Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

Abstract

Summary Background Only few chronic hepatitis C patients treated with interferon (IFN)‐free direct acting antiviral (DAA) combinations fail to clear the virus. Most patients can be cured by retreatment with another DAA combination; however, some still fail to eradicate the virus. So far, little is known about how to best retreat these patients. In this study we summarise our real world experience of re‐retreatments. Methods One hundred and two patients who completed a DAA‐retreatment after virological failure to an IFN‐free DAA therapy and reached at least follow‐up 12 were included in this study.Twenty‐one (20.6%) of them relapsed again after retreatment (mean age 50.0 ± 10.6, 18 male, three female, GT1a:8, GT1b:4, GT1c:1, GT3a:7; GT4:1; cirrhosis:15; resistance associated substitutions [RAS]: 17/19; relapse after:SOF/SMV:2; 3D ± RBV:4; SOF/DCV ± RBV:4; SOF/LDV ± RBV:6; SOF/VEL:3; SOF/VEL/VOX:1; EBV/GZV:1).Treatment duration and addition of RBV were at the discretion of the treating physician. These 21 patients were studied in detail. Results Seventeen of the 21 patients finished a third DAA therapy: 13 achieved SVR12, three relapsed again (cirrhosis:2; SOF/VEL/RBV:GT3a; SOF/LDV/RBV:GT1a; EBV/GZV/SOF/RBV:GT1b), one was lost to follow‐up. One (GT1a, cirrhosis) achieved SVR12 after the third retherapy with 24 weeks of 3D/SOF/RBV, and one (GT3a, cirrhosis) achieved SVR4 after 24 weeks of glecaprevir/pibrentasvir, but died shortly thereafter. Overall, 95 (93.1%) of 102 patients achieved SVR12 after one or more retreatments. Sex, cirrhosis, genotype, RAS or baseline viral load were not associated with retreatment failure. Conclusion Most patients with failure to a DAA therapy achieved SVR after retreatment with a different regimen; however, 13.7% of patients required multiple retreatments.

Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non‐target sites, for DAA‐based treatment and retreatment outcome

“…A similar finding has been reported, where patients were retreated after initial DAA failure. In one study, two patients required four DAA treatments in total to obtain SVR and a single patient still relapsed after the 4th treatment 45 . At present, systematic resistance testing before first‐line therapy is not recommended, since it will limit the access to care due to no standardized assay available.…”

“…In one study, two patients required four DAA treatments in total to obtain SVR and a single patient still relapsed after the 4th treatment. 45…”

Characterization of multi-DAA resistance using a novel hepatitis C virus genotype 3a infectious culture system

“…However, treatment failure after repeated courses of DAAs has already been reported, even after re-treatment with SOF/VEL/VOX. [34] Similarly to previous culture studies, [21] repeated NS5A-inhibitor treatment of viral variants with pre-existent NS5A-RASs led to very high VEL and PIB resistance. Hence, repeated unsuccessful treatment attempts in patients could lead to the emergence of highly NS5A-inhibitorresistant variants, which could decrease the efficacy of currently recommended regimens (all containing NS5A inhibitors) and also make re-treatment difficult.…”

Prophylaxe, Diagnostik und Therapie der Hepatitis-C-Virus(HCV)-Infektion

“…Eine Wiederholung des eingesetzten DAA-Therapieregimes ohne Beachtung von viralen Resistenzen ist nicht zu empfehlen [98,99]…”