Eltrombopag increases platelet numbers in thrombocytopenic patients with hcv infection and cirrhosis, allowing for effective antiviral therapy

Nezam H. Afdhal, Geoffrey M. Dusheiko, Edoardo G. Giannini, Pei Jer Chen, Kwang Hyub Han, Aftab Mohsin, Maribel Rodriguez-Torres, Sorin Rugina, Igor Bakulin, Eric Lawitz, Mitchell L. Shiffman, Ghias Un Nabi Tayyab, Fred Poordad, Yasser Mostafa Kamel, Andres Brainsky, James Geib, Sandra Y. Vasey, Rita Patwardhan, Fiona M. Campbell, Dickens Theodore

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Abstract

Background & Aims Thrombocytopenia 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. Methods Patients with HCV infection and thrombocytopenia (platelet count <75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy. Results More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P =.0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P =.0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2. Conclusions Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Original languageEnglish
Pages (from-to)442-452.e1
JournalGastroenterology
Volume146
Issue number2
DOIs
Publication statusPublished - 2014 Feb

Bibliographical note

Funding Information:
Conflicts of interest The authors disclose the following: Nezam Afdhal has received research support from Abbott Laboratories, Echosens, Gilead/Pharmasset, GlaxoSmithKline, Novartis, Quest, Merck/Schering-Plough, and Vertex; he provided consultancy and participated in advisory boards for Boehringer Ingelheim, Echosens, Gilead/Pharmasset, GlaxoSmithKline, Ligand, Medgenics, Novartis, Springbank, and Vertex; and holds equity ownership in Medgenics and Springbank. Geoffrey Dusheiko's institution received grant funding from GlaxoSmithKline, Merck/Schering-Plough, and Hoffman-LaRoche, and Geoffrey Dusheiko has received payment for provision of writing assistance, medicines, equipment, or administrative support from GlaxoSmithKline; received fees for participation in review activities such as data monitoring boards, statistical analysis, and end point committees from GlaxoSmithKline and Merck/Schering-Plough; has received consulting fees/honorarium from GlaxoSmithKline, Merck/Schering-Plough, and Hoffman-LaRoche; holds board membership and provided consultancy to GlaxoSmithKline, Merck/Schering-Plough, and Hoffman-LaRoche; and has received payment for lectures including service on speakers bureaus from GlaxoSmithKline and Merck/Schering-Plough. Edoardo Giannini has received support for travel to meetings from GlaxoSmithKline; holds board membership with GlaxoSmithKline; has provided consultancy for GlaxoSmithKline, Hoffman-LaRoche, and Merck/Schering-Plough; has provided expert testimony for and has received grants/has grants pending with GlaxoSmithKline; has participated in lectures for GlaxoSmithKline, Hoffman-LaRoche, and Merck/Schering-Plough; and has received reimbursement for travel, accommodations, or meeting expenses unrelated to activities listed from GlaxoSmithKline, Hoffman-LaRoche, and Merck/Schering-Plough. Pei-Jer Chen has received grants from Bristol Myers Squibb, Johnson & Johnson, and Hoffman-LaRoche; consulting fees/honoraria from Bayer, Bristol Myers Squibb, Merck/Schering-Plough Sharp & Dohme, Hoffman-LaRoche, and Taiha; travel support from Bristol Myers Squibb and Medigen; fees for participation in data monitoring boards, statistical analysis, end point committees, and the like from GlaxoSmithKline; paid for board membership or consultancy by Bristol Myers Squibb, Merck/Schering-Plough Sharp & Dohme, and Hoffman-LaRoche Taiwan; and has received payment from Bayer, Bristol Myers Squibb, and Bristol Myers Squibb China for lectures. Kwang–Hyub Han and Maribel Rodriguez–Torres's institutions received a grant from GlaxoSmithKline associated with this work; Maribel Rodriguez–Torres also has received payment for consultancy from Akros Pharmaceuticals, Bristol Myers Squibb, Genentech, Inhibitex, Janssen R&D Ireland, Pharmasset, Hoffman-LaRoche, Santaris Pharma A/S, and Vertex; and has grants/grants pending from Abbott, Akros Pharmaceuticals, Anadys Pharmaceuticals, Beckman Coulter, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, Gilead/Pharmasset, Human Genome Sciences, Idenix Pharmaceuticals, Idera Pharmaceuticals, Ihibitex, Johnson & Johnson, Merck/Schering-Plough Sharp & Dohme, Mochida Pharmaceuticals, Novartis, Pfizer, Pharmasset, Hoffman-LaRoche, Santaris Pharma, Scynexis, Inc, Siemens Healthcare Diagnostics, Vertex Pharmaceuticals, and ZymoGenetics. Eric Lawitz also has received consultant fees from Abbott, Achillion Pharmaceuticals (Achillion), Biolex Therapeutics, BioCryst, Biotica, Enanta Pharmaceuticals, Inc, GlobeImmune, GlaxoSmithKline, Idenix Pharmaceuticals, Inhibitex Pharmaceuticals, Janssen, Merck/Schering-Plough, Novartis, Pharmasset, Santaris Pharmaceuticals, Tibotec, Theravance, Inc, and Vertex Pharmaceuticals. Eric Lawitz's institution has grants/grants pending with Abbott, Achillion, Biolex Therapeutics, Bristol Myers Squibb, Boehringer Ingelheim, Gilead/Pharmasset, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck/Schering-Plough, Novartis, Pharmasset, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ViroChem Pharma, and ZymoGenetics; and payment for lectures from Gilead/Pharmasset, Merck/Schering-Plough, and Vertex. Mitchell Shiffman has received consultant fees/honorarium from Bristol Myers Squibb, Gilead/Pharmasset, GlaxoSmithKline, Janssen, Merck/Schering-Plough, and Vertex; and lecture and speaker fees from Genentech, Merck/Schering-Plough, and Vertex; his institution has received a grant from McGuire Research Institute and has grants pending from Abbott, Bristol Myers Squibb, Gilead/Pharmasset, and Merck/Schering-Plough. Fred Poordad has been included on the advisory committee/review panels for Achillion, Genentech, Gilead/Pharmasset, Merck/Schering-Plough, Onyx, Salix, and Vertex; has received grants from Abbott, Bristol Myers Squibb, Gilead/Pharmasset, Human Genome Sciences, Idenix Pharmaceuticals, Novartis, Onyx, Pfizer, Hoffman-LaRoche, Salix, Schering-Plough, ZymoGenetics, Valeant, and Vertex; and has been a speaker for Genentech, Gilead/Pharmasset, Merck/Schering-Plough, Onyx, and Salix; Yasser Mostafa Kamel, Sandra Vasey, Fiona Campbell, Rita Patwardhan, James Geib, and Dickens Theodore are employees of GlaxoSmithKline. Dickens Theodore has patents pending. Andres Brainsky was an employee of GlaxoSmithKline at the time of this study. The remaining authors disclose no conflicts.

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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