DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment

Abstract

BackgroundNovel direct-acting antivirals (DAAs) have completely changed the panorama of hepatitis C due to their high efficacy and optimal safety profile. Unfortunately, an unexpectedly high rate of early recurrence of hepatocellular carcinoma has been reported within weeks of starting treatment, but the mechanism is not known.MethodsWe monitored the serum level of vascular endothelial growth factor (VEGF) and changes in the pattern of circulating interleukins in 103 chronic hepatitis C patients during antiviral treatment with DAA-regimens. VEGF, epidermal growth factor (EGF), and several interleukins were assessed at baseline, during treatment, and after treatment. The biological effect of DAA-treated patient serum on human umbilical vein endothelial cell (HUVEC) proliferation was also confirmed.ResultsAfter 4 weeks of therapy, VEGF increased approximately 4-fold compared to baseline, remained elevated up to the end of treatment, and returned to the pre-treatment level after the end of therapy. In contrast, interleukin-10 and tumor necrosis factor-alpha significantly decreased during therapy, which was coincident with HCV clearance. The levels of both remained low after treatment. The addition of serum from patients collected during therapy induced HUVEC proliferation; however, this disappeared after the end of therapy.ConclusionsDAA administration induces an early increase in serum VEGF and a change in the inflammatory pattern, coinciding with HCV clearance. This may alter the balance between inflammatory and anti-inflammatory processes and modify the antitumor surveillance of the host. Fortunately, such modifications return reverse to normal after the end of treatment.

Liver Angiopoietin‐2 Is a Key Predictor of D e N ovo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct‐Acting Antivirals

“…From this perspective, DAAs might play a minor role through their demonstrated capacity to increase VEGF levels during treatment . The data from patients with cirrhosis enrolled in the prospective study of HCC development indicate that DAAs are capable of significantly favoring HCC onset, given that DAA use was independently related to HCC occurrence in regression analysis.…”

Oral direct-acting antivirals and the incidence or recurrence of hepatocellular carcinoma: a systematic review and meta-analysis

“…Alterations in immunosurveillance that remove the protective effect of the HCV may potentiate the risk of HCC by accelerating the process of regeneration. Studies have shown an increase in the levels of vascular endothelial growth factor after 4 weeks of therapy with oral DAA therapy and alterations in balance between inflammatory and anti-inflammatory processes 52. Additionally, it is possible that the immunostimulatory effects of IFN may have offered some protection in earlier studies.…”

Hepatocellular carcinoma in the setting of Interferon-free treatment for chronic HCV hepatitis - experience of a single center

“…This way, the protective effect of the inflammatory mechanisms is lost and liver regeneration as well as carcinogenesis may appear [22] . There is also evidence showing an elevated level of vascular endothelial growth factor after the initiation of IFN-free treatment [23] .…”