Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy

Reig, María; Mariñó, Zoe; Perelló, Christie; Iñarrairaegui, Mercedes; Ribeiro, Andrea; Lens, Sabela; Díaz, Alba; Vilana, R.; Darnell, Anna; Varela, Marı́a; Sangro, Bruno; Calleja, José Luís; Forns, Xavier; Bruix, Jordi

doi:10.1016/j.jhep.2016.04.008

Cited by 928 publications

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“…Recent studies highlighting the possibility of an increased incidence or recurrence of liver malignancy in patients with decompensated cirrhosis who achieve viral clearance with DAA regimens has led some to question the value of treating such patients [5,6].…”

Section: Discussionmentioning

confidence: 99%

“…Worldwide, large numbers of HCV-infected patients with decompensated cirrhosis have received antiviral therapy and although sustained virological response (SVR) rates are slightly reduced compared to patients with compensated disease, over 80% of treated patients still achieve viral clearance. Early analysis of patients who responded to therapy showed associated improvements in MELD and Child Pugh scores [1] [2][3][4], although some concerns have been expressed that the rate of malignancy may not change or may, paradoxically, increase [5,6]. Previous studies of interferon-based therapies have demonstrated that HCV clearance improves liver fibrosis, even in cirrhosis [7].…”

Section: Introductionmentioning

confidence: 99%

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Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Cheung

Walker

Hudson

et al. 2016

Journal of Hepatology

368

336

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Cheung, M. C. M. et al. (2016) Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. Journal of Hepatology, 65(4), pp. 741-747. (doi:10.1016Hepatology, 65(4), pp. 741-747. (doi:10. /j.jhep.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/123893/ There was no significant difference in liver cancer incidence (10/406 (2.5%) in months 6-15 and 17/406 (4%) in months 0-6 for treated patients vs 11/261 (4%) in untreated patients).2

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Cheung

Walker

Hudson

et al. 2016

Journal of Hepatology

368

336

View full text Add to dashboard Cite

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“…However, individuals who are chronically infected but remain untreated have the highest risk of developing liver cirrhosis and HCC. Recent clinical studies show that an HCV cure using DAA‐based antiviral therapy among patients with advanced liver cirrhosis does not eliminate HCC risk 1, 2, 3. The incidence of HCC after a viral cure with a DAA‐based therapy was found to be much higher than that of the earlier findings with an interferon (IFN)‐based antiviral therapy 4.…”

Section: Introductionmentioning

confidence: 94%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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“…Several studies have reported that achievement of SVR results in the resolution of liver fibrosis6, 7 and a decreased incidence of HCC 8. However, development of HCC is sometimes seen even in patients who achieve SVR after DAA treatment, indicating the need for continuous surveillance for HCC after the eradication of HCV 9, 10, 11, 12. Several previous studies have reported that the degree of liver fibrosis is closely associated with the risk of the development of HCC in patients with chronic hepatitis C 13.…”

Section: Introductionmentioning

confidence: 99%

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

et al. 2017

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Background and AimPredictive factors for hepatocarcinogenesis following eradication of hepatitis C virus by direct‐acting antivirals (DAAs) are unknown. The aim of the study was to investigate the relationships between liver stiffness (LS) using acoustic radiation force impulse (ARFI) erastograghy and the development of hepatocellular carcinoma (HCC) in patients who achieved sustained virological response (SVR) treated with DAA.MethodsIn this prospective study, we enrolled 263 hepatitis C patients with SVR who underwent ARFI before DAA treatment. Thirty patients had previous HCC.ResultsThe median LS value according to ARFI measurements was 1.34 m/s (range: 0.67–4.35). During the follow‐up period (median: 18.1 months), development of HCC occurred in 19 patients (7.2%; HCC occurrence in 7 patients and HCC recurrence in 12 patients). By multivariate Cox regression analysis, HCC history (hazard ratio [HR]: 10.634; 95% confidence interval [CI]: 4.13–27.37; P = 0.001), older age (HR: 4.638; 95% CI: 1.63–13.61; P = 0.004) and higher total bilirubin levels (HR: 4.189; 95% CI: 1.66–10.60; P = 0.002) were independent predictors for the development of HCC, and higher LS value (≥1.73 m/s) at baseline was an independent predictor for HCC occurrence (HR: 8.350; 95% CI: 1.62–43.09; P = 0.011). The cumulative recurrence of HCC was statistically similar according to the degree of LS in patients who were previously treated for HCC.ConclusionThe LS value at baseline is useful for predicting HCC occurrence. Thus, even if SVR is achieved, patients with higher LS at baseline must be followed carefully for HCC occurrence.

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Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy

Abstract: High rate of cancer recurrence after DAA treatment in patients with prior hepatocellular carcinoma. Disruption of immune surveillance may facilitate the emergence of metastatic clones.

Cited by 928 publications

References 33 publications

Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

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