Oncotarget

Research Papers:

Dynamics of PBMC gene expression in hepatitis C virus genotype 1-infected patients during combined peginterferon/ribavirin therapy

Ming-Ying Lu, Ching-I Huang, Ming-Yen Hsieh, Tusty-Juan Hsieh, Edward Hsi, Pei-Chien Tsai, Yi-Shan Tsai, Ching-Chih Lin, Meng-Hsuan Hsieh, Po-Cheng Liang, Yi-Hung Lin, Nai-Jen Hou, Ming-Lun Yeh, Chung-Feng Huang, Zu-Yau Lin, Shinn-Cherng Chen, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai and Ming-Lung Yu _

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Oncotarget. 2016; 7:61325-61335. https://doi.org/10.18632/oncotarget.11348

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Abstract

Ming-Ying Lu7, Ching-I Huang4, Ming-Yen Hsieh1, Tusty-Juan Hsieh8, Edward Hsi9, Pei-Chien Tsai1, Yi-Shan Tsai1, Ching-Chih Lin1, Meng-Hsuan Hsieh2,6, Po-Cheng Liang1, Yi-Hung Lin1, Nai-Jen Hou4, Ming-Lun Yeh1,2,7, Chung-Feng Huang1,2,5, Zu-Yau Lin1,2, Shinn-Cherng Chen1,2, Jee-Fu Huang1,2, Wan-Long Chuang1,2, Chia-Yen Dai1,2,7, Ming-Lung Yu1,2,3,10

1Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

2Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan

3Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

4Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

5Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

6Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

7Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

8Department of Genome Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

9Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

10Liver Center, Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Correspondence to:

Ming-Lung Yu, email: [email protected]

Chia-Yen Dai, email: [email protected]

Keywords: hepatitis C, interferon, sustained virologic response

Received: April 18, 2016     Accepted: August 10, 2016     Published: August 17, 2016

ABSTRACT

Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype.


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