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Background: During the 2019 severe influenza season, New South Wales (NSW) experienced the highest number of cases in Australia. This study retrospectively investigated the genetic characteristics of influenza viruses circulating in NSW in 2019 and identified genetic markers related to antiviral resistance and potential virulence. Methods: The complete genomes of influenza A and B viruses were amplified using reverse transcription‐polymerase chain reaction (PCR) and sequenced with an Illumina MiSeq platform. Results: When comparing the sequencing data with the vaccine strains and reference sequences, the phylogenetic analysis revealed that most NSW A/H3N2 viruses (n = 68; 94%) belonged to 3C.2a1b and a minority (n = 4; 6%) belonged to 3C.3a. These viruses all diverged from the vaccine strain A/Switzerland/8060/2017. All A/H1N1pdm09 viruses (n = 20) showed genetic dissimilarity from vaccine strain A/Michigan/45/2015, with subclades 6B.1A.5 and 6B.1A.2 identified. All B/Victoria‐lineage viruses (n = 21) aligned with clade V1A.3, presenting triple amino acid deletions at positions 162–164 in the hemagglutinin protein, significantly diverging from the vaccine strain B/Colorado/06/2017. Multiple amino acid substitutions were also found in the internal proteins of influenza viruses, some of which have been previously reported in hospitalized influenza patients in Thailand. Notably, the oseltamivir‐resistant marker H275Y was present in one immunocompromised patient infected with A/H1N1pdm09 and the resistance‐related mutation I222V was detected in another A/H3N2‐infected patient. Conclusions: Considering antigenic drift and the constant evolution of circulating A and B strains, we believe continuous monitoring of influenza viruses in NSW via the high‐throughput sequencing approach provides timely and pivotal information for both public health surveillance and clinical treatment. [ABSTRACT FROM AUTHOR]

Background/Aims We used next-generation sequencing (NGS) to analyze resistance-associated substitutions (RASs) and retreatment outcomes in patients with chronic hepatitis C virus (HCV) infection who failed direct-acting antiviral agent (DAA) treatment in South Korea. Methods Using prospectively collected data from the Korean HCV cohort study, we recruited 36 patients who failed DAA treatment in 10 centers between 2007 and 2020; 29 blood samples were available from 24 patients. RASs were analyzed using NGS. Results RASs were analyzed for 13 patients with genotype 1b, 10 with genotype 2, and one with genotype 3a. The unsuccessful DAA regimens were daclatasvir+asunaprevir (n=11), sofosbuvir+ribavirin (n=9), ledipasvir/sofosbuvir (n=3), and glecaprevir/pibrentasvir (n=1). In the patients with genotype 1b, NS3, NS5A, and NS5B RASs were detected in eight, seven, and seven of 10 patients at baseline and in four, six, and two of six patients after DAA failure, respectively. Among the 10 patients with genotype 2, the only baseline RAS was NS3 Y56F, which was detected in one patient. NS5A F28C was detected after DAA failure in a patient with genotype 2 infection who was erroneously treated with daclatasvir+asunaprevir. After retreatment, 16 patients had a 100% sustained virological response rate. Conclusions NS3 and NS5A RASs were commonly present at baseline, and there was an increasing trend of NS5A RASs after failed DAA treatment in genotype 1b. However, RASs were rarely present in patients with genotype 2 who were treated with sofosbuvir+ribavirin. Despite baseline or treatment-emergent RASs, retreatment with pan-genotypic DAA was highly successful in Korea, so we encourage active retreatment after unsuccessful DAA treatment.

Cytomegalovirus (CMV) retinitis caused by drug-resistant viruses poses a major challenge in immunocompromised patients. We present the case of a patient living with HIV with persistently low CD4+ T cells count despite effective antiretroviral therapy, who experienced multiple episodes of CMV retinitis associated with iterative acquisition of resistance. The failure of ganciclovir and foscarnet treatments led us to implement a combined therapy of intravenous cidofovir, high-dose ganciclovir, and anti-CMV immunoglobulin as well as intravitreal injections of ganciclovir. This triple therapy was successful but resulted in significant myelotoxicity. Furthermore, the relapse of CMV retinitis and/or CMV viremia with each therapeutic de-escalation reflects the high level of immunodeficiency in our patient, despite sustained control of HIV viremia for several months. This case report highlights the need for a particular management of CMV infection in patients living with HIV who are immunological nonresponders., Competing Interests: Declarations of competing interest There is nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inhibition of HIV-1 protease is a cornerstone of antiretroviral therapy. However, the notorious ability of HIV-1 to develop resistance to protease inhibitors (PIs), particularly darunavir (DRV), poses a major challenge. Using quantum chemistry and computer simulations, this study aims to investigate the interactions between two novel PIs, GRL-004 and GRL-063, as well as a wild-type (WT) HIV strain and a DRV-resistant mutant strain. To do this, we used molecular docking, molecular dynamics simulations, and quantum mechanical calculations to check how well GRL-004 and GRL-063 bound to both WT and DRV-resistant proteases. The results show that GRL-004 and GRL-063 bind very well to ASP29 in the WT strain. ASP29 is an important amino acid in the HIV protease dimer. Remarkably, amino acids such as ILE50 in the WT strains showed substantial binding energies to both drugs. Quantum energy calculations showed a slight reduction in the energy affinity of the interaction between the MUT strain and the ligand GRL-063, compared to the WT strain. GRL-004 showed similar interaction energy for both strains, suggesting that it has greater plasticity than GRL-063 despite its lower interaction affinity. Furthermore, GLY49B demonstrated strong binding energies regardless of mutations. Other relevant residues with strong binding energies include GLY49B, PHE82A, PRO81A, ASP29A, ASP25A and ALA28B. This study improves our understanding of receptor-ligand dynamics and the adaptability of new protease inhibitors (PIs), which has profound implications for the innovation of future antiretroviral drugs.

The antiviral drug tecovirimat* has been used extensively to treat U.S. mpox cases since the start of a global outbreak in 2022. Mutations in the mpox viral protein target (F13 or VP37) that occur during treatment can result in resistance to tecovirimat † (1,2). CDC and public health partners have conducted genetic surveillance of monkeypox virus (MPXV) for F13 mutations through sequencing and monitoring of public databases. MPXV F13 mutations associated with resistance have been reported since 2022, typically among severely immunocompromised mpox patients who required prolonged courses of tecovirimat (3-5). A majority of patients with infections caused by MPXV with resistant mutations had a history of tecovirimat treatment; however, spread of tecovirimat-resistant MPXV was reported in California during late 2022 to early 2023 among persons with no previous tecovirimat treatment (3). This report describes a second, unrelated cluster of tecovirimat-resistant MPXV among 18 persons with no previous history of tecovirimat treatment in multiple states., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Todd G. Smith reports that SIGA Technologies, the owner of TPOXX, provided the drug used in the study under a material transfer agreement. Nicole M. Green reports serving as president of the Southern California Society for Microbiology. Daisy McGrath reports support from the Oak Ridge Institute for Science and Education. Meilan Bielby reports unpaid membership on the Association of Public Health Laboratories (APHL) Infectious Disease and Public Health Preparedness committees. Danielle Haydel reports institutional support from APHL to attend the APHL conference. No other potential conflicts of interest were disclosed.

DNA polymerases are important drug targets, and many structural studies have captured them in distinct conformations. However, a detailed understanding of the impact of polymerase conformational dynamics on drug resistance is lacking. We determined cryoelectron microscopy (cryo-EM) structures of DNA-bound herpes simplex virus polymerase holoenzyme in multiple conformations and interacting with antivirals in clinical use. These structures reveal how the catalytic subunit Pol and the processivity factor UL42 bind DNA to promote processive DNA synthesis. Unexpectedly, in the absence of an incoming nucleotide, we observed Pol in multiple conformations with the closed state sampled by the fingers domain. Drug-bound structures reveal how antivirals may selectively bind enzymes that more readily adopt the closed conformation. Molecular dynamics simulations and the cryo-EM structure of a drug-resistant mutant indicate that some resistance mutations modulate conformational dynamics rather than directly impacting drug binding, thus clarifying mechanisms that drive drug selectivity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Maribavir was recently approved by the FDA, expanding treatment options for post-solid-organ transplant refractory/resistant CMV. We sought to describe the post-marketing experience with maribavir at a large academic transplant center., Methods: This was a retrospective observational study of all renal transplant recipients treated with maribavir for refractory/resistant CMV DNAemia/disease. CMV viral loads, immunosuppression regimens and management, resistance testing, and antiviral therapy durations were reviewed. Outcomes of interest included treatment success, defined as undetectable CMV DNAemia for two consecutive weeks or detected but unquantifiable DNAemia for five consecutive weeks, as well as the emergence of antiviral resistance, and recurrent DNAemia., Results: From 2021 to 2023, 5/10 (50%) patients achieved durable virologic suppression with maribavir (classified as responders). Among responders, 2/5 (40%) experienced low-level CMV DNAemia recurrence (defined as a viral load less than 1000 IU/mL) within 8 weeks of antiviral discontinuation. Among nonresponders, 2/3 (66.7%) were found to have UL97 protein mutations associated with maribavir resistance identified 85 and 75 days after initiation of maribavir. Two patients are currently on maribavir with clinical outcomes that are yet to be determined. Responders had a mean reduction of 200 mg (SD-274 mg) in mycophenolate dosing with nonresponders having a mean increase of 167 mg (SD-764 mg)., Conclusions: Maribavir, often in conjunction with mycophenolate dose reduction, was effective for many patients with refractory/resistant CMV DNAemia at our transplant center, though several experienced recurrent DNAemia. In patients who did not respond to therapy, resistance to maribavir was frequently detected. Clinicians treating these patients should remain vigilant for rebound CMV DNAemia and consider repeat antiviral resistance testing., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Helicase-primase is an interesting target for small-molecule therapy of herpes simplex virus (HSV) infections. With amenamevir already approved for varicella-zoster virus and herpes simplex in Japan and with pritelivir 's granted breakthrough therapy designation for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in helicase-primase inhibitors (HPIs). Here, we analyze the first patent application from Gilead in this field, which pursued a me-too approach combining elements from an old Bayer together with a recent Medshine HPI application (which covers the Phaeno Therapeutics drug candidate HN0037 ). The asset was contributed to Assembly Biosciences, where it is under development as ABI-1179 at the investigational new drug (IND) enabling stage for high-recurrence genital herpes. A structure proposal for indolinoyl derivative ABI-1179 is presented, showing its potential opportunities and limitations compared to other HPIs.

The Venezuelan State does not provide adequate antiretroviral therapy (ART) for the population living with HIV, resulting in pharmaceutical scarcity, involuntary treatment pauses, and adherence failures. Such a situation may result in the development of resistance to certain ART drugs, meaning that Venezuelans with HIV may have their treatment options reduced for the remainder of their lives. It can take a number of years for a person to acquire late-stage HIV/AIDS and for death to occur, and so I focus on the microbiological death of CD4 cells over time - a concept I call 'microthanatopolitics'. In this paper I argue that the microthanatopolitics of ART scarcity deprives those living with HIV of future treatment options, encourages resistance to ART drugs, and ultimately may contribute towards ill health long after treatment availability changes in Venezuela. To explore this in depth, the paper draws upon 6 interviews with Venezuelan HIV activists in Venezuela (2024), supported by 40 testimonies from Venezuelan migrants living with HIV in Colombia (2021-2024), with and without known ART resistance. It will be concluded that not only is this an issue for those currently living in Venezuela, but also for migrants and the global HIV response who will suffer from the promotion and circulation of ART-resistant viral strains in the long run. This microthanatopolitics is influenced by both the current Venezuela political system as well as humanitarian aid from the Global North; an important consideration of coloniality in post-colonial Latin America., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Dolutegravir (DTG) is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric subjects aged at least 4 weeks. The present work aimed to characterize the viral response based on a pooled analysis of exposure-response (E-R) from five studies in treatment-experienced and integrase-resistant (INI-r) patients infected with HIV-1. Importantly, model-based simulations of the E-R relationships with DTG provided insight into the clinical relevance of known intrinsic (e.g., sub-population with Q148-driven integrase mutation) and extrinsic (food, enzyme inducers, and metal cation-containing products) factors expected to influence the DTG E-R relationship. Model-based post hoc exposure metrics (C min and C avg ) were incorporated into a mechanistic population viral dynamic model describing the short-term effect of DTG on log10 HIV-1 RNA viral load over 8 or 10 days. In addition, the impact of DTG in combination with background ARTs on the 24-week HIV RNA response was also assessed using logistic regression. There was good concordance between model-based predictions and observed virologic response on day 10 and week 24. The E-R model-based simulations exploring the potential impact of a higher dose (100 mg b.i.d.) of DTG in subpopulations experiencing exposure changes due to covariates did not show clinically relevant changes in virological response compared with the approved 50 mg b.i.d. clinical dose. Overall, our study confirmed the current recommendation of dolutegravir 50 mg b.i.d. in the integrase inhibitor-resistant (INI-r) population., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Objectives: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains., Materials and Methods: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system., Results: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine., Conclusion: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients., (© 2023 Wiley Periodicals LLC.)

Background: Testing for syphilis and HIV is indicated in prenatal care in the United States. Effective antiretroviral therapy during pregnancy reduces mother-to-child HIV transmission (MTCT) to less than 1%. Syphilis infection in pregnant women with unsuppressed HIV increases the risk of MTCT, usually in utero. The incidences of syphilis in women of childbearing age and corresponding congenital syphilis are increasing in the United States., Methods: We report 3 cases of in utero HIV transmission associated with maternal syphilis that occurred during the ongoing syphilis epidemic., Results: All 3 women had untreated HIV infection and active syphilis with placentitis during late pregnancy. Their newborns were found to have symptomatic congenital syphilis and HIV infection from in utero transmission. The babies' antiretroviral resistance patterns were nearly identical to their mothers'., Conclusions: When untreated syphilis and uncontrolled HIV coincide in pregnancy, there is a high likelihood of in utero mother-to-child HIV transmission. The current syphilis epidemic in the United States may lead to an increase in MTCT., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS-CoV-2 virus., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The influenza virus causes one of the most prevalent and lethal infectious viral diseases of the respiratory system; the disease progression varies from acute self-limiting mild fever to disease chronicity and death. Although both the preventive and treatment measures have been vital in protecting humans against seasonal epidemics or sporadic pandemics, there are several challenges to curb the influenza virus such as limited or poor cross-protection against circulating virus strains, moderate protection in immune-compromised patients, and rapid emergence of resistance. Currently, there are four US-FDA-approved anti-influenza drugs to treat flu infection, viz. Rapivab, Relenza, Tamiflu, and Xofluza. These drugs are classified based on their mode of action against the viral replication cycle with the first three being Neuraminidase inhibitors, and the fourth one targeting the viral polymerase. The emergence of the drug-resistant strains of influenza, however, underscores the need for continuous innovation towards development and discovery of new anti-influenza agents with enhanced antiviral effects, greater safety, and improved tolerability. Here in this review, we highlighted commercially available antiviral agents besides those that are at different stages of development including under clinical trials, with a brief account of their antiviral mechanisms.

Background: As nucleos/tide analogue (NA) therapy (e.g. entecavir and tenofovir) for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. A systematic review to quantify resistance to these agents has not previously been undertaken., Methods: We performed a systematic review and random-effects meta-analysis to estimate the risk of HBV resistance to entecavir and tenofovir. We searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting treatment ≥48 weeks, with assessment of HBV resistance based on viral sequence data. Data were analysed according to prior exposure history to NA, and choice of NA agent. Analyses were performed in R., Findings: 62 studies involving a total of 12,358 participants were included. For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), resistance increased over time to 0.9 % at ≥5 years (95 %CI 0.1-2.3 %), and resistance was increased in NA-experienced individuals (18 studies; 1112 individuals), to 20.1 % (95 %CI 1.6-50.1 %) at ≥5 years. For tenofovir, pooled resistance risk was 0.0 % at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis., Interpretation: We have generated the first pooled estimates of HBV entecavir and tenofovir resistance over time. HBV resistance to entecavir in treatment-experienced groups in particular may represent a clinical and public health challenge. To date, tenofovir appears to have an excellent resistance profile, but due to data gaps, we caution that existing studies under-estimate the true real-world risk of resistance. Robust prospective data collection is crucial to reduce health inequities and reduce blind-spots in surveillance as treatment is rolled out more widely., Competing Interests: Declaration of competing interest CC receives doctoral funding support from GSK for a PhD supervised by PCM. YS receives research grant from Gilead Sciences., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work., Competing Interests: Potential conflicts of interest. P. L. has received research grants from AlloVir, MSD, Takeda, and Astellas; has received honoraria from MSD, Moderna, and Gilead; participates on Moderna and OctaPharma data and safety monitoring/advisory boards; and participates as a board member of the European Conference on Infections in Leukemia. R. F. C. has received research grants from Merck/MSD, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, and Eurofins-Viracor; reports consulting fees from ADMA Biologics, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Adagio Therapeutics, Tether, Oxford Immunotec, Karius, Moderna, and Ansun Pharmaceuticals; participates on ADMA Biologics, Merck/MSD, Takeda, Shinogi, AiCuris, Roche/Genentech, Tether, Karius, Moderna, and Ansun Pharmaceuticals data and safety monitoring/advisory boards; and reports stock options from Xenex. F. K. has received research grants from Eurofins Viracor and has received honoraria from MEDSCAPE. S. A. has received research grants from Takeda, Merck, MSD, BioMerieux, Hologic, and Elitech; has received honoraria from MSD, Biotest, and Takeda; has received support for attending meetings/travel from MSD, Biotest, and Takeda; and participates on Biotest, Takeda, MSD, QCMD, and GSK data and safety monitoring/advisory boards. R. A. has received research grants from AiCuris, Astellas, AstraZeneca, Chimerix, Merck, Oxford Immunotec, Qiagen, Regeneron, and Takeda. C. B. is an employee of Merck & Co. M. B. has received research grants from Merck. M. F. has received support for attending meetings/travel from, is employed by, and is a shareholder of Takeda. A. H. is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. T. K. is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. A. P. L. has received research grants from Merck, Moderna, and Takeda; reports consulting fees from Merck, GSK, and Novartis; and participates on the Novartis data and safety monitoring/advisory board. O. M. has received honoraria from Takeda, MSD, Biotest, and AstraZeneca. Y. N. reports consulting fees from Nobel Pharma. D. N. has received research grants from Pfizer, MSD, Abbot Diagnostics, and Roche Diagnostics; reports consulting fees from Roche Diagnostics, Takeda, and AstraZeneca; has received honoraria from Pfizer, MSD, Roche Diagnostics, Abbot Diagnostics, GSK, and BioMerieux; and has received support for attending meetings/travel from Pfizer. A. P. participates on the Antiretroviral Pregnancy Registry and is an employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. R. R. R. has received research grants from Regeneron, Roche Diagnostics, and Gilead; reports consulting fees from AlloVir; participates on the Novartis data and safety monitoring/advisory board; and participates in a leadership role for the American Society of Transplantation. G. W. is an employee of the Swedish Medical Products Agency, Uppsala, Sweden. V. M. has received research grants from AiCuris, AlloVir, Evrys Bio, Merck, Takeda, Symbio Pharma, Qiagen, Vera Therapeutics, and Eurofins-Viracor. P. D. G. reports consulting fees from Biotest, Evrys Bio, GSK, Hookipa, Takeda, and Moderna and reports the United Kingdom patent application 2020135.6 “Human CMV Vaccine,” assigned to University College London. C. N. K. reports consulting fees from Biotest, ExeVir, Evrys Bio, Hookipa, Takeda, Merck, Qiagen, Roche Diagnostics, and Abbot Laboratories; has received honoraria from Takeda, Roche Diagnostics, Qiagen, and Biotest; participates on Takeda, Roche Diagnostics, Abbot Laboratories, Biotest, ExeVir, and Evrys Bio data and safety monitoring/advisory boards; and participates in a leadership role for the Transplantation Society. 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.)

The HIV-1 maturation inhibitor (MI) VH3739937 (VH-937) inhibits cleavage between capsid and spacer peptide 1 and exhibits an oral half-life in humans compatible with once-weekly dosing. Here, the antiviral properties of VH-937 are described. VH-937 exhibited potent antiviral activity against all HIV-1 laboratory strains, clinical isolates, and recombinant viruses examined, with half-maximal effective concentration (EC 50 ) values ≤ 5.0 nM. In multiple-cycle assays, viruses less susceptible to other MIs, including A364V, were inhibited at EC 50 values ≤ 8.0 nM and maximal percent inhibition (MPI) values ≥ 92%. However, VH-937 was less potent against A364V in single-cycle assays (EC 50 , 32.0 nM; MPI, 57%) and A364V emerged in one of four resistance selection cultures. Other substitutions were selected by VH-937, although re-engineered viruses with these sequences were non-functional in multiple-cycle assays. Measured dissociation rates from wild-type and A364V-containing VLPs help explain resistance to the A364V mutation. Overall, the in vitro antiviral activity of VH-937 supports its continued development as a treatment for HIV-1.

Background: Tenofovir/lamivudine/dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen for people with HIV (PWH), including those who were previously virologically suppressed on nonnucleoside reverse transcriptase inhibitors (NNRTIs). We sought to estimate the real-world effectiveness of the TLD transition in Ugandan public-sector clinics., Methods: We conducted a prospective cohort study of PWH aged ≥18 years who were transitioned from NNRTI-based ART to TLD. Study visits were conducted on the day of TLD transition and 24 and 48 weeks later. The primary end point was viral suppression (<200 copies/mL) at 48 weeks. We collected blood for retrospective viral load (VL) assessment and conducted genotypic resistance tests for specimens with VL >500 copies/mL., Results: We enrolled 500 participants (median age 47 years; 41% women). At 48 weeks after TLD transition, 94% of participants were in care with a VL <200 copies/mL (n = 469/500); 2% (n = 11/500) were lost from care or died; and only 2% (n = 9/500) had a VL >500 copies/mL. No incident resistance to DTG was identified. Few participants (2%, n = 9/500) discontinued TLD due to adverse events., Conclusions: High rates of viral suppression, high tolerability, and lack of emergent drug resistance support use of TLD as the preferred first-line regimen in the region., Clinical Trials Registration: NCT04066036., Competing Interests: Potential conflicts of interest. V. C. M. received investigator-initiated research grants and consultation fees from Eli Lilly, Bayer, Gilead Sciences, Merck, and ViiV Healthcare. 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.)

Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.

Objectives: To evaluate polypharmacy, anticholinergic burden (ACB) and drug-drug interactions (DDIs) in people with four-class-resistant HIV (4DR-PWH)., Methods: We performed a cross-sectional study, including 4DR-PWH from the PRESTIGIO Registry taking at least one non-antiretroviral drug. Polypharmacy was defined as taking five or more non-antiretroviral drugs. ACB was calculated using the ACB scale: 0 = no AC effect, 1-2 = low/moderate risk, ≥3 = high AC risk. Participants' characteristics by ACB score were compared using the Kruskal-Wallis test, and Spearman's correlation coefficient was used to assess linear relationships. DDIs were evaluated using the Liverpool database., Results: Overall, 172 4DR-PLWH were evaluated: 75.6% males, median age 49.9 years (IQR = 45.6-56), 62 (27.1%) on polypharmacy, 124 (72.1%) using a boosting agent and 72 (41.8%) with four or more antiretrovirals. Based on ACB, 128 (74.45%), 33 (19.2%) and 11 (6.4%) had a no, low/moderate and high AC risk, respectively. The most common AC drugs were β-blockers (12.2%), diuretics (8.7%) and antidepressants (8.7%). The high ACB was significantly related to the number of drugs/person (r = 0.33, P < 0.0001) and the number of clinical events (r = 0.222, P = 0.004). Overall, 258 DDIs were found between antiretrovirals and co-medications in 115 (66.8%) PWH, and 14 (8.1%) PWH received contraindicated drug combinations., Conclusions: In 4DR-PWH, polypharmacy, DDIs and the proportion of people with moderate/high AC burden were high. In 4DR-PWH undetectability achievement and maintenance is the priority and use of boosted PIs is common. A strict collaboration (infectious diseases specialists, virologists, pharmacologists) is needed to limit the risk of ACB and DDIs and to explore the advantages of new antiretrovirals., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. 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.)

Patients undergoing allogeneic haematopoietic cell transplantation are prone to complications caused by viral infections. Cytomegalovirus (CMV) considerably impacts transplantation as it frequently requires antiviral intervention that evokes substantial side effects depending on the antiviral drug. Intermittent antiviral treatment may become necessary if CMV DNAemia cannot be permanently suppressed, and drug resistance may emerge that hampers and prolongs treatment. Despite sedulous endeavours, vaccination against CMV is not yet available. This review concisely summarises current approaches in managing CMV infection comprising risk factors, diagnostics including indications for resistance testing, and therapeutic options from antiviral drugs to virus-specific T cells., Competing Interests: Declaration of competing interest The author declares that there is no conflict of interest., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Evaluate cytomegalovirus (CMV) post-prophylaxis surveillance in high-risk (D+/R-) kidney and liver transplant recipients., Methods: Adult D+/R- patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre-CMV-stewardship-era (6/1/15-5/31/18), CMV-stewardship-era (6/1/18-6/30/20), and a surveillance-era (7/1/2020-11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV-related outcomes. The secondary objective was to assess graft and patient survival by era., Results: There were 328 patients in the study period; 133 in the pre-stewardship-era, 103 in the stewardship-era, and 92 in the surveillance-era. Replication rates in the surveillance-era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum-VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end-organ disease (p < 0.0001) and ganciclovir-resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era., Conclusions: Post-prophylaxis surveillance significantly reduced CMV end-organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Herpes simplex virus (HSV) infections in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pose significant challenges, with higher incidence, severity, and risk of emergence of resistance to antivirals due to impaired T-cell mediated immunity. This literature review focuses on acyclovir-refractory/resistant HSV infections in HSCT recipients. The review addresses the efficacy of antiviral prophylaxis, the incidence of acyclovir-refractory/resistant HSV infections, and the identification of risk factors and potential prognostic impact associated with those infections. Additionally, alternative therapeutic options are discussed. While acyclovir prophylaxis demonstrates a significant benefit in reducing HSV infections in HSCT recipients and, in some cases, overall mortality, concerns arise about the emergence of drug-resistant HSV strains. Our systematic review reports a median incidence of acyclovir-resistant HSV infections of 16.1%, with an increasing trend in recent years. Despite limitations in available studies, potential risk factors of emergence of HSV resistance to acyclovir include human leucocyte antigen (HLA) mismatches, myeloid neoplasms and acute leukaemias, and graft-versus-host disease (GVHD). Limited evidences suggest a potentially poorer prognosis for allogeneic HSCT recipients with acyclovir-refractory/resistant HSV infection. Alternative therapeutic approaches, such as foscarnet, cidofovir, topical cidofovir, optimised acyclovir dosing, and helicase-primase inhibitors offer promising options but require further investigations. Overall, larger studies are needed to refine preventive and therapeutic strategies for acyclovir-refractory/resistant HSV infections in allogeneic HSCT recipients and to identify those at higher risk., (© 2024 The Author(s). Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Temsavir binds directly to the HIV-1 envelope glycoprotein gp120 and selectively inhibits interactions between HIV-1 and CD4 receptors. Previous studies identified gp120 amino acid positions where substitutions are associated with reduced susceptibility to temsavir. The mechanism by which temsavir susceptibility is altered in these envelope glycoproteins was evaluated. Pseudoviruses encoding gp120 substitutions alone (S375H/I/M/N, M426L, M434I, M475I) or in combination (S375H + M475I) were engineered on a wild-type JRFL background. Temsavir-gp120 and CD4-gp120 binding kinetics and ability of temsavir to block CD4-gp120 binding were evaluated using the purified polymorphic gp120 proteins and a Creoptix® WAVE Delta grating-coupled interferometry system. Fold-change in half-maximal inhibitory concentration (IC 50 ) in JRFL-based pseudoviruses containing the aforementioned polymorphisms relative to that of wild-type ranged from 4-fold to 29,726-fold, while temsavir binding affinity for the polymorphic gp120 proteins varied from 0.7-fold to 73.7-fold relative to wild-type gp120. Strong correlations between temsavir IC 50 and temsavir binding affinity (r = 0.7332; P = 0.0246) as well as temsavir binding on-rate (r = -0.8940; P = 0.0011) were observed. Binding affinity of gp120 proteins for CD4 varied between 0.4-fold and 3.1-fold compared with wild-type gp120; no correlations between temsavir IC 50 and CD4 binding kinetic parameters were observed. For all polymorphic gp120 proteins, temsavir was able to fully block CD4 binding; 3 polymorphs required higher temsavir concentrations. Loss of susceptibility to temsavir observed for gp120 polymorphisms strongly correlated with reductions in temsavir binding on-rate. Nonetheless, temsavir retained the ability to fully block CD4-gp120 engagement given sufficiently high concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 ViiV Healthcare. Published by Elsevier B.V. All rights reserved.)

Respiratory syncytial virus (RSV) causes respiratory disease and complications in infants, the elderly and the immunocompromised. While three vaccines and two prophylactic monoclonal antibodies are now available, only one antiviral, ribavirin, is currently approved for treatment. This review aims to summarize the current state of treatments directly targeting RSV. Two major viral processes are attractive for RSV-specific antiviral drug discovery and development as they play essential roles in the viral cycle: the entry/fusion process carried out by the fusion protein and the replication/transcription process carried out by the polymerase complex constituted of the L, P, N and M2-1 proteins. For each viral target resistance mutations to small molecules of different chemotypes seem to delineate definite binding pockets in the fusion proteins and in the large proteins. Elucidating the mechanism of action of these inhibitors thus helps to understand how the fusion and polymerase complexes execute their functions. While many inhibitors have been studied, few are currently in clinical development for RSV treatment: one is in phase III, three in phase II and two in phase I. Progression was halted for many others because of strategic decisions, low enrollment, safety, but also lack of efficacy. Lessons can be learnt from the halted programs to increase the success rate of the treatments currently in development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Monitoring adherence presents a challenge in adolescents and it is prudent to explore several options for determining their level of adherence. This study sought to determine ART adherence levels in adolescents and young adults (on a tenofovir-containing regimen) failing ART as measured by self-reports, pill counts and DBS tenofovir concentrations and to compare levels of agreement among the methods and determine the ability of each method to predict virological suppression., Methods: This was a cohort study involving 107 adolescents and young adults between 10 and 24 years failing ART with viral load > 400copies/ml at enrolment. Pill count (PC) records, self-reports (SR) and DBS tenofovir concentrations (done by liquid Chromatography with tandem mass spectrometry (LC-MS/MS)) were used to determine adherence in adolescent participants failing ART in Harare. The latter was used as the reference method with a cut-off of 64 ng/ml. Determination of DBS tenofovir concentrations was also performed to rule out inadequate viral response due to low cumulative drug exposure despite high adherence (≥90 %). Longitudinal analysis was performed to determine the correlation of viral loads (VL) with adherence. The Kappa (k) coefficient was used to evaluate the level of agreement among the 3 methods., Results: Poor level of agreement was found between PC records and DBS tenofovir concentrations (k = -0.115). Moderate agreement was found between DBS and SR methods (k = 0.0557). Slight agreement was found between PC and SR methods (k = 0.0078). Adherence was dependent on age at HIV diagnosis (p = 0.0184) and ART initiation (p = 0.0265). Participants who were adherent were six times more likely to be suppressed at end point than their non-adherent counterparts (OR=5.7 CI 2.1 - 16.5, p < 0.0001)., Conclusions: Self-reported measure of adherence and pill counts exhibited poor agreement with the reference method used i.e. DBS tenofovir concentrations and are thus not effective methods of predicting virological suppression., Trial Identification: Participants in the present study were a subset of those in the PESU intervention ClinicalTrials.gov Identifier: NCT02833441., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.

Background: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs., Methods: Participants were nonhospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S-gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant., Results: Study participants receiving single- or dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared with single-active mAb treatment, treatment with dual-active mAbs led to faster viral load decline at study days 3 (P < .001) and 7 (P < .01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than with placebo (2.6% vs 0%; P < .001) and were more frequently detected in the setting of single-active compared with dual-active mAb treatment (7.3% vs 1.1%; P < .01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death., Conclusions: Compared with single-active mAb therapy, dual-active mAbs led to similar clinical outcomes but significantly faster viral load decline and a lower risk of emergent resistance., Competing Interests: Potential 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) 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: Children and adolescents with HIV taking antiretroviral therapy (ART) have high rates of viraemia. We assessed if genotypic resistance testing (GRT) to inform onward treatment improved treatment outcomes in Lesotho and Tanzania, two countries with little access to GRT., Methods: The Genotype-Informed Versus Empirical Management of Viremia (GIVE MOVE) open-label, parallel-group randomised controlled trial enrolled children and adolescents with HIV between the ages of 6 months and 19 years, taking ART, and with a viral load at least 400 copies per mL. Participants were recruited from ten clinical centres and hospitals in Lesotho and Tanzania. Participants were electronically randomly allocated 1:1 to receive either GRT with expert recommendation (GRT group) or repeat viral-load testing and empirical onward treatment (usual care group). Participants and study staff were not masked, but the endpoint committee and laboratory staff conducting viral-load testing were. Participants in both groups received at least three sessions of enhanced adherence counselling, and in the GRT group, blood for GRT assessed via Sanger sequencing was drawn at enrolment. The composite primary endpoint was death, hospitalisation, a new WHO HIV clinical stage 4 event, or not having documented viral suppression of less than 50 copies per mL at 36 weeks in the modified intention-to-treat population, which excluded participants who were retrospectively found to be ineligible after randomisation. Serious adverse events were analysed in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT04233242) and the trial status is completed., Findings: Between March 3, 2020, and July 5, 2022, 286 participants were enrolled and 284 were included in the modified intention-to-treat analysis (144 in the GRT group and 140 in the usual care group). Of these participants, 158 (56%) were female and 126 (44%) were male. Five (3%) in the GRT group and four (3%) in the usual care group did not complete follow-up but were included in the primary analysis. The median age across both groups was 14 years (IQR 9-16). The composite primary endpoint occurred in 67 (47%) participants in the GRT group and 73 (52%) in the usual care group (adjusted odds ratio 0·79 [95% CI 0·49 to 1·27]; adjusted risk difference -0·06 [95% CI -0·17 to 0·06]; p=0·34); all participants reaching the composite primary endpoint had no documented viral suppression at 36 weeks. No deaths were recorded, and only one clinical stage 4 event requiring hospitalisation occurred (in the usual care group); this was the only serious adverse event recorded in the study., Interpretation: GRT-informed management did not significantly improve treatment outcomes for children and adolescents with viraemia while taking ART., Funding: Fondation Botnar, Swiss National Science Foundation, and Gottfried and Julia Bangerter-Rhyner Foundation., Translations: For the Sesotho and Swahili translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests NDL reports having received travel grants to conferences from Gilead Sciences and ViiV Healthcare, and his division received honoraria for consultancies from ViiV Healthcare and for participation in a data safety monitoring board from Pharming. All other authors declare no competing interests., (Copyright © 2024 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.)

Background: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up., Methods: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing., Findings: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide., Interpretation: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities., Funding: Gilead Sciences., Competing Interests: Declaration of interests DAW has received grants, consulting fees, and speaker honoraria from Gilead Sciences; grants from Merck; consulting fees and speaker honoraria from ViiV Healthcare; and consulting fees and speaker honoraria from Janssen Pharmaceuticals. CDS has received funding, grants, consulting fees, and non-financial support from Gilead Sciences; grants and speaker honoraria from AbbVie; grants and personal fees from Janssen-Cilag; grants and personal fees from MSD, ViiV Healthcare, BioNtech, and Eli Lilly; grants from Cepheid; grants, personal fees, and non-financial support from B Braun Melsungen; consulting fees from AstraZeneca; personal fees, non-financial support, and other support outside the submitted work from Apeiron Biologics; and personal fees from GSK, Formycon, Moderna, Molecular Partners, Novartis, Roche, Sobi, and Pfizer. JF, PJR, and RMG have received research funding from Gilead Sciences. CBH has received research grant support from Gilead Sciences. SD-L has received research grant support (paid to their institution) from Gilead Sciences and Merck. J-MM has received grants (paid to their institution) from Gilead Sciences and Merck; consulting fees from Gilead Sciences, Merck, and ViiV Healthcare; and payments for participation on an advisory board from AELIX Therapeutics. AM has received research funding (paid to their institution) from Gilead Sciences, ViiV Healthcare, Merck, GSK, AbbVie, and TaiMed Biologics; speaker honoraria from Gilead Sciences, ViiV Healthcare, and EMD Serono; and payments for participation on an advisory board from Gilead Sciences and ViiV Healthcare. CB has received funding and speaker honoraria from Gilead Sciences; speaker honoraria from ViiV Healthcare; and support for attending principal investigator meetings from Gilead Sciences, ViiV Healthcare, GSK, PPD (Thermo Fisher Scientific), Merck, Viking Therapeutics, Syneos Health, Novo Nordisk, AbbVie, Regeneron Pharmaceuticals, Janssen, and Shionogi. MR has received funding and speaker and consulting fees from Gilead Sciences, speaker and consulting fees from ViiV Healthcare, consulting fees from MSD and Abbott, and speaker honoraria from AbbVie and Janssen. AC has received advisory boards fees from Gilead Sciences, ViiV Healthcare, MSD, and Theratechnologies; funding for clinical trials (paid to their institution) from Gilead Sciences, MSD, GSK, ViiV Healthcare, and Pfizer; speaker fees from MSD; and support for congress attendance from Gilead Sciences and ViiV Healthcare. GC has received research funding (paid to their institution) from Gilead Sciences for conducting research discussed in this manuscript. CM has received funding and speaker fees from Gilead Sciences and grants and speaker fees from ViiV Healthcare and Theratechnologies. CC, SC, JCH, YS, MD, AK, and JMB are shareholders and employees of Gilead Sciences. KMo has received funding from Gilead Sciences; speaker fees and advisory board fees from Gilead Sciences, ViiV Healthcare, Janssen Therapeutics, Theratechnologies, and Epividian; and funding for clinical trials (paid to their institution) from Gilead Sciences, ViiV Healthcare, and Janssen Therapeutics. KMa has received research funding from Gilead Sciences, and unrestricted grants and advisory board fees from Gilead Sciences and Merck., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: I declare no competing interests

Diagnosing and treating chronic hepatitis B virus (HBV) infection are key interventions to support progress towards elimination of viral hepatitis by 2030. Although nucleos/tide analogue (NA) therapy is typically highly effective, challenges remain for viral load (VL) suppression, including medication access, incomplete adherence and drug resistance. We present a case of a long-term HBV and HIV coinfected adult prescribed with sequential NA therapy regimens, with episodes of breakthrough viraemia. Multiple factors contribute to virological breakthrough, including exposure to old NA agents, initial high HBV VL, therapy interruptions, intercurrent illnesses and potential contribution from resistance mutations. The case underscores the importance of individualised treatment approaches and adherence support in achieving HBV suppression. Furthermore, it emphasises the need for improved clinical pathways addressing education, support and access to care, particularly for marginalised populations. Comprehensive data collection inclusive of under-represented individuals is crucial for maintaining retention in the care cascade and informing effective interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for human immunodeficiency virus type 1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merit further evaluation., Methods: We performed an in-depth clinical, virological, and pharmacokinetic analysis on the reasons behind and the impact of VF during LA CAB/RPV therapy in 5 cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF, and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cutoff (≤Q1) were considered to be low., Results: Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of nonnucleoside reverse transcriptase inhibitor-associated mutations in all cases, and integrase strand transfer inhibitor mutations in 4 cases. All cases displayed low drug levels of either CAB, RPV, or both during the treatment course, likely contributing to the occurrence of VF. In 3 cases, we were able to identify the potential mechanisms behind these low drug levels., Conclusions: This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological, and pharmacokinetic approach in case of failure., Competing Interests: Potential conflicts of interest. B. J. W. received a research grant from Gilead Health Sciences as well as speaker’s and advisory board fees from Gilead Health Sciences and ViiV Healthcare; all fees were paid to institution. J. H. G. reports participation as a speaker for the Masterclass Infectieziekten in the Netherlands, as well as President of Dutch Society of HIV treating physicians. M. V. received grants and consultancy fees from ViiV Healthcare, Gilead Health Sciences, and MSD, all paid to institution. D. B. received a research grant and honoraria for lectures from ViiV Healthcare. A. M. J. W. received investigator-initiated research grants from Gilead Sciences, AIDSfonds, and Nederlandse organisatie voor Wetenschappelijk Onderzoek; support for attending the Virology Education conference from the European AIDS Clinical Society; receipt of drug level kits from ARK, and consultancy fees from ViiV Healthcare/GSK and Gilead Sciences, all paid to institution; Member of the board of the European Society for Translational Antiviral Research and Chair of the IAS-USA resistance mutation group, all unpaid. 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.)

Background: The emergence of HIV drug resistance presents a substantial challenge. Current antiretroviral treatments, along with current classes, face the danger of becoming partially or entirely inactive. As a result, alternative treatment regimens are limited, and treatment choices are complicated. According to the recommendation of the WHO, nations should consider changing their first-line ART regimen if HIV drug resistance exceeds 10%. In spite of the fact that a number of primary studies have been performed on HIV drug resistance in Ethiopia, their pooled prevalence rate has not been determined in a systematic review and meta-analysis, which may provide stronger evidence. Therefore, the objective of this systematic review and meta-analysis will be to estimate the pooled prevalence rate of HIV1 drug resistance in patients with first-line treatment failure in Ethiopia., Methods: Primary studies will be identified from PubMed/MEDLINE, Scopus, Embase, Web of Science Core Collection, and Google Scholar. The period of search will be from 01 April to 30 June 2024. Studies identified through the search strategies will first be screened by titles and abstracts. Included studies meeting established criteria will be evaluated for risk of bias using the JBI checklist. Data will be extracted, and the pooled prevalence rate of HIV drug resistance will be computed using STATA 14 software. Random effect models will be used when heterogeneity is suspected. The I 2 statistic and its corresponding P value will be checked to distinguish heterogeneity. Additionally, publication bias and heterogeneity will be checked using visual funnel plots, Egger's test, trim-and-fill tests, meta-regression, and subgroup analysis. To present and synthesize the results, narrative synthesis will be performed to describe study characteristics and findings, and forest plots will be used to visually represent effect sizes and confidence intervals from individual studies., Discussion: Estimating the pooled prevalence rate of HIV drug resistance through a systematic review and meta-analysis improves the reliability of the evidence, the availability of effective HIV treatment options, and the ability to assist in making decisions for both clinical practice and public health policy in Ethiopia., Systematic Review Registration: PROSPERO CRD42024533975., (© 2024. The Author(s).)

Despite the significant progress made, CMV infection is one of the most frequent infectious complications in transplant recipients. CMV infections that become refractory or resistant (R/R) to the available antiviral drugs constitute a clinical challenge and are associated with increased morbidity and mortality. Novel anti-CMV therapies have been recently developed and introduced in clinical practice, which may improve the treatment of these infections. In this review, we summarize the treatment options for R/R CMV infections in adult hematopoietic cell transplant and solid organ transplant recipients, with a special focus on newly available antiviral agents with anti-CMV activity, including maribavir and letermovir.

Introduction: Since the coronavirus disease 2019-mandated social distancing policy has been lifted worldwide, the circulation of influenza is expected to resume. Currently, oseltamivir is approved as the first-line agent for influenza prevention and treatment., Areas Covered: This paper reviews the updated evidence in the pharmacology, resistance mechanisms, clinical pharmacy management, and real-world data on oseltamivir for influenza., Expert Opinion: Oseltamivir is an oral prodrug of oseltamivir carboxylate, an influenza A and B neuraminidase inhibitor. Recently, the therapeutic efficacy of oseltamivir has been demonstrated in several trials. Oseltamivir is generally well-tolerated but may lead to neuropsychiatric events and bleeding. Oseltamivir-resistant influenza virus has been associated with the H275Y mutation in the influenza A(H1N1)pdm09 virus, while most strains are still sensitive to oseltamivir. Dose adjustment for oseltamivir should be based on creatinine clearance and body weight in pediatric patients with renal failure. According to real-world data from Nanfang Hospital, the annual number of patients prescribed oseltamivir declined from 35,711 in 2019 to 8,971 in 2020, with marked increases in 2022 (20,213) and 2023 (18,071). Among the 206 inpatients, children aged < 6 years who were treated with oseltamivir had the shortest duration to defervescence.

Respiratory syncytial virus (RSV) can cause pulmonary complications in infants, elderly and immunocompromised patients. While two vaccines and two prophylactic monoclonal antibodies are now available, treatment options are still needed. JNJ-7184 is a non-nucleoside inhibitor of the RSV-Large (L) polymerase, displaying potent inhibition of both RSV-A and -B strains. Resistance selection and hydrogen-deuterium exchange experiments suggest JNJ-7184 binds RSV-L in the connector domain. JNJ-7184 prevents RSV replication and transcription by inhibiting initiation or early elongation. JNJ-7184 is effective in air-liquid interface cultures and therapeutically in neonatal lambs, acting to drastically reverse the appearance of lung pathology., Competing Interests: Declaration of competing interest The following authors were employees of Johnson & Johnson (the sponsor of the work) at the time when the described work was performed, and may hold Johnson & Johnson shares: BA, SdB, NV, KT, NCN, MVG, LK, NY, LV, EP, EL, AB, AP, AF, SWM, DL, JD, ZJ, AK, DR, PR, FH. The work of the other authors on this project was funded by Johnson & Johnson. BB is an employee of Antwerpen University and received funding from Johnson & Johnson and from Flanders Innovation & Entrepreneurship organization (VLAIO, HBC.2019.2157) for this work.RF has a sponsored research agreement with Merck & Co unrelated to the work presented here., (Copyright © 2024 Janssen Pharmaceutica NV. Published by Elsevier B.V. All rights reserved.)

COVID-19 has caused calamitous health, economic and societal consequences. Although several COVID-19 vaccines have received full authorization for use, global deployment has faced political, financial and logistical challenges. The efficacy of first-generation COVID-19 vaccines is waning and breakthrough infections are allowing ongoing transmission and evolution of SARS-CoV-2. Furthermore, COVID-19 vaccine efficacy relies on a functional immune system. Despite receiving three primary doses and three or more heterologous boosters, some immunocompromised patients may not be adequately protected by COVID-19 vaccines and remain vulnerable to severe disease. The evolution of new SARS-CoV-2 variants has also resulted in the rapid obsolescence of monoclonal antibodies. Convalescent plasma from COVID-19 survivors has produced inconsistent results. New drugs such as Paxlovid (nirmatrelvir/ritonavir) are beyond the reach of low- and middle-income countries. With widespread use of Paxlovid, it is likely nirmatrelvir-resistant clades of SARS-CoV-2 will emerge in the future. There is thus an urgent need for new effective anti-SARS-CoV-2 treatments. The in vitro efficacy of soluble ACE2 against multiple SARS-CoV-2 variants including omicron (B.1.1.529), was recently described using a competitive ELISA assay as a surrogate marker for virus neutralization. This indicates soluble wild-type ACE2 receptors are likely to be resistant to viral evolution. Nasal and inhaled treatment with soluble ACE2 receptors has abrogated severe disease in animal models of COVID-19. There is an urgent need for clinical trials of this new class of antiviral therapeutics, which could complement vaccines and Paxlovid., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A man with advanced HIV presented with verrucous plaques 2-3 months after initial mpox infection. He received two courses of tecovirimat without resolution of initial mpox lesions and development of new lesions raising concern for resistance. He was treated with two doses of brincidofovir and demonstrated improvement 6 months later., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: New South Wales (NSW) has one of the world's highest uptake rates of HIV pre-exposure prophylaxis (PrEP). This uptake has been credited with sharp declines in HIV transmission, particularly among Australian-born gay and bisexual men. Concerns have been raised around the potential for the emergence of tenofovir (TFV) and XTC (lamivudine/emtricitabine) resistance in settings of high PrEP use. Such an emergence could also increase treatment failure and associated clinical outcomes among people living with HIV (PLHIV). Despite low levels of nucleoside reverse-transcriptase inhibitor (NRTI) resistance relating to PrEP use in clinical settings, there are few published studies describing the prevalence of NRTI resistance among people newly diagnosed with HIV in a setting of high PrEP use., Methods: Using HIV antiretroviral drug resistance data linked to NSW HIV notifications records of people diagnosed from 1 January 2015 to 31 December 2021 and with HIV attributed to male-to-male sex, we described trends in TFV and XTC resistance. Resistance was identified using the Stanford HIV Drug Resistance genotypic resistance interpretation system. To focus on transmitted drug resistance, resistance prevalence estimates were generated using sequences taken less than 3 months post-HIV diagnosis. These estimates were stratified by timing of sequencing relative to the date of diagnosis, year of sequencing, birthplace, likely place of HIV acquisition, and stage of HIV at diagnosis., Results: Among 1119 diagnoses linked to HIV genomes sequenced less than 3 months following diagnosis, overall XTC resistance prevalence was 1.3%. Between 2015 and 2021, XTC resistance fluctuated between 0.5% to 2.9% and was 1.0% in 2021. No TFV resistance was found over the study period in any of the sequences analysed. Higher XTC resistance prevalence was observed among people with newly acquired HIV (evidence of HIV acquisition in the 12 months prior to diagnosis; 2.9%, p = 0.008)., Conclusions: In this Australian setting, TFV and XTC resistance prevalence in new HIV diagnoses remained low. Our findings offer further evidence for the safe scale-up of PrEP in high-income settings, without jeopardizing the treatment of those living with HIV., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)