Abstract

Afdhal et al found that eltrombopag increased platelet count in thrombocytopenic (<75,000/ μL) patients with chronic HCV infection and advanced fibrosis and cirrhosis.1Afdhal N.H. et al.Gastroenterology. 2014; 146: 442-452Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar By using eltrombopag they achieved increased rates of sustained virological response (SVR) in patients that would otherwise be ineligible to begin or maintain antiviral therapy. Both ENABLE-1 and ENABLE-2 are well designed trials and the results seem encouraging; yet, several aspects do require some attention. Both trials had an initiation phase using eltrombopag to increase platelet count above the threshold for treatment initiation (ENABLE-1: 90 × 109/L, using pegylated interferon α [PegIFN]-2a and ENABLE-2: 100 × 109/L, using PegIFN-2b). Afterwards patients were randomized to eltrombopag or placebo during the whole course of antiviral treatment. As the authors acknowledge in the discussion, the placebo group is not representative for the real-life setting since the investigators were instructed to follow the current local product labels for dose reductions and discontinuations. In many centers, treating physicians are applying less strict rules when dose reductions or discontinuations are considered. Data on the efficacy in such centers is needed, in order to be able to assess the incremental benefit of eltrombopag on SVR rates. Moreover, no discrimination is made between the reasons for the PegIFN induced dose reductions. In the light of eltrombopag, only the avoidance of dose reductions due to thrombocytopenia seems essential. The risk of bleeding during PegIFN induced thrombocytopenia has never been fully elucidated. We previously showed that the risk of bleeding during PegIFN and ribavirin treatment is associated with cirrhosis and a platelet count below 50 × 109/L. However, these bleedings were mild and mostly not clinically relevant.2Roomer R. et al.J Hepatol. 2010; 53: 455-459Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar One could therefore question whether, with eltrombopag, we are not merely treating the physician's fear for bleeding than a real clinical problem. Even in a large cohort of 546 patients with advanced hepatic fibrosis, we found that the risk of bleeding is generally mild during treatment with interferon-based regimens, also among patients with interferon-induced thrombocytopenia.3Maan R. et al.J Hepatol. 2014 Apr 26; (Epub ahead of print)PubMed Google Scholar Regarding side-effects, the safety of eltrombopag remains a concern, as the rates of hepatic decompensation and thromboembolic events were significantly higher in the group receiving eltrombopag. This is in line with a previous study of eltrombopag.4Afdhal N.H. et al.N Engl J Med. 2012; 367: 716-724Crossref PubMed Scopus (226) Google Scholar Moreover, by allowing patients with severe thrombocytopenia to undergo antiviral treatment, the risk of hepatic decompensation is considerably increased, as Hezode et al showed in a cohort of cirrhotic patients treated with triple therapy.5Hezode C. et al.J Hepatol. 2013; 59: 434-441Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar Especially when the full dose of PegIFN is maintained, this risk is substantial. This also raises the question whether we will be able to safely use eltrombopag in patients undergoing triple therapy. In our opinion, eltrombopag is a potent agent for treating thrombocytopenia, thereby allowing antiviral treatment. However, more data are needed to determine whether the side effects outweigh the benefit on SVR rates and bleeding risk of thrombocytopenic patients during triple therapy. Eltrombopag Increases Platelet Numbers in Thrombocytopenic Patients With HCV Infection and Cirrhosis, Allowing for Effective Antiviral TherapyGastroenterologyVol. 146Issue 2PreviewThrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV. Full-Text PDF ReplyGastroenterologyVol. 147Issue 1PreviewWe read with interest the 3 letters in response to our article on the use of eltrombopag in cirrhotic patients with portal hypertension undergoing pegylated interferon and ribavirin therapy.1 This population with thrombocytopenia represents a very difficult to treat group where there is a clear benefit of SVR but also a significant risk of worsening liver disease with decompensation, infections and even death.2 The SVR rates were significantly increased by eltrombopag and while they are lower than previous small reports suggest, we submit that our trial, which is not only the largest performed in thrombocytopenic patients, but is also a global randomized trial, is more likely to reflect the true SVR rate when compared to what is essentially the retrospective case series suggested by Dr Ji and colleagues in their letter. Full-Text PDF

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