Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization

Stranska, Ruzena Wiersum; Schuurman, Rob; Nienhuis, Elske; Goedegebuure, Irma W; Polman, Merjo; Weel, Jan; Dillen, Pauline M. Wertheim-van; Berkhout, Ron J. M.; Loon, Anton M. van

doi:10.1016/j.jcv.2004.04.002

Cited by 211 publications

(158 citation statements)

References 57 publications

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“…In a setting of antiviral prophylaxis, HSV-1 resistance was demonstrated by viral culture in 27% of patients with HSV. 13 In other studies, a prevalence of resistance of 14% was found using a colorimetric yield reduction assay 14 and of 18% using another colorimetric assay. 12 The retrospective analysis of resistance in our study hampers addressing the clinical significance of the infections with resistant HSV-1.…”

Section: Discussionmentioning

confidence: 90%

Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients

Beek

Laheij

Raber-Durlacher

et al. 2012

Bone Marrow Transplant

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Ulcerative oral mucositis and infection are frequent complications in hematopoietic stem cell transplant (HSCT) recipients. The aim of this study was to investigate the relationship between oral ulcerations and HSV-1, EBV and CMV excretion and the presence of aciclovir-resistant HSV-1 strains in HSCT recipients. This prospective observational study included 49 adult patients who underwent allogeneic HSCT. In total, 26 patients received myeloablative and 23 received non-myeloablative conditioning. Ulcerations on non-keratinized and keratinized oral mucosa were scored and oral rinsing samples were taken twice weekly. Viral loads were determined by real-time PCR. Samples from patients remaining HSV-1 positive despite antiviral treatment were studied for resistance to antivirals. Having an HSV-1 or EBV DNA --positive sample was a significant predictor for ulceration of keratinized mucosa. HSV-1 was a significant predictor for ulcerations on non-keratinized mucosa as well. Persistent HSV-1 infection occurred in 12 of 28 patients treated with antiviral medication and aciclovir-resistant HSV-1 was found in 5 persistent infections. In conclusion, HSV-1 is a predictor of ulcerations on non-keratinized as well as keratinized oral mucosa following HSCT. The role of EBV deserves further study. Persistent HSV-1 replication despite antiviral treatment is common and is due to resistance in 18% of treated patients.

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Section: Discussionmentioning

confidence: 90%

Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients

Beek

Laheij

Raber-Durlacher

et al. 2012

Bone Marrow Transplant

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“…A serine to asparagine change was detected at position 180 of the TK protein of HSV-1 strain 5123376433, but the role of this mutation in drug resistance is unknown. Strain C74106 harbored an arginine to histidine change at position 222 of the TK enzyme that was reported to induce resistance to ACV (20). HSV-1 strain C114093 contained the change of an arginine by a stop codon at position 281 of the TK that was associated with resistance to ACV (21).…”

Section: Cellsmentioning

confidence: 99%

Novel Method Based on Real-Time Cell Analysis for Drug Susceptibility Testing of Herpes Simplex Virus and Human Cytomegalovirus

2016

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The plaque reduction assay (PRA) is the gold standard phenotypic method to determine herpes simplex virus (HSV) and human cytomegalovirus (HCMV) susceptibilities to antiviral drugs. However, this assay is subjective and labor intensive. Here, we describe a novel antiviral phenotypic method based on real-time cell analysis (RTCA) that measures electronic impedance over time. The effective drug concentrations that reduced by 50% (EC 50 s) the cytopathic effects induced by HSV-1 and HCMV were evaluated by both methods. The EC 50 s of acyclovir and foscarnet against a reference wild-type ( H erpes simplex viruses 1 (HSV-1) and 2 (HSV-2) cause orolabial and genital infections as well as keratitis, encephalitis, and neonatal infections. Human cytomegalovirus (HCMV) is responsible for mononucleosis-like syndromes and organ-specific diseases in immunocompromised patients. All antiviral agents currently approved for the treatment of HSV and HCMV infections ultimately target the viral DNA polymerase (1). First-line antiviral agents for the treatment of HSV and HCMV infections include the nucleoside analogues acyclovir (ACV) and ganciclovir (GCV), respectively. Both drugs require a first phosphorylation by the thymidine kinase (TK) encoded by the UL23 gene (HSV) or the phosphotransferase encoded by the UL97 gene (HCMV) and two subsequent phosphorylations by cellular kinases to be converted into their active forms (2-4). The triphosphate forms compete with dGTP for incorporation into replicating DNA. Acyclovir triphosphate acts as a DNA chain terminator to inhibit viral replication, whereas ganciclovir triphosphate slows down DNA polymerization and eventually stops chain elongation. The pyrophosphate analogue foscarnet (FOS) is a second-line antiviral drug for the treatment of HCMV diseases and may also be used in the treatment of infections caused by nucleoside analogue-resistant HSV mutants. Foscarnet does not require any phosphorylation to be active (5). It directly inhibits the activity of the viral DNA polymerases encoded by UL30 (HSV) and UL54 (HCMV) genes. Foscarnet binds to the pyrophosphate binding site and blocks the release of pyrophosphate from the last nucleoside triphosphate added onto the growing DNA chain. Prolonged treatment with nucleoside analogues may be required to prevent or to manage HSV/HCMV infections in the immunocompromised host. Such prolonged antiviral therapy may result in the selection of viral isolates with reduced drug susceptibilities (6, 7).The plaque reduction assay (PRA) is the gold standard phenotypic method to determine the susceptibilities of HSV isolates to antiviral drugs and is approved as a standard protocol by the Clinical and Laboratory Standards Institute (8). The PRA has also been standardized in a consensus protocol for HCMV to decrease high interassay and interlaboratory variabilities (9). In this assay, cells are infected with a constant viral inoculum. The virus is then allowed to grow in the presence of serial drug dilutions for 2 to 3 (HSV) to 7 to 8 (HCMV) days before t...

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“…A study conducted in the Netherlands analyzed 542 HSV isolates and found ACV resistance in only 0.27% of immunocompetent patients. In contrast, the prevalence of ACV-resistant virus in immunocompromised patients was 7%, and the highest frequency of resistance (14.3%) was observed among patients after hematopoietic stem cell transplantation (7). ACV resistance frequencies of even more than 25% have been reported for patients in the allogeneic stem cell or bone marrow transplantation setting (8,9).…”

mentioning

confidence: 94%

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

Krawczyk

Arndt

Grosse‐Hovest

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

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Despite the availability of antiviral chemotherapy, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections remain a severe global health problem. Of particular concern is the growing incidence of drug resistance in immunocompromised patients, which stresses the urgency to develop new effective treatment alternatives. We have developed a humanized monoclonal antibody (mAb hu2c) that completely abrogates viral cell-to-cell spread, a key mechanism by which HSV-1/2 escapes humoral immune surveillance. Moreover, mAb hu2c neutralized HSV fully independent of complement and/or immune effector cell recruitment in a highly efficient manner. Prophylactic and therapeutic administration of mAb hu2c completely prevented infection-related mortality of severely immunodeficient mice being challenged with a lethal dose of HSV-1. The high neutralization capacity of mAb hu2c was fully maintained toward clinical HSV isolates being multiresistant to standard antiviral drugs, and infection was fully resolved in 7/8 nonobese diabetic/SCID mice being infected with a multidrug resistant HSV-1 patient isolate. Immunohistochemical studies revealed no significant cross-reactivity of the antibody toward human tissues. These features warrant further clinical development of mAb hu2c as an immunotherapeutic compound for the management of severe and particularly drugresistant HSV infections.acyclovir resistance | immunocompromised mice | stem cell transplantation

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Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization

Cited by 211 publications

References 57 publications

Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients

Viral loads and antiviral resistance of herpesviruses and oral ulcerations in hematopoietic stem cell transplant recipients

Novel Method Based on Real-Time Cell Analysis for Drug Susceptibility Testing of Herpes Simplex Virus and Human Cytomegalovirus

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody

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