title: Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens.
abstract: There is little information on retreatment efficacy and predictors of the combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) for patients who fail to respond to NS5A inhibitors. NS5A resistance variants are known to persist for long periods after such treatment. Here, we evaluated 54 patients with chronic HCV genotype 1b infection, free of decompensated cirrhosis, and hepatocellular carcinoma, for sustained virological response after 12 weeks (SVR12) of once-daily treatment with 90 mg ledipasvir and 400 mg sofosbuvir. Intention-to-treat analysis showed SVR12 of 70%. Using ultra-deep sequencing, non-responder to ledipasvir/sofosbuvir showed no change in the rates of detection of NS5A and NS5B resistant-variants at re-elevation of viral loads, relative to baseline. According to response to prior treatment, SVR12 rates were 18, 69, 94, and 100% in non response, viral breakthrough, relapse, and discontinuation due to adverse events, respectively. SVR12 rates in non response were significantly lower than those of the others. Multivariate analysis identified response to previous treatment (failure except for non response) and FIB4 index (<3.25) as significant determinants of SVR12. The SVR12 rates were significantly lower in patients with FIB4 index of ≥3.25 and had not responded to prior treatment, relative to others. The specificity, and positive- and negative-predictive values were high for prediction of poor response based on the combination of two predictors. In conclusion, our study indicated that ledipasvir/sofosbuvir is a potentially useful salvage treatment for patients who fail prior NS5A inhibitors-based therapy. Response to prior treatment was an important predictor of retreatment efficacy.
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Norio
authors.identifier: 0000-0001-5386-9672
authors.initials: N
authors.lastname: Akuta
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Sezaki
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Suzuki
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Fujiyama
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosaka
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Liver Research Laboratory, Toranomon Hospital, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Arase
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Hepatology, Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D005449:Fluorenes / Q000008:administration & dosage / Q000627:therapeutic use*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D016879:Salvage Therapy; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D016896:Treatment Outcome; D014542:Uridine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D005449:Fluorenes; D012367:RNA, Viral; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C000595958:ledipasvir, sofosbuvir drug combination; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: FIB4 index; HCV; asunaprevir; daclatasvir; direct-acting antiviral; ledipasvir; non response; resistance-associated variants; salvage therapy; sofosbuvir; ultra-deep sequencing