Gunson, R.N.

McNaughton, A.L.

McWilliam Leitch, E.C.

Templeton, K.

Thomson, E.C.

English

PubMed

McNaughton, Anna L

Thomson, Emma C

Templeton, Kate

Gunson, Rory N

Leitch, E Carol McWilliam

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Mixed genotype hepatitis C infections and implications for treatment

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          McNaughton, A.L., Thomson, E.C., Templeton, K., Gunson, R.N., and McWilliam Leitch, E.C. (2014) Mixed genotype hepatitis C infections and implications for treatment. Hepatology, 59 (3). p. 1209. ISSN 0270-9139    Copyright © 2014 The Authors   http://eprints.gla.ac.uk/81035/     Deposited on:  7 May  2014                           Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Mixed Genotype Hepatitis C Infections and Implications for TreatmentTo the Editor:The recently licensed direct-acting antivirals (DAAs) boceprevirand telaprevir used to treat hepatitis C virus (HCV) infection actin a genotype-specific manner. The potential outcome of DAAtreatment regimes on mixed HCV infections, consisting of concur-rent infection with more than one HCV genotype, has not beenconsidered. Standard genotyping methods are only capable of iden-tifying the dominant genotype present within a mixed infectionsample, leaving minor genotypes undetected. We propose thatDAA treatment of mixed infections may be associated with theoccurrence of genotype switching, whereby a previously undetectedminority variant drug-resistant genotype expands to replace thesuccessfully treated majority variant genotype. Such genotypeswitching could in some cases result in nonresponse to DAA treat-ment and could also be incorrectly interpreted as reinfection ifgenotyping is not repeated following treatment failure. As a matterof urgency, there is a need to assess the prevalence and clinicalimpact of mixed HCV infections.To determine the prevalence of mixed HCV infections in acohort of patients infected with genotype (gt) 3a (n5 47) or 1a(n5 48), we designed gt1a- and gt3a-specific primers providingpartial coverage of the envelope genes E1 and E2 of HCV. Nestedreverse transcription (RT) polymerase chain reaction (PCR)reactions were performed using gt1a primers with gt3a-infectedsamples and vice versa. Amplicons were sequenced and used toconstruct maximum likelihood phylogenetic trees using the MEGA5.0 software package to confirm genotype.The sensitivity of the RT-PCR reactions, as determined by 90%detection limits calculated from serial endpoint dilution RT-PCRand probit analysis, was nine copies/reaction. Of the gt3a-infectedpatient samples, 10.6% (5/47) harbored minority variant gt1astrains, whereas none of the gt1a-infected patient samples con-tained gt3a as a minority strain.These findings are in keeping with other studies that foundmixed HCV infections at rates of 5%-25.3%.1-3 Further work isrequired to assess the impact of minority variant strains on patientstreated with DAA therapy. If relapse following dual therapy for gt3infection is associated with emerging dominance of preexisting gt1strains, screening of baseline patient samples using genotype-specificmethods could result in improved treatment strategies; for example,the prescription of triple rather than dual antiviral therapy. Morework is required to assess the impact of multiple genotype infectionon clinical outcome, and this work is more pressing in the DAA era.ANNA L. MCNAUGHTON, M.SC.1EMMA C. THOMSON, PH.D., MRCP1KATE TEMPLETON, PH.D.2RORY N. GUNSON, FRCPATH3E. CAROL MCWILLIAM LEITCH, PH.D.11MRC-University of Glasgow Centre for Virus Research,Glasgow, UK2Edinburgh Specialist Virology Centre, Edinburgh, UK3West of Scotland Specialist Virology Centre, Glasgow, UKReferences1. Pham ST, Bull RA, Bennett JM, Rawlinson WD, Dore GJ, Lloyd AR,et al. Frequent multiple hepatitis C virus infections among injectiondrug users in a prison setting. HEPATOLOGY 2010;52:1564-1572.2. Yun H, Kim D, Kim S, Kang S, Jeong S, Cheon Y, et al. Highprevalence of HBV and HCV infection among intravenous drug users inKorea. J Med Virol 2008;80:1570-1575.3. Thomson, EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J,et al. Predicting spontaneous clearance of acute hepatitis C virus in alarge cohort of HIV-1-infected men. Gut 2011;60:837-845.Copyright VC 2013 Crown copyright. HEPATOLOGY Copyright VC 2013 theAmerican Association for the Study of Liver Diseases.This article is published with the permission of the Controller of HMSO andthe Queen’s Printer for Scotland.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.26544Potential conflict of interest: Nothing to report.Supported by MRC grant 63785.Unusual Oral Mucosa Damage During Telaprevir Treatment of Chronic Hepatitis CTo the Editor:The addition of hepatitis C virus (HCV) protease inhibitor telap-revir to pegylated interferon (Peg-IFN) and ribavirin (RBV) dramati-cally increases the likelihood of a sustained virological response(SVR) in patients with genotype 1 HCV infection who have failedprevious treatment with Peg-IFN/RBV combination.1 The higherprevalence of cutaneous adverse reactions (CAR) of different severitywas associated with the telaprevir combination treatment, in contrastto the treatment with Peg-IFN/RBV2; however, we could not findany published article about isolated mucosal lesions associated withthe telaprevir combination treatment before this case.A 29-year-old white male patient was referred to our departmentin May 2012 for reevaluation and retreatment after unsuccessful treat-ment for chronic HCV infection (genotype 1b). Previous treatment(PegIFN-a2b 120 lg/week plus RBV 1,200 mg/day) had achievedneither rapid nor early virological responses and was stopped afterweek 13 of treatment due to a low chance of SVR. The overall toler-ability of this treatment was satisfactory. During the treatment hemo-globin decreased to 97 g/L, absolute neutrophil and platelet countsdecreased but not below the alarm level, and no dermatologicaladverse events were noted. Due to advanced fibrosis and null-responseto the previous treatment with Peg-IFN/RBV, the patient was enrolledin the telaprevir early access program. Triple therapy with PegIFN-a2a180 lg subcutaneously once a week, RBV 600 mg twice daily andtelaprevir 750 mg three times a day was started. Overall tolerability ofthe therapy was satisfactory. A rapid virological response was achieved(PCR HCV RNA was negative on the fourth week of treatment). Noclinically significant hematological adverse events were noted.At week 6 of treatment the patient complained of a tickle in histhroat, but there were no skin lesions, flu-like symptoms, or fever.On the scheduled visit (week 8), vital signs were normal: weight76.8 kg, temperature 36.8C, blood pressure 120/70 mmHg, heart-beat 88/min. Mild hyperemia of oral mucosa plus multiple telan-giectasias and erythematous lesions located on the buccal mucosa,soft palate, and back wall of the throat were found (Fig. 1A,B). Skinwas normal, no regional lymph nodes were enlarged, no signs ofinfection were found, and the patient did not note any unusual tasteHEPATOLOGY, Vol. 59, No. 3, 2014 CORRESPONDENCE 1209

Mixed genotype hepatitis C infections and implications for treatment

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