Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial

Background Baricitinib has shown efcacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifcally on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/ critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modifed intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute diference and 95% CI −0.1% [−8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (−3.2% [−9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a signifcant interac‑ tion between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated partici‑ pants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to con‑ clude on a potential survival beneft of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these fnd‑ ings warrant further investigation in other trials and real-world studies

Clinical and Virological Study of Dengue Cases and the Members of Their Households: The Multinational DENFRAME Project

Dengue is the most important mosquito-borne viral disease in humans. This disease is now endemic in more than 100 countries and threatens more than 2.5 billion people living in tropical countries. It currently affects about 50 to 100 million people each year. It causes a wide range of symptoms, from an inapparent to mild dengue fever, to severe forms, including dengue hemorrhagic fever. Currently no specific vaccine or antiviral drugs are available. We carried out a prospective clinical study in South-East Asia and Latin America, of virologically confirmed dengue-infected patients attending the hospital, and members of their households. Among 215 febrile dengue subjects, 177 agreed to household investigation. Based on our data, we estimated the proportion of dengue-infected household members to be about 45%. At the time of the home visit, almost three quarters of (29/39) presented an inapparent dengue infection. The proportion of inapparent dengue infection was higher in South-East Asia than in Latin America. These findings confirm the complexity of dengue disease in humans and the need to strengthen multidisciplinary research efforts to improve our understanding of virus transmission and host responses to dengue virus in various human populations

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.[Background] Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants.[Methods] Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures.[Results] Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities.[Conclusion] This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu (2022-500385-99-00).EU-SolidAct is part of the European pandemic preparedness network EU RESPONSE, funded by the EU Horizon 2020 Research and Innovation programme, under grant number 101015736. EU-SolidAct has also received funding from CAPNET (France) and Klinbeforsk (Norway).Peer reviewe

Decreased mutation frequencies among immunoglobulin G variable region genes during viremic HIV-1 infection.

HIV-1 infection is complicated by high rates of opportunistic infections against which specific antibodies contribute to immune defense. Antibody function depends on somatic hypermutation (SHM) of variable regions of immunoglobulin heavy chain genes (VH-D-J). We characterized the frequency of SHM in expressed IgG mRNA immunoglobulin transcripts from control and HIV-1-infected patients.We compared utilization of genes in the most prominent VH family (VH3) and mutation frequencies and patterns of cDNA from VH3-IgG genes from 10 seronegative control subjects and 21 patients with HIV-1 infection (6 without and 15 patients with detectable plasma viremia).Unique IgG VH3 family cDNA sequences (n = 1,565) were PCR amplified, cloned, and sequenced from blood. Sequences were analyzed using online (Vbase) and in-house immunoglobulin alignment resources.Mutation frequencies in the antigen-binding hypervariable complementarity determining regions (CDR1/2) of IgG class-switched B cells were lower among viremic HIV-1-infected patients vs. controls for nucleotides (CDR1/2: 10±5% vs. 13.5±6%, p = 0.03) and amino acids (CDR: 20%±10 vs. 25%±12, p = 0.02) and in structural framework regions. Mutation patterns were similar among groups. The most common VH3 gene, VH3-23, was utilized less frequently among viremic HIV-1-infected patients (p = 0.03), and overall, mutation frequencies were decreased in nearly all VH3 genes compared with controls.B cells from HIV-1-infected patients show decreased mutation frequencies, especially in antigen-binding VH3 CDR genes, and selective defects in gene utilization. Similar mutation patterns suggest defects in the quantity, but not quality, of mutator activity. Lower levels of SHM in IgG class-switched B cells from HIV-1-infected patients may contribute to the increased risk of opportunistic infections and impaired humoral responses to preventative vaccines

Dinucleotide analysis of C∶T and A∶G Transition mutations.

<p>The percent either of R (A or G) or Y (C or T) nucleotides occurring in either the −1 (5′) position or the +1 (3′) position to a mutation were calculated. Medians are represented for the control (n = 10; black bars), aviremic (n = 6; gray bars), and viremic HIV-1-infected groups (n = 15; white bars).</p

Severe Acute Respiratory Syndrome Coronavirus 2 Seroprevalence Among HIV-Negative Participants Using Tenofovir/Emtricitabine-Based Preexposure Prophylaxis in 2020: A Substudy of the French National Agency for Research on AIDS and Viral Hepatitis PREVENIR and Inserm SAPRIS-Sero Cohorts

International audienceAbstract The potential preventive efficacy of tenofovir/emtricitabine on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was assessed in human immunodeficiency virus preexposure prophylaxis (PrEP) users. Prevalence of SARS-CoV-2 immunoglobulin G between May and October 2020 was similar in PrEP users and in a matched population-based cohort, suggesting that tenofovir/emtricitabine has no role in reducing the risk of SARS-CoV-2 acquisition

RGYW/WRCY motifs and targeted mutation frequencies in CDR and FR regions.

<p>Group medians are listed with the range of individual means in each group in parentheses. Overall p values are listed on the table.</p><p>^a Secondary analyses: control vs. viremic p<0.05; all other comparisons p>0.05.</p

Nucleotide mutation patterns and proportions in IgG V_H3 mRNA sequences.

<p>“% C nucleotides mutated” indicates the proportion of nucleotides in either the CDR1/2 or FR1/2/3 regions that were mutated relative to the total number of C nucleotides present in the unmutated reference sequence, expressed as a percent. “% of mutations that were C nts” indicates the proportion of mutations in either the CDR1/2 or FR1/2/3 regions that were C nucleotides in the unmutated reference sequence relative to the total number of mutations in the region expressed as a percent. The group medians are listed (individual patient mean ranges in parentheses). Overall p values are listed on the table.</p><p>^a Secondary analyses: all comparisons p>0.05.</p><p>^b Secondary analyses: control vs. viremic p<0.05; all other comparisons p>0.05.</p

Expression of V_H3, D, and J family genes.

<p>Data are shown as group medians among HIV-1-seronegative control subjects (n = 10; black bars or circles), aviremic patients (n = 6; gray bars or squares), and viremic HIV-1-infected patients with detectable plasma HIV-1 RNA (n = 15; white bars or triangles). Values were calculated from individual mean percent expression for each gene. A) V_H3 family gene expression. “Other” includes V_H3-13, -20, -43, -49, -64, -65, -66, -72, and unidentified genes which ranged from 0.4% to 12.6% expression. P values were calculated by Mann-Whitney test. Significant p values were found for V_H3-7 (p = 0.05), V_H3-9 (p = 0.05), V_H3-23 (p = 0.03), and V_H3-53 (p = 0.007). B) V_H3-23 expression. Each point represents the mean percentage of V_H3-23/total V_H3 genes for each patient. The solid bar indicates the group median. C) D gene expression was calculated as with V_H3 gene expression. “Other” includes D1-1, D1-7, D1-14, D1-20, D2-2, D2-8, D2-21, D3, D3-9, D3-16, D4, D4-b, D4-11, D4-23, D5-12, D6-6, and D6-25 which ranged from 0.4% to 4.3% expression. “No ID” (12.5–18.0% of sequences) indicates that gene identification could not be assigned. P values were calculated by Mann-Whitney test. Significant overall p values were found for D3-22 (p = 0.04), D5-24 (p = 0.05), and D6-19 (p = 0.04). D) J gene percent expression was calculated as described above. “Other” includes JH1, JH4a, JH4d, JH6a, and JH6c which ranged from 0.2% to 6.7% expression. Statistics were also calculated as above. A significant overall p value was found for JH6b (p = 0.01).</p

Amino acid mutation frequencies at each position do not differ significantly among groups.

<p>The percent of non-conservative (N; black bars) or conservative (C; gray bars) mutations relative to the total number of amino acids sampled at each position (Kabat numbering) are represented, the sums of which equal the total percent replaced amino acid mutation frequency at each position. The mean percent replacement amino acid mutation frequency was calculated for each individual at each amino acid position, and the median of the group mutation frequencies at each amino acid position was calculated from the individual means. Control subjects (A; n = 10), aviremic patients (B; n = 6), and viremic HIV-1-infected patients (C; n = 15).</p