title: HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial.
abstract: Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of alisporivir or interferon treatment with the observed amino acid changes.
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: lize.cuypers@kuleuven.be.
authors.forename: Lize
authors.initials: L
authors.lastname: Cuypers
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: joke.snoeck@nds.ox.ac.uk.
authors.forename: Joke
authors.initials: J
authors.lastname: Snoeck
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: lienkerremans@hotmail.com.
authors.forename: Lien
authors.initials: L
authors.lastname: Kerremans
authors.affiliation: Artificial Intelligence Lab, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: pieter.libin@vub.ac.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Libin
authors.affiliation: Debiopharm International S.A., Che. Messidor 5-7, P.O. Box 5911, 1002 Lausanne, Switzerland. Electronic address: rcrabbe@debiopharm.com.
authors.forename: Raf
authors.initials: R
authors.lastname: Crabbé
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: sonia.vandooren@uzbrussel.be.
authors.forename: Sonia
authors.initials: S
authors.lastname: Van Dooren
authors.affiliation: Debiopharm International S.A., Che. Messidor 5-7, P.O. Box 5911, 1002 Lausanne, Switzerland. Electronic address: gregoire.vuagniaux@debiopharm.com.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium; Center for Global Health and Tropical Medicine, Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Jungquiera 100, 1349-008 Lisbon, Portugal. Electronic address: annemie.vandamme@uzleuven.be.
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D010802:Phylogeny; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D016572:Cyclosporine; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; C097010:NS2 protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a; C499715:alisporivir
keywords: Alisporivir; Cyclophilin inhibitor; D320E; Drug resistance; Full-genome sequencing; HCV