Antiviral Resistance Research Articles

Designing a multi-epitope vaccine candidate against pandemic influenza a virus: an immunoinformatics and structural vaccinology approach.

Influenza A virus (IAV) remains a significant public health concern due to its annual epidemics and potential for global pandemics. Despite the availability of countermeasures such as vaccines and antiviral treatments, their effectiveness is often questioned due to the emergence of novel strains with antiviral resistance and the variable efficacy of influenza vaccines compared to other vaccines. Traditionally, influenza vaccination strategies have focused on matrix, neuraminidase, and nucleoproteins. In this study, considering the crucial roles of HA and RdRp (PA, PB1, and PB2) of Influenza A, a reverse vaccinology approach is put forth in designing a possible promising antigenic protein toward the development of vaccines against H1N1 viruses. With the development of immunoinformatics approach, one can design/construct potential candidates for vaccine formulation against IAV with the epitope segments identified based on B- and T-cell recognition linked via adjuvants like EAAAK, GPGPG, and AAY linkers. Computational assessments of physicochemical properties, antigenicity, immunogenicity, allergenicity, and toxicity predictions, conducted to evaluate the potential of designed vaccine construct, indicated high antigenicity and potential interactions with immune receptors. Molecular docking of the vaccine construct with human immune receptors (MHCI, MHCII, TLR4, TLR7, and TLR8) followed by molecular dynamics simulations demonstrated stable dynamics with strong binding affinity. The computational immune response modeling with multiple dosages suggested significant immune activation by this construct against IAV. In essence, these findings highlight the potential immune property of the vaccine construct, and put forth the need of thorough preclinical assessments in transforming this construct as a vaccine against the challenging IAV pathogens.

Evaluation of a next generation sequencing assay for Hepatitis B antiviral drug resistance on the oxford nanopore system.

Next-generation sequencing (NGS) for Hepatitis B virus (HBV) antiviral resistance (AVR) testing is a highly sensitive diagnostic method, able to detect low-level mutant subpopulations. Our clinical virology laboratory previously transitioned from DNA hybridization (INNO-LiPA) to NGS, initially with the GS Junior System and subsequently the MiSeq. The Oxford Nanopore Technology (ONT) sequencing system was evaluated for HBV resistance testing, with regards to sequencing accuracy and turn-around time. We performed amplicon sequencing of the HBV polymerase gene from patient plasma and external quality assessment (EQA) samples on the MiSeq Reagent Nano Kit v2 and GridION ONT with R10.4.1 flowcells. Mutational analysis and genotyping were performed by DeepChek®Assay-HBV (version 2.0). A total of 49 patient samples and 15 EQA samples were tested on both the MiSeq and ONT. There was high agreement for both patient and EQA samples between the MiSeq and ONT systems, with regards to total drug resistance mutations detected and total patient sample agreement, 68/70 (97 %) and 47/49 (96 %), respectively. The ONT NGS platform provided accurate HBV AVR results, with improved turn-around times. Sequencing error rates at AVR codons were below 1 %.

Identification of a Novel Alkaloid Zj6-11 as a Potent Inhibitor of Influenza Virus Infection via Repression of Virus-Induced Mitochondria-Dependent Apoptosis.

Influenza A virus (IAV) remains a major global public health threat, especially with the emergence of antiviral resistance, highlighting the urgent need for novel therapeutics. Alkaloids are known for their antiviral properties, and chemical synthesis has become a key strategy in developing new alkaloid compounds. In this study, we synthesized a series of novel alkaloids using the Ugi reaction and assessed their antiviral potential and mechanisms. Through screening and validation, Zj6-11 was identified as a promising compound that effectively inhibits IAV infection in vitro. Molecular docking and binding affinity assays showed that Zj6-11 binds with high affinity to IAV nucleoprotein (NP) and inhibits its interaction with nucleic acids. Further, in vitro nuclear translocation assays confirmed that Zj6-11 suppresses NP nuclear import. Mechanistically, Zj6-11 significantly inhibits IAV-induced apoptosis and mitigates mitochondrial membrane potential dysfunction. Zj6-11 also inhibits cytochrome c release, reduces the expression of cleaved Caspase-9 and Caspase-3, and suppresses IAV-induced apoptosis-inducing factor (Aif) expression, suppressing IAV-induced mitochondrial apoptosis. More importantly, Zj6-11 plays a crucial role in protecting mice from IAV infection and reducing IAV pathogenicity. Our study provides mechanistic insights into Zj6-11's control of IAV infection in vitro and in vivo, offering new perspectives for antiviral therapy development.

New Insights into Antiviral Natural Formulations: Biopolymeric Films for the Prevention and Treatment of a Wide Gamma of Viral Infections

Viral infections remain a major concern, as existing treatments often yield inadequate responses or lead to the development of antiviral resistance in some cases. Fucoidan extracted from Undaria pinnatifida (F) is a natural sulphated polysaccharide that exhibits antiviral action. Despite its potential, the biomedical application of F is limited due to its difficult administration through trans-mucosal, skin, or oral ingestion. The most effective way to solve these problems is to propose novel methods of administration aiming to ensure better contact between the biopolymers and pathogens, leading to their inactivation. In this work, the synthesis of films based on chitosan (Ch)-coupled F is reported, aiming to generate a synergic effect between both biopolymers in terms of their antiviral and antioxidant capability. Biocomposites were prepared by a sonochemical method. They were characterized to infer structural properties, functionality, and possible F-Ch interactions by using Zeta potential, FTIR, and XRD techniques. The biocomposites showed excellent film-forming ability. They also exhibited improved antioxidant activity with respect to F and Ch individually and proved to be non-cytotoxic. These results demonstrate, for the first time, the antiviral activity of F:Ch biocomposites against bovine coronavirus and human viruses (adenovirus, poliovirus, herpes simplex, and respiratory syncytial virus), which could be applied in film form to prevent or treat viral infections.

SENP2 negatively regulates RIG-I/MDA5 mediated innate immunity in black carp.

Mammalian SUMO specific peptidase 2 (SENP2) plays vital roles in a variety of biological procedures including the immune response. However, the effects of teleost SENP2 are still mostly unexplored. In this study, the SENP2 of black carp (Mylopharyngodon piceus) was cloned and characterized. The open reading frame of black carp SENP2 (bcSENP2) consists of 1800 nucleotides, which encode 600 amino acids. The reporter assay results showed that over-expression of bcSENP2 alone had a weak effect on interferon (IFN) promoter transcription activity, whereas it significantly reduced bcMDA5/bcRIG-I mediated IFN promoter transcription activity. The interaction between bcSENP2 and bcMDA5 or bcRIG-I was detected by immunoprecipitation experiments. The plaque assay and qPCR results indicated that bcMDA5 or bcRIG-I mediated antiviral capacity was attenuated by bcSENP2, while knockdown of bcSENP2 led to enhanced antiviral resistance to SVCV in host cells. In addition, the expression level of bcMDA5/bcRIG-I protein was attenuated by co-expressed bcSENP2 and MG132 treatment rescued this attenuating effect. All of these data support the conclusion that bcSENP2 inhibits bcMDA5/bcRIG-I mediated antiviral signaling by enhancing ubiquitin-proteasome mediated degradation of bcMDA5/bcRIG-I in black carp.

P-2328. Influenza and RSV Surveillance in the US Veterans Health Administration (VHA): 2023-2024 Season

Abstract Background Influenza and Respiratory Syncytial Virus (RSV) cause seasonal epidemics with substantial morbidity and mortality. Veterans Health Administration’s (VHA) large elderly population is at higher risk for complications, including hospitalization and death. Herein we summarize VHA’s annual surveillance data for influenza and RSV activity and vaccinations. Methods Influenza-like-illness (ILI) as well as influenza and RSV-coded outpatient visits and hospitalizations, laboratory testing, and antivirals were obtained from VHA data sources (10/1/2023-4/13/2024) and compared to prior years and CDC data. VHA and community vaccinations were captured starting August 1st each year, with rates calculated based on VHA users in each fiscal year. Influenza RT-PCR positive respiratory samples underwent whole genome sequencing (WGS) to analyze clade and antiviral resistance. Results Influenza vaccinations (including high dose) were increased compared to 2022-2023 (Table). Weekly ILI ranged from 0.6%-1.6% in primary/urgent care settings. Activity was highest for 2023 Week 52, matching national influenza trends and increased compared to last season (Fig.1). There were 28,853 influenza positives among 438,110 tests performed (6.6%). Median length of stay was 3 days in 4,059 hospitalizations. Among 139 deaths, 129 (92.8%) had Influenza A and 10 (7.2%) Influenza B (Table, Fig.2). 310 samples (in 5 states) were sequenced with no drug resistance mutations identified (237 A/H1; 30 A/H3; 43 B/Victoria), representing 4 subclades, which aligned with CDC reporting (Fig.3). Over 270,000 Veterans received an RSV vaccine in 2023-2024 (over 177,000 administered by VHA). RSV visits, hospitalizations and positive tests were increased compared to 2022-2023. Conclusion For 2023-2024, influenza vaccinations (including high dose) increased compared to prior years, and newly licensed RSV vaccines were available in VHA. Influenza and RSV activity was increased compared to the prior season. VHA influenza activity and WGS analysis tracks closely with national CDC reporting. Given risks associated with influenza and RSV in the elderly population, VHA will continue efforts to improve vaccination rates. Disclosures All Authors: No reported disclosures

Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infections in Immunocompromised Patients: Literature Review and Proposed Definitions for Use in Clinical Trials.

Herpes simplex virus (HSV) infection is one of the most prevalent viral infections worldwide. In general, host immunity is sufficient to clear viral shedding and recurrences, although it is insufficient to prevent subsequent virologic reactivations. In immunocompromised patients, prolonged and difficult-to-treat HSV infections may develop. The diagnosis of refractory HSV infection is based on the lack of clinical response to nucleoside analogs. Antiviral resistance is confirmed via genotypic and/or phenotypic testing. To provide consensus definitions of refractory and/or resistant (R/R) HSV mucocutaneous infections for clinical trial use, the HSV Resistance Working Group of the Transplant Associated Viral Infections Forum, which includes international clinicians, scientists, industry representatives, and regulatory officials, conducted a literature review of previously published data related to R/R HSV infections in immunocompromised patients. We propose definitions of R/R HSV mucocutaneous infections, which will be subject to re-evaluation and revision based on forthcoming data and future studies.

P-724. The epidemiology, phenotype, and phylogeny of an influenza A/H3N2 virus outbreak among vaccinated U.S. Navy midshipmen

Abstract Background Characterizing influenza outbreaks among vaccinated populations may support optimization of influenza prevention. We used a surveillance study at the United States Naval Academy (USNA) to characterize the epidemiology, phenotype, and phylogeny of a recent influenza A/H3N2 outbreak among vaccinated midshipmen (undergraduate students). Figure 1 Figure 1A: Influenza A/H3N2 case counts among USNA Midshipmen and Staff Evaluated in February 2024. Day 1 refers to the collection time of the first influenza A/H3N2 outbreak clonal sequence. ‘Mitigation strategies implemented’ included case isolation, case masking, and contact chemoprophylaxis. Figure 1B: Estimated Rt (effective reproductive number) of influenza A/H3N2 virus cases in February 2024. Day 1 refers to the collection timing of first clonal influenza sequence. Methods “Acute Respiratory Infections at the Academy” (ARIA) is a study of medically attended ARIs (MAARIs) among USNA midshipmen and staff presenting to the Brigade Medical Unit for clinical care; the USNA comprises ≈ 4000 midshipmen. ARIA abstracts epidemiological, clinical and laboratory data from MAARIs. Residual clinical respiratory tract swabs also undergo multiplex PCR and sequencing of respiratory viruses, including influenza viruses. Demographic, Clinical and Viral Characteristics of Influenza A/H3N2 Positive Cases Results An outbreak of influenza A/H3N2 emerged in February 2024, with declining cases and Rt following mitigation strategies (case masking, isolation, and post-exposure oseltamivir; Fig 1). A total of 87 A/H3N2 cases were recorded, predominantly in midshipmen. HA sequence data from 83 cases confirmed local clonal transmission (3C.2a1b.2a.2a.3a.1 clade), consistent with early Rt estimates (Fig 1, Fig 2). The median age of cases was 20 years and 90% received 2023/2024 Northern Hemisphere influenza vaccine (99% egg-based inactivated influenza vaccine) by October of 2023. Over half (55%) of cases were treated with oseltamivir, and no evidence of antiviral resistance was detected. No cases were hospitalized, and the median sick-in-quarters time was 3 days (Table 1). Phylogenetic analysis did not indicate major genetic divergence from the 2023-2024 Northern Hemisphere vaccine A/H3N2 HA sequence (Fig 3). Time-scaled phylogeny of influenza A/H3N2 HA segment genes sequenced from ARIA (red branches) with context background sequences from GISAID. Phylogenetic tree inferred by IQTree and visualized in Auspice using the NextStrain environment. Inset A captures the diversity of 2a.3a.1 influenza cases involved in this outbreak investigation. Inset B shows the largest cluster of cases (n=58) with identical HA gene sequences. The 2023-2024 Northern Hemisphere vaccine strain sequences are indicated. Clade numbers are annotated by color. Conclusion Influenza A/H3N2 outbreaks can be impactful in vaccinated congregate populations; further analysis is in progress to identify strain antigenicity markers which may have contributed to this outbreak and predict other outbreaks. Non-pharmaceutical countermeasures and chemoprophylaxis appeared effective in mitigating this outbreak. Our findings highlight the importance of further research into universal influenza vaccines, alternative vaccine dosing regimens, and optimal chemoprophylaxis strategies to prevent such outbreaks. Disclosures Simon Pollett, MBBS, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response Timothy Burgess, MD, MPH, AstraZeneca: The IDCRP and HJF were funded to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial as part of US Govt COVID Response

Interplay between the cyclophilin homology domain of RANBP2 and MX2 regulates HIV-1 capsid dependencies on nucleoporins.

Human immunodeficiency virus 1 (HIV-1) entry into the nucleus is an essential step in viral replication that involves complex interactions between the viral capsid (CA) and multiple cellular proteins, including nucleoporins (Nups) such as RANBP2. Nups also mediate the function of the antiviral protein myxovirus resistance 2 (MX2); however, determining the precise role of Nups in HIV infection has proved challenging due to the complex nature of the nuclear pore complex (NPC) and significant pleiotropic effects elicited by Nup depletion. We have used precise gene editing to assess the role of the cyclophilin domain of RANBP2 in HIV-1 infection and MX2 activity. We find that this domain affects viral infection, nucleoporin requirements, MX2 sensitivity, and integration targeting in a CA-specific manner, providing detailed insights into how RANBP2 contributes to HIV-1 infection.

Structural and functional analysis of the Nipah virus polymerase complex.

Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is highly pathogenic in humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a promising drug target. We determined the cryoelectron microscopy (cryo-EM) structure of the NiV polymerase complex, comprising the large protein (L)and phosphoprotein (P), and performed structural, biophysical, and in-depth functional analyses of the NiV polymerase. The L protein assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Docking studies with a known L inhibitor clarify mechanisms of antiviral drug resistance. In addition, we identified L protein features that are required for both transcription and RNA replication and mutations that have a greater impact on RNA replication than on transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.

Tenofovir and Doravirine Are Potential Reverse-Transcriptase Analogs in Combination with the New Reverse-Transcriptase Translocation Inhibitor (Islatravir) Among Treatment-Experienced Patients in Cameroon: Designing Future Treatment Strategies for Low- and Middle-Income Countries.

Islatravir (ISL) is a novel antiretroviral that inhibits HIV-1 reverse transcriptase translocation. The M184V mutation, known to reduce ISL's viral susceptibility in vitro, could arise from prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTI) (3TC). This study evaluated the predictive efficacy of ISL and identified potentially active antiretrovirals in combination among treatment-experienced patients in Cameroon, where NRTIs (3TC) have been the backbone of ART for decades now. Although ISL is a long-acting antiretroviral, it will provide other therapeutic options in combination with other reverse transcriptase inhibitors that remain effective. We analyzed 1170 HIV-1 sequences from patients failing first-, second-, and third-line ART using the CIRCB Antiviral Resistance Evaluation (CIRCB-CARE) database. Drug resistance mutations (DRMs) were interpreted using Stanford HIVdb.v9, and covariation patterns between M184V and major NRTI/NNRTI DRMs were assessed. The study population, with a median age of 40 years, showed a high prevalence of resistance to NRTIs (77.4%) and NNRTIs (49.2%). The most frequent NRTI DRMs were M184V/I (83.3%), M41L (25.0%), and T215FY (36.8%), while common NNRTI DRMs included K103NS (53.3%), Y181CIV (27.7%), and G190ASE (22.2%). In first-line ART failure, M184V significantly covaried with K70R, L74I, and M41L for NRTIs and K103N and G190A for NNRTIs. In second-line failure, the covariation with M184V extended to T215Y, M41L, and D67N for NRTIs and G190A, K103N, and K103S for NNRTIs. No significant covariation with M184V was observed in third-line treatment failures. Based on these covariations and on the effect of these mutations on available anti-HIV drugs, TDF (partial efficacy) and Doravirine (fully active) were identified as potentially suitable candidates in combination with ISL among patients failing the first, second, and third lines, and could serve as a valuable therapeutic option in LMICs facing similar treatment challenges.

Meta-QTL analysis for mining of candidate genes and constitutive gene network development for viral disease resistance in maize (Zea mays L.).

Viral diseases severely impact maize yields, with occurrences of maize viruses reported worldwide. Deployment of genetic resistance in a plant breeding program is a sustainable solution to minimize yield loss to viral diseases. The meta-QTL (MQTL) has demonstrated to be a promising approach to pinpoint the most robust QTL(s)/candidate gene(s) in the form of an overlapping or common genomic region identified through leveraging on different research studies that independently report genomic regions significantly associated with the target traits. Here, we employed an MQTL approach by targeting 39 independent research investigations aimed at genetic dissection of the resistance in maize against 14 viral diseases. We could project 27% (53) of the total 196 QTLs onto the maize genome. Our analysis found a robust set of 14 MQTLs on chromosomes 1, 3 and 10 that explain significant proportion of the variations for resistance against 11 viral diseases. Marker trait associations (MTAs) identified from genome-wide association studies (GWAS) provide evidence in support of the two MQTLs (MQTL3_2 and MQTL10_2) playing crucial roles in viral disease resistance (VDR) in maize. A total of 1,715 candidate genes underlie the identified MQTL regions, of which, we further examined the constitutively-expressed genes for their involvement in various metabolic pathways. The involvement of the identified genes in the antiviral resistance mechanism renders them a valuable genomic resource for allele mining and elucidating plant-virus interactions for maize research and breeding.

AMENAMEVIR: A BREAKTHROUGH IN HERPESVIRUS THERAPY

Amenamevir is a promising antiviral agent with strong activity against herpes simplex virus (HSV) and varicella-zoster virus (VZV). This review article aims to explore its pharmacodynamics, therapeutic potential, and safety profile in detail. Amenamevir functions by inhibiting the viral helicase-primase complex, a crucial step in viral DNA replication, distinguishing it from other antiviral drugs. The article examines the results from clinical trials assessing its efficacy in treating recurrent herpesvirus infections, its pharmacokinetic properties, and its suitability for patients with compromised immune systems. We also discuss the drugs safety and tolerability, identifying common side effects, drug interactions, and contraindications. Furthermore, the review highlights Amenamevirs potential role in managing antiviral resistance and its possible broader applications in the treatment of chronic viral infections. Finally, future directions are outlined, including the exploration of combination therapy and the development of more accessible oral formulations, to optimize the clinical use of Amenamevir.

CoMFA and CoMSIA Study of CD4-mimetic Small Molecules as HIV-1 Entry Antiviral Inhibitors

Studies conducted on the chain include nitrobenzoxadiazole (NBD) against HIV-1HXB2, based on comparative CoMFA and CoMSIA interpretations that consider quantitative structure-activity relationship analyses. The CoMFA type sees that the electrostatic and steric fields for the confirmed value of the learning set Q2 are equal to 0.625 with an estimate of R2 that equals 0.996 and SEE=0.043. Also, for the CoMSIA type, the value found for Q2 is 0.631, and a practically unvalidated evaluation value of R2 is 0.738, and SEE=0.298. This means that of all the inhibitors examined, the only one that shows high antiviral resistance against HIV-1HXB2 is NBD-14246 (S) and a high selection factor compared to various compounds.

Efficient in vitro assay for evaluating drug efficacy and synergy against emerging SARS-CoV-2 strains.

Novel and repurposed antiviral drugs are available for the treatment of coronavirus disease 2019 (COVID-19). However, antiviral combinations may be more potent and lead to faster viral clearance, but the methods for screening antiviral combinations against respiratory viruses are not well established and labor-intensive. Here, we describe a time-efficient (72-96 h) and simple in vitro drug-sensitivity assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using standard 96-well plates. We employ different synergy models (zero interaction potency, highest single agent, Loewe, Bliss) to determine the efficacy of antiviral therapies and synergistic combinations against ancestral and emerging clinical SARS-CoV-2 strains. We found that monotherapy of remdesivir, nirmatrelvir, and active metabolite of molnupiravir (EIDD-1931) demonstrated baseline EC50s within clinically achievable levels of 4.34 mg/L (CI: 3.74-4.94 mg/L), 1.25 mg/L (CI: 1.10-1.45 mg/L), and 0.25 mg/L (CI: 0.20-0.30 mg/L), respectively, against the ancestral SARS-CoV-2 strain. However, their efficacy varied against newer Omicron variants BA.1.1.15 and BA.2, particularly with the protease inhibitor nirmatrelvir. We also found that remdesivir and nirmatrelvir have a consistent, strong synergistic effect (Bliss synergy score >10) at clinically relevant drug concentrations (nirmatrelvir 0.25-1 mg/L with remdesivir 1-4 mg/L) across all SARS-CoV-2 strains tested. This method offers a practical tool that streamlines the identification of effective combination therapies and the detection of antiviral resistance. Our findings support the use of antiviral drug combinations targeting multiple viral components to enhance COVID-19 treatment efficacy, particularly in the context of emerging viral strains.

An NF-κB-regulated cytokine enhances the antiviral resistance of silkworm, Bombyx mori.

Insect NF-κB-like factor, Relish, is activated by viral infection and induces the production of antiviral proteins. In this study, we performed a transcriptomic analysis of BmE cells expressing the active form of BmRelish (BmRelishact) and identified BmVago-like as the most strongly-induced secreted-protein. Expression of BmVago-like was specifically triggered by Bombyx mori Nucleo Polyhedro Virus (BmNPV) infection and regulated by BmSTING-BmRelish pathway. Incubating the fresh culture of cells with supernatant medium of BmVago-like expressing cells or recombinant BmVago-like protein (rBmVago-like) significantly increased antiviral resistance. On the contrary, reducing the expression of Bmvago-like by RNA interference (RNAi) in BmE cells as well as in silkworm larvae impaired antiviral response. Furthermore, we constructed transgenic silkworm line over-expressing BmVago-like (BmVago-likeOV) and found they had markedly lower viral load and higher survival rate after BmNPV infection compared with the wild-type control. Co-immunoprecipitation assay showed Bmintegrin β1 interacts with BmVago-like and it was involved in BmVago-like mediated antiviral response. Finally, we found the expression level of signalling molecules in the JAK-STAT pathway increased in rBmVago-like-treated cells and BmVago-likeOV silkworm larvae but decreased in RNAi-treated cells. In summary, our research uncovered an inducible antiviral response in silkworm mediated by cytokine BmVago-like, which is the downstream effector of BmSTING-BmRelish pathway and functions as an antiviral cytokine.

Antiviral Drugs for Seasonal Influenza for 2024-2025

Influenza is generally a self-limited illness, but pneumonia, respiratory failure, and death can occur, especially in persons at increased risk for influenza complications (see Table 1). Updated information on influenza activity and antiviral resistance is available from the CDC at cdc.gov/flu.

Impact of an intern‐supported antiviral stewardship program for cytomegalovirus prophylaxis and management in high‐risk abdominal solid organ transplant recipients

AbstractIntroductionCytomegalovirus (CMV) infection is associated with increased graft loss and mortality after solid organ transplantation (SOT). CMV infection risk is highest among seronegative recipients of seropositive donors (D+/R‐). Careful monitoring is imperative to ensure appropriate care.ObjectivesThis study investigates the impact of intern‐supported pharmacist‐driven monitoring on CMV outcomes in D+/R‐ abdominal SOT recipients.MethodsA single‐center retrospective cohort study was conducted in CMV D+/R‐ abdominal SOT recipients transplanted between August 1, 2021, and July 31, 2023 to compare recipients undergoing pharmacy intern review versus standard monitoring. A pharmacy student intern reviewed a list of recipients maintained in the electronic health record weekly to ensure proper CMV prophylaxis and management. Following institutional protocols, the intern identified and recommended interventions to the pharmacists for implementation. Primary outcomes included the incidence of CMV infection within 9 months posttransplant and time to CMV eradication after infection. Secondary outcomes included the incidence of antiviral resistance, viral breakthrough, allograft loss, and recipient death.Results69 D+/R‐ SOT recipients were included (36 control, 33 intervention). Baseline demographics were similar. There was a nonsignificant decrease in CMV infection within 9 months posttransplant in the intervention group. However, the mean time to CMV eradication after infection was significantly shorter in the intervention group (63 days vs. 24 days, p = 0.004). No differences in secondary outcomes were observed.ConclusionsCMV infection rates remained elevated in D+/R‐ SOT recipients after transplant despite frequent reviews of prophylaxis and laboratory monitoring, which is likely a result of seronegative status and global immunosuppression. However, eradication of CMV infection can be significantly impacted by close monitoring, such as that provided by a pharmacy student intern, to reduce the time of active infection. This dramatic reduction in time to eradication has the potential to reduce the risk for negative allograft and recipient outcomes associated with CMV infection.

Real-World Comparison of Maribavir to Foscarnet for the Treatment of Cytomegalovirus in Solid Organ and Hematopoietic Stem Cell Transplant Recipients.

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.

Antiviral Stewardship in Transplantation.

Though antimicrobial stewardship programs (ASPs) are required for hospitals, the involvement of transplant recipients in programmatic interventions, protocols, and metrics has historically been limited. Though there is a growing interest in studying stewardship practices in transplant patients, optimal practices have not been clearly established. A component of ASPs, antiviral stewardship (AVS), specifically targeting cytomegalovirus (CMV), has been more recently described. Understanding AVS opportunities and interventions is particularly important for transplant recipients, given the morbidity and mortality associated with viral infections, challenging clinical syndromes, ultrasensitive molecular diagnostic assays, antiviral resistance, and costs of viral disease and medications, as well as antiviral drug toxicities. This review highlights opportunities for AVS for CMV, EBV, HSV, VZV, SARS-CoV-2, respiratory syncytial virus, and BK polyomavirus in transplant patients.