Observational Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2015; 21(43): 12430-12438
Published online Nov 21, 2015. doi: 10.3748/wjg.v21.i43.12430
Re-re-treatment of hepatitis C virus: Eight patients who relapsed twice after direct-acting-antiviral drugs
Joshua Hartman, Kian Bichoupan, Neal Patel, Sweta Chekuri, Alyson Harty, Douglas Dieterich, Ponni Perumalswami, Andrea D Branch
Joshua Hartman, Department of Medicine, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States
Kian Bichoupan, Neal Patel, Sweta Chekuri, Alyson Harty, Douglas Dieterich, Ponni Perumalswami, Andrea D Branch, Division of Liver Disease, Icahn School of Medicine at the Mount Sinai Medical Center, New York, NY 10029, United States
Author contributions: Hartman J, Bichoupan K, Perumalswami P and Branch AD designed the research; Hartman J, Bichoupan K, Patel N, Chekuri S, Harty A, Dieterich D, Perumalswami P and Branch AD performed the research; Hartman J, Bichoupan K, Perumalswami P and Branch AD analyzed the data; and Hartman J, Bichoupan K, Perumalswami P and Branch AD wrote the paper.
Supported by The Grants No. R01 DK090317 and No. R01 DA031095 (in part).
Institutional review board statement: The study was reviewed at approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board.
Informed consent statement: Study participants did not provide informed consent prior to study enrollment as the Icahn School of Medicine at Mount Sinai Institutional Review Board provided a waiver of authorization to release deidentified patient data for research purposes.
Conflict-of-interest statement: Kian Bichoupan is a paid consultant for Gilead Sciences and Janssen Pharmaceuticals, Inc. Dr. Andrea D. Branch is a paid consultant for Gilead Sciences and Janssen Pharmaceuticals, Inc. Dr. Douglas T. Dieterich serves as a paid lecturer, consultant and is a member on scientific advisory boards of companies which either develop or assess medicines used for the treatment of viral hepatitis. These companies include Gilead Sciences, Abbvie, Achillion, Bristol-Myers Squibb, Merck, and Janssen Pharmaceuticals, Inc. Alyson Harty is a paid consultant for Abbvie Pharmaceuticals, Gilead Sciences, and Janssen Pharmaceuticals, Inc. Dr. Sweta Chekuri, Dr. Joshua Hartman, Dr. Neal Patel, and Dr. Ponni V. Perumalswmi do not have any disclosures.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at andrea.branch@mssm.edu. Consent was not obtained but the presented data are anonymized and risk of identification is low.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Andrea D Branch, PhD, Division of Liver Disease, Icahn School of Medicine at the Mount Sinai Medical Center, 11th floor, Room 24, 1425 Madison Avenue, New York, NY 10029, United States. andrea.branch@mssm.edu
Telephone: +1-212-6598371
Received: March 31, 2015
Peer-review started: March 31, 2015
First decision: May 18, 2015
Revised: June 2, 2015
Accepted: July 8, 2015
Article in press: July 8, 2015
Published online: November 21, 2015
Processing time: 232 Days and 5.9 Hours
Abstract

AIM: To determine risk factors associated with hepatitis C virus (HCV) treatment failure after direct acting antivirals in patients with complex treatment histories.

METHODS: All HCV mono-infected patients who received treatment at our institution were queried. Analysis was restricted to patients who previously failed treatment with boceprevir (BOC) or telaprevir (TVR) and started simeprevir (SMV) and sofosbuvir (SOF) ± ribavirin (RBV) between December 2013 and June 2014. Patients with human immunodeficiency virus (HIV)/HCV co-infection or patients who received a liver transplant in the past were excluded. Viral loads were recorded while on treatment and after treatment. Data collection continued until December, 31st 2014 when data analysis was initiated. Patients missing virologic outcomes data were not included in the analysis. Analysis of 35 patients who had virologic outcome data available resulted in eight patients who were viral load negative at the end of treatment with SMF/SOF but later relapsed. Data related to patient demographics, HCV infection, and treatment history was collected in order to identify risk factors shared among patients who failed treatment with SMF/SOF.

RESULTS: Eight patients who were treated with the first generation HCV protease inhibitors BOC or TVR in combination with pegylated-interferon (PEG) and RBV who failed this triple therapy were subsequently re-treated with an off-label all-oral regimen of SMV and SOF for 12 wk, with RBV in seven cases. Treatment was initiated before the Food and Drug Administration approved a 24-wk SMV/SOF regimen for patients with liver cirrhosis. All eight patients had an end of treatment response, but later relapsed. Eight (100%) patients were male. Mean age was 56 (range, 49-64). Eight (100%) patients had previously failed PEG/RBV dual therapy at least once in addition to prior failure with triple therapy. Total number of times treated ranged from 3-6 (mean 3.8). Eight (100%) patients were male had liver cirrhosis as determined by Fibroscan or MRI. Seven (87.5%) patients had genotype 1a HCV. Seven (87.5%) patients had over 1 million IU/mL HCV RNA at the time of re-treatment.

CONCLUSION: This study identifies factors associated with SMV/SOF treatment failure and provides evidence that twleve weeks of SMV/SOF/RBV is insufficient in cirrhotics with high-titer genotype 1a HCV.

Keywords: Hepatitis C; Protease inhibitor; Relapse; Simeprevir; Sofosbuvir; Treatment failure

Core tip: Direct acting antivirals are revolutionizing the treatment of chronic hepatitis C (HCV) infection, but are also increasing the number of patients who have failed multiple rounds of treatment. Information about these patients is needed to plan salvage treatment strategies. We present eight patients who failed treatment with the first generation protease inhibitors and subsequently failed treatment with simeprevir and sofosbuvir. Their shared characteristics include a history of failed treatment with interferon/ribavirin and liver cirrhosis. Seven had genotype 1a HCV and a high viral load. Our findings suggest that patients with cirrhosis and high viral load remain hard-to-treat.