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Ruzasvir (MK‐8408, an NS5A inhibitor) and uprifosbuvir (MK‐3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct‐acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two‐drug combination of ruzasvir 60 mg plus  uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C‐BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C‐BREEZE 2: NCT02956629/Merck protocol PN041). Treatment‐naïve or interferon (with or without ribavirin)‐experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug‐related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug‐related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two‐drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3‐infected persons. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal diseases (PD) cause considerable morbidity and mortality in adults. V116 is an investigational 21-valent pneumococcal conjugate vaccine (PCV) specifically designed to protect adults from pneumococcal serotypes responsible for the majority of residual PD. This phase 3 study evaluated safety, tolerability, and immunogenicity of V116 in pneumococcal vaccine-experienced adults ≥50 years., Methods: A total of 717 adults were enrolled to receive a single dose of pneumococcal vaccine as follows: Cohort 1 (n=350) previously received PPSV23 and were randomized 2:1 to receive V116 or PCV15, respectively; Cohort 2 (n=261) previously received PCV13 and were randomized 2:1 to receive V116 or PPSV23, respectively; Cohort 3 (n=106) previously received PPSV23+PCV13, PCV13+PPSV23, PCV15+PPSV23, or PCV15 and all received open-label V116. Immunogenicity was evaluated 30 days postvaccination using opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) for all V116 serotypes. Safety was evaluated as the proportion of participants with adverse events (AEs)., Results: V116 was immunogenic across all 3 cohorts as assessed by serotype-specific OPA GMTs and IgG GMCs postvaccination for all 21 serotypes. V116 elicited comparable immune responses to serotypes shared with PCV15 (Cohort 1) or PPSV23 (Cohort 2), and higher immune responses to serotypes unique to V116. The proportions of participants with solicited AEs were generally comparable across cohorts., Conclusions: V116 is well tolerated with a safety profile comparable to currently licensed pneumococcal vaccines and generates IgG and functional immune responses to all V116 serotypes, regardless of prior pneumococcal vaccine received., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults., Methods: This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50-64, 65-74, 75-84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18-49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 - PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18-49 years to 50-64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732)., Findings: Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1-30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18-49 years were non-inferior compared with V116 participants aged 50-64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events., Interpretation: V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20., Funding: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD)., Competing Interests: Declaration of interests CB, LM, DF, WX, MW, JL, UKB, and HLP are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD) and may hold stock in Merck & Co, Rahway, NJ, USA. CGG reports serving on an advisory board for MSD and grants or contracts from the National Institutes of Health, the US Centers for Disease Control, Agency for Healthcare and Research Quality, the US Food and Drug Administration, and Syneos Health. JYS reports serving as a principal investigator for this study, and a grant for the investigator-initiated trial from MSD: non-randomized clinical trial to compare the immunogenicity of revaccination with 23-valent pneumococcal polysaccharide vaccine between healthy elderly and those with diabetes in Korea. EB reports clinical trial agreements with MSD, Astra-Zeneca, Janssen, GSK, Clover, and Moderna. DG-H reports serving as a principal investigator for this study. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID)., Objective: To evaluate elbasvir-grazoprevir in treating HCV infection in PWID., Design: Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688)., Setting: Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States., Patients: 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT)., Intervention: The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks., Measurements: The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events., Results: The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event., Limitation: These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID., Conclusion: Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT., Primary Funding Source: Merck & Co.

With antimicrobial resistance increasing worldwide, there is a great need to use automated antimicrobial decision support systems (ADSSs) to lower antimicrobial resistance rates by promoting appropriate antimicrobial use. However, they are infrequently used mostly because of their poor interoperability with different health information technologies. Ontologies can augment portable ADSSs by providing an explicit knowledge representation for biomedical entities and their relationships, helping to standardize and integrate heterogeneous data resources. We developed a bacterial clinical infectious diseases ontology (BCIDO) using Protégé-OWL. BCIDO defines a controlled terminology for clinical infectious diseases along with domain knowledge commonly used in hospital settings for clinical infectious disease treatment decision-making. BCIDO has 599 classes and 2355 object properties. Terms were imported from or mapped to Systematized Nomenclature of Medicine, Unified Medical Language System, RxNorm and National Center for Bitechnology Information Organismal Classification where possible. Domain expert evaluation using the "laddering" technique, ontology visualization, and clinical notes and scenarios, confirmed the correctness and potential usefulness of BCIDO.