Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2018; 24(40): 4554-4564
Published online Oct 28, 2018. doi: 10.3748/wjg.v24.i40.4554
Recovery of natural killer cells is mainly in post-treatment period in chronic hepatitis C patients treated with sofosbuvir plus ledipasvir
Xiao-Xiao Wang, Bi-Fen Luo, Han-Ji Jiang, Xu Cong, Qian Jin, Dan-Li Ma, Lai Wei, Bo Feng
Xiao-Xiao Wang, Bi-Fen Luo, Han-Ji Jiang, Xu Cong, Qian Jin, Dan-Li Ma, Lai Wei, Bo Feng, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing 100044, China
Author contributions: Wang XX, Luo BF, Wei L and Feng B designed the study, performed data analysis, and wrote and edited the manuscript; Luo BF, Jiang HJ, Jin Q and Ma DL enrolled the patients; Wang XX, Jiang HJ, and Cong X performed sample testing; all authors reviewed and approved the manuscript.
Supported by the National S&T Major Projects for Infectious Diseases Control, No. 2017ZX10302201-004-001.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Peking University People’s Hospital.
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Bo Feng, PhD, Chief Doctor, Professor, Research Fellow, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, No. 11, Xizhimen South Street, Beijing 100044, China.
Telephone: +86-10-88325980 Fax: +86-10-66515490
Received: July 27, 2018
Peer-review started: July 27, 2018
First decision: August 27, 2018
Revised: September 2, 2018
Accepted: October 5, 2018
Article in press: October 5, 2018
Published online: October 28, 2018
Research background

Chronic hepatitis C virus (HCV) infection can lead to mortality from hepatic as well as extra-hepatic causes. Until now, direct-acting antivirals (DAAs) have replaced pegylated-interferon (PEG-IFN)/ribavirin as a first-line treatment option. IFN-free DAAs take the virus life cycle as a target and can help us clarify the interaction between HCV clearance and the innate immune response, regardless of the IFN-α induced immune modulation. Previous studies showed that PEG-IFN-α can change natural killer (NK) cell subtype distribution and function in HCV-eliminated patients. However, it is controversial whether DAAs can change the phenotypes and function of NK cells.

Research motivation

More and more DAAs have been approved for clinical practice. In China, sofosbuvir/ledipasvir have been increasingly used among chronic hepatitis C (CHC) patients, especially those with genotype 1 HCV infection. Previous studies illustrated that NK cells play an important role in the antiviral immune defense and undergo great changes in subsets, phenotype and function during persistent viral infections. Therefore, it is meaningful to investigate how NK cells are affected in the elimination of HCV by sofosbuvir/ledipasvir.

Research objectives

The objectives of this study are to observe the dynamic changes of NK cell subsets, phenotypes and functional parameters during and after DAAs treatment, and investigate the effect of DAAs (sofosbuvir/ledipasvir) treatment on innate immunity in genotype 1b HCV-infected patients.

Research methods

Thirteen treatment-naïve and treatment-experienced CHC patients were treated with sofosbuvir/ledipasvir, and NK cells were detected at baseline, week 2 to 12 during therapy, and week post of treatment (Pt)-12 and 24 after the end of therapy by multicolor flow cytometry and compared with 13 healthy controls.

Research results

There was a significant decline in CD56bright NK cell frequencies at week 8 (P = 0.002) and week 12 (P = 0.003), which were altered to the level comparable to that of healthy controls at week Pt-12, but there was no difference in the frequency of CD56dim NK cells. Compared with healthy controls, the expression levels of NKG2A, NKp30 and CD94 on NK cells from CHC patients at baseline were higher. NKG2A, NKp30 and CD94 started to recover at week 12 and reached the levels similar to those of healthy controls at week Pt-12 or Pt-24. Before treatment, patients had higher IFN-γ and perforin levels than healthy controls, and IFN-γ started to recover at week 8 and reached the normalized level at week Pt-12.

Research conclusions

NK cells of CHC patients can be affected by DAAs, and NK cell phenotypes and function started to change at the later period of sofosbuvir/ledipasvir treatment and reversed to the normalized level of healthy individuals mainly after end of treatment. What we found in our research is different from previous studies which assumed that HCV clearance induced by DAAs can mediate NK recovery rapidly.

Research perspectives

In hepatitis B virus (HBV)/HCV coinfected patients, HBV reactivation often occurred at the later period or even after the end of DAAs treatment. Our study may provide an explanation for this observation. Whether dynamic changes of NK cells in DAA-treated patients are related to HCV reinfection or liver carcinogenesis after HCV elimination is a great topic in the future.