The impact of drug‐resistant cytomegalovirus in pediatric allogeneic hematopoietic cell transplant recipients: a prospective monitoring of <scp>UL</scp>97 and <scp>UL</scp>54 gene mutations

Choi, Suk Joo; Hwang, Ji-Young; Park, K.-S.; Kim, Y.; Lee, S.H.; Yoo, Keon Hee; Kang, Eun Suk; Ahn, Jin-Hyun; Sung, Ki Woong; Koo, Hong Hoe

doi:10.1111/tid.12311

Cited by 31 publications

(18 citation statements)

References 32 publications

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“…The rates of HCMV drug resistance vary widely, depending on type of patients, and several risk factors have already been identified: (1) patient and disease‐related factors such as SOT, underlying disease, type, and degree of host immunosuppression, and the occurrence of HCMV disease ; (2) treatment‐related factors such as prolonged antiviral therapy, suboptimal antiviral concentrations due to poor compliance or low drug absorption, and limited oral bioavailability ; and (3) viral factors such as the establishment of lifelong latency, which allows for late reactivations, the slow lytic replication cycle and higher viral load at the start of therapy . Indeed, drug resistance may be suspected if persistent or increasing blood viral load or overt HCMV disease occurs after at least 2 weeks of therapy .…”

Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

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Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Campos

Ribeiro

Boutolleau

et al. 2016

Reviews in Medical Virology

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Human cytomegalovirus (HCMV) infection is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant recipients. The significant clinical impact of HCMV infection and progression to HCMV disease among allogeneic hematopoietic stem cell transplant recipients has been reduced by prophylactic, preemptive, and curative treatments using ganciclovir, valganciclovir, foscarnet, and cidofovir. Resistance to (val)ganciclovir results from mutations localized in HCMV UL97 gene (encoding the pUL97 phosphotransferase), UL54 gene (encoding the pUL54 DNA polymerase), or both genes, whereas foscarnet and cidofovir resistance results from mutations localized within UL54 gene only. This review is focused on HCMV antiviral drug resistance, including the functions of target genes of antivirals, the mechanisms of antiviral resistance, the different mutations in pUL97 and pUL54 that have been identified in either clinical isolates or laboratory strains, and their impact on HCMV susceptibility to antiviral drugs. It emphasizes the importance of proving that observed genetic changes confer resistance so they can be distinguished from polymorphisms. Because of the emergence of HCMV resistance to currently available drugs, novel drugs are urgently needed for the therapeutic management of HCMV-resistant infections in hematopoietic stem cell transplant patients.

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Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

“…The majority of drug resistance mutations have been reported in immunocompromised hosts, especially in SOT and AIDS patients with very few data on HSCT patients . Overall, in HSCT recipients, HCMV resistance remains relatively rare, ranging from 1.7% to 5.1% .…”

Section: Human Cytomegalovirus Drug Resistancementioning

confidence: 99%

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Campos

Ribeiro

Boutolleau

et al. 2016

Reviews in Medical Virology

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“…Currently available antiviral therapy is often incompletely effective in these circumstances and resistance may develop in 5–12% [2]. Recent literature has drawn attention to other groups at risk of drug resistance, including haploidentical or allogeneic stem cell transplant recipients [6,7] and congenital CMV infection [8]. …”

Section: Risk Factors For CMV Drug Resistancementioning

confidence: 99%

Approach to drug-resistant cytomegalovirus in transplant recipients

Chou

2015

Current Opinion in Infectious Diseases

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Purpose of review updated information on diagnosis of CMV drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. Recent findings For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug resistant phenotype and may be genotyping artifacts. Next generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. Summary Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.

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“…CMV-infected infants after HSCT were found to develop ganciclovir resistance associated with the UL97 protein kinase (Ohta et al, 2001;Gohring et al, 2009;Kim et al, 2012;Erice et al, 1989). However, in some cases, multiple UL97 and UL54 (DNA polymerase) mutations that conferred resistance to ganciclovir and foscarnet (Choi et al, 2014) or to all three currently available anti-CMV drugs (i.e. ganciclovir, cidofovir and foscarnet) have been described (Blackman et al, 2004;Drouot et al, 2014;Springer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

et al. 2016

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The impact of drug‐resistant cytomegalovirus in pediatric allogeneic hematopoietic cell transplant recipients: a prospective monitoring of UL97 and UL54 gene mutations

Abstract: This study provides comprehensive information on the epidemiology of both UL97 and UL54 variants and mutations in alloHCT recipients.

Cited by 31 publications

References 32 publications

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

Approach to drug-resistant cytomegalovirus in transplant recipients

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

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