ABSTRACT
Background: SARS-CoV-2 Omicron sublineages exhibit evolving escape to in vitro neutralization by monoclonal antibodies (mAbs), with an unclear impact on in vivo treatment response. Our aim is to assess the impact of SARS-Cov-2 variants on the decline of viral load (VL) after treatment with 3 different drugs approved in EU for the early treatment of patients with mild-moderate COVID-19. Method(s): Post-hoc analysis from MONET (EudraCT: 2021-004188-28), phase 4 open-label RCT to assess efficacy of 500 mg intravenous sotrovimab (SOT), 600 mg intramuscular tixagevimab/cilgavimab (TIX/CIL) and oral 5-days course of NMV/r 300/100 mg BID, in non-hospitalized high-risk patients (pts) with early COVID-19. Pts' features were analyzed as binary variables by Chi-squared test. SARS-Cov-2 VL in nasopharyngeal swabs was carried out at randomization (1d) and at day 7 (7d) by cycle threshold value (Ct). Variant sequencing was performed at 1d. Ct variation was assessed by mixed effect log-linear model including random intercept at pts' level, log of Ct as independent variable, time, arm, viral variant as dependent variables, and interaction between time and arm. Multiple comparisons were adjusted by Bonferroni. Result(s): Among the 320 pts included between 4 Mar and 16 Nov, 2022, 108 (33.75%) received NMV/r, 103 (32.19%) TIX/CIL, and 109 (34.06%) SOT. Main characteristics were balanced across arms. Most of the pts were infected either with BA.2 (N=194;60.63%) or BA.4/BA.5 (N=100;31.25%) (Fig1A). VL at 1d was similar across the arms. In contrast, mean 7d VL was significantly lower in pts receiving NMV/r than in those receiving TIX/ CIL or SOT (P< 0.001) No significant VL variation was observed between the mAb arms (Fig1B). The analysis of the impact of viral variants suggests that while VL was significantly affected by variants (P=0.034), the superior effect of NMV/r over mAbs was homogeneous across all variant groups (P=0.290 for interaction) (Fig1C). Conclusion(s): Our study provides for the first time strong in vivo evidence that, when used against Omicron lineages, NMV/r exerts a stronger antiviral effect than mAbs. These results confirm previous in vitro evidence suggesting that mAbs may not retain neutralizing activity against all Omicron sublineages and provide preliminary information on how to use VL variation as a surrogate marker of efficacy. Further studies are needed to investigate whether the superior virologic activity of NMV/r over mAbs is confirmed for newly emerging variants, including BQ.1.1 or XBB.
ABSTRACT
Background: Few data are available about comparison of different monoclonal antibodies (MAbs) for COVID-19 in the real-world setting. We aim to compare effectiveness of bamlanivimab/etesevimab (BAM/ETE) versus (vs) casirivimab/imdevimab (CAS/IMD) and to estimate predictors of hospitalization/death. Methods: Observational analysis of all consecutive outpatients (pts) with mild/moderate COVID-19 enrolled within the AIFA access program in a single center in Rome, from March to October, 2021. At first baseline (BL) visit, RT-PCR from nasopharyngeal swab with cycle thereshold (CT) measurement and viral sequencing was performed. Pts received intravenous BAM/ETE (700/1400 mg) or CAS/IMD (1200/1200 mg) and were followed through day 30. Primary endpoint was hospitalization/death due to severe COVID-19 by day 30. Average treatment effect (ATE) in the multiplicative scale of the odds was the chosen estimand to compare the two treatments, adjusted for age, obesity, time from onset to infusion, median C-reactive protein (CRP), vaccination, variant of concern (VOC) and BL-CT. Predictors of clinical failure were explored by two different models of multivariable logistic regression. Results: 242 pts receiving BAM/ETE (n=76) or CAS/IMD (n=166) were included (male 54%;median age 65 yrs;median SpO2 97%;diabetes 12%;hypertension 40%;CVD 17%;COPD 26%;autoimmune diseases 12%;immunodeficiency 18%). Median time from symptoms onset to infusion was 4 days (IQR 3-6). No differences were observed between the two MAbs for BL characteristics except for BMI>35 (BAM/ETE 24%, CAS/IMD 12%), CRP (BAM/ETE 1.8, CAS/IMD 1.2), vaccination (BAM/ETE 26%, CAS/IMD 46%) and distribution of VOC (Alpha 46% BAM/ETE vs 22% CAS/IMD;Gamma 20% vs 7%;Delta 5% vs 55%). Proportion of patients with COVID-related hospitalization/death by day 30 was 12/76 (15.8%) for BAM/ETE and 6/166 (3.6%) for CAS/IMD. Estimate of causal effect of BAM/ETE exposure compared to CAS/IMD on primary end point by ATE is reported in Table 1a. Factors associated with an increased risk of clinical failure by fitting multivariable logistic regression were BMI >35 and P1/Gamma VOC;higher BL-CT was associated with a reduced risk (Table 1b-1c). Conclusion: In a real-life setting, receiving BAM/ETE was associated with a 4-fold higher risk of COVID-19 progression to hospitalization/death than CAS/IMD. SARS-CoV-2 P.1/Gamma, but not B.1617.2/Delta VOC, obesity and higher BL viral load also predicted an increased risk of clinical worsening.
ABSTRACT
Plain language summary Achievement of elimination of HCV as a major public health threat requires focus on vulnerable populations such as people in prison. The prison population is at high risk of HCV infection but their treatment is complicated by social issues such as mental health disorders and drug use. Simple and effective treatment regimens are required to increase access to treatment and improve cure rates. This real-world analysis across Europe and Canada analyzed data from 20 prison populations. HCV-infected individuals were treated with sofosbuvir/velpatasvir, a once daily treatment which requires minimal monitoring. This regimen achieved high cure rates in the prison population despite the existence of complicating social issues. Background: People in prison are at high risk of hepatitis C virus (HCV) infection and often have a history of injection drug use and mental health disorders. Simple test-and-treat regimens which require minimal monitoring are critical. Methods: This integrated real-world analysis evaluated the effectiveness of once daily sofosbuvir/velpatasvir (SOF/VEL) in 20 prison cohorts across Europe and Canada. The primary outcome was sustained virological response (SVR) in the effectiveness population (EP), defined as patients with a valid SVR status. Secondary outcomes were reasons for not achieving SVR, adherence and time between HCV RNA diagnosis and SOF/VEL treatment. Results: Overall, 526 people in prison were included with 98.9% SVR achieved in the EP (n = 442). Cure rates were not compromised by drug use or existence of mental health disorders. Conclusion: SOF/VEL for 12 weeks is highly successful in prison settings and enables the implementation of a simple treatment algorithm in line with guideline recommendations and test-and-treat strategies.
ABSTRACT
Infections are the most important cause of mortality in multiple myeloma (MM) patients. In the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pandemic, known as COVID-19, hematologic malignancies represent an important risk factor for COVID-19- associated deaths. Based on this data, there are major concerns over the outcome of COVID-19-infected MM patients. Recently published data showed that MM patients seem to be associated with higher risk of poor COVID-19 outcomes, due to both cancer and chemotherapy- related immune dysfunctions. Old age, renal impairment and acquired thrombophilia can be considered as additional risk factors of poor prognosis of COVID-19 disease in MM patients. We hereby, report the retrospective data on the baseline characteristics and outcome of COVID-19 infection in MM patients, collected by the MM GIMEMA Lazio Group. Between February and December 2020, data from 56 patients with MM and SARS-Cov-2 infection were reported from 13 Italian centers. The highest rate (80%) of SARS-Cov-2 infections occurred in October and November. The patients were 32 male (57%) and 24 female (43%). Median age was 68 years (range 44-88). At the time of COVID-19 infection, 31 patients were newly diagnosed with MM (55%), with 27 patients receiving first-line therapy;22 patients experienced relapse (39%) and 3 patients were in follow-up (5.4%). Overall, 46 patients were on active MM treatment (82%), 5 patients had previously received therapy within the last 12 months (8.9%) and 1 patient had been off-therapy for more than 12 months (1.8%). The recurrent MM therapy was immunomodulatory (IMiDs)-based regimens (37%), followed by combination of IMiDs and proteasome inhibitors (PIs) (28%), PIs-based regimens (16%) and monoclonal antibody-based regimens (17%);1 patient received autologous stem cell transplant (2%). Patients were confirmed positive by Sars-Cov2- tests using RT-PCR obtained from nasopharyngeal swabs. Patients with symptomatic infections were 54 (96.4%);2 patients had no symptoms (3.6%). The most common symptoms were fever (43%), followed by coughing, anosmia, dysgeusia and rhinitis. Pneumonia became a complication in 38 cases (68%) and 12 patients showed acute respiratory distress syndrome (ARDS) (21%). Patients requiring hospitalization were 39 (70%). We focused on analyzing hospitalized patients. The COVID-19 therapies were heterogeneous with the most frequent therapy including a combination of high-dose steroids, low-molecular-weight heparin and antibiotics. Remdesivir was used in 7 patients (32%);while 5 patients required mechanic ventilation (23%). The combination therapy based on antipyretics, pre-emptive heparin, oral steroids and antibiotics was the most common approach for non-hospitalized patients (30%). One patient required outpatient oxygen therapy. Three patients recovered without any treatment (10%). We analyzed possible variables influencing hospitalization and outcome. Univariate analysis identified a positive correlation between pneumonia and hospitalization (p<0.001). Pneumonia and ARDS were correlated with worse outcomes (p=0.003 and p=0.045). Hospitalization (p=0.007) and active anti-MM treatment (p=0.014) were correlated with poor outcomes. Twenty-two patients (39%) died following COVID-19 infections. Our data confirms the high mortality rate in hospitalized MM patients with COVID-19. Further studies are warranted to identify high-risk MM patients and effective pre-emptive strategies.