HCC, Cirrhosis, HCV Genotype Negatively Impact Response to Salvage Therapy


Retreatment with voxilaprevir/velpatasvir/sofosbuvir in patients with HCV and prior DAA failure is effective but may be impacted by hepatocellular carcinoma, cirrhosis, and genotype 3.

Christoph Sarrazin, MD | Credit: St. Josef's Hospital Wiesbaden

Christoph Sarrazin, MD

Credit: St. Josef's Hospital Wiesbaden

Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is an effective salvage therapy for patients with chronic hepatitis C virus (HCV) infection and prior direct-acting antiviral (DAA) failure, although findings from a recent study are highlighting several negative predictors of treatment response potentially hindering its efficacy in certain patient populations.1

The multicenter cohort study included 746 patients from Germany, Austria, Switzerland, Belgium, Italy, and Spain, showing an overall per protocol sustained virologic response (SVR) rate of 95% with VOX/VEL/SOF and further identifying hepatocellular carcinoma (HCC) onset, cirrhosis, and HCV genotype 3 as independent negative predictors of treatment response.1

“Representative data on the effectiveness of VOX/VEL/SOF in clinical practice are still scarce and the collection of a larger number of patients with difficult-to-treat cofactors including the assessment of resistance-associated substitution profiles is required before more specific recommendations for optimal re-treatment in these patients can be given,” wrote Christoph Sarrazin, MD, professor of medicine at JW Goethe University Hospital in Germany, and colleagues.1

According to the World Health Organization, DAAs are estimated to be able to cure more than 95% of the 58 million global HCV cases. Despite high SVR rates following DAA treatment in both clinical trials and real-world studies, many patients still fail treatment and require alternative options. Understanding negative factors influencing treatment failure and potentially hindering the effectiveness of retreatment is essential in order to provide adequate care to difficult-to-treat patient populations.1,2

To assess treatment effectiveness and predictors of virologic response to VOX/VEL/SOF, investigators performed an integrative analysis of 3 large multicenter, real-life cohorts of representative subgroups with difficult-to-treat and virologic failure patients. In total, 746 patients with chronic hepatitis C who had previously failed combined treatment with an interferon (IFN)-free regimen were included in the study.1

Investigators noted due to the differing availability of information on baseline characteristics, medians, ranges and percentages of each variable refer to the corresponding available data from each center. Among the cohort, the median age was 56 (16-88) years and 573 were male. At baseline, the median HCV RNA was 6.03 (1.8-7.9) log IU/ml and median alanine transaminase (ALT) values were 55 (10-538) U/L.1

All patients had previously received a DAA-based IFN-free regimen, the most common of which was ledipasvir/sofosbuvir (LDV/SOF; 29%), followed by velpatasvir/sofosbuvir (VEL/SOF; 17%), daclatasvir/sofosbuvir (15%), dasabuvir/ombitasvir/paritaprevir (15%) and elbasvir/grazoprevir (12%). Additionally, 96% of patients had failed an NS5A- and 37% an NS3/4A-containing regimen.1

By intention-to-treat analysis, 683 (92%) patients who commenced on VOX/VEL/SOF achieved SVR12. Among 746 patients retreated with VOX/VEL/SOF, 716 patients had available outcomes 12 weeks after the end of treatment and the per protocol SVR12 rate was 95%.1

Upon analysis, treatment effectiveness was significantly affected by elevated baseline ALT values (P = .02) and by HCV genotype (P = .001). Additionally, liver fibrosis (P = .001), cirrhosis (P <.001), and HCC (P <.001) were significantly associated with reduced SVR rates. Investigators noted there were no significant differences in SVR rates based on sex (P = .53), baseline HCV RNA (P = .59), RBV use (P = 1.00), baseline resistance-associated substitutions (P = .78), and liver transplant status (P = .08).1

They also pointed out response rates were significantly lower in patients previously failing VEL/SOF (SVR12, 90%; P = 0.01), while SVR12 rates were SVR rates of patients exposed to other previous DAA regimens were 92% in patients previously treated with daclatasvir/sofosbuvir, 98% in patients treated with LDV/SOF, and 100% in patients failing simeprevir/SOF.1

Patients with genotype 3 had significantly lower SVR rates (91%, P <.001) while treatment effectiveness was substantially greater in patients with genotype 1. HCC onset during or after retreatment with VOX/VEL/SOF was also significantly associated with a lack of SVR (79% vs 97%; P <.001), although investigators pointed out previous HCC history did not impact treatment effectiveness of VOX/VEL/SOF (P = .39).1

Despite the high prevalence of resistance-associated substitutions prior to re-treatment, treatment outcome was not significantly associated with the presence of resistance-associated substitutions. Additionally, neither the number of NS5A resistance-associated substitutions nor the presence of clinically relevant and major NS5A variants affected treatment outcomes on VOX/VEL/SOF.1

Further analysis revealed HCC onset during or after re-treatment with VOX/VEL/SOF (P = .002), cirrhosis (P = .02), and HCV genotype 3 (P = .004) had the greatest effect on SVR and were the only independent predictive factors of treatment failure.1

“Our study reports excellent effectiveness of VOX/VEL/SOF in a large cohort of patients with HCV and prior DAA failure treated in a European real-life setting,” investigators concluded.1 “HCV GT3, HCC and cirrhosis were identified as the only independent negative predictive factors of a SVR12 following treatment with VOX/VEL/SOF.”


  1. Graf C, D’Ambrosio R, Degasperi E, et al. Real-world effectiveness of voxilaprevir/velpatasvir/sofosbuvir in patients following DAA failure. J Hep Reports. https://doi.org/10.1016/j.jhepr.2023.100994
  2. World Health Organization. Hepatitis C. Newsroom. July 18, 2023. Accessed February 20, 2024. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
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