Direct-acting antivirals sofosbuvir and daclatasvir attenuate carbon tetrachloride-induced liver fibrosis in mice

Background and aim

Advanced liver fibrosis is a major risk for developing hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) patients. Direct-acting antivirals (DAAs) which are used for treating HCV infection, produce more than 90% cure rate but do not seem to diminish the rate of occurrence or recurrence of HCC. This study aimed to investigate the effect of DAAs sofosbuvir (SOF) and daclatasvir (DAC) on carbon tetrachloride (CCl₄)-induced fibrotic changes in mice.

Methods

Eighty adult male Swiss albino mice were randomly allocated into 8 groups (10 mice/group): normal control group, SOF group (receiving SOF 80 mg/kg body weight (BW), oral gavage, daily), DAC group (receiving DAC 30 mg/kg BW, oral gavage, daily), SOF + DAC group (receiving a combination of both, daily), CCl4 model group (receiving CCl₄ 2 mL/kg BW, intraperitoneal twice weekly) and three CCl₄-intoxicated groups receiving either SOF or DAC or their combination. All CCl₄ groups received CCl₄ for 12 weeks followed by DAAs for another 12 weeks.

Results

CCl₄-induced a significant elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and produced histopathological evidence of fibrosis and liver degeneration along with a significant increase (P ≤ 0.001) of the proliferation markers (proliferating cell nuclear antigen (PCNA) and Ki-67), hepatic stellate cells (HSCs) activation markers (alpha-smooth muscle actin (α-SMA) and glial fibrillary acidic protein (GFAP)), fibrosis marker (matrix metalloproteinase-9 (MMP-9)) and pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α)). CCl₄-intoxicated mice treated with SOF, DAC, or their combination revealed a significant amelioration (P ≤ 0.001) of CCl₄-induced elevation of liver enzymes, fibrotic changes, and liver degeneration along with a significant attenuation (P ≤ 0.001) of CCl₄-induced upregulation of all tested markers. The effects of SOF, DAC, and their combination on liver enzymes were comparable while the effect of SOF + DAC combination on mitigating CCl₄-induced upregulation of the proliferation and HSCs activation markers was significantly stronger than either SOF or DAC alone. As for MMP-9 and TNF-α, the effects of DAC and SOF + DAC combination were comparable and both were more significant than that of SOF alone.

Conclusions

SOF and DAC may possess an antifibrotic effect that is independent of their role as antiviral agents against CCl₄-induced liver injury. This might exclude the role of DAAs in early occurrence or accelerated recurrence of HCC through the progression of the HCV patients' pre-existing fibrosis. However, HCC patients treated with DAAs should be closely monitored with continuous HCC surveillance during and post-therapy.