February 25, 2014

Mixed genotype hepatitis C infections and implications for treatment


Volume 59, Issue 3, page 1209, March 2014


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Anna L. McNaughton M.Sc.1, Emma C. Thomson Ph.D., MRCP1, Kate Templeton Ph.D.2, Rory N. Gunson FRCPath3, E. Carol McWilliam Leitch Ph.D.1

Article first published online: 13 JAN 2014

DOI: 10.1002/hep.26544

Copyright © 2013 Crown copyright. HEPATOLOGY Copyright © 2013 the American Association for the Study of Liver Diseases.

Potential conflict of interest: Nothing to report.

This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

Supported by MRC grant 63785.

To the Editor:

The recently licensed direct-acting antivirals (DAAs) boceprevir and telaprevir used to treat hepatitis C virus (HCV) infection act in a genotype-specific manner. The potential outcome of DAA treatment regimes on mixed HCV infections, consisting of concurrent infection with more than one HCV genotype, has not been considered. Standard genotyping methods are only capable of identifying the dominant genotype present within a mixed infection sample, leaving minor genotypes undetected. We propose that DAA treatment of mixed infections may be associated with the occurrence of genotype switching, whereby a previously undetected minority variant drug-resistant genotype expands to replace the successfully treated majority variant genotype. Such genotype switching could in some cases result in nonresponse to DAA treatment and could also be incorrectly interpreted as reinfection if genotyping is not repeated following treatment failure. As a matter of urgency, there is a need to assess the prevalence and clinical impact of mixed HCV infections.

To determine the prevalence of mixed HCV infections in a cohort of patients infected with genotype (gt) 3a (n = 47) or 1a (n = 48), we designed gt1a- and gt3a-specific primers providing partial coverage of the envelope genes E1 and E2 of HCV. Nested reverse transcription (RT) polymerase chain reaction (PCR) reactions were performed using gt1a primers with gt3a-infected samples and vice versa. Amplicons were sequenced and used to construct maximum likelihood phylogenetic trees using the MEGA 5.0 software package to confirm genotype.

The sensitivity of the RT-PCR reactions, as determined by 90% detection limits calculated from serial endpoint dilution RT-PCR and probit analysis, was nine copies/reaction. Of the gt3a-infected patient samples, 10.6% (5/47) harbored minority variant gt1a strains, whereas none of the gt1a-infected patient samples contained gt3a as a minority strain.

These findings are in keeping with other studies that found mixed HCV infections at rates of 5%-25.3%.[1-3] Further work is required to assess the impact of minority variant strains on patients treated with DAA therapy. If relapse following dual therapy for gt3 infection is associated with emerging dominance of preexisting gt1 strains, screening of baseline patient samples using genotype-specific methods could result in improved treatment strategies; for example, the prescription of triple rather than dual antiviral therapy. More work is required to assess the impact of multiple genotype infection on clinical outcome, and this work is more pressing in the DAA era.

Anna L. McNaughton, M.Sc.1
Emma C. Thomson, Ph.D., MRCP1
Kate Templeton, Ph.D.2
Rory N. Gunson, FRCPath3
E. Carol McWilliam Leitch, Ph.D.1
1 MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
2 Edinburgh Specialist Virology Centre, Edinburgh, UK
3 West of Scotland Specialist Virology Centre, Glasgow, UK


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  3. Thomson, EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, et al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011;60:837-845. CrossRefWeb of Science® Times Cited: 24


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