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9‐13 November 2008, Ninth International Congress on Drug Therapy in HIV Infection, Glasgow, UK, The immune systems of patients with HIV infection are characterized by an immunodeficiency that develops in the setting of a global immune activation and a complex array of HIV‐specific immune [...]

Background. Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4(+) T cell expansions. The factors potentially affecting these expansions were investigated in the present study.Methods. A matched (for baseline CD4(+) T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a /=50% increase in CD4(+) T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups.Results. Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4(+) T cell count, nadir CD4(+) T cell count, or CD8(+) T cell count. At week 0, NRs had lower TREC levels per 1x106 T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4(+) T cells, with TREC levels per 1x106 CD4(+) T cells decreasing significantly only in control subjects.Conclusions. Increased immune activation can adversely affect CD4(+) T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed. This article is in the public domain, and no copyright is claimed. [ABSTRACT FROM AUTHOR]

Context: While interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART).Objective: To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone.Design and Setting: Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States.Patients: Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 10(6)/L to 500 x 10(6)/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study.Interventions: Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone.Main Outcome Measures: Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels.Results: The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log(10) copies for IL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving IL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received IL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed.Conclusions: Intermittent therapy with IL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end-point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with IL-2 therapy will translate into improved clinical outcomes. JAMA. 2000;284:183-189 [ABSTRACT FROM AUTHOR]

Background: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and Findings: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.Conclusions: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. [ABSTRACT FROM AUTHOR]

Background: rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation., Methods: In this open-label phase 2 randomised controlled trial, we compared antibody titres at month 36 in participants who had received a homologous booster dose at month 18 following primary immunisation with those who had received no booster. From Oct 25, 2016, to Jan 29, 2020, healthy adults aged 18 years or older deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region were recruited from four hospital clinics in the USA and one hospital clinic in Canada and received primary vaccination with 2×10 7 plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227)., Findings: Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment., Interpretation: In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure., Funding: The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency., Competing Interests: Declaration of interests We declare no competing interests., (Published by Elsevier Ltd.)

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Background: Reliable biomarkers of coronavirus disease 2019 (COVID-19) outcomes are critically needed. We evaluated associations of spike antibody (Ab) and plasma nucleocapsid antigen (N Ag) with clinical outcomes in nonhospitalized persons with mild-to-moderate COVID-19., Methods: Participants were nonhospitalized adults with mild-to-moderate COVID-19 enrolled in ACTIV-2 between January and July 2021 and randomized to placebo. We used quantitative assays for severe acute respiratory syndrome coronavirus 2 spike Ab and N Ag in blood and determined numbers of hospitalization/death events within 28 days and time to symptom improvement., Results: Of 209 participants, 77 (37%) had quantifiable spike Ab and 139 (67%) quantifiable N Ag. Median age was 50 years; 111 (53%) were female, 182 (87%) White, and 105 (50%) Hispanic/Latino. Higher risk of hospitalization/death was seen with unquantifiable (22/132 [16.7%]) versus quantifiable (1/77 [1.3%]) spike Ab (risk ratio [RR], 12.83 [95% confidence interval {CI}, 1.76-93.34]) and quantifiable (22/139 [15.8%]) vs unquantifiable (1/70 [1.4%]) N Ag (RR, 11.08 [95% CI, 1.52-80.51]). Increasing risk of hospitalizations/deaths was seen with increasing N Ag levels. Time to symptom improvement was longer with unquantifiable versus quantifiable spike Ab (median, 14 [interquartile range {IQR}, 8 to >27] vs 8 [IQR, 4-22] days; adjusted hazard ratio [aHR], 0.66 [95% CI, .45-.96]) and with quantifiable versus unquantifiable N Ag (median, 12 [7 to >27] vs 10 [5-22] days; aHR, 0.79 [95% CI, .52-1.21])., Conclusions: Absence of spike Ab and presence of plasma N Ag predicted hospitalization/death and delayed symptom improvement in COVID-19 outpatients., Clinical Trials Registration: NCT04518410., Competing Interests: Potential conflicts of interest. N. J. received salary support to the institution from Sagent Pharmaceuticals. D. A. W. has received funding to his institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. T. H. E. serves as a consultant for Tonix Pharmaceuticals. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV and research support through his institution from Gilead Sciences and GSK/ViiV. J. Z. L. has received research funding from Merck. J. J. E. is an ad hoc consultant to GSK/VIR, data monitoring committee chair for Adagio Phase 3 studies. J. S. C. has consulted for Merck and Company. D. M. S. has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. K. W. C. received research funding to the institution from Merck Sharp & Dohme and is a consultant for Pardes Biosciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Biomarker guided therapy could improve management of COVID-19 inpatients. Although some results indicate that antibody tests are prognostic, little is known about patient management using point-of-care (POC) antibody tests., Methods: COVID-19 inpatients were recruited to evaluate 2 POC tests: LumiraDX and RightSign. Ease of use data was collected. Blood was also collected for centralized testing using established antibody assays (GenScript cPass). A nested case-control study assessed if POC tests conducted on stored specimens were predictive of time to sustained recovery, mortality, and a composite safety outcome., Results: While both POC tests exhibited moderate agreement with the GenScript assay (both agreeing with 89% of antibody determinations), they were significantly different from the GenScript assay. Treating the GenScript assay as the gold standard, the LumiraDX assay had 99.5% sensitivity and 58.1% specificity while the RightSign assay had 89.5% sensitivity and 84.0% specificity. The LumiraDX assay frequently gave indeterminant results. Both tests were significantly associated with clinical outcomes., Conclusions: Although both POC tests deviated moderately from the GenScript assay, they predicted outcomes of interest. The RightSign test was easier to use and was more likely to detect those lacking antibody compared to the LumiraDX test treating GenScript as the gold standard., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A subset of antiretroviral therapy-treated persons with human immunodeficiency virus (HIV), referred to as immunological nonresponders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4 < 250 cells/µL) and 25 immunological responders (IRs; CD4 ≥ 250 cells/µL), we evaluated the potential contribution of transcriptionally competent defective HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV RNA (P = .034) and higher percentages of HLA-DR+ CD4+ T cells (P < .001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological nonresponse phenotype., Competing Interests: Potential conflicts of interest . J. A. K. and H. C. L. are investigators on a clinical trial of pembrolizumab being conducted under a Cooperative Research and Development Agreement between the NIH and Merck Sharp & Dohme Corp. J. A. K. is a principal investigator of a Cooperative Research and Development Agreement between the NIH and Matinas BioPharma Holdings, Inc to develop encochleated medications. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID)., Methods: Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes., Results: Average participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model., Conclusions: We discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches., (© 2024. The Author(s).)

Objectives: People with HIV-1 (PWH) on effective antiretroviral therapy (ART) continue to exhibit chronic systemic inflammation, immune activation, and persistent elevations in markers of HIV-1 infection [including HIV-DNA, cell-associated HIV-RNA (CA HIV-RNA), and antibodies to HIV-1 proteins] despite prolonged suppression of plasma HIV-RNA levels less than 50 copies/ml. Here, we investigated the hypothesis that nonreplicating but transcriptionally and translationally competent 'defective' HIV-1 proviruses may be one of drivers of these phenomena., Design: A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied., Methods: HIV-DNA, CA HIV-RNA, western blot score (measure of anti-HIV-1 antibodies as a surrogate for viral protein expression in vivo ), and key biomarkers of inflammation and coagulation (IL-6, hsCRP, TNF-alpha, tissue factor, and D-dimer) were measured in peripheral blood and analyzed using a combined cross-sectional and longitudinal approaches. Sequences of HIV-DNA and CA HIV-RNA obtained via 5'-LTR-to-3'-LTR PCR and single-genome sequencing were also analyzed., Results: We observed similar long-term persistence of multiple, unique, transcriptionally active 'defective' HIV-1 provirus clones (average: 11 years., range: 4-20 years) and antibody responses against HIV-1 viral proteins among all ART-treated participants evaluated. A direct correlation was observed between the magnitude of HIV-1 western blot score and the levels of transcription of 'defective' HIV-1 proviruses ( r  = 0.73, P  < 0.01). Additional correlations were noted between total CD8 + T-cell counts and HIV-DNA ( r  = 0.52, P  = 0.01) or CA HIV-RNA ( r  = 0.65, P  < 0.01)., Conclusion: These findings suggest a novel interplay between transcription and translation of 'defective' HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.

Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure., Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761., Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10)., Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy., Funding: National Institutes of Health., Competing Interests: Declaration of interests SMB reports funding from the National Institutes of Health during the conduct of the study and chairing a Data and Safety Monitoring Board (DSMB) for Hamilton Ventilators, outside of the study. CEB reports funding from the National Institutes of Health (NIH) for the Aviptadil study, during the conduct of the study. BG reports grants from the NIH, during the conduct of the study. SS reports a grant from the NIH, during the conduct of the study. ANP reports grants from the Wellcome Trust, the National Institute for Health and Care Research, UK Research and Innovation (UKRI), and the Bill & Melinda Gates Foundation, and consulting fees from the Bill & Melinda Gates Foundation, outside of the submitted work. IDP reports funding from NIH and the National Institute of General Medical Sciences, during the conduct of the study, a grant from Janssen for a study of influenza patient reported outcomes, and a contract with Regeneron for a COVID-19 therapy trial, outside of the submitted work. JRB reports a grant from the NIH, during the conduct of the study, grants from the NIH, Quantum Leap Healthcare Collaborative, and Sedana Medical, consulting fees from Sedana Medical, Biomarck, and Global Blood Therapeutics, and compensation from Hamilton Medical for participation as a medical monitor, outside of the submitted work. ESHa reports study materials from NeuroRx and Gilead through a National Heart, Lung, and Blood Institute (NHLBI) subcontract, during the conduct of the study, subcontracts with Bristol Meyers Squibb (BMS), Allergan, Gilead, and Janssen for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-1) clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the Therapeutics for Inpatients with COVID-19 (TICO) clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR) clinical trial, outside of the submitted work. EAM reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. MAGB reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. KSM reports grants and contracts from NIH, NHLBI, and the Society for Critical Care Medicine, participation as a steering committee member for Roivant-Kinevant Sciences, and employment as a clinical research physician at Chiesi USA, outside of submitted work. JM reports receiving study materials and funding from the Albert Einstein College of Medicine for the study protocol, during the conduct of the study. CH reports funding from the National Institute of Allergy and Infectious Diseases (NIAID) in the form of per-patient payments for A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with Acute Respiratory Distress Syndrome Associated with COVID-19, during the conduct of the study. AK reports grants from Eli Lilly, AstraZeneca, 4D Medical, United Therapeutics, Regeneron Pharmaceuticals, and Dompe Pharmaceuticals and consulting fees from Dompe Pharmaceuticals for clinical trial design, outside of the submitted work. AD reports grants from NHLBI Prevention and Early Treatment of Acute Lung Injury network and the US Centers for Disease Control and Prevention (CDC) and data safety monitoring board (DSMB) or advisory board participation for Alung Technologies, outside of the submitted work. SD reports a grant from Chest Sonosite Ultrasound to study the incidence of deep vein thrombosis in patients with COVID-19, during the conduct of the study. AJG reports payment from Sound Pharmaceuticals for participation as a medical monitor for a COVID therapeutic trial, outside of the submitted work. USS reports consulting fees from Shionogi, Paratek, and ViiV Healthcare for participation on advisory boards and speaking fees from Shionogi and Paratek, outside of the submitted work. NJJ reports grants from the CDC, the US Department of Defense (DOD), and NIH and participation on a DSMB for the Legacy Health System, outside of the submitted work. MAM reports grants from NIH and NIAID, during the conduct of the study. NRA reports funding from NIH, during the conduct of the study. JDC reports grants from NIH and DOD, outside of the submitted work. DDM reports funding from the Danish National Research Foundation (DNRF126), during the conduct of study. AAG reports funding from NIH, during the conduct of the study, grants or contracts from NIH, DOD, CDC, Faron Pharmaceuticals, and Abbvie, and participation on a DSMB or advisory board for NIH, outside of the submitted work. WHS reports funding from NIH and NIAID, during the conduct of the study. CFO reports contracts with NIH and NHLBI, outside of the submitted work. BTT reports a grant from NHLBI, consulting fees from Bayer, Genetec, and Novartis, and participation on a DSMB or advisory board for Aperion, outside of the submitted work. During a portion of this research, BTT had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19-associated ARDS. BTT's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies, and had no relationship to the agents studied. VK reports subcontracts with University of Minnesota, NIAID, and NIH for the TICO and Therapeutics for Severely Ill Inpatients with COVID-19 platform trials, outside of the submitted work. AGB reports a grant from University of Minnesota, during the conduct of the study, grants from the Medical Reserve Corps and UKRI, payment from NIAID for participation on a COVID-19 Vaccines DSMB, and participation on the WHO Trial Data and Safety Monitoring Committee, outside of the submitted work. JDN reports grants from NIAID, NIH, and Leidos Biomedical, outside of the submitted work. HCL reports employment from NIAID, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests.

Background: Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population., Methods: In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff., Findings: 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed., Interpretation: The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola., Funding: National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health., Competing Interests: Declaration of interests SGK reports support from the National Institute of Allergy and Infectious Diseases for travel to Liberia, to serve as site physician between May and June, 2015, and to attend the annual meeting in March, 2016. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The levels of immune response to SARS-CoV-2 infection or vaccination are poorly understood in African populations and is complicated by cross-reactivity to endemic pathogens as well as differences in host responsiveness. To begin to determine the best approach to minimize false positive antibody levels to SARS-CoV-2 in an African population, we evaluated three commercial assays, namely Bio-Rad Platelia SARS-CoV-2 Total Antibody (Platelia), Quanterix Simoa Semi-Quantitative SARS-CoV-2 IgG Antibody Test (anti-Spike), and the GenScript cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit (cPass) using samples collected in Mali in West Africa prior to the emergence of SARS-CoV-2. A total of one hundred samples were assayed. The samples were categorized in two groups based on the presence or absence of clinical malaria. Overall, thirteen out of one hundred (13/100) samples were false positives with the Bio-Rad Platelia assay and one of the same one hundred (1/100) was a false positive with the anti-Spike IgG Quanterix assay. None of the samples tested with the GenScript cPass assay were positive. False positives were more common in the clinical malaria group, 10/50 (20%) vs. the non-malaria group 3/50 (6%); p = 0.0374 using the Bio-Rad Platelia assay. Association between false positive results and parasitemia by Bio-Rad remained evident, after adjusting for age and sex in multivariate analyses. In summary, the impact of clinical malaria on assay performance appears to depend on the assay and/or antigen being used. A careful evaluation of any given assay in the local context is a prerequisite for reliable serological assessment of anti-SARS-CoV-2 humoral immunity., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Discrimination of bacterial and viral etiologies of childhood community-acquired pneumonia (CAP) is often challenging. Unnecessary antibiotic administration exposes patients to undue risks and may engender antimicrobial resistance. This study aimed to develop a prediction model using epidemiological, clinical and laboratory data to differentiate between bacterial and viral CAP., Methods: Data from 155 children with confirmed bacterial or mixed bacterial and viral infection ( N  = 124) and viral infection ( N  = 31) were derived from a comprehensive assessment of causative pathogens [Partnerships for Enhanced Engagement in Research-Pneumonia in Pediatrics (PEER-PePPeS)] conducted in Indonesia. Epidemiologic, clinical and biomarker profiles (hematology and inflammatory markers) were compared between groups. The area under the receiver operating characteristic curve (AUROC) for varying biomarker levels was used to characterize performance and determine cut-off values for discrimination of bacterial and mixed CAP versus viral CAP. Diagnostic predictors of bacterial and mixed CAP were assessed by multivariate logistic regression., Results: Diarrhea was more frequently reported in bacterial and mixed CAP, while viral infections more frequently occurred during Indonesia's rainy season. White blood cell counts (WBC), absolute neutrophil counts (ANC), neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), and procalcitonin (PCT) were significantly higher in bacterial and mixed cases. After adjusting for covariates, the following were the most important predictors of bacterial or mixed CAP: rainy season (aOR 0.26; 95% CI 0.08-0.90; p  = 0.033), CRP ≥5.70 mg/L (aOR 4.71; 95% CI 1.18-18.74; p  = 0.028), and presence of fever (aOR 5.26; 95% CI 1.07-25.91; p  = 0.041). The model assessed had a low R-squared (Nagelkerke R 2  = 0.490) but good calibration ( p  = 0.610 for Hosmer Lemeshow test). The combination of CRP and fever had moderate predictive value with sensitivity and specificity of 62.28 and 65.52%, respectively., Conclusion: Combining clinical and laboratory profiles is potentially valuable for discriminating bacterial and mixed from viral pediatric CAP and may guide antibiotic use. Further studies with a larger sample size should be performed to validate this model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Farida, Triasih, Lokida, Mardian, Salim, Wulan, Butar-butar, Sari, Budiman, Hayuningsih, Anam, Dipayana, Mujahidah, Setyati, Aman, Naysilla, Lukman, Diana, Karyana, Kline, Neal, Lane, Kosasih and Lau.)

Background: There is an incompletely understood increased risk for cardiovascular disease (CVD) among people with HIV (PWH). We investigated if a collection of biomarkers were associated with CVD among PWH. Mendelian randomization (MR) was used to identify potentially causal associations., Methods: Data from follow-up in 4 large trials among PWH were used to identify 131 incident CVD cases and they were matched to 259 participants without incident CVD (controls). Tests of associations between 460 baseline protein levels and case status were conducted., Results: Univariate analysis found CLEC6A, HGF, IL-6, IL-10RB, and IGFBP7 as being associated with case status and a multivariate model identified 3 of these: CLEC6A (odds ratio [OR] = 1.48, P = .037), HGF (OR = 1.83, P = .012), and IL-6 (OR = 1.45, P = .016). MR methods identified 5 significantly associated proteins: AXL, CHI3L1, GAS6, IL-6RA, and SCGB3A2., Conclusions: These results implicate inflammatory and fibrotic processes as contributing to CVD. While some of these biomarkers are well established in the general population and in PWH (IL-6 and its receptor), some are novel to PWH (HGF, AXL, and GAS6) and some are novel overall (CLEC6A). Further investigation into the uniqueness of these biomarkers in PWH and the role of these biomarkers as targets among PWH is warranted., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: There remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19., Methods: Blood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured., Results: Differences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all p <0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both p <0.05), and each had sensitivity and specificity >80% on cut-point analysis., Discussion: Elevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage., Competing Interests: LK consulted for Gamma Diagnostics and Cerus Corporation at the time of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Matthay, Fields, Wick, Jones, Lane, Herrera, Nuñez-Garcia, Gennatas, Hendrickson, Kornblith, Matthay, Kornblith and the COVID-19 Associated Coagulopathy Inflammation Thrombosis (Co-ACIT) Study Group.)

Background: For people with HIV and CD4 + counts >500 cells/mm 3 , early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4 + counts are <350 cells/mm 3 . Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain., Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4 + counts .500 cells/mm 3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021., Results: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4 + count was 648 and 460 cells/mm 3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4 + difference was 199 cells/mm 3 . After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4 + count difference was 155 cells/mm 3 . After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference)., Conclusions: Among adults with CD4 + counts >500 cells/mm 3 , excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Competing Interests: We declare no competing interests.

Background: The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants may have contributed to prolonging the pandemic, and increasing morbidity and mortality related to coronavirus disease 2019 (COVID-19). This article describes the dynamics of circulating SARS-CoV-2 variants identified during the different COVID-19 waves in Mali between April and October 2021., Methods: The respiratory SARS-CoV-2 complete spike (S) gene from positive samples was sequenced. Generated sequences were aligned by Variant Reporter v3.0 using the Wuhan-1 strain as the reference. Mutations were noted using the GISAID and Nextclade platforms., Results: Of 16,797 nasopharyngeal swab samples tested, 6.0% (1008/16,797) tested positive for SARS-CoV-2 on quantitative reverse transcription polymerase chain reaction. Of these, 16.07% (162/1008) had a cycle threshold value ≤28 and were amplified and sequenced. The complete S gene sequence was recovered from 80 of 162 (49.8%) samples. Seven distinct variants were identified: Delta (62.5%), Alpha (1.2%), Beta (1.2%), Eta (30.0%), 20B (2.5%), 19B (1.2%) and 20A (1.2%)., Conclusions and Perspectives: Several SARS-CoV-2 variants were present during the COVID-19 waves in Mali between April and October 2021. The continued emergence of new variants highlights the need to strengthen local real-time sequencing capacity and genomic surveillance for better and coordinated national responses to SARS-CoV-2., Competing Interests: None declared., (© 2022 The Author(s).)

Investment, collaboration, and coordination have been key.