The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir

• Published in: PloS one 2018-06, Vol.13 (6), p.e0198642-e0198642
• Main Authors: Mawatari, Seiichi, Oda, Kohei, Tabu, Kazuaki, Ijuin, Sho, Kumagai, Kotaro, Fujisaki, Kunio, Hashiguchi, Masafumi, Inada, Yukiko, Uto, Hirofumi, Hiramine, Yasunari, Kure, Takeshi, Hori, Takeshi, Taniyama, Oki, Kasai, Ai, Tamai, Tsutomu, Moriuchi, Akihiro, Ido, Akio
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antiviral agents; Antiviral drugs; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Biology and Life Sciences; Cohort Studies; Complications and side effects; Disease resistance; Dosage and administration; Drug resistance; Drug Resistance, Multiple, Viral - genetics; Drug therapy; Environmental science; Failure; Female; Fluorenes - pharmacology; Fluorenes - therapeutic use; Gastroenterology; Genetic aspects; Genotype; Genotype & phenotype; Genotypes; Hepacivirus - genetics; Hepacivirus - isolation & purification; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Hepatology; Hospitals; Humans; Identification methods; Infections; Interferon; Internal medicine; Lifestyles; Liver cancer; Liver diseases; Male; Medicine; Medicine and health sciences; Middle Aged; Multivariate analysis; Patients; Research and Analysis Methods; Sofosbuvir; Sustained Virologic Response; Therapy; Treatment Failure; University graduates; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - pharmacology; Uridine Monophosphate - therapeutic use; Viral Nonstructural Proteins - genetics; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0198642

The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs). Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed. Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%). Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.