Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 27, 2018; 10(11): 856-866
Published online Nov 27, 2018. doi: 10.4254/wjh.v10.i11.856
Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients
Dominique Salmon, Pascale Trimoulet, Camille Gilbert, Caroline Solas, Eva Lafourcade, Julie Chas, Lionel Piroth, Karine Lacombe, Christine Katlama, Gilles Peytavin, Hugues Aumaitre, Laurent Alric, François Boué, Philippe Morlat, Isabelle Poizot-Martin, Eric Billaud, Eric Rosenthal, Alissa Naqvi, Patrick Miailhes, Firouzé Bani-Sadr, Laure Esterle, Patrizia Carrieri, François Dabis, Philippe Sogni, Linda Wittkop, ANRS CO13 Hepavih study Group
Dominique Salmon, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Hôpital Hôtel Dieu, Unité des Maladies infectieuses et tropicales, Paris 75004, France
Dominique Salmon, Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France
Pascale Trimoulet, CHU de Bordeaux, Hôpital Pellegrin, Laboratoire de Virologie, Bordeaux 33000, France
Pascale Trimoulet, CNRS-UMR 5234, Microbiologie fondamentale et Pathogénicité, Université de Bordeaux, Bordeaux 3000, France
Camille Gilbert, Eva Lafourcade, Philippe Morlat, Laure Esterle, François Dabis, Linda Wittkop, Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, team MORPH3EUS, UMR 1219, CIC-EC 1401, Bordeaux F-33000, France
Caroline Solas, APHM, Hôpital La Timone, Laboratoire de Pharmacocinétique et Toxicologie, Marseille 13005, France
Julie Chas, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Service Maladies infectieuses et tropicales, Paris 75020, France
Lionel Piroth, Centre Hospitalier Universitaire de Dijon, Département d’Infectiologie, Dijon cedex 21079, France
Lionel Piroth, INSERM-CIC 1342 Université de Bourgogne, Dijon 21000, France
Karine Lacombe, Assistance Publique des Hôpitaux de Paris, GHUEP site Saint-Antoine, Services Maladies infectieuses et tropicales, Paris 75011, France
Karine Lacombe, Université Pierre et Marie Curie, UMR S1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris 75646, France
Christine Katlama, Université Paris-Sorbonne, Paris 75005, France
Christine Katlama, Assistance Publique des Hôpitaux de Paris Hôpital Pitié Salpêtrière, Services Maladies infectieuses et tropicales, Paris 75013, France
Gilles Peytavin, Assistance Publique des Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie, Paris 75877, France
Gilles Peytavin, IAME, UMR 1137, Sorbonne Paris Cité, INSERM, Université Paris Diderot, Paris 75890, France
Hugues Aumaitre, Centre Hospitalier de Perpignan, Service Maladies infectieuses et tropicales, Perpignan 66000, France
Laurent Alric, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Service Médecine interne-Pôle Digestif, Toulouse 31300, France
Laurent Alric, UMR 152 IRD Université Toulouse III, Paul Sabatier, Toulouse 31330, France
François Boué, Hôpital Antoine-Béclère, Assistance Publique des Hôpitaux de Paris, Université Paris Sud, Service Médecine interne et immunologie, Clamart 92140, France
Philippe Morlat, Centre Hospitalier Universitaire de Bordeaux, Service de médecine interne, Hôpital Saint-André, Bordeaux 33000, France
Isabelle Poizot-Martin, Aix-Marseille Univ, APHM Sainte-Marguerite, Service d’Immuno-hématologie clinique, Marseille 13274, France
Isabelle Poizot-Martin, Patrizia Carrieri, Sciences Economiques and Sociales de la Santéand Traitement de l’Information Médicale, UMR912 INSERM, Aix-Marseille Université, IRD, Marseille 13009, France
Eric Billaud, Department of Infectious Diseases, CHU de Nantes and CIC 1413, Inserm, Nantes 44000, France
Eric Rosenthal, Centre Hospitalier Universitaire de Nice, Service de Médecine Interne, Hôpital l’Archet, Nice 06202, France
Eric Rosenthal, Université de Nice-Sophia Antipolis, Nice 06100, France
Alissa Naqvi, Centre Hospitalier Universitaire de Nice, Service d’Infectiologie, Hôpital l’Archet, Nice 06100, France
Patrick Miailhes, Service des Maladies Infectieuses et Tropicales, Hospices Civils de Lyon, Hôpital de la Croix Rousse, Lyon 69004, France
Firouzé Bani-Sadr, Centre Hospitalier Universitaire de Reims, Service de Médecine Interne, Maladies Infectieuses et Immunologie Clinique, Reims 51100, France
Firouzé Bani-Sadr, Faculté de Médecine EA-4684/SFR CAP-SANTE, Université de Reims, Champagne-Ardenne, Reims 51100, France
Philippe Sogni, Assistance Publique des Hôpitaux de Paris, Hôpital Cochin, Service d’Hépatologie, Paris 75014, France
Philippe Sogni, Inserm U-1223 - Institut Pasteur, Paris 75015, France
Linda Wittkop, CHU de Bordeaux, Pôle de santé Publique, Service d’information médicale, Bordeaux F-33000, France
Author contributions: All the authors contributed to this work
Supported by Inserm-ANRS (French National Institute for Health and Medical Research - ANRS/France REcherche Nord and Sud Sida-hiv Hépatites).
Institutional review board statement: The study was approved by the Institutional Review Board Ile de France III, Paris, France
Informed consent statement: A written informed consent was obtained from each participant to the study.
Conflict-of-interest statement: Dominique Salmon has been speaker and received invitation to conferences by Gilead, Abott, and MSD. Laurent Alric received grant and personal fees from MSD, Gilead, Abbvie, Janssen and BMS outside the submitted work. Christine Katlama received consultancy fees and/or travel grants from MSD, Janssen, ViiV outside the submitted work. Karine Lacombe personal fees from Gilead, personal fees from Janssen, personal fees from Abbvie, personal fees from Merck outside the submitted work. Philippe Morlat received personal fees and non-financial support from GILEAD, Janssen, MSD and ViiV Health Care outside the submitted work. Gilles Peytavin received travel grants, consultancy fees or study grants from pharmaceutical companies including Abbvie, Bristol-Myers Squibb, Gilead sciences, Janssen, Merck and ViiV Healthcare outside the submitted work. Eric Rosenthal received personal fees from Gilead and Abbvie and travel grants, consultancy fees from Gilead, Abbvie, MSD and BMS outside the submitted work. Philippe Sogni received personal fees and non-financial support from Gilead, BMS, MSD Abvie outside the submitted work. Caroline Solas received personal fees from Gilead, Abbvie, Janssen, MSD and ViiV Healthcare outside the submitted work. Linda Wittkop reports grants from ANRS during the conduct of the study; personal fees from Janssen, Gilead, MSD, outside the submitted work. Other authors had nothing to declare.
STROBE statement: The guidelines of the STROBE Statement have been adopted. The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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: Dominique Salmon, MD, PhD, Professor, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Hôpital Hôtel Dieu, Unité des Maladies infectieuses et tropicales, Sorbonne Paris Cité, 1 place du Parvis Notre-Dame, Paris 75004, France. dominique.salmon@aphp.fr
Telephone: +33-1-42347956 Fax: +33-1-42348852
Received: June 15, 2018
Peer-review started: June 15, 2018
First decision: July 9, 2018
Revised: September 10, 2018
Accepted: October 10, 2018
Article in press: October 10, 2018
Published online: November 27, 2018
Processing time: 165 Days and 23.3 Hours
ARTICLE HIGHLIGHTS
Research background

In human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection, all-oral direct-acting antiviral (DAA) regimens achieve virological cures in > 95% of patients.

Research motivation

Risk factors for failure are mainly related to severity of cirrhosis in HCV monoinfected patients, but are unknown in the population of HIV HCV coinfected patients. We wanted to know whether additional factors related to non-adherence or HIV status could be involved in the occurrence of failures. We believed that identifying the risk factors for failure would allow for the adaptation of treatment to patients with higher risk of failure.

Research objectives

The main objectives were to determine the risk factors for virological treatment failure to DAA in HIV/HCV coinfected patients and to describe the frequency of RAS.

Research methods

HIV/HCV coinfected patients who started the first DAA regimen before February 2016 and who were included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defined as: i) Non-response (HCV-RNA remained detectable during treatment, at end of treatment (EOT)), ii) relapse (HCV-RNA suppressed at EOT but detectable thereafter). Sequencing analysis was performed to describe prevalence of drug class specific RAS. Factors associated with failure were determined using logistic regression models.

Research results

Research findings: Among 559 patients, 77% had suppressed plasma HIV-RNA < 50 copies/mL at DAA treatment initiation, 41% were cirrhotic, and 68% were HCV treatment-experienced. Virological treatment failures occurred in 22 patients and were mainly relapses (17, 77%) then undefined failure (3, 14%) and non-responses (2, 9%). Mean treatment duration was 16 wk overall. Post-treatment NS3, NS5A or NS5B RAS were detected in 10/14 patients with samples available for sequencing analysis. After adjustment for age, sex, RBV use, HCV genotype and treatment duration, low platelet count was the only factor significantly associated with a higher risk of failure (OR: 6.5; 95%CI: 1.8-22.6); Contributions to the field: In HIV/HCV coinfected patients, the risk factors of failure were more related to the severity of cirrhosis than to HIV immunovirological status or non-adherence issues. Problems that remain to be solved: It remains to be determined whether the low platelet count associated with a higher probability of failure reflects the severity of cirrhosis.

Research conclusions

In our study of HIV/HCV patients receiving all-oral DAA, only 3.9% HIV-HCV coinfected patients failed DAA regimens. RAS were found in 70% of those failing. Low platelet count was independently associated with virological failure. We think that this low platelet count reflects the severity of cirrhosis.

Research perspectives

As the treatment failure number is low, it would be useful to build international collaborations and gather data for several cohorts in order to gain significance power. The results obtained with first generation all-oral DAA could be compared with the newer, pangenotypic drug regimen.