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Background: Tenofovir-lamivudine-dolutegravir (TLD) is the WHO-preferred first-line regimen for people with HIV, but drug-drug interactions between dolutegravir (DTG) and rifampin (RIF) require an additional 50mg DTG (TLD+50) in people receiving tuberculosis (TB)/HIV co-treatment. RIF is a key drug in TB treatment, but is a potent inducer of metabolizing enzymes and efflux transporters, which can markedly lower drug concentrations. There are limited data on the effectiveness of TLD+50 in people with TB/HIV from program settings. Method(s): We conducted a prospective, observational study at 12 sites in 6 countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe). Participants received concomitant TLD+50 and RIF-based TB treatment provided as standard of care by HIV and TB treatment programs. Primary outcome was HIV-1 RNA <1000 copies/mL (cpm) at end of TB treatment. New DTG resistance mutations were defined as those present at end of TB treatment but not present at start. Result(s): From 11/2019-6/2021, we enrolled 91 participants with TB/HIV, including 75 ART-naive participants (82%) starting TLD+50 after a median of 15 days on TB treatment, 10 ART-naive participants (11%) starting TLD+50 and RIF together, 5 (5%) starting TB treatment and changing to TLD+50 after a median of 3.3y on TLD, and 1 (1%) starting RIF and TLD+50 after changing from EFV/3TC/TDF. Median age was 37y (IQR 32-43), 35% were female, 100% cis-gender, median CD4 count was 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment (week 4 disseminated TB, week 12 suspected COVID-19), 1 interrupted TLD+50 due to jaundice;and 1 discontinued TB treatment due to drug-induced liver injury. Among 89 surviving participants, 6 were lost to follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Primary virologic outcome was therefore assessed in 73 (80%), of whom 69 (95%, Wald 95% CI 89-100%) had HIV-1 RNA <=1000 cpm;68 (93%) had HIV-1 RNA <200 cpm. No sex specific differences in viral suppression were observed. No DTG resistance mutations were detected among 4 participants with HIV-1 RNA >1000 cpm. Conclusion(s): Concomitant RIF-containing TB treatment and TLD+50 was welltolerated and achieved excellent viral suppression in a cohort of predominantly ART-naive people with TB/HIV. These multi-country data from program settings support feasibility and effectiveness of current treatment approaches for TB/ HIV co-infection.
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Background: Immunocompromised persons are disproportionately affected by severe SARS-CoV-2 infection, but immune compromise is heterogenous, which may impact viral dynamics. We hypothesized that higher degrees of compromised immunity are associated with higher viral shedding and slower viral clearance in the absence of COVID-19 therapeutics. Method(s): Participants enrolled in ACTIV-2/A5401, a platform trial for COVID-19 therapeutics in non-hospitalized adults within 10 days of symptom onset, received either an active treatment or placebo between 8/2020 and 7/2021. Participants were categorized based on the extent of immunosuppression into none, mild, moderate and severe categories at enrollment (day 0). Longitudinal anterior nasal (AN) and plasma SARS-CoV-2 levels were measured with a quantitative PCR assay. Regression models assessed associations between immunocompromise severity and viral levels (VL) at day 0, and longitudinally among those on placebo with quantifiable RNA at day 0. Multivariate analyses adjusted for demographics and symptom duration and vaccination status at day 0. Result(s): Immunocompromised (mild 383, moderate 159, severe 35) and immunocompetent (1956) participants had comparable symptom durations at day 0 (median 6 days) and most were unvaccinated (~95%). AN VL at day 0 was higher in the moderate/severe group compared to the immunocompetent group (adjusted difference in means: 0.47 log10 copies/mL, 95% CI 0.12, 0.83). While AN VL decayed at similar rates among all groups from day 0 to 3, there was a trend towards higher cumulative AN VLs across the 28-day follow-up in the moderate/severe group compared to immunocompetent group (adjusted fold difference in VL AUC 1.63, 95%CI 0.95, 2.77). The mild group showed no differences in day 0 VL or AUC compared to the immunocompetent group. The frequency of detectable plasma SARS-CoV-2 RNA was similar at day 0 across all groups (overall 21%), but there appeared to be a higher proportion of immunocompromised participants with detectable plasma viral RNA at day 7 (moderate/severe 2/23 [9%], mild 5/44 [11%]) compared to the immunocompetent group (8/282, 3%). Conclusion(s): Before emergence of Omicron and widespread vaccination, moderate/severe immunocompromised status was associated with higher nasal viral levels at study enrollment and showed a trend towards higher cumulative AN viral load, and all immunocompromised groups appeared to have more persistent plasma viremia during follow-up.
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Background: Reliable biomarkers of COVID-19 severity and outcomes are critically needed for clinical and research applications. We evaluated associations between anti-Spike IgG and SARS-COV-2 nucleocapsid antigen (N Ag) in plasma with clinical outcomes in outpatients with COVID-19. Method(s): We used data from 229 non-hospitalized, US-based adults with COVID-19 who enrolled between January and July 2021 into the placebo arm of the ACTIV-2/A5401 platform trial within 10 days of symptom onset. Pretreatment (day 0) plasma was analyzed by the quantitative Simoa SARS-CoV-2 IgG antibody (anti-Spike) assay (lower limit of quantification [LLoQ] 0.77ug/ mL), and the quantitative Simoa SARS-CoV-2 N Protein Advantage (Quanterix) measuring N Ag (LLoQ 3pg/mL). In addition to analyses for < LLoQ vs >=LLoQ anti-Spike and N Ag, we categorized participants into five N Ag groups (< 3 pg/ml;3-< 100 pg/ml;100-< 1,000 pg/ml;1,000-< 2,500 pg/ml;>=2,500 pg/ ml). Associations between SARS-CoV-2 anti-Spike and N Ag levels and clinical outcomes (all-cause hospitalization/death through day 28 and time to symptom improvement or resolution for two consecutive days from day 0 status) were estimated using log-binomial and Cox regression models, respectively. Result(s): At day 0, 40% had anti-Spike levels >=LLoQ and 64% of participants had plasma N Ag levels >=LLoQ. Participants with anti-Spike levels < LLoQ compared to those who had quantifiable anti-Spike at day 0, had an increased risk of hospitalization/death (16% vs 2%, RR [95% confidence interval (CI)]: 7.3 [1.8, 30.1]), and a significantly longer time to symptom improvement (median [Q1, Q3] 14 days [8, >27] vs 9 days [4, 16], hazard ratio [HR]: 0.6 [95%: CI: 0.4, 0.8], p< 0.001). Participants with higher N Ag levels at day 0 had an increased risk of hospitalization or death, ranging from 1% for < 3 pg/ml to 70% for >=2500 pg/ml (Figure). Compared to individuals who had N Ag levels < LLoQ at day 0, those in the highest category of N Ag levels (>=2500 pg/mL) experienced a significantly longer time to symptom improvement (median [Q1, Q3]: 25 days [13, >27] vs 10 days [5, 20];HR: 0.4 [95% CI: 0.2, 0.7];p=0.04). Conclusion(s): At study entry, the absence of Spike antibodies and higher levels of plasma SARS-CoV-2 N Ag predicted hospitalizations and death in untreated outpatients with COVID-19. These parameters may serve as informative biomarkers for risk stratification in the evaluation of outpatients with COVID-19. (Figure Presented).
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Background: SARS-CoV-2 variants resistant to monoclonal antibodies, and drug-drug interactions and potential mutagenicity of direct acting antivirals, heightens the need for additional therapeutics to prevent progression to severe COVID-19. Exogenous interferon beta is a promising therapeutic option against SARS-CoV-2 given its broad-spectrum antiviral activity and data suggesting impaired endogenous IFN production in individuals with severe disease. Method(s): The safety and efficacy of orally inhaled nebulized interferon-beta1a (SNG001) was evaluated in a Phase II randomized controlled trial on the ACTIV-2/ A5401 platform (NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized to SNG001 once daily for 14 days or blinded pooled placebo. Primary outcomes included treatment-emergent Grade >=3 adverse event (TEAE) through day 28;time to symptom improvement of 13 targeted COVID-19 symptoms collected by daily study diary through day 28;and SARS-CoV-2 RNA < lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs at days 3, 7, and 14. All-cause hospitalization or death through day 28 was a key secondary outcome. Result(s): Of 221 participants enrolled at 25 US sites between February and August 2021, 220 (110 SNG001, 110 placebo) initiated study intervention, with a median age of 40 years, 55% female, and 20% SARS-CoV-2 vaccinated. There was no significant difference between SNG001 and placebo in Grade >=3 TEAEs (4% vs 8%, Fisher's exact test p=0.25). Median time to symptom improvement was 13 days for SNG001 and 9 days for placebo (Gehan-Wilcoxon test p=0.17). There was no difference in the proportion of participants with SARS-CoV-2 RNA < LLoQ at day 3, 7 or 14 (SNG001 vs placebo, Day 3: 28% vs. 39%;Day 7: 65% vs. 66%;Day 10: 91% vs. 91%;joint Wald test p=0.41). There were fewer hospitalizations with SNG001 (n=1;1%) compared with placebo (n=7;6%), but this difference was not statistically significant (Fisher's exact test p=0.07;Figure). All hospitalizations were due to COVID-19 and occurred among unvaccinated participants without protocol-defined high-risk factors. Conclusion(s): Inhaled nebulized SNG001 was safe and well tolerated but did not reduce SARS-CoV-2 RNA levels in the nasopharynx nor decrease time to improvement of COVID-19 symptoms in outpatients with mild-to-moderate COVID-19. The non-statistically significant decrease in hospitalizations among SNG001 participants warrants further investigation in a phase 3 clinical trial. Cumulative incidence of hospitalization or death comparing SNG001 vs. placebo.
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Adaptive platform trials are randomized clinical trial designs that enable the evaluation of multiple interventions in a single, highly standardized trial framework undertaken using a master protocol. Fundamental to these designs is allowance for interventions to be added during the course of the study, sharing of a control group in evaluating multiple interventions in parallel, and decision criteria for dropping interventions for futility or efficacy based on interim analyses. Other more complex adaptations may also be incorporated, such as changing allocation ratios across randomized arms in response to interim results, seamless phase II to III transitions, and sample size re-estimation. A large number of platform trials were initiated in response to the COVID-19 pandemic. I will review some key features of platform trial designs with illustrations from the COVID-19 arena, and discuss advantages and challenges of using them in comparison to traditional randomized trials.
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Background: Whether early antiviral therapy reduces the risk of Long COVID is not known. The combination SARS-CoV-2 monoclonal antibodies amubarvimab+romlusevimab (A+R) were highly effective in reducing 28-day all-cause hospitalization/death among high-risk adults with mild-to-moderate COVID-19 in the randomized, placebo-controlled ACTIV-2/A5401 trial. We assessed the impact of A+R on late outcomes including Long COVID in ACTIV-2. Method(s): A long-term (LT) symptom diary and 2 health-related quality of life questionnaires (EQ-5D-5L and SF-36v2) were completed at week 36. The primary analysis compared the proportion of participants with the composite outcome of self-reported Long COVID (having any COVID-19 symptoms present on a global assessment question in LT diary) at week 36, or hospitalization or death by week 36 between A+R and placebo using regression models with inverse probability weighting to account for incomplete outcome data;supplemental analysis compared the proportion with Long COVID among those alive. Other analyses were restricted to observed data only. Result(s): 807 were randomized and received A+R (n=405) or placebo (n=402) from Jan-July 2021. At entry, median age was 49 years, 51% were female, >99% cis-gender, 17% Black/African American, 50% Hispanic/Latino, and 9% previously received COVID vaccination. 70 (17%) on A+R and 93 (23%) on placebo met the primary outcome;113 (14%) had incomplete data for determining the outcome (Figure 1). Accounting for incomplete data, weighted Risk Ratio [wRR]=0.74;95% CI: 0.56, 0.97;p=0.03. The difference was driven by fewer hospitalizations/deaths in the A+R arm (5%) than placebo arm (15%), particularly by day 28. Excluding 12 participants who died by week 36, frequency of Long COVID was similar in the arms, 16% for A+R and 14% for placebo (wRR=1.09;95%CI: 0.75, 1.58;p=0.64). There were no differences in the proportions reporting return to pre-COVID health (global assessment) or individual symptoms, or in number of symptoms reported or distribution of worst symptom severity. RRs favored the A+R arm on several EQ-5D-5L domains, but none met statistical significance. No differences were observed on SF-36v2 assessments. Conclusion(s): While A+R was highly effective in preventing all-cause hospitalizations and deaths in high-risk outpatients with mild-to-moderate COVID-19, there was no meaningful effect of treatment on measures of Long COVID at 36 weeks. Additional interventions are needed for Long COVID prevention. (Figure Presented).
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Background: Rebound of SARS-CoV-2 RNA and symptoms has been reported in people treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories during COVID-19 have not been well described, we evaluated the incidence of viral rebound and symptom relapse in untreated individuals with mild-to-moderate COVID-19. Method(s): This analysis included 563 participants randomized to placebo in the ACTIV-2/A5401 platform trial. Participants recorded the severity (scored as 0-3) of each of 13 targeted symptoms daily from days 0-28, with symptom score being the summed score (0-39). Symptom rebound was defined as >=4 point increase in symptom score between the maximum and the preceding minimum score. Anterior nasal (AN) swabs were collected for SARS-CoV-2 RNA testing on days 0-14 and 28. Viral rebound was defined as a >=0.5 log10 RNA copies/mL increase from the immediately preceding time point to a level >=3.0 log10 RNA copies/mL, with high-level rebound defined as an increase of >=0.5 log10 copies/mL to a level >=5.0 log10 RNA copies/mL. To mirror the timing of a 5-day nirmatrelvir/ritonavir course, a supportive analysis was conducted where participants were only classified as rebounders if their rebounds occurred on or after day 5. Result(s): Symptom rebound was identified in 26% of participants at a median [Q1, Q3] of 6 [4, 9] days after study entry and 11 [9, 14] days after initial symptom onset. Individuals with symptom rebound were more likely to be female, at high risk for progression to severe disease, have shorter time since symptom onset at study entry, and have higher symptom score and higher AN viral levels day 0. Viral rebound was detected in 32%, with high-level rebound in 13% of participants. Participants with viral rebound were older, more likely to be at low risk for progression to severe disease and had higher median AN viral level at day 0. Most symptom and viral rebound were transient with 89% of symptom rebound and 95% of viral rebound events occurring for only a single day before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants. In the supportive analysis of rebound occurring >=5 days after study entry, 22% and 20% of participants met symptom and viral rebound criteria, respectively, but only 1.2% of participants met criteria for both symptom and high-level viral rebound. Conclusion(s): Symptom or viral rebound in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.
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Background: Amubarvimab and romlusevimab are anti-SARS-CoV-2 monoclonal antibodies (mAbs) that significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. SARS-CoV-2 variants (e.g., Delta, Epsilon, Lambda) harbor mutations against romlusevimab. We evaluated viral kinetics and resistance emergence in individuals treated with mono versus dual-active mAbs. Method(s): The study population included 789 non-hospitalized participants at high risk of progression to severe COVID-19 enrolled in the ACTIV-2/ A5401 platform trial (NCT04518410) and received either placebo (n=400) or amubarvimab plus romlusevimab (n=389). Anterior nasal (AN) swabs were collected for SARS-CoV-2 RNA testing on days 0-14, and 28. Spike (S) gene nextgeneration sequencing were performed on samples collected at study entry and the last sample with viral load >=2 log10 SARS-CoV-2 RNA copies per ml. We compared viral load kinetics and resistance emergence with single versus dual-active mAbs by categorizing participants as harboring variants sensitive to amubarvimab alone (Delta, Epsilon, Lambda, Mu) versus those sensitive to both mAbs (Alpha, Beta, Gamma, Others). Result(s): Study participants receiving single and dual-active mAbs had similar demographics, baseline AN viral load, baseline symptom score and duration since symptom onset. The most common SARS-CoV-2 variant in the study population was Delta (26%) followed by Gamma (19%), Alpha (12%), and Epsilon (10%). In those with successful sequencing, 37% (N=111) were infected with a variant sensitive to amubarvimab alone and 63% (N=188) were infected with a variant sensitive to both mAbs. Compared to treatment with a singleactive mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p=0.0001) and day 7 (p=0.003). Treatment-emergent resistance mutations were significantly more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P=0.0008). mAb resistance was also more frequently detected in the setting of single-active mAb treatment compared to dual-active mAb treatment (7.2% vs 1.1%, p=0.007). Participants with emerging mAb resistance had significantly higher pretreatment SARS-CoV-2 nasal viral RNA levels. Conclusion(s): Compared to single-active mAb therapy, dual-active mAb therapy led to significantly faster viral load decline and lower risk of emerging mAb resistance. Combination mAb therapy should be prioritized for the next generation of mAb therapeutics.
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Background: Within the ACTIV-2/A5401 platform (NCT04518410), the safety and efficacy of tixagevimab/cilgavimab (T/C), an anti-SARS-CoV-2 monoclonal antibody combination, was studied in outpatients with COVID-19. Intravenous (IV) and intramuscular (IM) administration of T/C were assessed. Method(s): Non-hospitalized adults >=18 years enrolled within 10 days of positive SARS-CoV-2 test and symptom onset. Participants at higher risk of disease progression were eligible for IV T/C 300mg (150mg each component) or placebo;all were eligible for IM T/C 600mg (300mg each) administered to the lateral thigh or placebo. Co-primary outcomes were: time to symptom improvement through day 28;nasopharyngeal (NP) SARS-CoV-2 RNA below lower limit of quantification (LLoQ) on days 3, 7 or 14;and treatment emergent Grade >=3 adverse events. Result(s): Between February and May 2021, 223 participants (106 T/C, 117 placebo) initiated study intervention and were included in the IM analysis and 114 participants (58 T/C, 56 placebo) in the IV analysis;the IV study was stopped early for administrative reasons. Both studies enrolled 45% Latinx;the IM and IV populations included 12% and 19% Black participants, 49% and 59% female sex at birth, and median age was 39 and 44 years, respectively, all of which were balanced between active vs placebo for each. Median (IQR) days from symptom onset at enrollment was 6 (4, 7). There were no differences in time to symptom improvement comparing IM T/C to placebo (median 8 (IQR 7, 12) vs 10 (8, 13) days;p=0.35) or IV T/C to placebo (11 (9, 15) vs 10 (7, 15) days;p=0.71). A significantly greater proportion (80%) in the IM T/C arm had NP SARS-CoV-2 RNA below LLoQ at day 7 compared to placebo (65%), but not days 3 or 14, overall p=0.003 across visits. Secondary and post-hoc analyses revealed antiviral effects within the smaller IV study. There was no difference in Grade >=3 AEs with either administration route. Fewer participants were hospitalized who received T/C vs placebo (4 vs 7 in IM group;0 vs 4 in IV group), neither group reaching statistical significance. Conclusion(s): Tixagevimab/cilgavimab administered IM or IV was well-tolerated and demonstrated antiviral activity and a trend towards fewer hospitalizations, but did not change time to symptom improvement in mild-to-moderate COVID-19 compared to placebo. Monoclonal antibodies administered intramuscularly to the thigh may present a valuable alternative for early SARSCoV-2 infection. Virologic Outcomes of Tixagevimab/Cilgavimab treatment 600mg IM (panels A and B) or 300mg IV (panels C and D) versus placebo.
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This study examines the practice of corporate social responsibility (CSR) during COVID-19. Little is known about how organizations practice CSR during acute exogenous crises. Overlooking how CSR practices change during a crisis matters because organizations are compelled into trade-offs that carry implications for their CSR initiatives. Analysis of interview data with CSR managers, from 21 Dubai-based business organizations during COVID-19, uncovers changes in the content and process of CSR during the pandemic. The results show that the practice of CSR underwent a fundamental change in focus as organizations shifted to an employee-centric model of CSR and away from an environmental one. Measures placed on organizations and society to combat the pandemic also led to a recalibration of stakeholder and issue salience, with notable effects on CSR that challenge the capability of the power–legitimacy–urgency framework to anticipate these shifts. We consider the impacts associated with the shift in the content of CSR initiatives and process of their implementation and discuss the implications of the findings for CSR theory, research, policy, and practice. © 2023 The Authors. Business Ethics, the Environment & Responsibility published by John Wiley & Sons Ltd.
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Rational: Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics. Cell functions are interwoven pathways, so understanding the effect of COVID-19 across neutrophil function may identify therapeutic targets. We examined neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia (CAP) patients. Method(s): Isolated neutrophils underwent ex vivo analyses for migration, phagocytosis and NETosis, and the effect of PI3K inhibition. Circulating DNAse 1 activity and levels of cfDNA were measured. Result(s): Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397, A) and NETosis (p=0.0366, B), but impaired phagocytosis (p=0.0236, C) associated with impaired ROS generation (p<0.0001). COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001, D). Ex vivo inhibition of PI3K gamma and delta reduced NET release by COVID-19 neutrophils (p=0.0156). Conclusion(s): COVID-19 is associated with neutrophil dysfunction across all main effector functions, with elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function via PI3k may help modulate COVID-19 severity. (Figure Presented).
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OBJECTIVE: To learn about the challenges, policies, and needed resources to serve people with intellectual disability and protect staff during the COVID-19 pandemic. From the perspective of intellectual disability service providers. METHODS: We conducted in-depth qualitative interviews with 16 intellectual disability organization administrators throughout Illinois, USA from November 2020 through February 2021. We coded and analyzed the data using thematic analysis. RESULTS: Three major themes emerged: (1) COVID-19 caused considerable challenges to people with intellectual disability and staff and service providers, (2) intellectual disability organizations reinvented service provisions in response to COVID-19 challenges, and (3) the interrelatedness of intellectual disability organizations, public policies, and community entities became evident. CONCLUSIONS: Exhibiting responsiveness to needs and developing innovative solutions were strategies championed by intellectual disability organizations during the pandemic. Fostering collaboration with community entities may assist these organizations in navigating pandemic challenges and developing resilient infrastructure for future environmental threats.
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Background. Predictors of SARS-CoV-2 RNA levels and changes over time during early COVID-19 are not well characterized. Methods. ACTIV-2 is a phase II/III randomized, placebo-controlled, platform trial to evaluate investigational agents for treatment of COVID-19 in non-hospitalized adults. Participants enrolled within 10 days of symptom onset. Nasopharyngeal samples were collected for SARS-CoV-2 RNA testing on Days 0, 3, 7, 14 and 28;RNA was quantified with qPCR assay. SARS-CoV-2 seropositivity was defined as detectable IgG to any of nucleocapsid, receptor binding domain, S1 and S2 antigens by Bio-Plex multiplex assay. Censored linear regression and repeated measures Poisson models evaluated predictors of RNA including age, sex, race, ethnicity, risk of severe COVID-19, diabetes, BMI, obesity (BMI > 35 kg/m2) and serostatus. Results. The study enrolled 537 participants from Aug 2020 to July 2021 at US sites. Median age was 48 years;49% were female sex, >99% cis-gender, 83% white, 29% Hispanic/Latino, and 21% had BMI > 35 kg/m2. At Day 0, median symptom duration was 6 days, 50% were seropositive (2 were vaccinated) and 17% had RNA below the lower limit of quantification (LLoQ). Higher Day 0 RNA was associated with shorter symptom duration (Spearman correlation = -0.40, p< 0.001), as well as older age, white race, lower BMI and seronegativity, even when adjusting for symptom duration (all p< 0.03). Among the 203 on placebo with Day 0 RNA >= LLoQ, female sex had larger decreases in RNA at Day 3 vs male sex (difference in mean change: -0.8 log10 copies/mL (95% CI: -1.2, -0.4), p< 0.001) when adjusted for symptom duration and Day 0 RNA;this difference was also observed when evaluating the proportion with RNA < LLoQ at Day 3 (Risk Ratio (95% CI): 2.38 (1.11, 5.09)). Seropositivity at Day 0 was associated with higher probability of RNA < LLoQ at Days 3 and 7 (p< 0.001) in adjusted models. Seropositivity at Day 0 did not differ by sex. Conclusion. In this well characterized clinical trial cohort, shorter symptom duration, older age, white race, lower BMI and seronegativity were associated with higher RNA in early infection. Female sex and seropositivity were associated with earlier viral clearance. Further research is needed to determine if viral decay differences mediated by these host factors influence clinical outcomes.
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Background. Symptoms during acute COVID-19 can limit daily activities and delay return to work and school. Little is known about the association between SARS-CoV-2 burden in either the upper airway or plasma and the duration of COVID-19 symptoms. Methods. ACTIV-2/A5401 is a platform trial for COVID-19 treatments in nonhospitalized symptomatic adults enrolled within 10 days of symptom onset. We included participants randomized to placebo from August 2020 to July 2021. Participants self-reported severity of 13 symptoms daily from day 0 (baseline) to 28 as Absent 0, Mild 1, Moderate 2, Severe 3;total symptom score was calculated as the sum of all scores. Anterior nasal (AN) and plasma SARS-CoV-2 RNA levels at day 0 were measured with a quantitative qPCR assay. The relationship between day 0 RNA and time to symptom improvement or resolution (first of 2 consecutive days of all symptoms improved or resolved from day 0, respectively) was evaluated using proportional hazards regression adjusted for time from symptom onset. Time to resolution of distinct symptoms was also assessed. Results. Among 570 participants randomized to placebo, median age was 48 years, 51% were female, and median time since symptom onset at baseline was 6 days;7% had prior COVID-19 vaccination. At day 0, AN RNA was detectable in 80% with a median of 4.1 log10 copies/ml (n=533, quartiles: 1.7, 6.0) and plasma RNA was detectable in 19% (91/476). Detectable plasma RNA at day 0, but not AN RNA, was associated with more severe symptoms at day 0 (2.4-point higher mean total symptom score, P=0.001). Both high AN (>=6 vs < 2 log10 copies/ml, adjusted hazard ratio [aHR] 0.63, P=0.001) and detectable plasma RNA (aHR 0.74, P=0.03) at day 0 predicted delayed symptom improvement. High AN RNA at day 0 also predicted a delay in symptom resolution (aHR 0.59, P=0.001). Both high AN RNA and detectable plasma RNA levels predicted delays in the resolution of cough and shortness of breath. Detectable plasma RNA also predicted delayed body pain resolution.
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Background. Data are currently limited on the performance of SARS-CoV-2 RNA levels as predictors or surrogate markers for clinical outcomes in outpatients with mild-to-moderate COVID-19. Methods. This exploratory analysis used data from 2205 non-hospitalized adults who enrolled between August 2020 and July 2021 and participated in placebocontrolled evaluations of two monoclonal antibody (mAb) agents (bamlanivimab [n=317] or amubarvimab/romlusevimab [n=837]), and an open-label cohort of bamlanivimab recipients [n=1051] as part of the ACTIV-2/A5401 platform trial. SARS-CoV-2 RNA levels were measured in anterior nasal (AN) swabs and plasma at day 0 (pre-treatment) and AN at day 3. We fit regression models to estimate the association between RNA level or detection and subsequent hospitalization/death within 28 days of enrollment. Results. One-hundred four participants (53/571 [9%] on placebo and 51/ 1634 [3%] on mAb) died or were hospitalized through day 28. Median AN RNA levels were lower at day 3 compared to day 0 in both placebo (2.5 vs 4.0 log10 copies/mL [cp/mL]) and mAb (2.3 vs 4.9) groups. For placebo recipients, higher Day 0 AN RNA was associated with an increasing risk of hospitalization/ death, ranging from 3% to 16% for < 2 and >= 6 log10 cp/mL, respectively. Although only 1% had quantifiable plasma SARS-CoV-2 RNA, there was a similar trend for day 0 plasma RNA: 5% hospitalizations/death for undetectable RNA, 16% for detectable but not quantifiable RNA, and 80% for >= 2 log10 cp/mL. Among 485 placebo recipients with days 0 and 3 ANRNA results, the risk of subsequent hospitalization/death was highest among those with >= 5.0 log10 cp/mL at both days [8/78;10%] and lowest for those with unquantifiable levels at both days [0/124;0%]. Higher AN RNA at day 3 (adjusted for day 0 RNA) was associated with subsequent hospitalization/death among placebo recipients (relative risk (RR): 1.4 per log10 cp/mL;95%CI: 1.0, 2.1), but not mAb recipients (RR: 1.0;95%CI: 0.7, 1.6). Conclusion. These findings suggest that AN and plasma SARS-CoV-2 RNA levels are predictive of hospitalization/death in the natural history setting. However, different associations for mAb and placebo recipients raises concerns for using AN RNA as a surrogate for clinical outcomes in mAb trials. (Table Presented).
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S94 Figure 1Comparison of neutrophil effector functions between COVID-19 variants (alpha n=33, delta n=13, omicron n-14). A.% change in phagocytosis significantly increased between alpha and delta patients (p=0.0162). B. Fold change in cells migrated through a transwell pore to IL8 compared to vehicle control significantly reduced in omicron patients compared alpha and delta (vs alpha p=0.0018, vs delta p=0.0370). C. Neutrophil extracellular trap production after stimulation with PMA compared to vehicle control significantly reduced in omicron patients compared to alpha (p=0.0396)[Figure omitted. See PDF]DiscussionOur results showing changes in neutrophil „function and phenotype differ between variants of COVID-19 infection, potentially reflect viral evolution. This change in neutrophil function may contribute to the evolving clinical phenotype observed in patients. Our population of ward-based COVID-19 patients represents the majority of inpatient hospital burden where early intervention may prevent clinical deterioration. Targeting neutrophil function may be an effective way of improving infection outcome in the future.ReferenceBelchamber K, et al. Altered neutrophil phenotype and function in non-ICU hospitalised COVID-19 patients correlated with disease severity. medRxiv, 2021: p. 2021.06.08.21258535.
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Gastro-oesophageal reflux disease (GERD) is associated with substantial morbidity in patients with systemic sclerosis. Although the introduction of proton pump inhibitors (PPIs) into clinical care represents a major achievement in the management of gastro-oesophageal problems in systemic sclerosis, PPIs are seldom fully effective in patients with systemic sclerosis, and the use of maximum PPI doses is a very frequent clinical practice. However, there is little evidence to support the empirical use of PPIs in systemic sclerosis. This scarcity of evidence is especially relevant with regards to the safety concerns of long-term exposure, which have been raised in the general population. The purpose of this Viewpoint is to highlight the substantial beneficial impact of PPIs on GERD in patients with systemic sclerosis, while considering the potential adverse effects in this patient population. Furthermore, we highlight the unmet needs of people with systemic sclerosis and GERD and propose an agenda for future research to optimise the safe and effective use of PPIs in systemic sclerosis. Copyright © 2022 Elsevier Ltd
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The Covid-19 pandemic prompted changes in the ways that individuals access healthcare services and accelerated the transition to digital methods of care. For some, this opened doors for easier and more convenient access. For people already experiencing exclusion and marginalisation however, digital access can create additional barriers for accessing health care. NHS Digital (2019) identified several groups as more likely to be digitally excluded: © 2022. Journal of Community Nursing. All Rights Reserved.