Treatment-failure to direct antiviral HCV regimens in real world: frequency, patient characteristics and rescue therapy – data from the German hepatitis C registry (DHC-R)

Abstract

Background Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. Patients and methods Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. Results Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p < 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p < 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). Conclusions Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective.

Are There Still Difficult-to-Treat Patients with Chronic Hepatitis C in the Era of Direct-Acting Antivirals?

“…Another unfavorable factor that reduced the chance of successful treatment, confirmed by the current study, was the history of previous therapy. The unsatisfactory effectiveness of 77% was achieved, especially in the group of DAA-experienced patients, and our findings on the worst therapeutic response in this subpopulation are consistent with other reports [44][45][46].…”

“…At the same time, non-cirrhotic individuals were still treated with IFN-based therapies achieving a higher response rate. Despite the increased effectiveness of therapy after the introduction of highly potent pangenotypic drugs, the cure rate in GT3 infected patients is still inferior compared to other genotypes, and the difference is more pronounced in the presence of other factors, such as liver cirrhosis and history of previous therapy, and it was also confirmed by our study [46,57,58].…”

Real‐world re‐treatment outcomes of direct‐acting antiviral therapy failure in patients with chronic hepatitis C

“…The various factors, which may result in the failure of DAA therapy, are not exactly known 4,5 . Resistance associated substitution (RAS) in the HCV genome, which confer resistance to some DAA, may be present at baseline or get selected in those with therapy failure 6 .…”

“…The various factors, which may result in the failure of DAA therapy, are not exactly known. 4,5 Resistance associated substitution (RAS) in the HCV genome, which confer resistance to some DAA, may be present at baseline or get selected in those with therapy failure. 6 RAS are clinically significant when they are present in the NS5A position for genotypes 1a and 3 and constitute > 15% of the viral population to have a negative impact on virus clearance.…”

Is it time for China to prioritize pan-genotypic regimens for treating patients with hepatitis C?

“…Key assumptions in the decision tree model structure were that, first, for patients who must choose treatment based on the genotyping test results, we hypothesized that 5.8% of patients would be lost due to the absence of genotyping facility or other reasons [ 8 , 26 , 27 ]. Second, 75% of patients who failed initial treatment were assumed to continue treatment with the SOF/VEL/VOX regimen, while those who failed second-line treatment were no longer receiving antiviral therapy [ 28 – 30 ]. Third, due to the short treatment time and efficacy of direct antiviral therapy, which needed only oral medication, we assumed 100% compliance with treatment and patients would not reinfect and relapse after obtaining SVR.…”