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Houldcroft CJ, Bryant JM, Depledge DP, et al. Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus. Front Microbiol. 2016;7:1317doi: 10.3389/fmicb.2016.01317.
Houldcroft, C. J., Bryant, J. M., Depledge, D. P., Margetts, B. K., Simmonds, J., Nicolaou, S., Tutill, H. J., Williams, R., Worth, A. J., Marks, S. D., Veys, P., Whittaker, E., & Breuer, J. (2016). Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus. Frontiers in microbiology, 71317. https://doi.org/10.3389/fmicb.2016.01317
Houldcroft, Charlotte J, et al. "Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus." Frontiers in microbiology vol. 7 (2016): 1317. doi: https://doi.org/10.3389/fmicb.2016.01317
Houldcroft CJ, Bryant JM, Depledge DP, Margetts BK, Simmonds J, Nicolaou S, Tutill HJ, Williams R, Worth AJ, Marks SD, Veys P, Whittaker E, Breuer J. Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus. Front Microbiol. 2016 Sep 09;7:1317. doi: 10.3389/fmicb.2016.01317. eCollection 2016. PMID: 27667983; PMCID: PMC5016526.
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Front Microbiol. 2016 Sep 09;7:1317. doi: 10.3389/fmicb.2016.01317. eCollection 2016.

Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus.

Frontiers in microbiology

Charlotte J Houldcroft, Josephine M Bryant, Daniel P Depledge, Ben K Margetts, Jacob Simmonds, Stephanos Nicolaou, Helena J Tutill, Rachel Williams, Austen J J Worth, Stephen D Marks, Paul Veys, Elizabeth Whittaker, Judith Breuer

Affiliations

  1. Infection, Immunity, Inflammation and Physiological Medicine, Institute of Child Health, University College LondonLondon, UK; Division of Infection and Immunity, University College LondonLondon, UK.
  2. Division of Infection and Immunity, University College London London, UK.
  3. Infection, Immunity, Inflammation and Physiological Medicine, Institute of Child Health, University College LondonLondon, UK; Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College LondonLondon, UK.
  4. Great Ormond Street Hospital for Children NHS Foundation Trust London, UK.
  5. Infection, Immunity, Inflammation and Physiological Medicine, Institute of Child Health, University College LondonLondon, UK; Great Ormond Street Hospital for Children NHS Foundation TrustLondon, UK.
  6. Infection, Immunity, Inflammation and Physiological Medicine, Institute of Child Health, University College LondonLondon, UK; Division of Infection and Immunity, University College LondonLondon, UK; Great Ormond Street Hospital for Children NHS Foundation TrustLondon, UK.

PMID: 27667983 PMCID: PMC5016526 DOI: 10.3389/fmicb.2016.01317

Abstract

Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.

Keywords: antivirals; herpesviruses; immune deficiency; immune suppression; next-generation sequencing

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