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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).
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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.
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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.
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Background: Antivirals and monoclonal antibodies (mAbs) were approved for early treatment of COVID-19 based on data from trials conducted in unvaccinated people before the Omicron era. The comparative effectiveness of different treatments is unknown. We present the results of the interim analysis of MONET trial (EudraCT: 2021-004188-28). Method(s): In this ongoing multicenter, open-label, phase 4 trial, we randomly assigned, in a 1:1:1 ratio, non-hospitalized patients with early symptomatic Covid-19 (<=5 days after symptoms onset) and >=1 risk factor for disease progression, to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TIX/CIL) or oral 5-days course of NMV/r 300/100 mg BID. Primary outcome was hospitalization or death for any cause within 29 days after randomization, reported as cumulative incidence per 100 (95% CI), and P-value calculated by Fisher's exact test. Inflammatory marker (CRP, d-dimer, and neutrophils-to-lymphocytes ratio) and antibody level (serum anti-S IgG and anti-N IgG) analysed by mixed linear regression with random intercept and P-values for time trend calculated by ANOVA-style test with Bonferroni correction. Result(s): Prespecified interim analysis, including 400 patients (SOT =133, TIX/ CIL=130, NMV/r=137) enrolled from Mar 4 to Nov 16, 2022 (Fig.1A). Overall, 5 pts (3/5 immunosuppressed) had disease progression leading to hospitalization [1.25% (95% CI 0.4%-2.89%)], 1 in SOT (0.75%, 95% CI 0.01%-4.1%), 4 in TIX/CIL (3.08%, 95% CI 0.84%-7.69%) and none in NMV/r arm (P=0.030). No deaths or ICU admissions were observed. Among the hospitalized pts, 3 were infected with BA.2 (1 SOT, 2 TIX/CIL), one with BA.4/5, and one BQ.1.1 (both TIX/ CIL). No serious adverse events and no kidney or liver toxicity were reported. Temporal trend of inflammation markers was similar in the three arms, and their estimates are shown in Fig.1B. Kinetics of antibody was reported in Fig.1C. The plot shows a rapid increase of anti-S in both mAb arm and a linear increase of IgG in the NMV/r arm. Anti-N IgG kinetics was similar in the three arms. Conclusion(s): By these data the overall cumulative risk of clinical failure in mild Covid-19 occurring in the Omicron era is low. The hypothesis that differences in clinical progression among the three arms could be related to different activity against the Omicron subvariant observed in vitro should be further investigated. Type of treatment does not seem to influence the development of the natural antibody response.
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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.
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Background: Insomnia, mood decline, anxiety, and cognitive impairment are described following COVID-19, and the mechanisms underlying these symptoms are not fully clarified. Aims of this analysis were to describe prevalence and predictors of impaired neuropsychological performance after COVID-19. Methods: We included patients referred to the post-COVID19 service with and without a previous hospitalization (PH and nPH, respectively) assessed at 3,6 and 12 months (3M,6M,12M) post-COVID19. Patients underwent to a comprehensive neuropsychological assessment using a standardized battery of 10 tests across 4 domains (speed of information processing, /executive, attention/working memory, memory). Neurocognitive impairment (NCI) was defined by: score >1 standard deviation (SD) below the mean on at least 2 tests, or >2 SD below 1 test. Change in NPZ-10 (mean, SD) was analyzed as an outcome. In addition, the Beck Anxiety Inventory (BAI), the Beck Depression Inventory (BDI) and the Pittsburgh Sleep Quality Index (PSQI) were administered. Mann-Whitney and Chi-square tests were used for comparisons, and logistic and linear regression were used to identify factors associated with test results. Results: N=302 participants: median age of 55 years (IQR 47-61), 52% female, median education of 13 yrs (13-18), 63% with >1 comorbidity, 58% PH (mainly males, higher age and higher BMI vs nPH). Overall, the prevalence of NCI was 42%, higher in PH vs nPH (46% vs 36%;p=0.07) (Figure 1a) with a not statistically significant mean decrease of NPZ10 [-0.12 (0.49)]. More in detail, we observed a significant decrease of z-score in the speed of information processing domain in PH vs nPH [-0.29(0.48) vs-0.12(0.31);p<0.001]. NCI prevalence resulted significantly higher in PH vs nPH only at 3M (Figure 1b). A higher proportion of nPH vs PH complained anxiety (BAI>85%) at 3M [55.6% vs 31.4%);p=0.028], sleep disturbances were more frequent in PH vs nPH at 3 and 12M (Figure 1d,c). Male gender appear to be the only associated factor with a lower alteration of BAI>85% and PSQI>5 [OR 0.28 (0.12-0.65);p=0.003;0.22 (0.09-0.52);p=0.001;respectively]. No predictors of NCI or BDI>85% were found. Conclusion: Our preliminary data show a consistent prevalence of NCI, significantly higher in PH vs nPH. This finding remains quite stable up to 12 months of observation. Also a worse sleep quality in PH was observed. Women seem to be at higher risk of anxiety-depressive and sleep disorders than men.
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Background: In Italy in September 2021, administration of a booster shot (BS) of COVID-19 vaccine was approved for PLWH with advanced disease (current CD4 count<200 cell/mm3 and/or previous AIDS). The aim of this analysis was to investigate the degree of immunogenicity after BS by current CD4 count. Methods: In PLWH attending INMI Spallanzani Hospital in Rome, Italy and receiving a BS of BNT162b2 or mRNA-1273 >28 days after a complete mRNA vaccination cycle, immunogenicity was assessed at time of BS (T0) and at day 15 (T1) by anti-RBD CLIA, microneutralization assay [MNA90] and IFNγ production. Participants were stratified by CD4 count at T0 (severe immunodeficiency, SID: <200/mm3;minor immunodeficiency, MID: 200-500/mm3;no immunodeficiency, NID: >500/mm3). Immune response was defined: anti-RBD >7.1 BAU/mL, MNA90 titres >1:10 and IFNγ >12 pg/mL. A paired t-test was used to test overall changes (log2 scale) over T0-T1. ANOVA and truncated regression models were used to compare change in titers from T0 to T1, association between current CD4 count and the lack of immune response was determined by fitting a multivariable logistic regression adjusted for age, time from HIV diagnosis, CD4 nadir, cancer and HIV-RNA a T0. Results: We included 216 PLWH on ART (n=76 SID, n=96 MID, n=44 NID): median age 54 yrs (IQR 47-59), median CD4 nadir 45 cell/mm3 (20-122), 93% HIV-RNA <50 c/mL, 7yrs (3-12) since HIV diagnosis and 5yrs (2-8) since AIDS if diagnosed. Participants received BS after a median of 142 (132-156) days from second dose. Response rate was 95.5% in SID, 100% in MID, 100% in NID for anti-RBD (p=0.02);86.3%, 97.9% and 98.7% for nAbs (p=0.002), and 70%, 95.6% and 97.2% for IFNγ (p<0.0001). Overall we observed a significant increase of BS immunogenicity [anti RBD: mean Log2 4.5 (SD 1.9),p<0.0001;nAbs: 3.7 (2.2),p<0.0001;IFNγ: 0.77 (2.9),p=0.0003]. However, there was no evidence for a difference in mean change of humoral immunogenicity, anti-RBD, nAbs and IFNγ changes by CD4 count groups (Figure 1 A-C). A current CD4 count <200 cell/mm3 was not associated with the risk of failing to elicit neutralizing and cell-mediated response by logistic regression (Figure1D). Conclusion: A mRNA BS strongly boosted humoral response in PLWH with advanced disease, regardless of CD4 count at the time of booster. Although clinical implications of the observed immunological response remain uncertain, our data support the usefulness of BS in PLWH with immune dysregulation.
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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.
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Background: After the acute phase of infection, new, recurring or ongoing symptoms related to COVID19 may persist for weeks or months. Aims of our study were to size the impact of these symptoms on physical (PH) and mental (MH) health status and quality of life (QoL), reported by patients (pts), and to investigate factors influencing the perception of PH, MH, and QoL. Methods: We included pts referred to the post-COVID19 outpatient service, with and without prior hospitalization (PHosp), evaluated at 3,6 and 12 months after the acute infection. Demographic, clinical and pharmacological data were collected in an electronic system. At each visit, the Short-Form 36-item questionnaire (SF-36), assessing the perception of PH and MH, and the Visual Analogue Scale (VAS), ranging from 0 to 100, of the EQ5D, assessing QoL, were administered. Student's T-test was employed for comparisons and linear regression was used to identify factors associated with PH, MH, and QoL. In a subgroup of patients, we assessed the presence of anxiety and depressive symptoms and sleep disturbances through the Beck Anxiety Inventory (BAI), the Beck Depression Inventory (BDI II) and the Pittsburgh Sleep Quality Index (PSQI) questionnaires, respectively. Results: Out of a total of 914 assessments, we considered the first one of each pt (n=572): median (IQR) age of 55 years (47-62), 53% male, 38% with at least 1 comorbidity, 54% with PHosp, median distance from acute infection of 4.8 months (3.6-7.1). The mean of each subscale assessed in SF-36 was significantly lower than the normative values of the Italian population (Figure 1) and it remained stable over time. Female gender, the presence of comorbidities, and the use of corticosteroids during the acute infection were associated with a worse perception of PH, MH, and QoL;pts with PHosp reported a better MH overall (Figure 2). Alterations in BAI, BDI II, and PSQI were associated with worse perceptions of PH, MH, and HRQoL, in the subgroup of 265 patients in whom they were evaluated. Conclusion: In our study, post-COVID19 pts reported a significantly worse perception of PH and MH status compared to the Italian normative group, and a higher risk was demonstrated for female pts, pts with comorbidities and pts treated with corticosteroids. Moreover, the presence of anxious-depressive symptoms and poor sleep quality was correlated to a worse perception of health status and QoL. A systematic monitoring of these aspects is mandatory to properly manage pts in the post-COVID19 period.
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Background: Waning of vaccine protection against SARS-CoV-2 infection is currently a concern and durability of specific immunity after vaccination in PLWH is still unknown. The aim of this analysis was to evaluate persistence of immune response to mRNA vaccines in PLWH with advanced disease. Methods: PLWH with a CD4 count ≤200/mm3 and/or previous AIDS, enrolled in a SARS-CoV-2 vaccination program at INMI hospital in Rome, Italy, were evaluated >90 days after 2nd dose of BNT162b2 or mRNA-1273 (time T1). Anti-RBD by CLIA, neutralizing antibody (nAb) titers by microneutralization assay (MNA90) and IFNγ production were assessed and response defined as having anti-RBD >7.1 BAU/mL, nAbs ≥1:10, IFNγ >12 pg/mL. Participants were stratified by CD4 count (severe immunodeficiency, SID, ≤200/mm3;minor immunodeficiency, MID, 201-500/mm3;no immunodeficiency, NID, >500/mm3). Waning of immune response was evaluated in a subgroup of responders for whom two values post 2nd dose were available. Paired t-test was used to test the overall decline. ANOVA and logistic regression analysis controlling for age, viral load, CD4 nadir and cancer were used for comparisons by CD4 groups. Results: 221 pts were included (SID=47;MID=98;NID=76);81% male;median age 55 yrs (IQR 49-60);median time from HIV diagnosis 7 yrs (3-15);74% previous AIDS diagnosis;median CD4 nadir 44/mm3 (16-122). All pts receiving ART, 87% with HIV-RNA<50 cp/mL. After a median of 145 (133-157) days after 2nd dose, a detectable anti-RBD response was still present in 83% of SID, 96% of MID and 98% of NID (P=0.0009);nAbs in 38% of SID, 78% of MID and 88% of NID (P<0.0001);IFNγ in 67% of SID, 90% of MID and 92% of NID (P=0.0002). Magnitude of residual immune response at T1 was significantly lower in SID (Figure 1a). By logistic regression, risk of nAbs undetectability was higher in SID (aOR 5.03;95% CI 1.22-20.81) and in MID (aOR 3.77;11.4-12.48) vs NID, while no evidence for a difference was found for anti-RBD and IFNγ. A significant decline of immune response was observed for all immune parameters [mean log2 (SD):-2.66 (1.08), p<0.001, for anti-RBD;-1.23 (1.26), p<0.001, for nAbs;and-0.51 (2.3), p=0.05, for IFNγ], regardless of CD4 groups (Figure 1b/c). Conclusion: A high proportion of PLWH with advanced disease showed a lack of immune response after a median of 5 months from SARS-CoV-2 mRNA vaccination, suggesting an urgent need for a booster dose. A current CD4 ≤200/mm3 was associated with higher risk of vanishing of neutralizing activity.
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This chapter analyses data concerning international tourism in Italy from January 1997 to December 2019. It confirms that the mode of transport chosen to reach a tourist destination plays a role in determining the seasonal pattern of tourism demand, widening the list of possible seasonality causes. Although the COVID-19 pandemic has temporarily reduced international tourism, the results of the analysis suggest that the tourism sector can play a crucial role in the recovery of the Italian economy, especially if the relationship with transport systems is adequately considered.
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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
Background: There is conflicting evidence on how HIV influences COVID19 infection. Aim of this study was to compare characteristics at presentation and clinical outcomes of people living with HIV (PLWH) versus HIV negative patients (non-PLWH) hospitalized with COVID-19. Methods: Patients ≥18 years with SARS-CoV-2 infection, defined as positive RT-PCR from nasal/oropharyngeal swab or positive serology, admitted at L. Spallanzani Institute (Italy) were included. Primary endpoint: time to invasive ventilation/death. Secondary endpoints: time to ventilation/death, time to symptoms resolution (resolution of fever or waning from oxygen). In order to control for measured confounders, Cox regression model was used. Results: A total of 905 hospitalized patients were included in the analysis (22 [2.4%] PLWH, 883 non-PLWH): 65% males, 66% with at least one comorbidity, median PaO2/FiO2 at admission 343 mmHg (260-405). PLWH were slightly younger (56 vs 62 years, p=0.057), less likely with pneumonia (59% vs 87%, p<0.001) and with PaO2/FiO2 <300 mmHg at admission (10% vs 31%, p=0.088), with less alterations in lymphocytes (1505 cells/mm vs 1170, p=0.025) and D-dimer (473 ng/mL vs 661, p=0.015) compared with non-PLWH. Symptoms at presentation were similar in the two groups apart from headache and myalgia that were more frequent in PLWH (both p<0.001). Among PLWH, nadir CD4 was 80 (33-284) cells/μl, CD4 at COVID19 diagnosis 350 cells/μl (138-515), all of them were on antiretroviral therapy and 94% had HIV-1 RNA < 50 copies/mL. The cumulative probability of invasive ventilation/death at day 14 was 9.1% (95% CI 2.4-31.7) in PLWH versus 14.7% (12.3-17.6) in non-PLWH (p=0.492). The cumulative probability of non-invasive or invasive ventilation/ death at day 14 was 14.3% (4.8-38.0) in PLWH versus 24.4% (21.4-27.8) in non-PLWH (p=0.372). Following adjustment for age, gender, comorbidities, PaO2/FiO2 and pneumonia at admission, adjusted hazard ratio (aHR) of mechanical ventilation/death of PLWH was 0.95 (95% CI 0.13-6.98, p=0.958) versus non-PLWH;similarly, aHR of non-invasive or invasive ventilation/death of PLWH was 1.05 (95% CI 0.26-4.28, p=0.947). The probability of symptoms resolution at day 14 was similar in the two groups (aHR 1.16;0.65-2.09;p=0.614). Conclusion: A less severe presentation and no difference in clinical outcomes with Covid-19 even in the adjusted models were observed in PLWH compared to non-PLWH, but further investigations are warranted due to the small sample size of HIV+ population. (Figure Presented).
ABSTRACT
Coronavirus disease 2019 (COVID-19) can act as a dual prong attack against management of people living with human immunodeficiency virus (HIV); it induces harm on both individual and national levels. People living with HIV may show rapid deterioration in severe acute respiratory syndrome coronavirus 2 infection as a result of physiological or psychological vulnerability. Additionally, the spread of COVID-19-especially in low- and middle-income countries-may limit HIV control measures, delivery and linkage to HIV care and prevention. Attention should be given to pregnant women and the LGBTQI+ community for their higher susceptibility to poor outcomes. Engagement of both governmental and non-governmental organizations is encouraged for better results.
ABSTRACT
We report two cases of HIV positive patients with SARS-CoV-2 infection and a recent diagnosis of opportunistic infections of central nervous system (CNS). We investigated the potential impact of coinfection with SARS-CoV-2 on HIV replication in CNS.