On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C

Abstract

Background and aimsInterferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs.MethodsWe conducted a clinical practice-based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN-combined protease inhibitor.ResultsWe found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92).ConclusionsOn-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs.

The benefits of hepatitis C virus cure: Every rose has thorns

“…In contrast, IFN‐based therapy possessed anti‐proliferative and immune regulatory properties, possibly creating an immune response against malignant cells. Interestingly, the decline in group D (NKG2D) activating receptor expression by natural killer cells type 2 correlated with early emergence of HCC post‐DAA therapy, suggesting that a defect in this danger‐associated sensor may play a role in reduced NK immune surveillance …”

“…The most intriguing and controversial problem after HCV cure is the therapy, suggesting that a defect in this danger-associated sensor may play a role in reduced NK immune surveillance. 25 A number of critiques of these studies were published, the most relevant of which concerned the rather poor statistical methodology. 26 Because it would be ethically unacceptable to design randomized control trials (RCTs) with an untreated control arm, a robustness estimate of the actuarial HCC recurrence rates could only be obtained by meta-analysis of untreated control arms as the benchmark reference control.…”

Hepatocellular carcinoma after direct‐acting antiviral drug treatment in patients with hepatitis C virus

“…After HCV clearance, decreased levels of inflammation may lead to reduced tumor immunosurveillance by the host and promote HCC. 30,31 Moreover, a reduction in natural killer group 2 member D, which is associated with cancer immunity, 32 and increased serum levels of vascular endothelial growth factor during the DAA treatment 33 significantly before versus after DAA treatment. 34 It is not clear whether DAA increases the malignant potential of HCC.…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…Two studies found that reduced NKG2D and ligand expression in HCC correlates with HCC recurrence and early occurrence. 340,341 MICA, which is one of the ligands for the NKG2D and their interaction, is vital for NK-cell cytotoxic effect for HCC cells. HCC sheds membranebound MICA as soluble MICA and downregulates the expression of NKG2D on the NK cell surface, explaining a mechanism of how HCC escape NK-cell mediated immune surveillance.…”