ABSTRACT
Background: Aim of the study was to analyze neutralizing activity against BA.5,BQ.1.1 and T cell response after 3rd booster dose [3BD (5th shot)] with BA.4/5 bivalent vaccine by hybrid immunity (HI) and CD4 count in advanced PLWH. Method(s): In PLWH with previous AIDS and/or CD4< 200/mm3 receiving 3BD (original strain/BA.4/5),immunogenicity was assessed at time of 3BD (T0) and at day 15 (T1) by microneutralization assay [MNA90] against Omicron BA.5, BQ.1.1 and by IFNgamma-ELISA. PLWH were stratified by HI vs. nHI and by CD4 count at T0 ( >or< 500/3). For crude mean comparisons, neutralizing antibodies (nAbs) were expressed in natural scale and fold changes, IFNgamma and all values for regression analyses in log2 scale, paired t-test used to test changes over T0-T1. Two 2-arms parallel trials were emulated: HI and CD4 count as exposure, log2 nAbs and IFNgamma as outcome. Average treatment effect (ATE) of the two exposures were estimated by marginal models weighted for potential confounders (age, CD4 nadir, years from AIDS;when HI was the exposure also CD4 count). Result(s): N=48 PLWH on ART, 15% female, median age 56 yrs, 45% >1 comorbidity, 87% with previous AIDS, median CD4 nadir 44 cell/mm3 (16-102), 98% with HIV-RNA < 50 cps/mL. A significant increase of nAbs against BA.5 (fold-increase 8.8,p< 0.0001) and BQ.1.1 (6.4, p< 0.0001) was observed from T0 to T1. At T1, in nHI (n=29), mean nAb was 176 and 53 against BA.5 and BQ.1.1, respectively, with a fold change reduction (FCR) vs BA.5 of 3.3;in HI (n=19), 496 and 128, respectively, with a FCR of 3.8 (Fig.1A). After controlling for confounders, HI was associated with a higher level of neutralizing response against BA.5 [ATE=1.17 log2 (95%CI 0.34;2.00), P=0.006] but not against BQ.1.1 [0.65 log2 (-0.18;1.48), p=0.124]. At T1, among PLWH with CD4 count< 500 (n=29), mean nAb was 290.8 and 83.9 against BA.5 and BQ.1.1, respectively, with a FCR of 3.4;in those with CD4 count >500 (n=19), 230.4 and 64.3, respectively, with a FCR of 3.6 (Fig. 1C).There was no impact of CD4 count on neutralization after controlling for potential confounding factors. No evidence for a difference between T0 and T1 was detected for IFNg (Fig.1B,D). Conclusion(s): In PLWH with advanced diseases, bivalent BA.5 3BD elicited strong neutralization against BA.5, and retained cross-neutralization against BQ.1.1, even if 3 times lower. HI but not CD4 count >500 appeared to enhance neutralization against BA.5. Importantly, bivalent vaccine appeared to have no effect on T-cell mediated response. (Figure Presented).
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: Early treatment for preventing severe outcome of COVID-19 in high-risk not-hospitalized patients (pts) by monoclonal antibodies or antivirals represented a high-priority approach. Real-world evidence (RWE) from observational studies could give information on clinical effectiveness and predictors of treatment failure. Method(s): Single-center observational study on SARS-CoV-2 pts, not requiring hospital admission but having high-risk of severe outcome from COVID-19. All were selected for early treatment with monoclonal antibodies or antivirals from March 2021 to November 2022. Participants were classified according to whether they were hospitalized due to severe COVID-19 or died by day 30 from starting treatment in the outpatient setting (baseline). We conducted a logistic regression analysis with this binary endpoint and 4 main exposures of interest measured at baseline: i) age ( >75 years old) ii) vaccination status iii) VoC, and iv) immunosuppression or having received immunosuppressive therapy. We built a separate model for each of these exposures, which included a specific set of potential confounders. Result(s): 3,491 pts, female 48.6%, median age 67 yrs (IQR 55-77), fully vaccinated 83.7%;previous infection 4.6%;CVD 52.2%;cancer 24.6%;immunodeficiency 40.6%. Prevalence of SARS-CoV-2 VoC: delta 8.7%, BA.1 16.9%, BA.2 6.8%, BA.4/5 12.2, BQ 0.1%, other 3.0% (Tab.1A). Treatment exposure was BAM/ETE 569 (16.5%), CAS/IMD 262 (7.6%), SOT 935 (27.1%), TIX/CIL 79 (2.3%), NMV/r 555 (16.1%), MLP 684 (19.8%), RDV 356 (10.3%). Primary endpoint occurred in 80/3,491 pts with a day-30 incident risk of 2.3% (95%CI 1.8-2.9). Tab.1B shows the unadjusted and adjusted odds ratios (OR) of hospitalization due to COVID-19 or death by day 30. After controlling for potential confounders, higher risk was observed for the unvaccinated (OR 1.95;95%CI 1.03-3.71) and for those affected by immunodeficiency [1.73;1.04-2.89). Having delta as reference variant, an increased risk was observed for BA.2 [2.08;1.00-2.34]. No evidence for a difference was seen by age or other comorbidities. Conclusion(s): In this RWE study, largely represented by vaccinated people and prevalently observed in the Omicron era, the estimated risk of clinical failure of early treatment was slightly higher than that recorded in the experimental arms of randomized studies. The analysis confirms that among those eligible for early treatment, the unvaccinated and those with severe immunodeficiency are at higher risk of developing severe COVID-19. Table 1 -A. Main characteristics of 3,491 not-hospitalized people with mildto-moderate COVID-19 at high risk of severe disease observed between March 2021 to November 2022 according to reaching (n=80) or not reaching (3,411) primary clinical endpoint. B. Odds ratios (OR) of having a COVID-19-related hospitalization or death by different exposure factors.