Date Published: June 1, 2018
Publisher: Public Library of Science
Author(s): Seiichi Mawatari, Kohei Oda, Kazuaki Tabu, Sho Ijuin, Kotaro Kumagai, Kunio Fujisaki, Masafumi Hashiguchi, Yukiko Inada, Hirofumi Uto, Yasunari Hiramine, Takeshi Kure, Takeshi Hori, Oki Taniyama, Ai Kasai, Tsutomu Tamai, Akihiro Moriuchi, Akio Ido, Tatsuo Kanda.
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.
Direct acting antiviral (DAA) therapy is associated with a high sustained virologic response (SVR) rate in patients with chronic hepatitis type C in comparison to conventional interferon (IFN) therapy. In July 2014, daclatasvir (DCV) (a NS5A inhibitor) and asunaprevir (ASV) (an NS3-4A protease inhibitor) were authorized for the treatment of chronic hepatitis or compensated cirrhosis in patients with hepatitis C virus (HCV) genotype 1 in Japan. It was reported that baseline resistance-associated substitutions (RASs) of NS3 D168, NS5A L31 and Y93 predicted the effects of DAA treatment in patients undergoing DCV/ASV combination therapy. We previously reported that in patients without NS5A L31 or Y93 RASs and a history of protease inhibitor therapy, the virologic effect of DCV+ASV therapy was associated with the presence of NS5A Q24, L28, and/or R30 RASs and concomitant F37 and Q54 RASs before treatment.
We revealed, for the first time, that most SOF/LDV-treated patients with virologic failure had RASs of NS5B A218 and/or C316, and these RAS was significantly associated with virologic failure. Donaldson et al. reported that NS5B C316 was associated with virologic failure ; however while many studies have reported the analysis of large study populations [19–25], no reports have indicated that NS5B A218 RAS is associated with virologic failure in SOF/LDV-treated patients. The reason why we paid attention to NS5B A218 and/or C316 RAS was that 8 of the 11 patients with virologic failure had coexisting NS5B A218 and C316 RAS (Table 2). In addition, NS5B A218 and C316 showed a high rate of coexistence at baseline. Iio et al. showed a similar report about the coexistence of NS5B A218 and C316 in patients with virologic failure . Donaldson et al. reported that NS5B C316N may interfere with the ability of SOF to enter the active site by blocking the space ; thus, these RASs might have inhibited the activity of SOF cooperatively.