptoms and sleep disorders, a worse HRQoL was also reported. A systematic monitoring of these aspects is recommended to properly manage the post-COVID-19 period.

In vivo virological efficacy of monoclonal antibodies and direct antiviral agents against the SARS-CoV-2 BA.1 and BA.2 Omicron sublineages (preprint)

Background Omicron variant questioned the efficacy of the approved therapies for the early COVID-19. In vitro data show retained neutralizing activity against BA.1 and BA.2 for remdesivir (RDV), molnupiravir (MLN), and nirmatrelvir/ritonavir (NRM/r), while poor efficacy for Sotrovimab (STR) against BA.2. No data about the risk of clinical failure and in vivo antiviral activity are available. Material and methods Single-center observational comparison study enrolling all consecutive patients with a confirmed SARS-CoV-2 Omicron (BA.1 or BA.2) diagnosis and who met eligibility criteria for treatment with RDV, MLN, NRM/r, or STR. Treatment allocation was subject to drug availability, time from symptoms onset, and comorbidities. Patients were followed through day 30. Nasopharyngeal swab (NPS) VL was measured on day 1 (D1) and D7 and was expressed by log2 cycle threshold (CT) scale. Comparisons between groups were made by Chi-square and Wilcoxon paired-test. 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 infusion, duration of symptoms, and immunodeficiency. Secondary endpoints were the proportion of D7 undetectable VL in NPS and clinical outcomes compared by treatment groups using a Chi-square test. Results A total of 521 pts received treatments (STR 202, MLN 117, NRM/r 84, and RDV 118): female 250 (48%), median age 66 yrs (IQR 55-76), 90% vaccinated; 15% with negative baseline serology. At D1, median time from symptoms onset was 3 days (2,4). 378 (73%) pts were infected with BA.1 and 143 (27%) with BA.2. D1 mean viral load was 4.12 log2 (4.16 for BA.1 and 4.01 for BA.2). The adjusted analysis showed that NRM/r significantly reduced VL compared to all the other drugs in pts infected with BA.1 while no evidence for a difference vs. MLP was seen in those infected with BA.2. MLN had comparable activity to STR against BA.1 and to NRM/r against BA.2. There was no significant difference between STR and RDV for BA.2. At D7, 35/521 (6.7%) pts had undetectable VL. Of these, 31 were infected with BA.1 [9 (9%) MLN, 7 (14%) NRM/r, 7 (8%) RDV, and 8 (5%) STR)], and only 4 with BA.2, all treated with NRM/r. After 30 days of follow-up, 9/568 pts experienced COVID-19-related clinical failure [7/226 STR (5 BA.1) and 2/87 NRM /r (2 BA.1)]. Conclusions In this analysis of in vivo early VL reductions, NRM/r appears to be the drug showing the greatest antiviral activity regardless of the VoC, together with MLN, although the latter limited to people with BA.2. In the Omicron era, due to the high prevalence of vaccinated people and the lower probability of hospital admission, VL decrease can be a valuable surrogate of drug activity.

Emulation of a target trial from observational data to compare effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for early treatment of non-hospitalized patients with COVID-19 (preprint)

Objectives Comparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta. Methods Allocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7. Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period. Results COVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% -1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharingeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7. Conclusions In a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.

Prophylactic heparin and risk of orotracheal intubation or death in patients with mild or moderate COVID-19 pneumonia (preprint)

Prophylactic low molecular weight heparin (pLMWH) is currently recommended in COVID-19 to reduce the risk of coagulopathy.  The aim of this study was to evaluate whether the antinflammatory effects of pLMWH could translate in lower rate of clinical progression in patients with COVID-19 pneumonia.Patients admitted to a COVID-hospital in Rome with SARS-CoV-2 infection and mild/moderate pneumonia were retrospectively evaluated. The primary endpoint was the time from hospital admission to orotracheal intubation/death (OTI/death).  A total of 449 patients were included: 39% female, median age 63 (IQR, 50-77) years. The estimated probability of OTI/death for patients receiving pLMWH was: 9.5% (95%CI 3.2-26.4) by day 20 in those not receiving pLMWH vs. 10.4% (6.7-15.9) in those exposed to pLMWH;p-value=0.144. This risk associated with the use of pLMWH appeared to vary by PaO2/FiO2 ratio: aHR 1.40 (95%CI 0.51-3.79) for patients with an admission PaO2/FiO2 < 300 mmHg and 0.27 (0.03-2.18) for those with PaO2/FiO2 >300 mmHg;p-value at interaction test 0.16. pLMWH does not seem to reduce the risk of OTI/death mild/moderate COVID-19 pneumonia, especially when respiratory function had already significantly deteriorated. Data from clinical trials comparing the effect of prophylactic vs. therapeutic dosage of LMWH at various stages of COVID-19 disease are needed.