ABSTRACT
Resistance-associated substitutions (RASs) in hepatitis C virus (HCV) appear upon failure of treatment with direct-acting antivirals (DAAs). However, their origin has not been clarified in detail. Among 11 HCV genotype 1b patients who experienced virologic failure with asunaprevir (ASV)/daclatasvir (DCV), 10 had major NS5A L31M/V-Y93H variants after treatment. L31M/V-Y93H variants were detected as a minor clone before therapy in 6 patients and were the most closely related to the post-treatment variants by phylogenetic tree analysis in 4 patients. Next, to consider the involvement of a trace amount of pre-existing variants below the detection limit, we analysed human hepatocyte chimeric mice infected with DAA-naïve patient serum. L31V-Y93H variants emerged after treatment with ledipasvir (LDV)/GS-558093 (nucleotide NS5B inhibitor) and decreased under the detection limit, but these variants were dissimilar to the L31V-Y93H variants reappearing after ASV/DCV re-treatment. Finally, to develop an infection derived from a single HCV clone, we intrahepatically injected full-genome HCV RNA (engineered based on the wild-type genotype 1b sequence) into chimeric mice. A new Y93H mutation actually occurred in this model after LDV monotherapy failure. In conclusion, post-treatment RASs appear by 2 mechanisms: the selection of pre-existing substitutions among quasispecies and the generation of novel mutations during therapy.
Subject(s)
Drug Resistance, Viral/genetics , Hepacivirus/genetics , Mutation , Animals , Anti-Retroviral Agents/pharmacology , Carbamates , Evolution, Molecular , Hepacivirus/classification , Hepacivirus/drug effects , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Imidazoles/pharmacology , Imidazoles/therapeutic use , Isoquinolines/pharmacology , Isoquinolines/therapeutic use , Mice , Phylogeny , Pyrrolidines , Selection, Genetic , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Valine/analogs & derivativesABSTRACT
A 50-year-old man underwent radiofrequency ablation (RFA) for a hepatocellular carcinoma, located in the S8 area adjacent to the diaphragm. 20 months later, he was admitted because of severe right hypochondralgia and dyspnea. Computed tomography revealed a prolapsed large intestine through a defect on the right diaphragm, and emergency surgery was performed. Patients who have undergone RFA for a hepatic tumor adjacent to the diaphragm should be carefully followed up for possible diaphragmatic hernia, even after a long postoperative interval.
