Analysis of resistance-associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents.
Several direct-acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon-free treatment regimens. Resistance-associated substitutions (RASs) have been reported both in treatment-naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV-infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next-generation sequencing to analyse full-length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1-GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN-free regimens were rarely detected in combination. Low-frequency RASs (<10% of the viral population) were also shown to have a GT-specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale-up.
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
A A
AA
Eltahla
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
C
C
Rodrigo
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
B
B
Betz-Stablein
The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
J
J
Grebely
The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
T
T
Applegate
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
F
F
Luciani
Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Center for Infection and Immunity Amsterdam, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands.|GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands.
J
J
Schinkel
The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
G J
GJ
Dore
Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
K
K
Page
CRCHUM, Université de Montréal, Montreal, QC, Canada.
J
J
Bruneau
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
M D
MD
Morris
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
A L
AL
Cox
Harvard Medical School, Boston, MA, USA.
A Y
AY
Kim
CRCHUM, Université de Montréal, Montreal, QC, Canada.
N H
NH
Shoukry
Harvard Medical School, Boston, MA, USA.
G M
GM
Lauer
The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
L
L
Maher
Burnet Institute, Melbourne, Vic, Australia.|Department of Infectious Diseases, Alfred Hospital, Melbourne, Vic, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Vic, Australia.
M
M
Hellard
Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Center for Infection and Immunity Amsterdam, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands.|GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands.
M
M
Prins
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
A R
AR
Lloyd
School of Medical Sciences, Faculty of Medicine, UNSW Australia, Sydney, NSW, Australia.
R A
RA
Bull
D000328:Adult; D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D050505:Mutant Proteins / Q000235:genetics; D058974:Phylogeography; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D050505:Mutant Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase

DAA
; antiviral; hepatitis C virus; inhibitors; resistance
J Hepatol. 2014 Nov;61(1 Suppl):S45-57
25086286
Lancet. 2015 Oct 17;386(10003):1537-45
26456905
Antimicrob Agents Chemother. 2012 Jun;56(6):3359-68
22430955
Antiviral Res. 2014 Aug;108:181-91
24911972
J Infect Dis. 2015 Apr 15;211(8):1288-95
25389307
Hepatology. 2014 Jan;59(1):318-27
24115039
J Virol. 2011 Dec;85(23):12334-42
21957306
Antimicrob Agents Chemother. 2015 Feb;59(2):988-97
25451053
JAMA. 2015 May 5;313(17):1728-35
25942723
Bioinformatics. 2012 Jun 15;28(12):1647-9
22543367
J Hepatol. 2016 Feb;64(2):486-504
26409317
Nat Rev Gastroenterol Hepatol. 2013 Sep;10(9):553-62
23817321
Viruses. 2015 Sep 29;7(10):5206-24
26426038
J Hepatol. 2015 May;62(5):1008-14
25445400
Antimicrob Agents Chemother. 2015 Feb;59(2):979-87
25451055
PLoS One. 2014 Aug 20;9(8):e105569
25140696
Int J Epidemiol. 2013 Dec;42(6):1649-59
23203695
Gastroenterology. 2011 Mar;140(3):1032-42
21111742
Clin Infect Dis. 2016 Feb 1;62(3):280-288
26521268
Liver Int. 2016 Jan;36 Suppl 1:47-57
26725897
Hepatology. 2009 Apr;49(4):1335-74
19330875
N Engl J Med. 2014 Apr 24;370(17):1594-603
24720703
Nat Methods. 2012 Mar 04;9(4):357-9
22388286
N Engl J Med. 2014 May 22;370(21):1983-92
24795200
Antimicrob Agents Chemother. 2014 Dec;58(12):7215-24
25246395
J Virol. 1992 May;66(5):3225-9
1313927
Gastroenterology. 2014 Sep;147(3):599-601.e1
24859204
Antiviral Res. 2015 Apr;116:10-6
25614456
J Clin Virol. 2007 May;39(1):43-7
17369083
Hepatology. 2013 Sep;58(3):902-11
23504694
PLoS One. 2015 Apr 02;10(4):e0122232
25837807
Hepatology. 2013 Apr;57(4):1333-42
23172780
PLoS Pathog. 2011 Sep;7(9):e1002243
21912520
Antimicrob Agents Chemother. 2010 May;54(5):1878-87
20176898