Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy

Dietz J, Di Maio VC, de Salazar A, Merino D, Vermehren J, Paolucci S, Kremer A, Lara M, Pardo MR, Zoller H, Degasperi E, Peiffer KH, Sighinolfi L, Téllez F, Graf C, Ghisetti V, Schreiber J, Fernández-Fuertes E, Boglione L, Muñoz-Medina L, Stauber R, Gennari W, Figueruela B, Santos J, Lampertico P, Zeuzem S, Ceccherini-Silberstein F, García F, Sarrazin C, Aghemo A, Allice T, Andreoni M, Angelico M, Baldanti F, Barbaliscia S, Bertoli A, Borghi V, Calvaruso V, Cariti G, Craxì A, Francioso S, Perno CF, Pozzoni P, Toniutto PL, Zazzi M, Pérez AB, Quilez C, Alados JC, Cabezas J, Ruiz-Tapiador JIA, Jimenez M, Pascasio-Acevedo JM, Rodriguez MAM, Zabal JMR, Deltoro MG, Sapiña AMM, Fuentes A, Chueca N, Berg CP, Herrmann A, Stallmach A, Port K, Katja Deterding M, Wedermeyer H, Cornberg M, Manns MP, Moreno C, Wiesch JSz, Piecha F, Lohse A, Kordecki N, Magenta L, Jäger B, Möller H, Heyne R, Beyer T, Grunwald S, Baumgarten A, Jägel-Guedes E, Schmidt W, Siebler J (2021)

Publication Type: Journal article

Publication year: 2021


DOI: 10.1016/j.jhep.2020.11.017


Background & Aims: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 15/19 (79%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (79%).

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Involved external institutions

Ospedale Amedeo di Savoia IT Italy (IT) Hospital Universitario Nuestra Señora de Candelaria (HUNSC) ES Spain (ES) Hospital Universitario Puerto Real ES Spain (ES) Hospital Universitario Puerta del Mar ES Spain (ES) Hospital Juan Ramón Jiménez ES Spain (ES) Medizinische Universität Innsbruck AT Austria (AT) Università degli Studi di Ferrara IT Italy (IT) Università degli Studi di Roma 'Tor Vergata' IT Italy (IT) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) University of Eastern Piedmont / Università degli Studi del Piemonte Orientale "Amedeo Avogadro" IT Italy (IT) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE) Hospital Universitario Virgen de la Victoria ES Spain (ES) Azienda Socio Sanitaria Territoriale (ASST) Lecco IT Italy (IT) Hospital Universitario San Cecilio ES Spain (ES) Università degli Studi di Siena (UNISI) / University of Siena IT Italy (IT) Policlinico di Modena IT Italy (IT) Hospitales Universitarios Virgen Macarena y Virgen del Rocío ES Spain (ES) Humanitas Research Hospital / IRCCS Istituto Clinico Humanitas IT Italy (IT) Hospital Costa del Sol ES Spain (ES) Policlinico Tor Vergata IT Italy (IT) Hospital Universitario Virgen de Valme ES Spain (ES) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Università degli studi di Milano IT Italy (IT) Medizinische Universität Graz AT Austria (AT) Universitätsklinikum Tübingen DE Germany (DE) Hôpital Erasme BE Belgium (BE) Hospital de Poniente ES Spain (ES) Hospital Universitario Miguel Servet ES Spain (ES) Hospital Marina Baixa ES Spain (ES) Hospital Universitario Reina Sofía de Córdoba Edificio IMIBIC ES Spain (ES) Universitätsklinikum Jena DE Germany (DE) Donostia University Hospital / Donostia Unibertsitate Ospitalea ES Spain (ES) Hospital General Universitari de València ES Spain (ES) University of Turin / Università degli Studi di Torino (UNITO) IT Italy (IT) Università degli Studi di Palermo IT Italy (IT) University of Udine / Università degli Studi di Udine IT Italy (IT) Hospital Regional de Málaga ES Spain (ES) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico IT Italy (IT) ASL Città di Torino IT Italy (IT) Policlinico San Matteo Pavia Fondazione IRCCS IT Italy (IT) Marqués de Valdecilla University Hospital / Hospital Universitario de Marqués de Valdecilla (HUMV) ES Spain (ES)

How to cite


Dietz, J., Di Maio, V.C., de Salazar, A., Merino, D., Vermehren, J., Paolucci, S.,... Siebler, J. (2021). Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy. Journal of Hepatology.


Dietz, Julia, et al. "Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy." Journal of Hepatology (2021).

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