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Does Eltrombopag Really ENABLE SVR? Editorial
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Download the PDF here
February 2014
See "Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy," by Afdhal NH, Dusheiko GM, Giannini EG, et al, [below]
Patients with hepatitis C (HCV) cirrhosis and thrombocytopenia represent a particularly high-risk group for future liver decompensation, death, and hepatocellular carcinoma.1 These patients are among those who most desperately require therapy and cannot afford to wait for new treatment developments. However, these are also the patients for whom current therapies pose the highest risk of complications.2 Bone marrow suppression is a well-known complication of interferon treatment, with falling blood counts during therapy often leading to dose reductions, dose interruptions, and early cessation of treatment, all of which may lower the likelihood of attaining a sustained virologic response (SVR).3 Cirrhotic patients with significant thrombocytopenia are largely excluded from clinical trials of promising new therapies and therefore must rely on existing interferon-based regimens. Strategies to enhance rates of treatment initiation and completion have the potential to maximize SVR in this difficult-to-treat population.
Eltrombopag is a new oral platelet growth factor that acts as a thrombopoietin (TPO) receptor agonist, resulting in differentiation and proliferation of megakaryocytes. It acts in an additive fashion with endogenous TPO by binding and activating the TPO receptor through an alternate binding site.4Eltrombopag has been studied in patients with immune thrombocytopenia purpura, cirrhosis (from any cause), and in those undergoing interferon-based therapy for HCV. To clarify whether eltrombopag would enhance rates of SVR in patients with HCV and thrombocytopenia, the ENABLE 1 and ENABLE 2 trials (Eltrombopag to initiate and maintain interferon antiviral treatment to benefit subjects with HCV-related liver disease) were carried out in North America and Europe, the results of which are published together in this edition of Gastroenterology.5
Before the ENABLE study, McHutchison et al6 evaluated the use of eltrombopag in 74 patients with HCV-related cirrhosis and platelet counts between 20,000 and 70,000/μL. Patients were randomized to increasing doses of eltrombopag (30, 50, and 75 mg) for 4 weeks before initiation of interferon and then for 12 weeks during interferon-based therapy. Between 75% and 95% of treated patients achieved the primary endpoint of an increase in platelet count to 100,000/μL during the initiation phase. Higher rates were seen in those treated with higher doses of eltrombopag. Between 36% and 65% of patients treated with eltrombopag maintained a platelet count >50,000/μL and were able to complete 12 weeks of interferon therapy compared with only 6% in the placebo group. Interestingly, no thromboembolic events were seen in this small study.
The ENABLE 1 and ENABLE 2 studies were thus undertaken to assess the effect of eltrombopag on rates of SVR in patients with HCV cirrhosis undergoing interferon-based antiviral therapy. The studies differed only in the pegylated interferon used and the corresponding platelet threshold set for initiation of treatment. Both trials recruited patients with chronic HCV with platelet counts <75,000/μL. Before starting antiviral therapy, all patients received open-label eltrombopag during the study initiation phase. Eltrombopag was initiated at a dose of 25 mg/d and increased gradually to a maximum of 100 mg/d until platelet levels crossed the recommended thresholds for initiating interferon-based therapy according to the peginterferon product label. Only patients who responded to eltrombopag were eligible for randomization in a 2:1 ratio to eltrombopag maintenance treatment during antiviral therapy or placebo (ie, antiviral therapy alone). The primary endpoint of the study was the effect of eltrombopag on the attainment of SVR. Adverse events were recorded as safety endpoints.
The patient population consisted mainly of middle-aged Caucasian men with genotype 1 infection and Child-Pugh A cirrhosis. The median platelet count at trial enrollment was 59,000/μL. Patient characteristics, including interleukin (IL)-28B status, were similar in all groups. During the initiation phase, 96%-97% of patients achieved the required platelet levels to proceed with therapy, with 86% doing so on 25 or 50 mg of eltrombopag. Adverse events were minor and included headache, nausea, and diarrhea. During the antiviral phase of the trial, a significantly higher proportion of eltrombopag-treated patients attained SVR (ENABLE 1, 23% vs 14% [P = .0064]; ENABLE 2, 19% vs 13% [P = .02]) and the treatment effect remained consistent across HCV genotypes. Patients treated with eltrombopag required fewer peginterferon dose reductions and were maintained on full-dose peginterferon for a longer amount of time. Notably, however, portal vein thrombosis (PVT) occurred more frequently in the eltrombopag-treated patients (n = 12 for eltrombopag vs n = 2 for placebo). Rates of thromboembolic complications did not correlate with platelet count or eltrombopag dose. Hepatic decompensation, specifically ascites and hepatic encephalopathy, were also more frequently seen in the eltrombopag-treated group (10% eltrombopag vs 5% placebo).
The ENABLE study was an ambitious effort to improve SVR rates in a very difficult-to-cure population. Although the study nicely confirmed that eltrombopag has potent platelet stimulatory effects, it is difficult to determine whether the improved rates of SVR seen in the trial will translate to better outcomes in general clinical practice. Study investigators were required to lower peginterferon doses according to the product labels rather than clinical judgment. Most seasoned clinicians do not strictly adhere to the thresholds in the label because clinical experience has shown that maximizing medication exposure is important and clinically significant bleeding events with moderate degrees of thrombocytopenia are very rare.7, 8 The differences in SVR were owing to greater peginterferon exposure in the eltrombopag arms. Had investigators had the freedom to adjust the peginterferon dose, it is likely that patients in the placebo arm would have received more cumulative peginterferon, which may have improved their rates of SVR. The trial design clearly favored the eltrombopag arms. The authors acknowledge this limitation in the discussion; however, it is difficult to overstate the importance of this issue in interpreting the effect of eltrombopag on treatment outcome and the overall significance of the study.
Predicting the risk of bleeding in patients with cirrhosis is complex because end-stage liver disease reduces both procoagulant and anticoagulant factors. In cirrhosis, the cause of thrombocytopenia is multifactorial. In addition to splenic sequestration resulting from portal hypertension, coating of platelets by circulating immunoglobulins may lead to increased platelet destruction by the reticuloendothelial system.9 Platelet production may also be impaired owing to reduced levels of endogenous TPO4 and HCV-related bone marrow suppression.5 However, despite the low platelet counts seen, which can fall significantly further during interferon treatment, data suggest that clinically significant bleeding is uncommon in patients with liver disease-related thrombocytopenia. This may be partially explained by effects on platelet function. In patients with cirrhosis, platelet function may be enhanced due to a decrease in production of ADAMTS13, a plasma metalloprotease that normally limits the effect of von Willebrand factor on platelets.10 Furthermore, high levels of von Willebrand factor, a common finding in patients with cirrhosis, enhance platelet adhesion to the subendothelium at sites of vascular injury.9Other studies in patients with cirrhosis, have found that platelet counts as low as 60,000/μL are able to generate thrombin levels in the normal range.10 All of these factors enhance platelet function and may limit bleeding, even with low absolute platelet counts. Roomer et al8 recorded bleeding events in a cohort of HCV patients with and without cirrhosis treated with peginterferon and ribavirin. Although epistaxis and gingival bleeding were relatively common in patients with platelet counts of <50,000/μL, only 1 major bleeding event was recorded, which occurred at a platelet level of 65,000/μL.8 Hence, a clinically relevant platelet threshold for interferon dose reduction or cessation is not known and accurately predicting the bleeding risk of an individual patient in the office is currently very difficult. However, it is fair to say that the peginterferon product labels are relatively conservative and most clinicians would be comfortable maintaining full-dose peginterferon at platelet counts well below those recommended for dose reduction.
Even if we may be comfortable with lower platelet counts than in the product labels, there is no doubt that clinicians would sleep easier if they did not have to worry about thrombocytopenia during interferon-based therapy-but at what cost? The major concern with eltrombopag in patients with cirrhosis is the potential for an increased risk of thromboembolic complications. This was borne out in the ENABLE study with a higher number of thromboembolic events in the eltrombopag-treated group compared with those who received placebo. This phenomenon has been observed in previous studies11, 12 and is biologically plausible. Interestingly, a high absolute platelet count or high dose of eltrombopag was not correlated with thromboembolic events, making it difficult to predict who is at highest risk. A post hoc analysis of a previous study11 identified a platelet counts of >200,000/μL as a risk factor for thrombotic events. The most common thromboembolic event in the ENABLE study was PVT, which is a well-known complication of advanced cirrhosis. The prevalence of PVT in a large, retrospective, Italian study of 701 patients with cirrhosis was 11%13 and PVT occurs more frequently in those with more advanced disease.14 The effect of PVT on the natural history of cirrhosis is not entirely clear, with studies coming to varying conclusions. A large, retrospective study of 3295 patients awaiting liver transplantation found that the presence of PVT was an independent factor associated with death,15whereas a prospective study of 290 patients awaiting liver transplantation did not show a significant effect of PVT on mortality.16 The effect of PVT post liver transplantation is more evident. In a recent, large, systematic review by Rodriguez-Castro et al,17 the presence of an occlusive PVT was associated with an increased 30-day and 1-year mortality post liver transplantation. This finding may be particularly relevant in the ENABLE cohort of patients, whose advanced liver disease and poor response to treatment may necessitate a future liver transplant.
Beyond PVT, there was a higher rate of hepatic decompensation among eltrombopag-treated patients. The reasons for this are not entirely clear, because it was not directly correlated with PVT or other obvious thrombotic events. Interferon-based therapy is associated with a risk of decompensation; therefore, it is conceivable that the greater cumulative exposure to interferon pushed some patients to develop hepatic complications. This study confirmed what we already knew; interferon is relatively ineffective and potentially very dangerous in patients with advanced cirrhosis.2 We were reminded of this with the introduction of first-generation protease inhibitors, for which thrombocytopenia and low albumin have been recognized as predictors of serious complications, presumably because of greater exposure to interferon in patients who might otherwise have stopped therapy earlier owing to virologic failure.18 Another intriguing possibility is that decompensation itself may be a thrombotic complication. Recently, Villa et al19 showed that low-dose enoxaparin treatment in patients with cirrhosis reduced not only PVT but also lowered the rate of hepatic decompensation and improved survival. It has been proposed that the benefits of enoxaparin may relate to prevention of microthrombi in the intrahepatic circulation. Fortunately, the rates of decompensation with eltrombopag were low, but it is conceivable that increased platelet counts may promote microthrombosis, which may be clinically relevant in a very cirrhotic liver.
Eltrombopag has also been evaluated for other treatment indications in cirrhosis. The ELEVATE study (Eltrombopag Evaluated for Its Ability to Overcome Thrombocytopenia and Enable Procedures) assessed the short-term use of eltrombopag in patients with cirrhosis and thrombocytopenia (platelet count <50,000/mm3) who required an invasive procedure.11 The primary endpoint was avoidance of platelet transfusion, and a key secondary endpoint was the occurrence of bleeding. The study demonstrated that patients treated with eltrombopag were significantly less likely to require a platelet transfusion compared with patients receiving placebo (72% vs 19%), but the rate of bleeding was not different between the 2 groups. Thromboembolic events, predominantly PVT, were more common in the treated group (odds ratio, 3.04). The ELEVATE study again confirms the potent physiologic effect of eltrombopag on platelet production but it also demonstrates that the risk of thromboembolic events is present even after short-term use. Although no clear dose or platelet level was associated with thrombosis, if one elects to use eltrombopag, it would seem prudent to use the lowest dose possible to maintain a safe platelet level. Eltrombopag is a potentially useful tool for treating clinically relevant thrombocytopenia in patients with advanced liver disease. The ENABLE study provides further evidence that eltrombopag is effective at increasing the number of eligible patients for interferon-based therapy, as well as decreasing the number of interferon dose reductions and interruptions. However, owing to the likely difference between the very conservative study protocol and routine clinical practice for platelet count-based initiation and continuation of interferon therapy, the true effect of eltrombopag on SVR rates is uncertain. The widespread use of eltrombopag should further be tempered by the increased rates of thromboembolic events associated with its use. At present, no tools are available to accurately predict the risk of bleeding or thrombosis in an individual cirrhotic patient with thrombocytopenia or to identify in whom the benefit of eltrombopag would likely outweigh the risk. It is important to note that even with eltrombopag, the absolute rates of SVR were very low (19%-23%) and the rates of serious adverse events were high (20%) in this difficult-to-cure population. It would seem, therefore, that eltrombopag should be reserved for a carefully selected subset of patients with severe thrombocytopenia who cannot wait for new therapies and are under the care of clinicians with experience treating patients with advanced cirrhosis. If one opts to use eltrombopag, the minimum effective dose should be used. In this case, rather than a randomized, controlled trial, real-world data will ENABLE us to understand the true effect of eltrombopag on SVR, but hopefully by the time such data emerge, interferon and the need for support with eltrombopag will be a thing of the past.
Eltrombopag Increases Platelet Numbers in Thrombocytopenic Patients With HCV Infection and Cirrhosis, Allowing for Effective Antiviral Therapy
Nezam H. Afdhal,1 Geoffrey M. Dusheiko,2 Edoardo G. Giannini,3 Pei-Jer Chen,4 Kwang-Hyub Han,5 Aftab Mohsin,6 Maribel Rodriguez-Torres,7 Sorin Rugina,8 Igor Bakulin,9
Eric Lawitz,10 Mitchell L. Shiffman,11 Ghias-Un-Nabi Tayyab,12 Fred Poordad,10 Yasser Mostafa Kamel,13 Andres Brainsky,14 James Geib,14 Sandra Y. Vasey,14 Rita Patwardhan,14 Fiona M. Campbell,13 and Dickens Theodore15 1Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; 2University College London Medical School, London, United Kingdom; 3University of Genoa, Genoa, Italy; 4National Taiwan University Hospital, Taipei, Taiwan; 5Severance Hospital, Seoul, Korea; 6Services Institute of Medical Sciences, Lahore, Pakistan; 7Fundacion de Investigacion, San Juan, Puerto Rico; 8Spitalul Clinic de BoliInfectioase, Constanta, Romania; 9Central Scientific Research Institution of Gastroenterology of the Moscow Health Department, Moscow, Russia; 10The Texas Liver Institute/University of Texas Health Science Center, San Antonio, Texas; 11Liver Institute of Virginia, Richmond, Virginia; 12Post Graduate Medical Institute, Lahore, Pakistan; 13GlaxoSmithKline, Stockley Park, Uxbridge, United Kingdom; 14GlaxoSmithKline, Collegeville, Pennsylvania; 15GlaxoSmithKline, Research Triangle Park, North Carolina
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.
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.
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.
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. Thrombocytopenia (TCP) is a common complication of chronic liver disease associated with hepatitis C virus (HCV) infection and correlates with disease severity and portal hypertension.1, 2, 3 Antiviral therapy with peginterferon-α (PEG) and ribavirin (RBV) further reduces platelet counts through bone marrow suppression.4 Initiation of PEG-based antiviral therapy is recommended if platelets exceed 90,000/μL (PEG-2a) or 100,000/μL (PEG-2b), and dose reduction is recommended if platelet counts decrease to less than 50,000/μL.5, 6 PEG dose reductions, particularly during the initial weeks of treatment, diminish the likelihood of sustained virologic response (SVR).7, 8, 9
Eltrombopag (Promacta; GlaxoSmithKline, Research Triangle Park, NC) is an oral, nonpeptide, thrombopoietin receptor agonist recently approved in the United States for treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. In a phase 2 study of patients with HCV-related cirrhosis and TCP, eltrombopag 30-75 mg once daily increased platelet counts to a level sufficient to initiate PEG-based therapy in 71%-91% of patients.10
Few studies of HCV antiviral therapy have been conducted in patients with cirrhosis, TCP, and presumed portal hypertension because of the risk of aggravated TCP. The objective of the Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE) studies was to assess the ability of supportive eltrombopag therapy to increase platelets to levels sufficient to initiate and maintain PEG+RBV antiviral therapy, avoiding dose reductions/discontinuations, and potentially improving SVR rates in this population.
Patients and Methods
Design and Treatment

The ENABLE-1 (PEG-2a) and ENABLE-2 (PEG-2b) studies were designed similarly (Figure 1), differing only in the PEG used and their corresponding platelet thresholds for initiating antiviral therapy (ENABLE-1, 90,000/μL; ENABLE-2, 100,000/μL). The protocols for both studies (ClinicalTrials.gov numbers: NCT00516321 and NCT00529568) were reviewed and approved by the applicable ethics committee or institutional review boards at each center, in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice and applicable country-specific requirements. All authors had access to the study data and reviewed and approved the final manuscript. Each patient provided written informed consent before performing any study-specific procedures. The ENABLE-1 study was conducted between October 30, 2007, and March 31, 2011. ENABLE-2 was conducted between November 15, 2007, and August 23, 2011. Both studies comprised 2 parts. During the initiation phase, thrombocytopenic patients with chronic HCV received open-label eltrombopag in a dose-escalating fashion dependent on platelet response (25 mg, 50 mg, 75 mg, or 100 mg once daily) for 2-9 weeks. Patients whose platelet counts reached the predefined minimal threshold for initiating antiviral therapy were randomized 2:1 to eltrombopag or placebo in the subsequent double-blind, antiviral phase and treated for 24 or 48 weeks according to the HCV genotype. Patients receiving eltrombopag 100 mg/day for 3 weeks who failed to meet the platelet count threshold were entered into the follow-up period of the study. The trial ended when the last patient completed the last follow-up visit.
Patients successfully randomized into the antiviral phase in ENABLE-1 received PEG-2a 180 μg weekly subcutaneously and oral RBV as per the package insert; for ENABLE-2, patients received PEG-2b 1.5 μg/kg weekly subcutaneously plus oral RBV as per the package insert (Figure 1). Standardized stopping and futility rules were applied for PEG-interferon according to the American Association for the Study of Liver Diseases guidelines.11
A centralized computer-generated randomization list was generated through a validated system (RandALL) by the study sponsor, using the predefined strata (HCV genotype, baseline platelet count, and baseline HCV-RNA level). The study centers registered and randomized patients by telephone using an interactive voice response system.
Patients were stratified at randomization to the antiviral phase by HCV genotype (2/3 vs non-2/3), baseline platelet counts (<50,000 vs ≥50,000/μL), and baseline HCV-RNA level (<800,000 vs ≥800,000 IU/mL). The interactive voice response system was available 24 hours a day, 7 days a week. The patients and all study personnel were blinded to the treatment assignment.
Investigators were instructed to follow the current local product labels for PEG dose reductions and discontinuations. Eltrombopag dose was reduced if platelets exceeded 200,000/μL, and treatment was both interrupted and the dose was reduced if platelets exceeded 400,000/μL.
Patient Population
Patients were enrolled into each study from approximately 150 centers across 23 countries. Eligible patients were 18 years and older, with confirmed HCV infection, baseline platelet count less than 75,000/μL, and otherwise adequate hepatic, renal, and hematologic function to receive antiviral therapy. Patients were eligible if, in the investigator's opinion, they were appropriate candidates for PEG+RBV therapy and could have received prior treatment with PEG+RBV if the reason for stopping treatment was documented thrombocytopenia. Key study exclusion criteria included nonresponders to previous PEG+RBV for reasons other than thrombocytopenia; decompensated liver disease; serious cardiac, cerebrovascular, or pulmonary disease that would preclude PEG+RBV therapy; history of thromboembolic events (evidence of portal vein thrombosis, or arterial or venous thrombosis, and any additional 2 risk factors); hepatitis B virus or human immunodeficiency virus infection; any condition involving active bleeding or need for anticoagulation with heparin or coumadin; and a history of clinically significant bleeding from esophageal or gastric varices.
End Points and Assessments
The primary objective of both studies was to evaluate the effect of eltrombopag treatment on SVR, defined as the proportion of patients with undetectable serum HCV-RNA levels 24 weeks after completing antiviral therapy (Supplementary Appendix). HCV-RNA level was assessed at screening, antiviral baseline, weeks 4 and 12, completion of antiviral therapy, and post-therapy weeks 12 and 24. Secondary efficacy end points included platelet counts throughout the study; PEG and/or RBV dose reductions or discontinuation; and rates of rapid virologic response (RVR), early virologic response (EVR), complete EVR, and end-of-treatment response (ETR). The RVR, EVR, complete EVR, and ETR were not adjusted and are included as supportive data only. Safety end points included adverse events (AEs) using the Division of AIDS AE grading table.12 Treatment-emergent AEs were considered to have occurred within 30 days after the last dose of study medication, except for death, malignancies, and cataracts, which were assessed until the last study visit. An independent data monitoring committee reviewed safety data throughout the study and efficacy data at predefined milestones. An independent committee reviewed all ophthalmic evaluations because ocular findings in preclinical studies of immature rodents indicated a risk of cataract formation. After the study, a blinded independent adjudication panel reviewed all events suggestive of hepatic decompensation.
Data Analysis
Sample size was determined assuming an SVR of 10% in the placebo group vs 20% in the eltrombopag group. The power of each study to detect this anticipated treatment effect was 92.5%, with an overall 2-sided level of significance of 5%. A total of 675 patients (eltrombopag, n = 450 patients; placebo, n = 225 patients) were required to be randomized. We estimated that approximately 10% of patients would not complete the pre-antiviral treatment phase. Therefore, 750 patients were enrolled to randomize 675 patients. However, because the proportion of patients with missing data and how they would be handled in the primary analysis was taken into account in determining the assumed proportions with SVR (placebo, 10%; eltrombopag, 20%), the number randomized was not adjusted to account for missing data.
Efficacy was analyzed using the intent-to-treat population, comprising all randomized patients. Safety analyses were based on the safety population, comprising all patients who received study medication. All statistical comparisons and confidence intervals (CIs) were 2-sided; continuous variables were summarized using descriptive statistics, and categoric variables were summarized using frequency counts and percentages. The proportions of patients achieving SVR and other virologic end points were compared between eltrombopag and placebo using stratified Cochran-Mantel-Haenszel chi-square test statistics, adjusted for stratification factors.
For the primary analysis, if a patient had a missing value between visits, then the previous nonmissing HCV-RNA assessment and associated classification was carried forward to fill in the missing value. If a patient's HCV-RNA value at the 24-week follow-up assessment was missing for any reason, the patient was considered a nonresponder. A patient with missing data owing to premature discontinuation of treatment, or from discontinuation of the study for any reason, was considered a nonresponder for all subsequent visits. Sensitivity analyses were conducted (6 preplanned and 1 post hoc), including assessment of the overall impact of patients who were missing post-treatment assessments, to determine their impact on the primary efficacy end point (SVR).
Patient Characteristics

Treatment groups were well matched within each study and between studies (Table 1). Patient flow during both studies is shown in Supplementary Figure 1. Median platelet counts at screening were approximately 59,000/μL in both studies. The study population comprised predominantly genotype 1 (62%-65%) with compensated liver disease (94%-97% Child-Pugh13, 14 A: score, 5-6). A high proportion of patients (78%) had a FibroSURE score equivalent to METAVIR F3 or F4, indicative of bridging fibrosis or cirrhosis (9% patients had a METAVIR score of F0/1/2, 13% patients were missing a score). The interleukin 28B status was balanced across groups and studies.
Initiation Phase: Efficacy
During the initiation phase of ENABLE-1 and ENABLE-2, 97% and 96% of patients, respectively, achieved the required platelet thresholds. The median time to achieve these thresholds was 2 weeks; 85% and 78% of patients in ENABLE-1 and ENABLE-2, respectively, achieved this platelet threshold within the first 4 weeks of treatment. Eighty-six percent received either 25 mg or 50 mg of eltrombopag daily (Supplementary Appendix).
Initiation Phase: Safety
During the initiation phase, the most common AEs (Table 2) were headache (ENABLE-1, 7%; ENABLE-2, 4%), nausea, and diarrhea (3% each in both studies). No thromboembolic events (TEEs) were reported during the initiation phase, and less than 1% of patients experienced hepatic decompensation. In the initiation phase, 8 patients (1%) experienced 9 serious AEs (SAEs) in ENABLE-1, and 9 patients (1%) experienced 9 SAEs in ENABLE-2, none of which were considered related to eltrombopag by investigators. No deaths occurred during the initiation phase of ENABLE-1. Two patients died as a result of events (hepatorenal syndrome and hepatocellular carcinoma [HCC]), originally recorded during the initiation phase of ENABLE-2, neither of which was considered related to eltrombopag by investigators.
Antiviral Phase: Efficacy
Compared with placebo, a significantly higher proportion of eltrombopag-treated patients achieved SVR (ENABLE-1, 23% vs 14%, P = .0064; ENABLE-2, 19% vs 13%, P = .0202; Figure 2A and B15). The ability of eltrombopag to improve SVR was unaffected by stratification factors and was consistent across subgroups (Supplementary Appendix). Eltrombopag was superior to placebo for all virologic response measures except RVR (Figure 2A and B).
In univariate analyses, the treatment effect observed in the overall population was similar in patients infected with genotype 2/3 (percentage difference in ENABLE-1, 9.2 [CI, -3.0 to 21.5]; ENABLE-2, 10.4 [CI, -2.4 to 23.3]) compared with patients infected with nongenotype 2/3 (percentage difference in ENABLE-1, 7.6 [CI, 1.4-13.7]; ENABLE-2, 5.3 [CI, 0.1-10.6]).
Substantial differences in median platelet counts were apparent by week 2 of the antiviral phase between the eltrombopag and placebo arms (ENABLE-1, 111,000/μL vs 79,000/μL; ENABLE-2, 124,000/μL vs 89,500/μL), and persisted throughout treatment (Figure 2C and D). In contrast to patients receiving placebo, the median platelet counts for eltrombopag patients remained higher than thresholds for antiviral dose reductions throughout treatment. In ENABLE-1 and ENABLE-2, 69% and 81% of eltrombopag patients vs 15% and 23% of placebo patients maintained platelet counts of 50,000/μL or greater throughout the antiviral phase.
During the antiviral phase, patients in the eltrombopag group, who had higher median platelet counts than patients in the placebo group, experienced significantly longer time to first PEG dose reduction (Kaplan-Meier estimates: ENABLE-1: median, undefined vs 6.1 wk; hazard ratio, 0.41; 95% CI, 0.33-0.52; P < .0001; ENABLE-2: median, 43.1 vs 6.1 wk; hazard ratio, 0.39; 95% CI, 0.30-0.49; P < .0001; Figure 2E and F).
Eltrombopag-treated patients required fewer PEG dose reductions; 57% and 59% of eltrombopag patients in ENABLE-1 and ENABLE-2, respectively, avoided PEG dose reductions compared with 30% and 32% of placebo patients, respectively. Consequently, the overall median cumulative exposure to PEG in the eltrombopag groups was 60% and 69% higher than in the placebo groups for ENABLE-1 and ENABLE-2, respectively (Supplementary Appendix).
The results of the sensitivity analyses were consistent with those observed in results of the primary analysis (intent-to-treat population).
Antiviral Phase: Safety
Adverse events

The incidence and type of AEs during this phase was similar between the treatment groups in both studies (Table 2).
SAEs were more common in the eltrombopag arm (eltrombopag 20% vs placebo 15% for both studies), although incidence rates were similar when normalized to actual exposure to antiviral treatment (ENABLE-1: eltrombopag, 31.71/100 patient-years [PYs], 95% CI, 25.16-38.26; placebo, 28.45/100 PYs; 95% CI, 19.02-37.88; ENABLE-2: eltrombopag, 31.25/100 PYs; 95% CI, 25.09-37.41; placebo, 29.06/100 PYs; 95% CI, 19.70-38.42). A greater proportion of placebo patients (eltrombopag, 19%; placebo, 27%) permanently discontinued antiviral treatment because of AEs (ENABLE-1, 17% and 28%; ENABLE-2, 21% and 26%, respectively).
Cataracts (incident or worsening) were more common in eltrombopag patients for ENABLE-1 (eltrombopag, 8%; placebo, 3%) but similar between treatment arms for ENABLE-2 (eltrombopag, 7%; placebo, 6%).
HCC and death were similar between arms in each study. Malignancies were diagnosed in a similar proportion of patients in each arm (eltrombopag, 5%; placebo, 4%). Thirty-nine patients (3%) died during the course of the studies, 29 (3%) in the eltrombopag group and 10 (2%) in the placebo group, mostly from complications of chronic liver disease (Supplementary Appendix). Deaths that were attributed to investigational products including eltrombopag during the double-blind phase included 5 patients on treatment for 30 days or fewer post-treatment (treatment days during the double-blind phase: hepatic failure on day 72, death on day 38, esophageal varices hemorrhage on day 117, sudden death on day 104, and hematemesis on day 182); and 1 death at more than 30 days post-treatment (thrombocytopenia on day 383). Deaths that were attributed to TEEs are listed in Table 3, and all deaths occurring during the study are listed in the Supplementary Appendix.
Thromboembolic events
During the antiviral phase, there were 34 TEEs in 31 eltrombopag patients (3%) and 5 TEEs in 5 placebo patients (1%) (Table 3). Portal vein thrombosis (PVT) was the most common TEE in both treatment groups (n = 12, 1% eltrombopag; n = 2, <1% placebo). Summary characteristics and outcomes of these TEEs are presented in the Supplementary Appendix. Thirty-eight percent of TEEs were detected by scheduled regular surveillance (Doppler of portal vein, ocular surveillance) and were asymptomatic.
We observed a higher incidence of TEEs during the antiviral phase of ENABLE-2; 20 patients (4%) in the eltrombopag group experienced 22 TEEs, and 1 patient (0.4%) in the placebo group experienced 1 TEE (2.5% and 1.7%, respectively, in ENABLE-1). Observation time-adjusted incidence rates were higher for the eltrombopag group than for the placebo group in ENABLE-2 (eltrombopag, 5.95/100 PYs; 95% CI, 3.34-8.56; placebo, 0.73/100 PYs; 95% CI, 0-2.17) but similar in ENABLE-1 (eltrombopag, 3.58/100 PYs; 95% CI, 1.46-5.70; placebo, 3.03/100 PYs; 95% CI, 0.06-6.00). PVT was observed in 7 (1%) eltrombopag patients but no placebo patients. No correlation with high proximal platelet counts or dose was observed, but in multivariable analyses pretreatment albumin level less than 3.5 g/dL was a risk factor (data not shown).
Hepatic decompensation
During the antiviral phase, hepatic decompensation (ascites, hepatic encephalopathy, variceal hemorrhage, or spontaneous bacterial peritonitis) was more common in eltrombopag-treated vs placebo-treated patients (both studies: eltrombopag, 10%; placebo, 5%) (Supplementary Appendix). Ascites and hepatic encephalopathy were the primary reasons for the difference (ascites: eltrombopag, 6%; placebo, 3%; encephalopathy: eltrombopag, 3%; placebo, <1%).
In total, 55% and 53% of eltrombopag-treated patients vs 24% and 25% of placebo-treated patients for ENABLE-1 and ENABLE-2, respectively, had a total bilirubin level more than 2x upper limit of normal. Consistent with eltrombopag's inhibition of UGT1A1, the primary enzyme for bilirubin glucuronidation, these increases were predominantly from indirect bilirubin (Supplementary Appendix). The median bilirubin values decreased rapidly after the end of treatment and were similar to baseline values by week 4 of follow-up evaluation. Bilirubin increases were not correlated with prolongation of the prothrombin time.
ENABLE-1 and ENABLE-2 clearly showed eltrombopag's ability to increase platelet counts and allow initiation and maintenance of interferon-based therapy. Eltrombopag in combination with interferon-based therapy improved SVR in a difficult-to-treat group of hepatitis C patients with advanced fibrosis/cirrhosis and TCP, who have been excluded from prior studies. In both studies, eltrombopag increased platelets to concentrations permitting antiviral therapy in more than 95% of patients whose baseline platelet counts would have made them ineligible or marginal candidates for PEG therapy.
Eltrombopag treatment delayed and/or prevented PEG dose reductions and discontinuations, leading to significant increases in SVR rates compared with placebo.
The low SVR rate observed in the placebo arm (13%) was similar to that reported in previous studies in patients with portal hypertension.16, 17 Greater adherence to PEG therapy was observed in the eltrombopag group. As observed in other studies, greater adherence to PEG therapy was associated with higher SVR in ENABLE-1 and ENABLE-2 (data not shown). Eltrombopag-treated patients showed higher EVR and ETR. In particular, the high relapse rate (50%) is consistent with previous findings and reflects the known shortcomings of PEG therapy and the insensitivity to PEG therapy in patients with cirrhosis.
The prognosis for patients with chronic HCV and platelet counts less than 100,000/μL is poor. Annualized incidence rates for HCC or clinical decompensation, death or liver transplantation, or death alone are as high as 7.9%, 7.3%, and 5.3%, respectively.18 These incidence rates mean that 2 of 5 patients with chronic HCV and platelet counts less than 100,000/μL will have a life-threatening complication in the next 5 years, and at least 1 of 4 will die during the same period. Although not evaluated in this study, the importance of SVR on reducing morbidity in patients with hepatitis C is reflected by a reported 4- to 10-fold decrease in mortality and a 2- to 4-fold decrease in the incidences of decompensated liver disease and HCC in patients achieving SVR compared with those with persistent HCV infection who did not achieve SVR in a previous study.19 Moreover, achieving an undetectable HCV-RNA level or SVR before liver transplantation can improve outcomes after transplantation by avoiding HCV recurrence.19
Since the initiation of the ENABLE studies, the standard of care for treatment of chronic HCV genotype 1 has progressed to a combination of a protease inhibitor (telaprevir or boceprevir), PEG, and RBV.20 This triple therapy improves overall SVR rates, including for patients with cirrhosis, but SVR rates are lower for patients with cirrhosis compared with patients without cirrhosis. Hepatic decompensation, primarily ascites and hepatic encephalopathy, was observed at a higher rate in patients treated with eltrombopag and PEG+RBV. In both studies, eltrombopag-treated patients had significantly longer median exposure to PEG, which likely explains the observed differences in hepatic function because interferon has been associated with abnormalities in liver chemistry values and with hepatic decompensation in patients with advanced liver disease.
Although there are no studies comparing the 2 treatment regimens, interim results of an ongoing French cohort study (Compassionate Use of Protease Inhibitors in viral C Cirrhosis [CUPIC] trial) with triple therapy using PEG+RBV and a protease inhibitor (292 patients on triple therapy with telaprevir and 205 patients on boceprevir) in genotype 1 cirrhosis patients reported grade 3/4 liver decompensation in 12 (2.4%) patients.21 The demographic profile of the patients was somewhat similar to those in the ENABLE studies in that they all had cirrhosis, but the majority were compensated. The mean platelet count at baseline was 152,000/μL (range, 18,000-604,000/μL) for telaprevir and 146,000/μL (range, 33,900-346,000/μL) for boceprevir. The investigators reported SAEs in 45.2% and 32.7%, respectively, and discontinuations because of SAEs in 14.7% and 7.3%, respectively. There were 24 grade 3/4 infections. Six deaths occurred during the study, most of which were related to severe infection. Grade 3/4 hepatic decompensation was reported in 6 patients in each treatment group. These results were similar to what we reported in a much larger and more advanced population in the ENABLE trials and confirm the need for careful monitoring and treatment of patients with cirrhosis and thrombocytopenia only by experienced clinicians.
The second major safety finding was that a higher proportion of eltrombopag-treated patients experienced TEEs. In contrast to ENABLE-1, both total TEEs and PVTs (a known complication of cirrhosis) were observed more commonly in ENABLE-2, although in this study placebo-treated patients had lower than expected PVT incidence.22 Low albumin levels appeared to be a risk factor for TEEs. The vast majority of TEEs resolved either spontaneously or after anticoagulation treatment, without requiring eltrombopag discontinuation and without interfering with the antiviral therapy. It is recommended that patients being considered for eltrombopag treatment be evaluated for TEE risk and be monitored during treatment, as was performed in this study.
This study had several limitations. When dose reductions/discontinuations were required, investigators were instructed to follow the current local prescribing information. However, many experienced clinicians do not reduce the dose of PEG in accordance with product labels, which could significantly bias the results in favor of the eltrombopag arms because treatment may have stopped sooner than what is done in routine practice. Because this was an international trial, we followed the recommendations in the prescribing information for the PEGs, despite the possibility of lower thresholds being used in practice. However, clinicians should implement PEG dose reductions/discontinuations at platelet thresholds at which they are comfortable.
The results of ENABLE-1 and ENABLE-2 suggest that eltrombopag can be used safely in patients with HCV-related liver disease and TCP. Eltrombopag increased platelets to levels sufficient for initiation and maintenance of interferon-based antiviral therapy for patients who otherwise would be ineligible or marginal candidates, resulting in clinically meaningful and statistically significant increases in SVR. In patients with cirrhosis and TCP, eltrombopag should be evaluated in the setting of newer treatment regimens with triple therapies or quadruple therapies, in which an incremental benefit in SVR may be achieved if thrombocytopenia is avoided or adequately treated.

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