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International Journal of STD & AIDS Apr 2024Herpes simplex virus (HSV) is the leading cause of genital ulcers worldwide. In rare cases, mostly among immunocompromised hosts, HSV infections can present as...
Herpes simplex virus (HSV) is the leading cause of genital ulcers worldwide. In rare cases, mostly among immunocompromised hosts, HSV infections can present as hypertrophic pseudotumoral forms simulating malignancies or often mistaken as other viral infections, usually resistant to conventional antiviral therapy and often requiring alternative therapeutic approaches. A high level of clinical suspicion is needed. We present a case of woman living with HIV with pseudotumoral vulvar herpes refractory to oral acyclovir, successfully treated with systemic foscarnet and topical imiquimod.
Topics: Female; Humans; Herpes Genitalis; Antiviral Agents; Acyclovir; Foscarnet; HIV Infections
PubMed: 38031871
DOI: 10.1177/09564624231218759 -
Chemical & Pharmaceutical Bulletin Jan 2024The spectrum of P-NMR is fundamentally simpler than that of H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative P-NMR...
The spectrum of P-NMR is fundamentally simpler than that of H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative P-NMR (P-qNMR) than using quantitative H-NMR (H-qNMR), which has been already established as an absolute determination method. We have previously reported a P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using P-qNMR at multiple laboratories. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d were selected as the reference standards (RSs) for P-qNMR and H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CDOH was selected as the solvent for P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CDOD was the solvent of choice for the H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional H-qNMR for the determination of organophosphorus compounds.
Topics: Protons; Organophosphorus Compounds; Reference Standards; Water; Solvents
PubMed: 37899177
DOI: 10.1248/cpb.c23-00635 -
JAMA Dermatology Oct 2023
Topics: Male; Humans; Foscarnet; Penile Diseases; Antiviral Agents; Ulcer; Skin Diseases; Penis
PubMed: 37647057
DOI: 10.1001/jamadermatol.2023.2592 -
Journal of Clinical Virology : the... Oct 2023Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have...
BACKGROUND
Antiviral resistance in human herpes simplex viruses (HSV) remains a significant clinical challenge in immunocompromised populations. Although molecular tests have largely replaced viral culture for HSV diagnosis and molecular antiviral resistance testing is available for many viruses, HSV resistance testing continues to rely on phenotypic, viral culture-based methods, requiring weeks for results. Consequently, treatment of suspected HSV resistance remains largely empiric.
METHODS
We used HSV whole genome sequencing and a database of previously characterized HSV acyclovir and foscarnet resistance mutations to evaluate the performance of genotypic antiviral resistance testing among 19 control strains compared to in-house plaque reduction assay (PRA) and 25 clinical isolates sent for reference lab PRA antiviral resistance testing.
RESULTS
Among control strains, 23/29 (79.3%) results were concordant, 5 (17.2%) were indeterminate, and 1 (3.4%) was discordant. Indeterminate results were caused by variants of uncertain significance (VUS), including mutations without published phenotypes and mutations with contradictory results. Among clinical isolates, 14/40 (35%) results were concordant, 17 (42.5%) were indeterminate, and 9 (22.5%) were discordant. All discordant results were in reportedly phenotypically-susceptible HSV-1 strains yet possessed resistance mutations. Three contained resistant subpopulations. 6/8 (75%) discordant phenotypes were concordant with resistant genotypes upon repeat PRA.
CONCLUSIONS
These data support the combination of genotypic and phenotypic testing to diagnose HSV resistance more accurately and likely more rapidly than phenotypic testing alone. Genotypic context of resistance mutations and the ability of viral strains to form plaques in culture may affect phenotypic resistance results, highlighting the limitations of PRA alone as a gold standard method.
Topics: Humans; Antiviral Agents; Herpesvirus 2, Human; Acyclovir; Foscarnet; Herpesvirus 1, Human; Genotype; Drug Resistance, Viral; Herpes Simplex
PubMed: 37586184
DOI: 10.1016/j.jcv.2023.105554 -
Journal of Virology Aug 2023The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's...
The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCE Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.
Topics: Humans; Infant, Newborn; Cytidine Deaminase; Cytomegalovirus; DNA Replication; DNA, Viral; Epstein-Barr Virus Infections; Herpesviridae Infections; Herpesvirus 1, Human; Herpesvirus 4, Human; Immediate-Early Proteins; Minor Histocompatibility Antigens; Ribonucleotide Reductases; Viral Proteins; Virus Replication
PubMed: 37565748
DOI: 10.1128/jvi.00781-23 -
Antiviral Research Aug 2023Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis...
Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis by next-generation sequencing (NGS). Here, we report novel UL23 and UL30 substitutions for HSV1 and HSV2 identified in immunocompromised patients treated for hematological malignancies during the last 6 years of HSV resistance surveillance at the University Hospital of Lyon. For HSV1, 35 novel UL23 substitutions and 52 novel UL30 substitutions were identified. For HSV2, 2 novel UL23 substitutions and 12 novel UL30 substitutions were identified. These results allow to complete the database of HSV1 and HSV2 substitutions, related either to polymorphism or to ACV and FOS resistance.
Topics: Humans; Antiviral Agents; Herpes Simplex; Herpesvirus 1, Human; Viral Proteins; Drug Resistance, Viral; Acyclovir; Foscarnet
PubMed: 37453453
DOI: 10.1016/j.antiviral.2023.105672 -
Oral Diseases Apr 2024Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in... (Review)
Review
Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.
Topics: Humans; Antiviral Agents; Drug Resistance, Viral; Acyclovir; Herpesvirus 1, Human; Immunocompromised Host; Stomatitis, Herpetic; Herpesvirus 2, Human; Cidofovir; Foscarnet
PubMed: 37279074
DOI: 10.1111/odi.14635 -
BMC Neurology May 2023Pseudorabies virus (PRV) was thought to only infect animals. Recent studies have shown that it can also infect human.
BACKGROUND
Pseudorabies virus (PRV) was thought to only infect animals. Recent studies have shown that it can also infect human.
CASE PRESENTATION
We report a case of pseudorabies virus encephalitis and endophthalmitis, diagnosed 89 days after onset, confirmed with intraocular fluid metagenomic next generation sequencing (mNGS) after the result of two cerebrospinal fluid (CSF) mNGS tests were negative. Although treatment with intravenous acyclovir, foscarnet sodium, and methylprednisolone improved the symptoms of encephalitis, significant diagnostic delay resulted in permanent visual loss.
CONCLUSIONS
This case suggests that pseudorabies virus (PRV) DNA in the intraocular fluid may have a higher positivity than that in the CSF. PRV may persist in the intraocular fluid for an extended period and may thus require extended antiviral therapy. Patients with severe encephalitis and PRV should be examined with the focus on pupil reactivity and light reflex. A fundus examination should be performed in patients with a central nervous system infection, specifically, those in a comatose state, to help reduce eye disability.
Topics: Pseudorabies; Encephalitis, Viral; Endophthalmitis; Herpesvirus 1, Suid; Metagenomics; High-Throughput Nucleotide Sequencing; Delayed Diagnosis; Humans; Male; Middle Aged; Aqueous Humor; Acyclovir; Foscarnet; Methylprednisolone; Antiviral Agents; Blindness; DNA, Viral
PubMed: 37194001
DOI: 10.1186/s12883-023-03227-1 -
Antiviral Research Jul 2023Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence...
Cytomegalovirus (CMV) is a significant human pathogen, especially for immunocompromised patients, often treated with one or more antiviral drugs. Although the prevalence of resistance is low, the impact of drug resistant CMV infections on patient outcomes is high and genotypic testing is recommended when resistance is suspected. To assess the prevalence of CMV drug resistance mutations among samples submitted for genotypic testing, 2750 patient sample results were analyzed. Testing was performed by sequencing for ganciclovir (GCV), cidofovir (CDV), foscarnet (FOS), maribavir (MBV) and/or letermovir (LMV) resistance conferring mutations. Of the 2750 patient samples, 826 (30.04%) had resistance to one or more anti-CMV drug. Resistance mutations were most common in UL97, with 27.64% and 9.96% of samples having GCV and MBV mutations, respectively. Resistance mutations in UL54 were less common, with 6.11%, 5.98% and 1.76% of samples having GCV, CDV and FOS mutations, respectively. For LMV, resistance mutations in UL56 were present in 7.17% of samples, with mutations at codon 325 representing 80.95% of the observed LMV resistance mutations. Resistance to two drugs was identified in 215 samples and to 3 or more drugs in 35 samples. While a high prevalence of CMV resistance mutations was identified, this must be taken in the context of healthcare providers submitting samples from patients with suspected resistant CMV strains. For these patients, rapid monitoring for resistance allows treatment modifications based on objective results rather than empiric drug selection, which is particularly relevant given the presence of mutations conferring resistance to more than one drug.
Topics: Humans; Cytomegalovirus; Prevalence; Transplant Recipients; DNA-Directed DNA Polymerase; Viral Proteins; Antiviral Agents; Ganciclovir; Foscarnet; Cidofovir; Drug Resistance, Viral; Mutation; Benzimidazoles
PubMed: 37150409
DOI: 10.1016/j.antiviral.2023.105623 -
The Journal of Antimicrobial... Jun 2023
Topics: Humans; Foscarnet; Herpesvirus 6, Human; Hematopoietic Stem Cell Transplantation; Antiviral Agents; Encephalitis, Viral; Roseolovirus Infections; DNA, Viral
PubMed: 37071595
DOI: 10.1093/jac/dkad117