Eltrombopag Increases Platelet Numbers in Thrombocytopenic Patients with HCV Infection and Cirrhosis, Allowing for Effective Antiviral Therapy

Gastroenterology. 2013 Oct 11. pii: S0016-5085(13)01436-4. doi: 10.1053/j.gastro.2013.10.012. [Epub ahead of print]

Afdhal NH, Dusheiko GM, Giannini EG, Chen PJ, Han KH, Mohsin A, Rodriguez-Torres M, Rugina S, Bakulin I, Lawitz E, Shiffman ML, Tayyab GU, Poordad F, Kamel YM, Brainsky A, Geib J, Vasey SY, Patwardhan R, Campbell FM, Theodore D.

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address: nafdhal@bidmc.harvard.edu.

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-α (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 -2, investigated the ability of eltrombopag to increase numbers of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV.

METHODS: Patients with HCV infection and thrombocytopenia (platelets <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 daily) for ≤9 weeks. Patients whose platelet counts reached the predefined minimal threshold for initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were randomly assigned (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary endpoint 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 platelets ≥50,000/μL 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.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

KEYWORDS: AEs, CIs, ETR, EVR, HCV, IRs, ITT, PEG, PYs, RBV, RVR, SAEs, SVR, TCP, TEEs, TPO-R, ULN, adverse events, blood clot, cEVR, complete early virologic response, complication, confidence intervals, early virologic response, end of treatment response, hepatitis C virus, incidence rates, intent-to-treat, liver disease, patient years, peginterferon alfa, portal hypertension, rapid virologic response, ribavirin, serious adverse events, sustained virologic response, thrombocytopenia, thromboembolic events, thrombopoietin receptor, upper limit normal

PMID: 24126097 [PubMed - as supplied by publisher]

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Blood Tests OK for Fibrosis Dx in Hep C

By Salynn Boyles, Contributing Writer, MedPage Today

Published: June 03, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

• While liver biopsy remains the gold standard for predicting disease progression in people with HCV infection, it is no longer recommended as necessary in all patients before the initiation of antiviral therapy with newer medications.
• This study suggests that blood tests can help to identify HCV-infected patients with clinically significant fibrosis, with somewhat greater accuracy for identifying cirrhosis than for less advanced fibrosis.

Blood testing can accurately identify clinically significant fibrosis and cirrhosis in people with hepatitis C virus (HCV) infection and may be an alternative to liver biopsy in some patients, a new study found.

The analysis of 172 studies comparing various blood tests to biopsy in HCV patients revealed that some of the simplest, cheapest blood tests performed as well as more expensive, complex tests, reported Roger Chou, MD, and Ngoc Wasson, MPH, from the Evidence-Based Practice Center at Oregon Health and Science University in Portland.

Six tests identified clinically meaningful fibrosis with a median positive likelihood ratio of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range 0.71 to 0.86), they wrote in the June 4 issue of the Annals of Internal Medicine.

The tests were the platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index.

In addition, three of those tests, platelet count, age-platelet index, APRI, plus Hepascore, all identified cirrhosis with median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range 0.80 to 0.91).

"Our results suggest that blood tests can help to identify HCV-infected patients with clinically significant fibrosis, with somewhat greater accuracy for identifying cirrhosis than for less advanced fibrosis," the researchers wrote.

Liver biopsy remains the gold standard for predicting disease progression in people with HCV infection, but it is no longer recommended in all patients before the initiation of antiviral therapy. Drawbacks of liver biopsy include the potential for sampling error and risk for complications such as bleeding, severe pain, and infection,

Blood tests have been proposed as a less invasive alternative to liver biopsy, and more than two dozen tests have been studied for this purpose.

"We expect to see all-oral, interferon-free HCV treatment regimens in a few years, and that means many more people are likely to begin antiviral therapies," they wrote. "Having blood tests to help identify patients who can benefit from these treatments will be increasingly important."

Using MEDLINE, the Cochrane Library database, and other reference lists, the authors identified studies that compared blood tests to liver biopsy for diagnosing fibrosis or cirrhosis in HCV-infected people.

Most of the studies included in the analysis were conducted in the U.S., Europe, Asia and northern Africa, and 15 were rated as good quality studies, while five were rated poor quality. The remainder were considered fair quality.

Chou said one of the most surprising findings was that the simple APRI blood test performed as well or better than more complex and expensive tests.

"This test provided useful information about the severity of underlying liver disease," he told MedPage Today. "For patients trying to decide if they should begin antiviral therapy, this and other blood tests may be an alternative to biopsy."

In a subanalysis in which APRI was compared to FibroTest (known as FibroSure in the U.S.), the predictive value of the two tests was very similar, Chou said.

FibroTest is a patented, six blood serum test for liver damage marketed by French company BioPredictive.

APRI was associated with a slightly lower AUROC than the FibroTest for fibrosis (18 studies: median difference, -0.03; range, minus 0.10-0.07), but there was no difference for cirrhosis (seven studies; median difference, 0.0; range, minus 0.04 to 0.06).

Chou and Wasson noted several limitations to their analysis, including the fact that only English-language studies were included and that most trials failed to describe blinded interpretation of liver biopsy specimens. Many also included inadequate descriptions of enrollment methods.

The added that the results may not apply to populations excluded from the review, including patients coinfected with hepatitis B virus, HIV, and those receiving hemodialysis.

The study was funded by a grant from the Agency for Healthcare Research and Quality.

Primary source: Annals of Internal Medicine
Source reference:
Chou R, et al "Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis c virus infection" Ann Intern Med 2013; 158.

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