Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome
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Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome. / Fahnøe, Ulrik; Pedersen, Martin S.; Sølund, Christina; Ernst, Anja; Krarup, Henrik B.; Røge, Birgit T.; Christensen, Peer B.; Laursen, Alex L.; Gerstoft, Jan; Thielsen, Peter; Madsen, Lone G.; Pedersen, Anders G.; Schønning, Kristian; Weis, Nina; Bukh, Jens.
In: Journal of Viral Hepatitis, Vol. 28, No. 2, 2021, p. 302-316.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non-target sites, for DAA-based treatment and retreatment outcome
AU - Fahnøe, Ulrik
AU - Pedersen, Martin S.
AU - Sølund, Christina
AU - Ernst, Anja
AU - Krarup, Henrik B.
AU - Røge, Birgit T.
AU - Christensen, Peer B.
AU - Laursen, Alex L.
AU - Gerstoft, Jan
AU - Thielsen, Peter
AU - Madsen, Lone G.
AU - Pedersen, Anders G.
AU - Schønning, Kristian
AU - Weis, Nina
AU - Bukh, Jens
PY - 2021
Y1 - 2021
N2 - Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.
AB - Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV full-length open reading frame deep-sequencing was performed. The proportion of HCV NS5A-RASs at baseline was higher in treatment-failure (82%) than matched SVR patients (25%) (p =.0063). Also, treatment failure was associated with slower declines in viraemia titres. Viral population diversity did not differ at baseline between SVR and treatment-failure patients, but failure was associated with decreased diversity probably caused by selection for RAS. The NS5B-substitution 150V was associated with sofosbuvir treatment failure in genotype 3a. Further, mutations identified in NS2, NS3-helicase and NS5A-domain-III were associated with DAA treatment failure in genotype 1a patients. Six retreated HCV patients (35%) experienced 2nd treatment failure; RASs were present in 67% compared to 11% with SVR. In conclusion, baseline RASs to NS5A inhibitors, but not virus population diversity, and lower viral titre decline predicted HCV treatment failure. Mutations outside of the DAA targets can be associated with DAA treatment failure. Successful DAA retreatment in patients with treatment failure was hampered by previously selected RASs.
KW - direct-acting antivirals
KW - genome-wide association studies
KW - hepatitis C virus
KW - next-generation sequencing
KW - resistance-associated substitution
KW - treatment failure
U2 - 10.1111/jvh.13430
DO - 10.1111/jvh.13430
M3 - Journal article
C2 - 33131178
AN - SCOPUS:85096683109
VL - 28
SP - 302
EP - 316
JO - Journal of Viral Hepatitis
JF - Journal of Viral Hepatitis
SN - 1352-0504
IS - 2
ER -
ID: 252679193