Nezam H Afdhal1, Geoffrey M Dusheiko2, Edoardo G Giannini3, Pei-Jer Chen4, Kwang-Hyub Han5, Aftab Mohsin6, Maribel Rodriguez-Torres7, Sorin Rugina8, Igor Bakulin9, Eric Lawitz10, Mitchell L Shiffman11, Ghias-Un-Nabi Tayyab12, Fred Poordad10, Yasser Mostafa Kamel13, Andres Brainsky14, James Geib14, Sandra Y Vasey14, Rita Patwardhan14, Fiona M Campbell13, Dickens Theodore15. 1. Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. Electronic address: nafdhal@bidmc.harvard.edu. 2. University College London Medical School, London, United Kingdom. 3. University of Genoa, Genoa, Italy. 4. National Taiwan University Hospital, Taipei, Taiwan. 5. Severance Hospital, Seoul, Korea. 6. Services Institute of Medical Sciences, Lahore, Pakistan. 7. Fundacion de Investigacion, San Juan, Puerto Rico. 8. Spitalul Clinic de BoliInfectioase, Constanta, Romania. 9. Central Scientific Research Institution of Gastroenterology of the Moscow Health Department, Moscow, Russia. 10. The Texas Liver Institute/University of Texas Health Science Center, San Antonio, Texas. 11. Liver Institute of Virginia, Richmond, Virginia. 12. Post Graduate Medical Institute, Lahore, Pakistan. 13. GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom. 14. GlaxoSmithKline, Collegeville, Pennsylvania. 15. GlaxoSmithKline, Research Triangle Park, North Carolina.
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.
RCT Entities:
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 thrombocytopenicpatients 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.
Authors: J A Mira; K Neukam; L F López-Cortés; A Rivero-Juárez; F Téllez; J A Girón-González; I de los Santos-Gil; G Ojeda-Burgos; D Merino; M J Ríos-Villegas; A Collado; A Torres-Cornejo; J Macías; A Rivero; M Pérez-Pérez; J A Pineda Journal: Eur J Clin Microbiol Infect Dis Date: 2015-06-27 Impact factor: 3.267