Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment

Kozbial, K; Moser, Stephan; Schwarzer, R; Laferl, Hermann; Al‐Zoairy, Ramona; Stauber, Rudolf; Stättermayer, Albert Friedrich; Beinhardt, Sandra; Graziadei, Ivo; Freissmuth, C; Maieron, A; Gschwantler, Michael; Straßer, Michael; Peck-Radosalvjevic, Markus; Trauner, Michael; Hofer, Harald; Ferenci, Péter

doi:10.1016/j.jhep.2016.06.009

Cited by 211 publications

(213 citation statements)

References 16 publications

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“…This hypothesis is supported by reports of increased hepatocellular carcinoma recurrence in patients after interferon-free direct antiviral therapy [19,20,21,22], which is thought to occur from the mechanism exposed above. Nonetheless, studies on this matter are conflicting and still under debate.…”

Section: Discussionsupporting

confidence: 56%

Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy

Andrade¹,

Paz²,

Nassar³

et al. 2018

Acta Haematol

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Introduction: Hepatitis C infection is highly prevalent worldwide and has a well-known association with B-cell lymphoid malignancies. Antiviral therapy has successfully decreased the rate of liver cirrhosis and improved the outcome in patients with hepatitis C-associated lymphomas. However, although there are a few case reports of aggressive lymphomas after successful hepatitis C therapy, the mechanism behind this association remains unclear. Case Presentation: We present the case of a 55-year-old man with chronic hepatitis C infection and liver cirrhosis who received antiviral therapy with sofosbuvir and ribavirin and achieved a sustained complete virological response. One year after successful therapy, there was an unexplained decline of his liver function and atypical liver nodularity, which led to the diagnosis of a primary liver diffuse large B-cell lymphoma. Discussion: We review the evidence supporting possible mechanisms of lymphomagenesis after successful hepatitis C therapy, particularly involving late “second-hit” mutations after viral-induced DNA damage and antiviral therapy facilitating the emergence of latent malignant B-cell clones by decreasing local inflammation and immune surveillance. More reports may help elucidate any association between hepatitis C antiviral therapy and late lymphoid malignancies.

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Section: Discussionsupporting

confidence: 56%

Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy

Andrade¹,

Paz²,

Nassar³

et al. 2018

Acta Haematol

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“…Particularly worrying was the fact that patients who developed HCC after DAAs were younger (median age 56 vs. 73 years) and that, among 16 recurrent cases described by Reig et al, 50% were multinodular and 20% were infiltrative or showed extra-hepatic lesions. In addition, another study observed the occurrence of HCC in advanced liver diseases after DAA administration [8]. …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…There was no significant difference in the baseline variables that could be associated with an increased risk of HCC [13]. A Letter to the Editor evidenced an incidence in the HCC rate of 6.6% [14].…”

Section: The Impact Of Ifn-free Regimens On Hcc Occurrencementioning

confidence: 91%

Hepatocellular Carcinoma Occurrence and Recurrence after Antiviral Treatment in HCV-Related Cirrhosis. Are Outcomes Different after Direct Antiviral Agents? A Review

Spârchez

Mocan²

2017

JGLD

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Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC) worldwide. In the last decades, several studies have showed a lower rate of HCC occurrence or recurrence in patients with HCV-related cirrhosis after interferon-based antiviral therapies compared to untreated controls, even without reaching viral clearance. Unfortunately, interferon regimens could only yield viral clearance in approximately half of the patients. The recent development of new all-oral regimens with direct-acting antivirals (DAAs) has radically improved the cure rate to above 90%. In respect to these findings, many would have thought that interferon-free regimens would decrease the development and recurrence of HCC. Literature data have unexpectedly reported high rates of both the occurrence and recurrence of HCC after therapy with DAAs. However, it is probably too early to express some concerns. More recent data showed that both occurrence and recurrence of HCC are decreased by the DAAs. Interferon-free therapy is definitely not without limits. Together with the initial thoughts of an increased risk of HCC, these may lead to an unwanted restricted access to interferon-free regimens in specific subpopulations. This issue should be settled as soon as possible because millions of hepatitis C patients are and will be using DAAs in the present and future. Our purpose is to review the existing literature and to offer a more precise and rational interpretation of the existing data.Key words: – – e – .Abreviations: AFP: alpha-fetoprotein; DAA: direct antiviral agent; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; HR: hazard ratio; IFN: interferon; LDV: Ledispavir; SMV: Simeprevir; SOF: Sofosbuvir; SVR: sustained virologic response.

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Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment

Cited by 211 publications

References 16 publications

Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy

Primary Liver Diffuse Large B-Cell Lymphoma following Complete Response for Hepatitis C Infection after Direct Antiviral Therapy

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

Hepatocellular Carcinoma Occurrence and Recurrence after Antiviral Treatment in HCV-Related Cirrhosis. Are Outcomes Different after Direct Antiviral Agents? A Review

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