Faldaprevir/peginterferon/ribavirin improved SVR, shortened therapy for chronic HCV

 EASL Coverage @ Healio

Faldaprevir/peginterferon/ribavirin improved SVR, shortened therapy for chronic HCV
April 29, 2013

The addition of faldaprevir to pegylated interferon/ribavirin therapy significantly improved rates of sustained virologic response and allowed for shorter treatment duration among patients with chronic hepatitis C in a study presented at the International Liver Congress in Amsterdam.
In the STARTVerso1 study, patients with chronic HCV genotype 1 received 48 weeks of therapy with peginterferon alfa-2a and ribavirin (PEG/RBV) and were randomly assigned either placebo (n=132) for 24 weeks, 120 mg faldaprevir (FDV, Boehringer Ingelheim Pharmaceuticals) (n=259) for 12 or 24 weeks, or 240 mg FDV (n=261) for 12 weeks. HCV RNA below 25 IU/mL after 4 weeks and undetectable RNA at 8 weeks were considered early success among treated patients, and therapy, including PEG/RBV, was stopped at 24 weeks.

Sustained virologic response (SVR) at 12 weeks occurred in more 120-mg (79%) and 240-mg (80%) treated patients than placebo participants (52%, P<.0001). Treatment was stopped at 24 weeks due to early response in 87% and 89% of the 120-mg and 240-mg groups, respectively, compared with 22% of placebo recipients. Among those who stopped treatment early, SVR12 was achieved by 86% of the 120-mg group, 89% of the 240-mg group and 90% of placebo patients.

Serious adverse events occurred at similar rates (6% of placebo recipients; 7% of treated groups), as did treatment discontinuation due to adverse events (4% of the placebo and 120-mg groups; 5% of the 240-mg group). Discontinuation of FDV, but not PEG/RBV, due to adverse events occurred in 1% of the 120-mg group and 3% of the 240-mg group. Anemia, rash and GI issues were reported most commonly.

“Faldaprevir has shown efficacy in a range of genotype-1a and 1b HCV patients with and without cirrhosis,” researcher Peter Ferenci, MD, Medical University of Vienna, said in a press release. “The viral cure rates and potential for shorter treatment duration seen in STARTVerso1 are very encouraging for the many patients currently facing a year of interferon-based treatment.”

For more information:
Ferenci P. #1416: Faldaprevir Plus Pegylated Interferon Alfa-2A and Ribavirin in Chronic HCV Genotype-1 Treatment-Naive Patients: Final Results From STARTVerso1, A Randomized, Double Blind, Placebo-Controlled Phase III Trial. Presented at: The International Liver Congress 2013; April 24-28, Amsterdam.

Meeting News Coverage

Interferon-free, triple-DAA regimen safe, effective for chronic HCV
April 26, 2013

Gene variants linked to steatosis, fibrosis, steatohepatitis
April 25, 2013

Slides @ NATAP/ EASL Coverage @ NATAP

FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAIVE PATIENTS

Coverage @Clinical Care Options
CCO's independent conference coverage

STARTVerso1: Faldaprevir Plus Peginterferon/Ribavirin Highly Effective, Well Tolerated in Treatment-Naive Patients Infected With Genotype 1 HCV

Most patients receiving faldaprevir (88%) were able to shorten therapy to 24 weeks total, without compromising sustained virologic response, which was 88% in this subgroup.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

 

Gilead Receives Complete Response Letters from U.S. Food and Drug Administration for Elvitegravir and Cobicistat

Gilead Receives Complete Response Letters from U.S. Food and Drug Administration for Elvitegravir and Cobicistat


FOSTER CITY, Calif.--(BUSINESS WIRE)--Apr. 29, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the company has received Complete Response Letters from the U.S. Food and Drug Administration (FDA) for its New Drug Applications (NDAs) for elvitegravir and cobicistat for use as part of HIV treatment regimens.

In its communications, FDA states that it cannot approve the applications in their current forms. The letters state that during recent inspections, deficiencies in documentation and validation of certain quality testing procedures and methods were observed. Gilead is working with FDA to address the questions raised in the Complete Response Letters and move the applications forward.

Elvitegravir and cobicistat are also components of Gilead’s once-daily single tablet HIV-1 regimen Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), which was approved by FDA in August 2012 for treatment-naïve adults. This regulatory action does not affect the marketing authorization or continued use of Stribild.

Gilead submitted its NDAs for elvitegravir and cobicistat in June 2012. Marketing applications are also pending in Europe.

About Elvitegravir

Elvitegravir is a member of the integrase inhibitor class of antiretroviral compounds. Integrase inhibitors block the ability of HIV to integrate into the genetic material of human cells. Elvitegravir was licensed by Gilead from Japan Tobacco Inc. (JT) in March 2005. Under the terms of Gilead’s agreement with JT, Gilead has exclusive rights to develop and commercialize elvitegravir in all countries of the world, excluding Japan, where JT retains rights.

About Cobicistat

Cobicistat is Gilead’s proprietary potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A), an enzyme that metabolizes drugs in the body. Unlike ritonavir, cobicistat acts only as a pharmacoenhancing or “boosting” agent and has no antiviral activity.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that we may be unable to remedy the deficiencies cited by the FDA in the Complete Response Letters on a timely basis and that our inability to address those deficiencies could adversely impact currently marketed products and products in development. There is also the risk that health authorities in other countries where applications are pending will undertake similar additional reviews which could delay the approval of such products in those countries. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Stribild is available at www.gilead.com.

Stribild is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.


Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Erin Rau, 650-522-5635 (Media)

BioLineRx Enrolls First Patient in Phase I/II Trial for BL-8020, an Oral, Interferon-Free Treatment for Hepatitis C

BioLineRx Enrolls First Patient in Phase I/II Clinical Trial for BL-8020, an Oral, Interferon-Free Treatment for Hepatitis C

- Interim results are expected by the end of 2013 -

JERUSALEM, Apr 29, 2013 (BUSINESS WIRE) --  BioLineRx (NASDAQ: BLRX; TASE: BLRX), a biopharmaceutical development company, announced today enrollment of the first patient in a Phase I/II trial for BL-8020, an orally available, interferon-free treatment for the Hepatitis C virus (HCV). The patient was enrolled at the Hopital Cochin in Paris, France.

The study is an open-label trial to evaluate the efficacy, safety and tolerability of BL-8020 in patients infected with HCV. It will be conducted at two clinical sites in France and will include up to 32 HCV-infected patients of any genotype who have previously failed or relapsed following treatment with the standard-of-care. BL-8020 is a proprietary fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ), which results in an improved version of Ribavirin. The primary endpoint of the study is to evaluate the effect of a 16-week combination therapy with Ribavirin and HCQ. The study is specifically designed to allow intra-subject analysis, in order to determine the extent to which HCQ enhances Ribavirin's antiviral activity.

BL-8020 is an orally available HCV treatment with a unique mechanism of action that targets the host cell, and thus differs from other currently used anti-HCV agents. This suggests pan-genotypic efficacy and the ability to be combined with other HCV therapeutics as part of an interferon-free regimen. BL-8020's mechanism of action involves the inhibition of HCV-induced autophagy in the host cells. Autophagy is a mechanism by which cells degrade damaged or unnecessary cellular components, and is known to be used by HCV during viral replication. BL-8020 inhibits the autophagy mechanism and thus reduces the ability of HCV to replicate in the human cell.

BL-8020's safety and efficacy have been demonstrated in a number of pre-clinical studies. These studies have shown that BL-8020 has a synergistic effect with other anti-HCV agents. This effect on other therapies is likely to increase their potency and reduce the numerous adverse effects often associated with these drugs by enabling utilization of lower dosages. The use of multiple therapies with different modes of action is also likely to be beneficial for patients who have developed resistance or do not respond to current treatments and is a common practice in current HCV treatment regimens.

"We are very pleased with the initiation of a clinical trial for our first anti-HCV agent, BL-8020. HCV induces a chronic infection in over one-half of individuals infected and, depending on the virus genotype, as few as 60% completely recover. In addition, current standard-of-care treatment options are lengthy and not well tolerated," stated Dr. Kinneret Savitsky, CEO of BioLineRx. "Accordingly, there is a clear need for new drugs that can increase the effectiveness of existing treatments, especially in patients who have already undergone treatment, but have previously failed to respond or relapsed. In this respect, this study would be a first step in establishing in patients the synergistic potential of BL-8020 in combination with other HCV treatments. Based on its pre-clinical results, unique mechanism of action and synergistic effect with other anti-HCV compounds, we are very hopeful that BL-8020 will indeed enhance the activity of other available Hepatitis C treatments, thereby improving Hepatitis C care. We look forward to the partial results from the Phase I/II trial expected towards the end of 2013."

"We are also excited about the initiation of the Phase I/II clinical trial with BL-8020," stated Professor Stanislas Pol from Hopital Cochin in Paris, the lead principal investigator in the study. "Preclinical results in our ex-vivo model of infected human liver slices showed a time and dose-dependent inhibitory effect on HCV replication and infectivity. We hope that this drug, especially when combined with other available Hepatitis C drugs, will improve the treatment outcome of previously non-responsive patients," said Professor Pol.

About BL-8020

BL-8020 was licensed under a worldwide, exclusive agreement from Genoscience, a French company focused on viral disease therapeutics. It was developed as an anti-viral therapy by Professor Philippe Halfon, Co-Founder and President of Genoscience and a world-renowned scientist for his work on HIV, HPV (human papilloma virus causing cervical cancer) and Hepatitis.

About Hepatitis C

Hepatitis C infection is a blood-borne infection of the liver caused by the Hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to a 2011 report from Decision Resources, about 180 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The global Hepatitis market was estimated at $6 billion in 2011 and is forecasted to grow to $20 billion by the end of the decade.

About BioLineRx

BioLineRx is a publicly-traded biopharmaceutical development company. BioLineRx is dedicated to building a portfolio of products for unmet medical needs or with advantages over currently available therapies. BioLineRx's current portfolio consists of seven clinical stage candidates: BL-1040, for prevention of pathological cardiac remodeling following a myocardial infarction, which has been out-licensed to Ikaria Inc., is currently undergoing a pivotal CE-Mark registration trial; BL-5010 for non-surgical removal of skin lesions has completed a Phase I/II study; BL-7040 for treating inflammatory bowel disease (IBD) has completed a Phase IIa trial; BL-8040 for treating acute myeloid leukemia (AML) and other hematological cancers will shortly commence a Phase II study; BL-1021 for neuropathic pain is in Phase I development; BL-8020 for hepatitis C (HCV) is commencing a Phase I/II study; and BL-1020 for schizophrenia. In addition, BioLineRx has five products in various pre-clinical development stages for a variety of indications, including central nervous system diseases, infectious diseases, cardiovascular and autoimmune diseases.

BioLineRx's business model is based on acquiring molecules mainly from biotechnological incubators and academic institutions. The Company performs feasibility assessment studies and development through pre-clinical and clinical stages, with partial funding from the Israeli Government's Office of the Chief Scientist (OCS). The final stage includes partnering with medium and large pharmaceutical companies for advanced clinical development (Phase III) and commercialization. For more information on BioLineRx, please visit www.biolinerx.com, the content of which does not form a part of this press release.

Various statements in this release concerning BioLineRx's future expectations, including specifically those related to the development and commercialization of BL-8020, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 12, 2013. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

SOURCE: BioLineRx

        
        KCSA Strategic Communications 
        Garth Russell / Todd Fromer 
        1 212-896-1250 / 1 212-896-1215 
        grussell@kcsa.com / tfromer@kcsa.com 
        or 
        BioLineRx 
        Tsipi Haitovsky 
        Public Relations 
        +972-52-598-9892 
        tsipih@netvision.net.il

EASL- MK-5172 : New Drug Holds Promise in Hepatitis C

New Drug Holds Promise in Hepatitis C

By Michael Smith, North American Correspondent, MedPage Today
Published: April 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

AMSTERDAM -- An investigational protease inhibitor for hepatitis C (HCV) achieved high response rates in treatment-naive patients when given in what one expert called an "old-fashioned" regimen.

Action Points

This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

An investigational protease inhibitor (MK-5172) for hepatitis C achieved higher response rates than treatment with an approved protease inhibitor, boceprevir, in treatment-naive patients who also received pegylated interferon and ribavirin.

Point out that only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

The drug (MK-5172) rendered the virus undetectable 24 weeks after the end of therapy in almost 90% of patients with the difficult-to-treat HCV genotype 1, according to Michael Manns, MD, of Hannover Medical School in Hannover, Germany.

In contrast, treatment with an approved protease inhibitor, boceprevir (Victrelis), led to an SVR24 in just 54%, Manns reported at the meeting of the European Association for the Study of the Liver (EASL).

But both drugs were combined with pegylated interferon and ribavirin, medications that are widely regarded as likely to fade from practice as a range of investigational direct-acting agents reaches the clinic.

The direct-acting agents, such as boceprevir and MK-5172, attack elements of the virus, in contrast to interferon and ribavirin, which respectively boost the immune system and target general viral replication.

Both have a range of unpleasant side effects and interferon in particular is seen as both difficult to tolerate and dangerous to use.

MK-5172 "is a very good drug," commented Alessio Aghemo, MD, of the University of Milan in Italy, who was not involved with the study but who moderated the EASL session at which it was presented.

But he told MedPage Today that clinicians and researchers are withholding judgment until it is tested without interferon and perhaps without ribavirin.

"The SVR rates are high with (interferon and ribavirin) but it's an old-fashioned regimen," he said. "It needs to go into an interferon-free regimen."

The study, Manns reported, included 332 treatment-naïve patients with genotype 1 virus and without cirrhosis. They were randomly assigned to one of four doses (100, 200, 400, or 800 mg) of MK-5172 or to boceprevir as a control. All patients also received pegylated interferon, and ribavirin for durations that varied according to early treatment response.

Manns presented data on the proportion of patients in each arm who reached SVR24 or who had undetectable virus at their last visit if that occurred before they completed 24 weeks after the end of therapy.

When the data were compiled in March, 311 patients had either reached the 24-week mark or had dropped out of the study before then, but all patients had completed treatment.

Analysis showed that the SVR24 rates in the MK-5172 arms ranged from 86% to 92%, compared with 54% in the boceprevir arm.

When the researcher added those who had not reached the 24-week mark, but who had undetectable virus at their last study visit, the rates ranged from 92% to 99% for MK-5172 and rose to 67% in the boceprevir arm.

Interestingly, there was little variation when the researchers stratified patients by polymorphisms of the IL28B gene, which predicts response to interferon, although the favorable CC allele tended to yield slightly better response rates numerically.

Manns noted that some patients getting higher doses of MK-5172 (400 and 800 mg ) were "down-dosed" to 100 mg daily, which will be the dose used in future studies.

There were no deaths on the study and the rates of serious adverse events were similar – 9% in the combined MK-5172 arms and 8% in the boceprevir arm, Manns said. Adverse events included gastrointestinal problems, rash, and anemia.

Only 7% of patients stopped therapy owing to adverse events in the combined MK-5172 arms compared with 14% in the boceprevir arm.

A total of 26 patients had bilirubin elevations, possibly because MK-5172 inhibitors some transporter molecules and enzymes, he said. The elevations mostly occurred early and were not associated with decreases in hemoglobin.

In general, the drug was well tolerated but the investigators noted dose-related elevations in liver enzymes, he said.

The study was supported by Merck. Manns reported financial links with the company, as well as with Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Novartis, Roche, Idenix, and Valeant.

Aghemo reported financial links with Roche, Gilead, Jannsen, and Merck.

Primary source: EASL 2013
Source reference:
Manns M, et al. "High Sustained Viral Response at 12- and 24-Week Follow-Up of MK-5172 with Pegylated Interferon Alfa-2B and Ribavirin (PR) in HCV Genotype Treatment-Naive Non-Cirrhotic Patients" EASL 2013;abstract 66.

EASL Coverage @ MedPage Today

Updates

Triple Therapy Can Help in Advanced Hep C
4/28/2013   
AMSTERDAM -- About 40% of people with advanced hepatitis C (HCV) can benefit from triple therapy even if they have cirrhosis and previous treatment failures, a researcher said here.
more

Shunt Correction Eases Hepatic Encephalopathy

4/28/2013

AMSTERDAM -- Elimination of spontaneous liver shunts, or reducing the size of surgically placed shunts, is an effective treatment for hepatic encephalopathy in cirrhotic patients, researchers said here. 

more

 

Read more @ MedPage Today

Slides @ NATAP EASL Coverage @ NATAP

High Sustained Viral Response of MK-5172 with Pegylated Interferon Alfa-2b and Ribavirin in HCV Genotype 1 Treatment-Naive Non-Cirrhotic Patients -

Hepatitis C - Will physicians go off label, and prescribe Sofosbuvir and Daclatasvir?

Hello folks,
In short, as most of you know Daclatasvir is a Bristol-Myers-Squibb drug - Sofosbuvir is Gilead's drug. The controversy began when Gilead refused to move forward with Phase III trials testing Bristol-Myers drug with their own.

The HCV community was in an uproar, as you may remember one patient refused to stand by in silence, soon an online petition was implemented by Margaret Dudley urging Gilead and Bristol-Myers to collaborate on the promising new treatment for hepatitis C.

The two articles below emphasize the highly successful HCV drug regimen; hinting at an off label use after both drugs are FDA approved, the backstory and results presented Saturday at the liver conference;

April 27
Bloomburg article by Simeon Bennett: Gilead-Bristol Hepatitis C Drug Combo Cures All in Study on the highly effective combination

In a study among 41 patients of Gilead’s sofosbuvir combined with Bristol’s daclatasvir, with or without the generic antiviral ribavirin, 40 had undetectable virus in their blood 12 weeks after finishing six months of treatment, according to results presented today at a meeting in Amsterdam. The other patient didn’t turn up to the last appointment and was later found to be virus-clear. Patients in both groups had failed prior treatment with either Vertex Pharmaceuticals Inc. (VRTX)’s Incivek or Merck & Co. (MRK)’s Victrelis.

Still, doctors may be tempted to prescribe the Gilead- Bristol combo “off-label” once both drugs are approved, said Mark Thursz, secretary-general of the European liver association.  

Prescribing the two drugs as an off-label combination may be too expensive because they’ll probably have high prices as individual therapies whereas Gilead’s cocktail may be cheaper, he said.

Off-label use may also be dangerous, said Jean-Michel Pawlotsky, a professor of medicine at the University of Paris- Est.

“We don’t have enough safety data,” Pawlotsky said in an interview. “If a doctor does that and there’s a major accident, the doctor is liable. It’s dangerous but I know that people will do it.”

Read the full article : Gilead-Bristol Hepatitis C Drug Combo Cures 100% in Study

April 28
The controversy continues over at FierceBiotech as well, in an article written today by John Carroll: Shunned Gilead/Bristol-Myers hep C combo may be too good for docs to ignore.
The author writes;

What if you had a great combination of rival drugs that worked in 100% of patients, but one of the companies involved refused to participate in the trials needed for an approval? If you're Gilead, the answer is to continue to ignore compelling data, shun the competitor drug and stay focused on an in-house combo that could deliver a big segment of the market. But some patients and doctors appear willing to consider taking matters into their own hands.

 

Read the entire article here...

Conference Coverage @ HIVand Hepatitis

EASL 2013: Daclatasvir + Sofosbuvir Offers Rescue Therapy after Current Standard of Care
Published on Sunday, 28 April 2013 00:00
Written by Liz Highleyman
An interferon-free regimen of daclatasvir plus sofosbuvir, with or without ribavirin, cured all previously treated hepatitis C patients who did not respond to interferon-based triple therapy using the approved HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivek), according to a report presented at the EASL International Liver Congress (EASL 2013) this week in Amsterdam
Continue reading...

         

Conference Coverage @ NATAP

 

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC)    

Coverage @Clinical Care Options
CCO's independent conference coverage
 

Daclatasvir Plus Sofosbuvir ± Ribavirin Achieves 95% to 100% SVR12 Rate in Patients With Previous Virologic Failure on Telaprevir or Boceprevir

Virologic response rates to all-oral, once-daily 24-week regimen unaffected by baseline NS3 variants conferring protease inhibitor resistance.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

EASL: PI-Based Triple Therapy Improves Virological Response Rates in Liver Transplant Recipients With HCV

Source: DGNews |

PI-Based Triple Therapy Improves Virological Response Rates in Liver Transplant Recipients With HCV

By Shazia Qureshi

AMSTERDAM, the Netherlands -- April 27, 2013 -- Sustained virological response 4 weeks after the end of treatment (SVR-4) was reached by as many as 65% liver transplant recipients with hepatitis C virus (HCV) genotype 1 who were receiving antiviral triple therapy with pegylated interferon, ribavirin, and a protease inhibitor (PI).

“However, these results must be balanced with high rates of adverse events observed,” said Elizabeth Verna, MD, Columbia University College of Physicians and Surgeons, New York, New York, on April 25 at the 48th Annual Meeting of the European Association for the Study of the Liver (EASL).

The study cohort included 112 liver transplant recipients with HCV who were receiving antiviral triple therapy with pegylated interferon, ribavirin, and a PI (telaprevir or boceprevir).

The median time from liver transplantation to start of triple therapy was 3.7 years. Prior to triple therapy, 96% of patients had undergone a lead-in period with only pegylated interferon plus ribavirin, mainly because the PIs used in the study only recently became available in 2011. Immunosuppression treatment was also administered and included cyclosporine, tacrolimus, steroids, and mycophenolate mofetil (MMF).

From the data collected so far, 64% of patients have shown an extended rapid virological response (eRVR), defined as undetectable HCV RNA levels at weeks 4 and 12.

So far, 48 patients have had the opportunity to reach SVR-4 (48 weeks of treatment plus 4 weeks of follow-up). Among them, 63% have shown eRVR and 65% have shown SVR-4. In addition, SVR-4 rates were 93% among those with eRVR -- which may be an important predictor of response, according to Dr. Verna.

Six percent of patients died (4% liver-related, 2% non-liver-related). Hospitalisation due to serious adverse events occurred in 21% of patients, with the rate being higher among the 30 patients with advanced disease (38%) than among the 82 patients without advanced disease (16%; P = .02).

Renal failure -- defined as an increase in serum creatinine level of >0.5 mg/dl -- was reported in 34% of the whole cohort, again with a difference between patients with and without advanced disease (47% vs 30%).

“The results are preliminary, and improving tolerability and identifying predictors of SVR is critical to optimising the risks and benefits of post-liver transplant triple [antiviral] therapy,” said Dr. Verna.

[Presentation title: A Multicenter Study of Protease Inhibitor-Triple Therapy in HCV-Infected Liver Transplant Recipients: Report From the CRUSH-C Group. Abstract 23]

EASL 2013 Highlights - CCO's independent conference coverage

 

Program Overview

 

2013 Annual Meeting of the European Association for the Study of the Liver*

 

April 24-28, 2013 | Amsterdam, The Netherlands

   

CCO's independent conference coverage of the 2013 Annual Meeting of the European Association for the Study of the Liver includes 2 CME-certified slidesets with faculty analysis and downloadable slidesets that focuses on key issues highlighted at the conference.

 

**Free registration required

 

Latest Content
Daclatasvir Plus Asunaprevir Plus BMS-791325 Achieves ≥ 88% SVR Rates in Noncirrhotic Treatment-Naive Patients With Genotype 1 HCV

The all-oral regimen combining an NS5a inhibitor, a protease inhibitor, and a nonnucleoside polymerase inhibitor was well tolerated at both doses of BMS-791325 studied.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 5/3/2013

HBV DNA Seroclearance Significantly Reduces Risk of HCC in Patients With High Baseline Viral Loads
Seroclearance of HBeAg, HBsAg did not significantly decrease HCC risk in adjusted analysis.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/2/2013

CONCISE: Interim Results Show High SVR Rates With Either 12 or 24 Weeks of Telaprevir Plus Peginterferon/Ribavirin in Patients With HCV Genotype 1 and IL28B CC Genotype
Among patients who completed 12 weeks of triple therapy, 100% SVR12 rate among patients who continued to receive peginterferon/ribavirin through 24 weeks vs 89% SVR4 rate among patients who stopped all therapy at 12 weeks.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/2/2013

QUEST-1: Simeprevir Plus PegIFN/RBV Significantly Improves SVR12 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 1 HCV
Triple therapy was well tolerated and 85% of patients were able to shorten treatment to 24 weeks, of whom 91% achieved SVR12.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/1/2013

COMMAND: Daclatasvir Plus PegIFN/RBV Improves SVR24 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 2/3 HCV
The triple-drug regimen allowed 83% of patients to receive shorter treatment durations of only 12 or 16 weeks, and safety and tolerability was comparable to pegIFN/RBV alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

QUEST-2: Simeprevir Plus PegIFN/RBV Superior to PegIFN/RBV for SVR12 in Treatment-Naive Patients With Genotype 1 HCV
Triple therapy was well tolerated and enabled most patients (91%) to shorten the duration of therapy to 24 weeks while maintaining a high SVR12 rate of 86% in this subgroup.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

POSITRON: Sofosbuvir/Ribavirin Superior to Placebo With 78% SVR12 Rate in Genotype 2/3 HCV–Infected Patients Intolerant of, Ineligible for, or Unwilling to Receive IFN
Sofosbuvir plus ribavirin is a safe, effective, IFN-free alternative for patients chronically infected with genotype 2/3 HCV who have no other treatment options available.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Observed HCC Incidence Lower Than Predicted in Patients With Chronic Hepatitis B Receiving Tenofovir in Phase III Clinical Trials
The effect of tenofovir was more noticeable in noncirrhotic patients, emerging at 2 years of treatment and reaching statistical significance by 6 years of treatment.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Prolonged Tenofovir-Based Antiviral Therapy Maintains HBV DNA Suppression in Patients With Chronic HBV, Normal ALT Levels, and High HBV DNA Levels
HBV DNA suppression was increased with tenofovir plus emtricitabine vs tenofovir alone, but safety profiles of both regimens were favorable through 192 weeks of study.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

FISSION: Sofosbuvir/Ribavirin Noninferior to Peginterferon/Ribavirin for SVR12 in Treatment-Naive Patients With HCV Genotype 2/3

Efficacy was similar between the 2 treatment arms, but sofosbuvir/ribavirin demonstrated superior safety and tolerability with shorter therapy compared with peginterferon/ribavirin.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

 

NEUTRINO: Sofosbuvir Plus Peginterferon/Ribavirin Achieves High SVR12 Rate, Well Tolerated in Treatment-Naive Patients With Genotype 1, 4, 5, or 6 HCV

The triple-therapy regimen yielded 90% SVR12 in the overall population, and all patient subgroups attained at least 80% SVR12 rate, including patients with cirrhosis and those with IL28B non-CC genotype.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

FUSION: Sofosbuvir/Ribavirin Superior to Historical Controls for SVR12 in Treatment-Experienced Patients With Genotype 2/3 HCV

Significantly better rates of SVR12 with both 12 and 16 weeks of therapy compared with historical controls, with better outcomes with 16 weeks of therapy among patients with genotype 3 HCV

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

 

STARTVerso1: Faldaprevir Plus Peginterferon/Ribavirin Highly Effective, Well Tolerated in Treatment-Naive Patients Infected With Genotype 1 HCV

Most patients receiving faldaprevir (88%) were able to shorten therapy to 24 weeks total, without compromising sustained virologic response, which was 88% in this subgroup.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013 

Daclatasvir Plus Sofosbuvir ± Ribavirin Achieves 95% to 100% SVR12 Rate in Patients With Previous Virologic Failure on Telaprevir or Boceprevir            

Virologic response rates to all-oral, once-daily 24-week regimen unaffected by baseline NS3 variants conferring protease inhibitor resistance

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

QUANTUM: Interferon-Free Sofosbuvir/Ribavirin Regimen Achieves 52% to 72% SVR12 Rate in Treatment-Naive Patients With Chronic HCV Infection
QUANTUM also identified marked elevations in ALT and/or AST associated with the guanidine nucleotide analog GS-0938, which resulted in GS-0938—containing arms being halted.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

 

Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

AVIATOR: ABT-450/Ritonavir, ABT-267 and/or ABT-333, and RBV Achieves SVR24 Rates ≥ 90% in Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
The 4-drug peginterferon-free regimens also yielded SVR rates ≥ 89% in treatment-naive patients and previous null responders regardless of sex, HCV subtype, baseline HCV RNA, IL28B genotype, and fibrosis severity.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/26/2013

High Rate of Advanced Fibrosis in Patients With HBV/HIV Coinfection, Despite HBV Suppression With Antiretroviral Therapy
Patients with HBV/HIV coinfection treated with HBV-suppressing antiretrovirals continue to demonstrate high rates of advanced fibrosis.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/26/2013

ELECTRON: Addition of Second DAA to Sofosbuvir and Ribavirin Yields Rapid, Sustained Antiviral Suppression in Both Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
Combining ledipasvir with sofosbuvir/ribavirin yielded SVR12 rates of 100% in both treatment-naive patients and previous null responders, lending further support to ongoing development of the sofosbuvir/ledipasvir fixed-dose combination tablet.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver

 

EASL: Liver Imaging Tests Vie to Replace Biopsy

Also See- FDA Approves FibroScan for Noninvasive Liver Diagnosis


Liver Imaging Tests Vie to Replace Biopsy

By John Gever, Deputy Managing Editor, MedPage Today

Published: April 26, 2013

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here.

Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that multiple studies demonstrate the ability of novel imaging modalities to predict liver fibrosis in patients with liver disease.

Be aware that there are limitations to these new technologies, including the fact that many do not perform well in obese patients.

In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice.

There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation.

The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device.

All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves.

Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy
Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011.

Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis.

Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported.

Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller.

For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55).

"The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography
Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs.

Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate.

But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded.

He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice.

From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard.

The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%.

But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods.

Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained.

RTSWE Versus Transient Elastography Versus Biopsy
Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy.

Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls.

Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing.

RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well.

Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa).

Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0).

Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0).

RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans.

Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis.

The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort.

For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively.

The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%.

Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver

Source reference:

Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver

Source reference:

Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL 2013; Abstract 15.

Additional source: European Association for the Study of the Liver

Source reference:

Ferraioli G, et al "Performance of ELASTPQ® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

EASL Coverage @ MedPage Today

http://www.medpagetoday.com/MeetingCoverage/EASL/38707