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ZusammenfassungDie antivirale Erstlinientherapie mit direkt antiviral wirkenden Medikamenten (DAA) bei Patienten mit chronischer Hepatitis-C-Virus-Infektion (HCV) führt in >90% der Fälle zu einer Ausheilung der Erkrankung. Selbst nach Versagen der Erstlinientherapie gibt es eine etablierte und gut wirksame Behandlungsoption mit Sofosbuvir + Velpatasvir + Voxilaprevir (SOF/VEL/VOX). Allerdings gibt es einige Patienten, die selbst nach einer zweiten antiviralen Therapie keine Ausheilung erreichen. Oftmals gibt es Faktoren wie das Vorliegen einer Leberzirrhose oder einer Virusvariante, die mit einem Therapieversagen assoziiert sind. Zurzeit empfehlen europäische und amerikanische Leitlinien den Einsatz von SOF in Kombination mit Glecaprevir/Pibrentasvir (G/P) + Ribavirin (RBV) als Reservetherapie. Jedoch gibt es derzeit nur unzureichende Evidenz, um die Wirksamkeit bei diesen schwer zu behandelnden Patienten zu bestätigen. Im Folgenden wird über 2 Patienten mit HCV-Infektion (Genotyp 3 mit Y93H-Variante) und Leberzirrhose berichtet, bei denen mit einer Kombination von SOF + G/P ± RBV eine dauerhafte HCV-Ausheilung erzielt werden konnte. Bei einem Patienten lag zum Zeitpunkt des Therapiestarts bereits eine Child-B-Zirrhose vor, es kam zu keinerlei schweren Nebenwirkungen. Diese Daten unterstützen also einen Einsatz von SOF + G/P ± RBV bei Patienten mit Re-Therapieversagen nach SOF/VEL/VOX-Therapie.

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 17/21 (81%) 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 (81%).