Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients

Fisher, Cynthia E.; Knudsen, Janine; Lease, Erika D.; Jerome, Keith R.; Rakita, Robert M.; Boeckh, Michael; Limaye, Ajit P.

doi:10.1093/cid/cix259

Cited by 92 publications

(104 citation statements)

References 21 publications

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“…Studies in the last 15 years that included at least 6 transplant recipients who were treated with foscarnet for established CMV infection, and that reported mortality outcomes, are summarized in Table 4. Other than the case-control study by Fisher et al 22 , the others are case series, and most have focused on SOT recipients. All-cause mortality rates in these studies varied, but the mortality rates reported in the studies by Pierce et al 23 (32%) and Minces et al 21 (31%) were similar to that in the current study.…”

Section: Discussionmentioning

confidence: 99%

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection

Avery¹,

Arav‐Boger²,

Marr³

et al. 2016

Transplantation

121

129

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Background Antiviral-resistant or refractory CMV infection is challenging, and salvage therapies, foscarnet and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments, to facilitate clinical trial design for new drugs. Methods Records of solid organ (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. Results Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11/39 (28%) had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13/39 (33%) and relapses of viremia occurred in 31%. Mortality was 12/39 (31%) and was higher in HCT than SOT (p=0.001), although ganciclovir resistance was more common in SOT (p = 0.003). Doses of ganciclovir or valganciclovir were low in 10/39 (26%) at some time prior to switching to foscarnet. Renal dysfunction occurred in 20/39 (51%) by end of treatment and in 7/25 (28%) after 6 months. Conclusions Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents.

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Section: Discussionmentioning

confidence: 99%

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection

Avery¹,

Arav‐Boger²,

Marr³

et al. 2016

Transplantation

121

129

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“…[23] Ganciclovir 16 is ag uanine analogue that is used as av irostatic DNA polymerase inhibitor against human cytomegalovirus. [24] Owing to very low oral bioavailability of the compound ( % 3.6 %), it is usually administered intravenously.T he oral bioavailability (15.3 %) of 14 is four times higher than that of the parent drug, whereas forb enzyl ether 15,n os ignificant plasma levels of ganciclovir 16 are observed;t his suggests that the esterasetriggered hydrolysis of the acetate is responsible for releaseo f ganciclovir 16 from prodrug 14.…”

Section: Esterase-sensitive Tmls Ystemsmentioning

confidence: 99%

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

Okoh

Klahn

2018

ChemBioChem

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Trimethyl lock (TML) systems are based on ortho-hydroxydihydrocinnamic acid derivatives displaying increased lactonization reactivity owing to unfavorable steric interactions of three pendant methyl groups, and this leads to the formation of hydrocoumarins. Protection of the phenolic hydroxy function or masking of the reactivity as benzoquinone derivatives prevents lactonization and provides a trigger for controlled release of molecules attached to the carboxylic acid function through amides, esters, or thioesters. Their easy synthesis and possible chemical adaption to several different triggers make TML a highly versatile module for the development of drug-delivery systems, prodrug approaches, cell-imaging tools, molecular tools for supramolecular chemistry, as well as smart stimuliresponsive materials.

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“…Current treatments for HCMV target only productive replication, carry significant toxicities (7), and select for drug-resistant mutants (8).…”

mentioning

confidence: 99%

The Membrane-Spanning Peptide and Acidic Cluster Dileucine Sorting Motif of UL138 Are Required To Downregulate MRP1 Drug Transporter Function in Human Cytomegalovirus-Infected Cells

Gelbmann

Kalejta

2019

J Virol

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The human cytomegalovirus (HCMV) UL138 protein downregulates the cell surface expression of the multidrug resistance-associated protein 1 (MRP1) transporter. We examined the genetic requirements within UL138 for MRP1 downregulation. We determined that the acidic cluster dileucine motif is essential for UL138mediated downregulation of MRP1 steady-state levels and inhibition of MRP1 efflux activity. We also discovered that the naturally occurring UL138 protein isoforms, the full-length long isoform of UL138 and a short isoform missing the N-terminal membrane-spanning domain, have different abilities to inhibit MRP1 function. Cells expressing the long isoform of UL138 show decreased MRP1 steady-state levels and fail to efflux an MRP1 substrate. Cells expressing the short isoform of UL138 also show decreased MRP1 levels, but the magnitude of the decrease is not the same, and they continue to efficiently efflux an MRP1 substrate. Thus, the membranespanning domain, while dispensable for a UL138-mediated decrease in MRP1 protein levels, is necessary for a functional inhibition of MRP1 activity. Our work defines the genetic requirements for UL138-mediated MRP1 downregulation and anticipates the possible evolution of viral escape mutants during the use of therapies targeting this function of UL138. IMPORTANCE HCMV UL138 curtails the activity of the MRP1 drug transporter by reducing its steady-state levels, leaving cells susceptible to killing by cytotoxic agents normally exported by MRP1. It has been suggested in the literature that capitalizing on this UL138-induced vulnerability could be a potential antiviral strategy against virally infected cells, particularly those harboring a latent infection during which UL138 is one of the few viral proteins expressed. Therefore, identifying the regions of UL138 required for MRP1 downregulation and predicting genetic variants that may be selected upon UL138-targeted chemotherapy are important ventures. Here we present the first structure-function examination of UL138 activity and determine that its transmembrane domain and acidic cluster dileucine Golgi sorting motif are required for functional MRP1 downregulation.

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Risk Factors and Outcomes of Ganciclovir-Resistant Cytomegalovirus Infection in Solid Organ Transplant Recipients

Cited by 92 publications

References 21 publications

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection

Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection

Trimethyl Lock: A Multifunctional Molecular Tool for Drug Delivery, Cellular Imaging, and Stimuli‐Responsive Materials

The Membrane-Spanning Peptide and Acidic Cluster Dileucine Sorting Motif of UL138 Are Required To Downregulate MRP1 Drug Transporter Function in Human Cytomegalovirus-Infected Cells

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