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We read with great interest the publication in Gut by Himmelsbach et al1 in which they assessed whether the modulation of c-Raf by sorafenib affects hepatitis C virus (HCV) replication using the in vitro replicon system. The authors showed that sorafenib blocks HCV replication in vitro, by decreasing c-Raf phosphorylation and by affecting the post-translational processing of NS5A, which is required for the replication of the virus. We would like to report here a clinical observation that could suggest the clinical potential interest of kinase pathway inhibitors as a therapeutic option in chronic hepatitis C.
Erlotinib is a highly selective kinase inhibitor targeting epidermal growth factor receptor (EGFR), the signalling pathway of which includes the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular-related-signal kinase (ERK) pathway. Erlotinib has been approved in non-small cell lung cancer, and a phase II clinical trial has shown modest benefit in hepatocellular carcinoma treatment.2
A 40-year-old male patient was diagnosed with cirrhosis secondary to chronic genotype 1 hepatitis C infection and excessive alcohol intake. Alcohol consumption was stopped. A first treatment with α-interferon alone had to be interrupted because of thrombopenia. Seven years later, treatment with ribavirin and α-interferon was resumed for 8 months with initial decrease in viraemia, but haematological side effects required dose reduction, which led to a viraemia breakthrough and treatment cessation. Aged 50, the patient had liver transplantation performed for hepatocellular carcinoma. The immunosuppressive regimen included tacrolimus, corticoids and mycophenolate mofetil. One year later, liver biopsy showed significant fibrosis (Metavir A2F2) and high hepatitis C viral load (5log IU/ml). Tacrolimus was switched to ciclosporin, and treatment with α2a-interferon (180 μg/week), ribavirin (800 mg/day), epoietin α (300 μg/week) and lenograstim (34 MIU/week) was initiated. After 3 months of treatment (M3) HCV RNA was still high (6.67log IU/ml), and ribavirin was decreased to 400 mg/day because of anaemia (haemoglobin 7.2 g/dl). At M8, interferon was reduced (90 μg/week) because of severe fatigue and ribavirin was further reduced (200 mg/day) at M9 because of persistent anaemia. At M12, viral load was still decreasing (3.93log IU/ml) and reached undetectability at M13 and M17 using Cobas Amplicor Roche (lower limit of detection: 50 IU/ml; Roche Diagnostics, Meylan, France). Treatment was thus maintained. At M20, the patient was diagnosed with metastatic extrahepatic hepatocellular carcinoma. At this time, the HCV treatment was stopped leading to rapid HCV RNA recurrence demonstrated by HCV RNA = 5log IU/ml 8 weeks later. Erlotinib 150 mg daily was started at M23 and ciclosporin was stopped. Surprisingly, the introduction of this new compound was followed by a rapid disappearance of serum HCV RNA 13 weeks later, which remained negative on monthly controls until the death of the patient at M35. The evolution of clinical and virological features is illustrated in figure 1.
Hepatitis C recurrence after liver transplantation is a hard-to-treat condition with poor tolerance and low sustained virological response rate.3 In the present report, interferon/ribavirin treatment allowed delayed virological response but with rapid relapse after treatment discontinuation. Introduction of erlotinib, without any other concomitant antiviral therapy, was followed by rapid and sustained negativation of HCV RNA. Albeit the observation of this single case precludes any conclusion about the usefulness of erlotinib in HCV treatment, it suggests, in regard to the in vitro study presented by Himmelsbach et al,1 the possible relevance of kinase inhibitors in this situation. It is of major interest to note that in the SHARP trial,4 which led to approval of sorafenib for hepatocellular carcinoma treatment, one-third of patients were HCV carriers and were distributed evenly between the placebo and sorafenib arm. Data about HCV status during treatment, if available, could thus give useful information about kinase inhibitors in HCV treatment.
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