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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.

Background: Virological failures of first-line second-generation (SG) INSTI-based regimens are rare, usually characterized by low viremia and absence of drug resistance mutations., Objectives: To explore the efficacy of rescue regimens introduced after virological failure (VF) to a first-line SG-INSTI therapy., Patients and Methods: This was a retrospective study on people living with HIV (PWH) failing a first-line SG-INSTI regimen [DTG/3TC, BIC/FTC/TAF, DTG-based three-drug regimen (DTG-3DR)] between 24 March 2016 and 31 December 2021. Follow-up accrued from the second viral load (VL) ≥ 50 copies/mL under SG-INSTI regimen (baseline) until virological success (VS, achievement of at least one VL < 50 copies/mL after baseline) or last visit. Cumulative probabilities of VS were estimated by Kaplan-Meier curves and compared using a log-rank test., Results: Overall, of 521 naïve PWH who started a first-line SG-INSTI regimen, 45 (8.6%) had VF after a median of 14.9 (IQR = 6.9-25.9) months: 33/395 (8.4%) individuals failed a DTG-3DR, 11/102 (10.8%) a BIC/FTC/TAF and 1/24 (4.2%) failed a DTG/3TC.At baseline, 12/45 (27%) PWH changed antiretroviral therapy [median baseline VL 134 (IQR = 81-233) copies/mL], while 33 (73%) maintained their failing regimen [median baseline VL 75 (IQR = 60-145) copies/mL].During a median follow-up of 5.13 (IQR = 3.8-7.1) months, 34 (75.6%) PWH achieved VS: 25/33 (75.8%) maintaining their failing regimen, 9/12 (75%) switched regimen; the estimated 6- and 12-months probabilities of VS were 59% and 84%, respectively.There was no difference in VS curves between PWH who maintained their failing regimen and those who switched therapy., Conclusions: Most individuals remained on their failing regimen, achieving spontaneous virological suppression in most cases. These data help to understand a real-life VF scenario in the context of the current SG-INSTI era., (© 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.)

The biological applications of noncationic porphyrin-fullerene (P-F) dyads as anti-HIV agents have been limited despite the established use of several cationic P-F dyads as anti-cancer photodynamic therapy (PDT) agents. This article explores the potential of amphiphilic non-cationic porphyrin-fullerene dyads as HIV-1 inhibitors under both PDT (light-treated) and non-PDT (dark) conditions. The amphiphilic P-F dyads, PB 3 C 60 and PB 3 C 70 , demonstrated enhanced efficacy in inhibiting the entry and production of HIV-1 (subtypes B and C). Under light-harvested conditions, the dyads exhibited potent inhibitory effects (EC 50 for PB 3 C 60 and PB 3 C 70  < 10 nM) and also maintained significant inhibition under non-PDT conditions (EC 50 for PB 3 C 60  = 1.43 μM and PB 3 C 70  = 1.50 μM), while displaying notably reduced toxicity compared to their water-soluble porphyrin precursor. The P-F dyads exhibited substantial efficacy in neutralizing the T20-resistant strain 9491, both at the entry and postentry phases, thereby addressing the challenge of drug resistance., (© 2025 Wiley Periodicals LLC.)

Significant advances in treatment have turned HIV-1 into a manageable chronic condition. This has been achieved due to highly active antiretroviral therapy (HAART), involving a combination regimen of medications, including drugs that target Reverse Transcriptase, Protease, Integrase, and viral entry, explored in this review. This paper also highlights novel therapies, such as Lenacapavir, and avenues toward functional cure targeting the CCR5 co-receptor, including the Δ32 mutation. Challenges of HAART include lifelong adherence, toxicity, drug interactions, and drug resistance. Future therapeutic strategies may focus on underexplored antiviral targets. HIV-1 Tat and Rev proteins have essential HIV-1 regulatory functions of transcriptional elongation of the viral long terminal repeat and nuclear export of intron-containing HIV-1 RNA, respectively. These non-enzymatic proteins should thus be investigated to identify small molecules that inhibit HIV-1 replication, without causing undue toxicity. Continued innovation is essential to address therapeutic gaps and bring us closer to a potential HIV-1 cure., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Published by Elsevier Inc.)

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Although interferon-free direct-acting antivirals have led to significant advancements in the treatment of HCV infection, the high genetic variability of the virus and the emergence of acquired drug resistance pose potential threats to their effectiveness. In this study, we develop a broad-spectrum aptamer-based proteolysis targeting chimera, designated dNS5B, which effectively degrades both pan-genotypic NS5B polymerase and drug-resistant mutants through ubiquitin proteasome system. To achieve hepatocyte-specific uptake, we further develop Gal-dNS5B by coupling the dNS5B with a trivalent N -acetylgalactosamine (tri-GalNAc), a ligand for the liver-specific asialoglycoprotein receptor. Gal-dNS5B exclusively accumulates in hepatocytes and suppresses HCV replication by degrading NS5B. Collectively, our research lays the groundwork for a scalable strategy in the development of antiviral medications aimed at addressing current and future challenges posed by hepatitis viruses and other re-emerging viral pandemics.

The currently circulating S31N variant of the M2 proton channel of influenza A is resistant to antiviral drugs. Recently, there has been a growing concern regarding the impact of the lipid environment on the structural features of the S31N variant. The native symmetry of the M2 tetramer remains controversial. Here we show that S31N M2 persists in a dimer-of-dimers structure in different lipid preparations independent of the amount of solvating lipids up to at least 180 lipids per tetramer. NMR spectra clearly detect the characteristic resonances of the dimer-of-dimers of M2 (residues 18-60 or 18-62) reconstituted in lipids. NMR-based distance measurements indicate that two isoleucine residues with upfield shifted alpha carbon resonances, typical of extended conformations, are compatible with a particular side-chain rotameric state and helical backbone geometry. These chemical shifts are therefore compatible with the expected native transmembrane helical fold. Symmetry breaking at the pH sensing H37 residues, detected via peak doubling, is a stable feature of S31N M2 based on the reference strain Udorn/1972(H3N2). By contrast, the spectrum is dramatically altered for Columbia/2014/(H3N2) M2, which differs in sequence in the amphipathic helices. This highlights an allosteric coupling between the amphipathic helices and the pH sensing residues., (© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH.)

The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088. Both MMF and IMP-1088 drugs exhibited strong dose-dependent antiviral activity against VACV and mpox, and potent synergistic effects in conjunction with TPOXX. Our findings support combination therapy of direct-acting (TPOXX) and host-targeted (MMF and IMP-1088) antivirals as a promising approach to treat mpox and prevent the emergence and spread of TPOXX-resistant MPXV variants.

Antiretroviral therapy is the standard treatment for HIV, but it requires daily use and can cause side effects. Despite being available for decades, there are still 1.5 million new infections and 700,000 deaths each year, highlighting the need for better therapies. Broadly neutralizing antibodies (bNAbs), which are highly active against HIV-1, represent a promising new approach and clinical trials have demonstrated the potential of bNAbs in the treatment and prevention of HIV-1 infection. However, HIV-1 antibody resistance (HIVAR) due to variants in the HIV-1 envelope glycoproteins (HIV-1 Env) is not well understood yet and poses a critical problem for the clinical use of bNAbs in treatment. HIVAR also plays an important role in the future development of an HIV-1 vaccine, which will require elicitation of bNAbs to which the circulating strains are sensitive. In recent years, a variety of methods have been developed to detect, characterize and predict HIVAR. Structural analysis of antibody-HIV-1 Env complexes has provided insight into viral residues critical for neutralization, while testing of viruses for antibody susceptibility has verified the impact of some of these residues. In addition, in vitro viral neutralization and adaption assays have shaped our understanding of bNAb susceptibility based on the envelope sequence. Furthermore, in vivo studies in animal models have revealed the rapid emergence of escape variants to mono- or combined bNAb treatments. Finally, similar variants were found in the first clinical trials testing bNAbs for the treatment of HIV-1-infected patients. These structural, in vitro , in vivo and clinical studies have led to the identification and validation of HIVAR for almost all available bNAbs. However, defined assays for the detection of HIVAR in patients are still lacking and for some novel, highly potent and broad-spectrum bNAbs, HIVAR have not been clearly defined. Here, we review currently available approaches for the detection, characterization and prediction of HIVAR., Competing Interests: A patent application on anti-HIV-1 broadly neutralizing antibodies has been filed by the University of Cologne and lists PS as one of the inventors. PS has received payments from the University of Cologne for licensed antibodies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Odidika, Pirkl, Lengauer and Schommers.)

Human immunodeficiency virus (HIV) targets the host immune system causing acquired immunodeficiency syndrome (AIDS). Although significant advancements have been made on investigating HIV and related infections, eradicating the virus from the host immune system is still challenging. Nevertheless, the combination therapies using drugs targeting different stages in the viral life cycle are used for treatment in which HIV protease plays a vital role. Hence, it is essential to understand the structure and function of HIV protease. This review focuses on these aspects from different perspectives such as catalytic mechanism, subtypes and role of flaps in drug binding. Further, we highlight the factors affecting drug binding, evolution of drug resistance, and inhibitors reported in the literature using 3D QSAR studies., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: HIV is a global disease affecting millions of people. While treatments have improved over the past decades, treatment failure remains a significant issue for treatment experienced patients. Doravirine/islatravir is a new dual-therapy regimen with a promising resistance profile and reductions in central nervous system effects. Recent trials have shown non-inferiority compared to current standards of care. However, current research suggests that CD4 counts decrease in an islatravir-dose dependent manner, but more data is needed to determine the full extent of this effect at lower doses., Areas Covered: Doravirine/islatravir is a therapeutic combination for the treatment of HIV which is currently in Phase 3 trials. This article reviews key studies regarding the safety and efficacy of the combination., Expert Opinion: When approved, doravirine/islatravir should be considered for patients who have previously failed treatment due to viral resistance. It expands the selection of two-drug single-pill therapies and introduces a novel mechanism of action to the market. However, more data is needed regarding the effects of islatravir on CD4 counts. ISL doses as low as 0.25 mg proved non-inferior to current treatments. Therefore, evaluation of the long-term efficacy and safety of DOR/ISL should focus on reduced doses of ISL and minimizing CD4 reduction.

Purpose: The purpose of this study was to describe the efficacy and tolerance of amenamevir (AMNV), an inhibitor of the viral helicase-primase, for the treatment of recalcitrant herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACVR) herpes simplex virus 1 strains., Methods: In this retrospective case series, 6 consecutive patients with HSK caused by an ACVR herpes simplex virus 1 strain with a failure of conventional antiviral therapy were included after having been treated with AMNV (there was no control group of comparable patients for whom previous treatment would have been continued despite its inefficacy). Medical files were assessed for clinical data including reason(s) for AMNV introduction (frequent recurrences despite appropriate preventive antiviral treatment and/or clinical resistance to suppressive antiviral treatment of an ongoing clinical relapse), genotypical resistance to herpes simplex virus 1 documentation, immune status, clinical types and number of HSK episodes before and during AMNV treatment, adverse effects observed during AMNV treatment, and best corrected visual acuity., Results: Of 6 patients, 4 (66%) did not experience a single recurrence during AMNV therapy while 2 others had recurrences (1 over 24 months of treatment and 2 over 23 months, ie two-fold less frequently than with conventional preventive treatment). On the overall history of these 6 patients, AMNV appeared to be associated with a reduction in HSK recurrences, with a mean of only 0.02 ± 0.04 episodes/month during follow-up under AMNV as compared to 0.14 ± 0.04 episodes/month in the year preceding AMNV introduction ( P = 0.03). Improvement in vision acuity was also observed (mean best corrected visual acuity 0.17 ± 0.12 logarithm of the minimum angle of resolution at the end of follow-up vs. 0.30 ± 0.35 before AMNV onset), albeit nonsignificant probably due to the limited number of patients ( P = 0.38). Neither clinical nor biological adverse effects were observed while under AMNV during the follow-up (16.5 ± 5.8 months)., Conclusions: Although there was no control group, AMNV may be a valuable option to reduce ACVR HSK recurrences., Competing Interests: D. Boutolleau has been an occasional consultant on subjects outside the scope of this work for bioMérieux, Qiagen, DiaSorin Molecular and Roche Diagnostics. M. Labetoulle has been an occasional consultant on subjects outside the scope of this work for Alcon, Allergan, Bausch and Lomb, Dompe, Horus, GSK, MSD, Novartis, Santen, Shire, and Thea. A. Rousseau has been an occasional consultant on subjects outside the scope of this work for Thea, Horus Pharma, Allergan, Alnylam, Glaukos, Bauch and Lomb. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The emergence of the H3N2 influenza virus in 1968 marked a significant event as it crossed the species barrier. This shift led to a pandemic, resulting in the deaths of one million people globally and highlighting the virus's severe impact on older individuals due to antigenic drift., Area Covered: This review comprehensively examines the virological characteristics, evolutionary trends, and global epidemiology of the Influenza A (H3N2) virus. It delves into vaccination strategies, antiviral interventions, and emerging diagnostic approaches. The impact of antigenic variation on vaccine design and effectiveness, seasonal outbreak patterns, and pandemic potential are explored. Additionally, the interplay between viral factors and host immune responses is assessed. Researchers are actively investigating innovative strategies to enhance vaccine efficacy against H3N2 mutations, such as precise antigenic material administration, controlled release patterns, understanding immune system mechanisms, and glycan engineering., Expert Opinion: The ongoing mutational dynamics of the H3N2 virus necessitate regular vaccine updates, as advocated by the WHO. Research in the Western Pacific region underscores the need for heightened awareness and effective control strategies. Evaluating antiviral therapies and addressing drug resistance requires multidisciplinary approaches involving researchers, healthcare professionals, and policymakers. This comprehensive understanding of H3N2 is vital for improving public health interventions and preparing for future influenza challenges.

Cytomegalovirus (CMV) infection in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients may increase the risk of rejection or allograft dysfunction, other infection(s), and morbidity and mortality. Treatment can be challenging due to medication-associated toxicities. Maribavir (MBV) is a promising option for the treatment of resistant or refractory (R/R) CMV infection in lieu of foscarnet (FOS), which has long been the recommended therapy for (val)ganciclovir-resistant infection. This was a single-center retrospective study of clinical outcomes of patients who received MBV compared to a control group who received FOS for an episode of CMV infection. Each cohort consisted of 27 episodes of CMV infection. Twenty patients in the MBV cohort and from the FOS cohort cleared the infection, with five and three patients developing MBV or FOS resistance, respectively. There were no statistically significant differences in failure of therapy as evidenced by persistent DNAemia ( p = 0.56) or development of antiviral resistance ( p = 0.24). In conclusion, MBV was as effective as FOS for the treatment of R/R CMV infection and was better tolerated without increased risk of antiviral resistance.

Coronaviruses such as the Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2, causing MERS, SARS, and Coronavirus disease-19, respectively, are highly pathogenic to humans. Notably, several antiviral drugs against SARS-CoV-2, such as nirmatrelvir and remdesivir, have been approved. However, no approved vaccines or antiviral agents are available for other highly pathogenic β-coronaviruses. In this study, we identified two compounds, thapsigargin and X-206, that exhibit antiviral activities against SARS-CoV, MERS-CoV, and SARS-CoV-2. Notably, both compounds effectively inhibited the cell-to-cell fusion mediated by the Spike proteins of all three β-coronaviruses. X-206 exhibited antiviral activity against nirmatrelvir- and remdesivir-resistant SARS-CoV-2 isolates and SARS-CoV-2 variants, including Delta, BA.5, and XBB.1. Consequently, the mechanism of action of these compounds with anti-β-coronavirus activities may differ from that of the approved direct-acting drugs for SARS-CoV-2, thereby offering potential use as a cocktail with other antivirals, and serving as a chemical basis for developing therapeutic agents against β-coronaviruses in preparation for the next spillover and pandemic., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kota Kodama reports financial support was provided by Kumagaya gumi. Kota Kodama reports financial support was provided by Sumitomo Life Insurance. Kota Kodama reports financial support was provided by Merge System. Kota Kodama reports financial support was provided by Pasona. Akihiko Sato belongs to Shionogi & Company, Limited. If there are other authors, they 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.)

Antiviral drugs have classically been developed by directly disrupting the functions of viral proteins. However, this strategy has been largely unsuccessful due to the rapid generation of viral escape mutants. It has been well established that as compared to the virus-centric approach, the strategy of developing antiviral drugs by targeting host-dependency factors (HDFs) minimizes drug resistance. However, recent reports have indicated that drug resistance against some of the host-targeting antiviral agents can in fact occur under some circumstances. Long-term selection pressure of a host-targeting antiviral agent may induce the virus to use an alternate cellular factor or alters its affinity towards the target that confers resistance. Alternatively, virus may synchronize its life cycle with the patterns of drug therapy. In addition, virus may subvert host's immune system to perpetuate under the limiting conditions of the targeted cellular factor. This review describes novel potential mechanisms that may account for the acquiring resistance against agents that target HDFs., 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 Inc. All rights reserved.)

Background: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB)., Aims: Here, we report the studies' final 8-year results., Methods: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping., Results: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFR CG ) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFR CG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF., Conclusion: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance., Clinicaltrials: gov numbers NCT01940341 and NCT01940471., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

The influenza B virus is one of the causes of seasonal influenza, which has a long history of existence in various populations. Adolescents, children, pregnant women, the elderly, as well as patients with major diseases such as high blood pressure, diabetes, and cancer, and those with low immunity are more susceptible to infection by the influenza virus. During the influenza seasons, the influenza B virus can cause significant harm and economic burden. At present, neuraminidase inhibitors, hemagglutinin inhibitors and RNA polymerase inhibitors are the main antiviral drugs that are used in the clinical treatment of influenza B. Due to the repeated use of antiviral drugs in recent years, the emergence of resistant strains of the influenza virus exacerbated. By combining anti-viral drugs with different mechanisms of action or using a combination of traditional Chinese medicine and chemical drugs, the problem of reduced drug sensitivity can be improved. This article introduces the drug targets of the influenza B virus and the mechanism of virus resistance. It also emphasizes the clinically used antiviral drugs and their mechanisms of action, thereby providing a reference basis for the development of new anti-influenza drugs., 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. Published by Elsevier Ltd.)

Introduction: This review encapsulates the recent strides in the development of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, focusing on the novel structural designs that promise to overcome limitations of existing therapies, such as drug resistance and toxicity., Areas Covered: We underscore the application of computational chemistry and structure-based drug design in refining NNRTIs with enhanced potency and safety., Expert Opinion: Highlighting the emergence of diverse chemical scaffolds like diarylpyrimidines, indoles, DABOs and HEPTs, the review reveals compounds with nanomolar efficacy and improved pharmacokinetics. The integration of artificial intelligence in drug discovery is poised to accelerate the evolution of NNRTIs, laying the foundation for addressing drug resistance in the era of anti-HIV therapy through innovative designs and multi-target strategies.

Maribavir is approved for management of post-transplant cytomegalovirus (CMV) infections refractory and/or resistant to CMV therapies at a dose of 400 mg twice daily (BID). Population pharmacokinetic (PopPK) and exposure-response analyses were conducted to support the appropriateness of 400 mg BID dosing. A PopPK model was developed using non-linear mixed-effects modeling with pooled maribavir plasma concentration-time data from phase 1 and 2 studies (from 100 mg up to 1200 mg as single or repeated doses) and the phase 3 SOLSTICE study (400 mg BID). Exposure-response analyses were performed for efficacy, safety, and viral resistance based on data collected in the SOLSTICE study. Maribavir PK after oral administration was adequately described by a two-compartment model with first-order elimination, first-order absorption, and an absorption lag-time. There was no evidence that maribavir PK was affected by age, sex, race, diarrhea, vomiting, disease characteristics, or concomitant use of histamine H 2 blockers, or proton pump inhibitors. In the SOLSTICE study, higher maribavir exposure was not associated with increased probability of achieving CMV DNA viremia clearance, nor with reduced probability of treatment-emergent maribavir-resistant CMV mutations. A statistically significant association with maribavir exposure was identified for taste disturbance, fatigue, and treatment-emergent serious adverse events, while transplant type, enrollment region, CMV DNA level at baseline, and/or CMV resistance at baseline were identified as additional risk factors for these safety outcomes. In conclusion, the findings of these PopPK and exposure-response analyses provide further support for the recommended maribavir dose of 400 mg BID., Competing Interests: Declarations. Competing interests: IH Song, G Chen, and K Sun are employees of Takeda Development Center Americas, Inc., and receive stocks (and stock options) from Takeda. S Hayes and C Farrell are employees of ICON plc. C Jomphe and NH Gosselin are employees of Certara., (© 2024. The Author(s).)

Objective: We studied the transition to dolutegravir-containing antiretroviral therapy (ART) at HIV treatment clinics within the International epidemiology Databases to Evaluate AIDS (IeDEA)., Design: Site-level survey conducted in 2020-2021 among HIV clinics in low- and middle-income countries (LMICs)., Methods: We assessed the status of dolutegravir rollout and viral load and drug resistance testing practices for persons on ART switching to dolutegravir-based regimens. We used generalized estimating equations to assess associations between clinic rollout of both first- and second-line dolutegravir-based ART regimens (dual rollout) and site-level factors., Results: Of 179 surveyed clinics, 175 (98%) participated; 137 (78%) from Africa, 30 (17%) from the Asia-Pacific, and 8 (5%) from Latin America. Most clinics (80%) were in low- or lower-middle-income countries, and there were a mix of primary-, secondary- and tertiary-level clinics. Ninety percent reported rollout of first-line dolutegravir, 59% of second-line, 94% of first- or second-line and 55% of dual rollout. The adjusted odds of dual rollout were higher among tertiary-level [adjusted odds ratio (aOR) 4.00; 95% confidence interval (CI) 1.39-11.47] and secondary-level clinics (aOR 3.66; 95% CI 2.19-6.11) than in primary-level clinics. Over half (59%) of clinics that introduced first- or second-line dolutegravir-based ART required recent viral load testing before switching to dolutegravir, and 15% performed genotypic resistance testing at switch., Conclusions: Dolutegravir-based ART was rolled out at nearly all IeDEA clinics in LMICs, yet many switched persons to dolutegravir without recent viral load testing and drug resistance testing was rarely performed. Without such testing, drug resistance among persons switching to dolutegravir may go undetected., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Antiretroviral (ARV) drug resistance poses a threat to ending the HIV epidemic. As the rates of integrase resistance continue to increase globally, the availability of options for HIV treatment becomes limited. Heavily treatment-experienced (HTE) people with HIV (PWH) are limited to two or fewer available fully active ARV classes and are more likely to have an AIDS-defining event. Appropriate identification and management of HTE PWH is crucial to improving patient outcomes and reducing the future spread of drug-resistant HIV. As treatment options become more limited owing to drug resistance, the availability of more potent drugs with a marked increase in virologic suppression is needed in the current ART era. The purpose of this narrative review is to review the identification of HTE PWH, novel mechanisms of resistance, and management of HTE PWH in resource-rich and resource-limited settings using novel ARVs and combination ART., Competing Interests: Declaration of conflicting interestMB discloses honoraria for a presentation on long-acting injectables for HIV treatment and prevention at MATEC (Midwest AIDS Training and Education Committee), has received honoraria from ViiV and Gilead for serving on the advisory boards, and is a member of the Speaker’s Bureau of ViiV (APRETUDE and CABENUVA) and Gilead (BIKTARVY and SUNLENCA). CF discloses grants from Gilead Sciences, ViiV Health Care, Merck, and Moderna to the institution.

Remdesivir (RDV, Veklury®) is the first FDA-approved antiviral treatment for COVID-19. It is a nucleotide analogue (NA) carrying a 1'-cyano (1'-CN) group on the ribose and a pseudo-adenine nucleobase whose contributions to the mode of action (MoA) are not clear. Here, we dissect these independent contributions by employing RDV-TP analogues. We show that while the 1'-CN group is directly responsible for transient stalling of the SARS-CoV-2 replication/transcription complex (RTC), the nucleobase plays a role in the strength of this stalling. Conversely, RNA extension assays show that the 1'-CN group plays a role in fidelity and that RDV-TP can be incorporated as a GTP analogue, albeit with lower efficiency. However, a mutagenic effect by the viral polymerase is not ascertained by deep sequencing of viral RNA from cells treated with RDV. We observe that once added to the 3' end of RNA, RDV-MP is sensitive to excision and its 1'-CN group does not impact its nsp14-mediated removal. A >14-fold RDV-resistant SARS-CoV-2 isolate can be selected carrying two mutations in the nsp12 sequence, S759A and A777S. They confer both RDV-TP discrimination over ATP by nsp12 and stalling during RNA synthesis, leaving more time for excision-repair and potentially dampening RDV efficiency. We conclude that RDV presents a multi-faced MoA. It slows down or stalls overall RNA synthesis but is efficiently repaired from the primer strand, whereas once in the template, read-through inhibition adds to this effect. Its efficient incorporation may corrupt proviral RNA, likely disturbing downstream functions in the virus life cycle., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

The treatment of refractory CMV is often associated with high toxicity. Maribavir (MBV) is a novel oral antiviral, known for its favourable safety profile in fragile patients. We describe a case of CMV disease with end organ damage following kidney transplantation at high risk, for recipient-donor serological mismatch. A 54-year-old female with history of obesity, hypertension, and chronic kidney disease, on prednisone and tacrolimus after kidney transplantation in November 2022, soon after developed primary CMV infection, treated with Valganciclovir and CMV Ig. In January 2023 the patient presented with fever and dyspnea. Pulmonary miliary opacities and right-upper lobe consolidation were found at CT-scan along with CMV-DNA positivity on BAL and serum. Lung biopsy confirmed CMV infection. Antiviral was switched to Ganciclovir. Despite initial benefit, fever and respiratory failure happened 8 days later, leading to intubation at day 15. Due to slow decrease serum CMV-DNA and detection of UL97 mutation, conferring resistance to valganciclovir and ganciclovir, the patient was started on foscarnet and letermovir. She was extubated after a gradual respiratory improvement and discharged from ICU to rehabilitation department with HFNC; reduction in serum CMV-DNA, but persistently elevated CMV-DNA on BAL were documented. At week 8, MBV was started and letermovir continued, for a 8 weeks course, without notable adverse effects. Respiratory function improved but soon after septic shock occurred. A bone marrow biopsy resulted in lymphoma, without indications for treatment: the patient developed coma and died 6 months after admission. MBV has recently been approved in Europe for treatment of R/R CMV in HSCT and SOT recipients. MBV showed superior rates of viraemia clearance after 8 weeks compared to SOC, demonstrating also a favourable safety profile with fewer patients discontinuing treatment and being affected by nephrotoxicity and neutropenia. Its main side effects are taste impairment, gastro-intestinal symptoms and asthenia. Based on actual promising perspectives regarding antiviral stewardship, more data are required to corroborate benefit of MBV in terms of toxicity and impact on mortality in highly fragile populations as SOT recipients. MBV received approval for the treatment of refractory or resistant CMV infections to other antiviral agents. Nevertheless, real-life data on efficacy and safety of MBV are still lacking. We conducted a narrative review of the current literature on MBV as treatment for CMV infection in kidney transplant recipients to understand clinical characteristics, safety and outcomes of MBV in this population. A search was run on the main scientific databases. 194 papers were identified, of which 188 were excluded by title and abstract evaluation. Subsequently, 6 papers were included. We performed descriptive statistics on the entire study population. The studies included in our analysis showed a higher prevalence of male subjects. The median age was 57 year. CKD was the most frequently reported comorbidity. Seven patients reported a donor/recipient mismatch (D+/R-). The case report and the cohort of patients collected from the literature show that MBV was used as an option in R/R CMV, notably for the presence or suspicion of CMV resistance to previous treatment. The clinical presentation of CMV in kidney SOT was heterogenous and varied from isolated reactivation of CMV-DNAemia, isolated fever or gastrointestinal involvement. For mild to moderate CMV disease, as with the cases reported in our review, or for proven ganciclovir, foscarnet or cidofovir resistance, MBV could be a valuable option. Outcomes of the patients treated with MBV were not reported in all the studies; however, where reported, 45.4% of the cases developed virological failure during MBV treatment with the development of specific resistance to MBV. MBV was generally well-tolerated, with low rates of toxicity, normally reversible. The introduction of new oral antivirals, such as MBV, could improve treatment, prophylaxis and preemptive treatment strategies, especially in anti-CMV treatment experienced patients., Competing Interests: Declaration of competing interest All the authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: COVID-19 pandemic has turned our world upside down by meddling with our normal lives. While there is no definitive drug against SARS-CoV-2, antiviral drugs that are already in the market, are being repurposed against it, could now complete long-term as well as all age-specific investigations, and they are successful in saving millions of lives. Nevertheless, side-effects are emergingly seen in the patients undergoing treatment, and ineffectiveness is increasingly found due to the emerging notorious variants of the virus. Many of them are also facing serious co-infections including black fungus, Zika, and H1N1 virus to name a few., Objectives: Therefore, this review highlights both drug resistance, their side-effects, and the significance for proper and long-term clinical trials of all age groups including children., Methods: We have explored and proposed the mechanisms of drug resistance that may arise due to the misuse or overuse of drugs based on available experimental reports., Results: The review provides solutions to the aforesaid issues of drug-resistance and side-effects by providing combination therapies, ancillary treatments, and other preventive strategies that can be useful in preventing drawbacks thereby curbing COVID-19 or similar future infections to maintain our normal lives., Conclusion: COVID-19 and its long-term effects, if any, can be eradicated with strategic and mindful use of related therapeutics in a controlled manner., Competing Interests: Declarations Conflict of interest Declared none., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

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.

The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016-2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide-ranging anti-HIV medications is anticipated., (© 2024 Wiley Periodicals LLC.)

Cytomegalovirus (CMV) infection is one of the most prevalent opportunistic infections after hematopoietic stem cell transplantation (HSCT). Prophylaxis and preemptive therapy have demonstrated promise in reducing the incidence of CMV infection and CMV disease, but the management of refractory/resistant (R/R) CMV infections after HSCT remains a challenge that significantly affects the prognosis of patients undergoing HSCT. Intolerance and resistance to antivirals are the primary reasons for developing refractory CMV infections. CMV DNA quantification PCR combined with CMV-specific cell-mediated immunity monitoring may help to optimize diagnosis and enable personalized management of R/R CMV infection. Novel antiviral drugs and other immunotherapies, including intravenous immunoglobulin and adoptive CMV T cell therapy, constitute an appealing option.

Purpose: Long-acting cabotegravir/rilpivirine (LA-CAB/RPV) was approved for use in virally suppressed patients with human immunodeficiency virus (HIV) in January 2021. While this was a paradigm shift for many patients living with HIV, as LA-CAB/RPV was the first injectable complete regimen for the treatment of HIV, several patient populations, including those lacking virologic suppression, have not been able to easily access this advance in science and care., Summary: In this article, we provide an update on 2 patients from our previous report and describe one further patient who experienced treatment failure following initiation of LA-CAB/RPV. Additionally, we review reports published to date of the clinical outcomes of patients with viremia who have accessed LA-CAB/RPV in the setting of baseline resistance-associated mutations (RAMs) to either component and any resulting RAMs at virologic failure. On the basis of this evidence, we recommend that hybrid or all-injectable regimens be considered for patients who have struggled with adherence to oral antiretroviral therapy or have partial or full resistance to one component of LA-CAB/RPV., Conclusion: The case series reported here adds to literature supporting the notion that LA-CAB/RPV can be successfully used in patients who are viremic., (© American Society of Health-System Pharmacists 2024. 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.)

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.)

Background: Clinical data on patients infected with influenza B Victoria (BV) after the approval of baloxavir is lacking., Methods: This observational study of the Japanese 2023-2024 influenza season analyzed data from 25 outpatients with A(H1N1)pdm09, 36 with A(H3N2), and 65 with BV. Viral samples were collected before and after administering an antiviral (70 patients received baloxavir and 56 received a neuraminidase inhibitor), on days 1, 5, and 10. Isolated viruses after culturing were amplified using RT-PCR and sequenced to detect mutations of concern, including acidic protein (PA)-amino acid (AA) E23X/I38X for influenza A and M34X/I38X for BV. Fever and symptoms were tracked via self-reporting diaries., Results: No PA-AA-substituted virus was detected from 126 pre-treatment samples. In the baloxavir cohort, one (7.1%, 1/14) PA I38F-substituted A(H1N1)pdm09 and two (11.1%, 2/18) PA I38T-substituted A(H3N2) viruses were isolated on day 5 but not on day 10. No (0%, 0/37) PA-AA-substituted BV was detected on day 5 or after. The virus isolation rate on day 5 was higher among patients with BV than with influenza A in both baloxavir (35.1% vs. 14.3% for A(H1N1)pdm09 and 16.7% for A(H3N2)) and oseltamivir-treated patients (44.4% vs. 0% for A(H1N1)pdm09 and 33.3% for A(H3N2)). Patients with PA-AA-substituted influenza A after baloxavir administration did not have longer fever duration than those without virus isolation or with wild-type virus on day 5, for both A(H1N1)pdm09 and A(H3N2)., Conclusions: Baloxavir-resistant variants were not detected in influenza BV before treatment, as with A. The emergence of PA-AA-substituted influenza A after baloxavir administration was temporal and did not cause prolonged symptoms. No baloxavir-resistant BV variants were observed after baloxavir administration., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

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.)

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.

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.)

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.)

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.)

Introduction: Cytomegalovirus (CMV) is a classic opportunistic infection in transplant recipients. Treatment-refractory CMV infections are of concern, with growing identification of strains that have developed genetic mutations which confer resistance to standard antiviral therapy. Resistant and refractory CMV infections are associated with worse patient outcomes, prolonged hospitalization, and increased healthcare costs., Areas Covered: This article provides a comprehensive practical overview of resistant and refractory CMV infections in transplant recipients. We review the updated definitions for these infections, antiviral pharmacology, mechanisms of drug resistance, diagnostic workup, management strategies, and host-related factors including immune optimization., Expert Opinion: Resistant and refractory CMV infections are a significant contributor to post-transplant morbidity and mortality. This is likely the result of a combination of prolonged antiviral exposure and active viral replication in the setting of intensive pharmacologic immunosuppression. Successful control of resistant and refractory infections in transplant recipients requires a combination of immunomodulatory optimization and appropriate antiviral drug choice with sufficient treatment duration.

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: 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.)

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.)

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.)

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.