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HIV-1-infected individuals are treated with lifelong antiretroviral drugs to control the infection. A means to strengthen the antiviral T cell response might allow them to control viral loads without antiretroviral drugs. We report the development of a lentiviral vector-based dendritic cell (DC) vaccine in which HIV-1 antigen is co-expressed with CD40 ligand (CD40L) and a soluble, high-affinity programmed cell death 1 (PD-1) dimer. CD40L activates the DCs, whereas PD-1 binds programmed death ligand 1 (PD-L1) to prevent checkpoint activation and strengthen the cytotoxic T lymphocyte (CTL) response. The injection of humanized mice with DCs transduced with vector expressing CD40L and the HIV-1 SL9 epitope induced antigen-specific T cell proliferation and memory differentiation. Upon HIV-1 challenge of vaccinated mice, viral load was suppressed by 2 logs for 6 weeks. Introduction of the soluble PD-1 dimer into a vector that expressed full-length HIV-1 proteins accelerated the antiviral response. The results support development of this approach as a therapeutic vaccine that might allow HIV-1-infected individuals to control virus replication without antiretroviral therapy.

The safety of casirivimab + imdevimab (CAS + IMD) (anti-severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] monoclonal antibodies [mAbs]) in pediatric outpatients with coronavirus disease 2019 (COVID-19) was evaluated in a randomized phase 1/2/3 trial. Consistent with adults, CAS + IMD was generally well tolerated with low drug-induced immunogenicity rates. The findings support the development of next-generation anti-SARS-CoV-2 mAbs for at-risk pediatric patients. [ABSTRACT FROM AUTHOR]

Objective: Pregnant women with COVID-19 are at elevated risk for severe outcomes, but clinical data on management of these patients are limited. Monoclonal antibodies, such as casirivimab plus imdevimab (CAS+IMD), have proven effective in treating non-pregnant adults with COVID-19, prompting further evaluation in pregnant women., Methods: A phase 3 portion of an adaptive, multicentre, randomised, double-blind, placebo-controlled trial evaluated the safety, clinical outcomes, pharmacokinetics and immunogenicity of CAS+IMD (1200 mg or 2400 mg) in the treatment of pregnant outpatients with COVID-19 (NCT04425629). Participants were enrolled between December 2020 and November 2021, prior to the emergence of Omicron-lineage variants against which CAS+IMD is not active. Safety was evaluated in randomised participants who received study drug (n=80); clinical outcomes were evaluated in all randomised participants (n=82). Only two pregnant participants received placebo, limiting conclusions regarding treatment effect. Infants born to pregnant participants were followed for developmental outcomes ≤1 year of age., Results: In pregnant participants, CAS+IMD was well tolerated, with no grade ≥2 hypersensitivity or infusion-related reactions reported. There were no participant deaths, and only one COVID-19-related medically attended visit. Although two pregnancies (3%) reported issues in the fetus/neonate, they were confounded by maternal history or considered to be due to an alternate aetiology. No adverse developmental outcomes in infants ≤1 year of age were considered related to in utero exposure to the study drug. CAS+IMD 1200 mg and 2400 mg rapidly and similarly reduced viral loads, with a dose-proportional increase in concentrations of CAS+IMD in serum. Pharmacokinetics were consistent with that reported in the general population. Immunogenicity incidence was low., Conclusion: CAS+IMD treatment of pregnant outpatients with COVID-19 showed similar safety, clinical outcomes and pharmacokinetic profiles to that observed in non-pregnant adults. There was no evidence of an impact on developmental outcomes in infants ≤1 year of age., Trial Registration Number: NCT04425629., Competing Interests: Competing interests: TDN, MT, SG, SA, JC, AW, JX, JDD, SCI, CP, DA, DS, BK, ATD, RB, GPG, EC, NB and PD are employees and stockholders at Regeneron Pharmaceuticals, Inc. ATH is a Regeneron employee/stockholder and former Pfizer employee and current stockholder. KCT, JDH and GAH are Regeneron employees and stockholders, and have a patent pending, which has been licensed and receiving royalties, with Regeneron. JAB is a site PI for Regeneron Pharmaceuticals, Inc. multicentred clinical trials, Enanta multicentred clinical trials and Pfizer multicentred clinical trials; a sub-investigator for Novavax multicentred clinical trials; and an advisory board/panel member for Avalere, Pfizer, Moderna, Sobi and Valneva., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Data that can be used to guide perioperative antibiotic prophylaxis in our era of emerging antibiotic resistance are limited. We reviewed orthopedic surgeries complicated by surgical site infections (SSIs). Eighty percent of 69 arthroplasty and 80 spine fusion SSIs were infected with Gram-positive bacteria; most were staphylococcal species; and more than 25% of Staphylococcus aureus and more than 65% of coagulase-negative staphylococci were methicillin-resistant. Gram-negative bacteria were isolated from 30% of arthroplasty SSIs and 25% of spine fusion SSIs. Resistance to cefazolin was higher than 40%. A significant proportion of SSIs were caused by resistant organisms, and antibiotic guidelines were altered to provide more adequate surgical prophylaxis.

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.