Hepatitis C - Adverse events from DAAs can persist for months after treatment

Of Interest
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Side effects associated with different hepatitis C direct-acting antiviral drugs 

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Patient-Reported Outcomes After HCV Treatment With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir 

May 30, 2018

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV 

Article

Adverse events from DAAs can persist for months after treatment, study finds

Liz Meszaros, MDLinx | August 21, 2018
Adverse events (AEs) related to treatment with direct-acting antivirals (DAAs) may persist after treatment in a significant number of patients with chronic hepatitis C, according to results from a study published in the European Journal of Gastroenterology and Hepatology. Clinicians and patients should be aware of this possibility.

Abstract: Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

“This real-life study is to the best of our knowledge the first to examine the rate of AEs in patients with hepatitis C virus (HCV) genotype (GT) 1 infection, randomized to one of two different DAA regimens in a real-world setting,” noted these authors, led by Christina Sølund, MD, PhD, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.

Recently, the development of DAA agents has revolutionized the treatment of chronic hepatitis C, which is estimated to affect more than 70 million people worldwide. Before the advent of DAAs, the standard of care for these patients consisted of treatment with pegylated-interferon and ribavirin (RBV), lasting for 24 to 48 weeks, which not only had significantly lower cure rates and tolerability, but also carried a high incidence of severe AEs.

Now in their second iteration, DAAs have changed the playing field in the treatment of chronic hepatitis C by directly targeting the proteins responsible for viral replication. Improved sustained virologic responses (SVR) of 90% or more and good tolerability and efficacy in patients who have historically been difficult to treat—such as those with liver cirrhosis, liver transplantation, or previous treatment failures—have characterized the second-generation DAAs.

Few studies, however, have compared different DAA regimens. For this reason, Dr. Sølund and colleagues conducted their investigation. They included 96 patients with chronic hepatitis C with either GT1 or GT3, who were randomized to two different treatment arms. The first was comprised of 72 patients infected with GT1, who were treated for 12 weeks with ledipasvir/sofosbuvir/RBV vs paritaprevir/ombitasvir/ritonavir/dasabuvir/RBV. The second group consisted of 24 patients infected with GT3, who were treated with daclatasvir/sofosbuvir/RBV for 12 weeks vs a 24-week course of sofosbuvir/RBV.

Unfortunately, due to a change in national treatment guidelines, the GT3 treatment arm was prematurely terminated. Therefore, efficacy data are available from both GT3 and GT1 patients, but the incidence of AEs is available only for GT1 patients.

Cure was achieved by 97% of GT1 patients and 83% of GT3 patients, with SVR at 12 months. Virologic failure occurred in only one G3 patient.

Adverse events occurred in 97% of GT1 patients with the most common being anemia, fatigue, and headache.

“We found no statistically significant difference in AEs, neither between treatment groups nor in relation to anemia or cirrhosis. The overall rate of AEs was comparable to other real-world studies, but the frequency of the most common AEs, such as anemia (78%), fatigue (74%), headache (74%), pruritus/eczema (46%), and heartburn/abdominal discomfort (38%), was higher in our study,” they added.

Only 3% of GT1 patients discontinued treatment due to AEs. Notably, 45% of patients with AEs thought to be related to a DAA regimen still manifested the AEs at 4 weeks after treatment. At 12 weeks this was still the case in 11% of patients.

“We consider this an important finding that can be used when informing the patient about AEs that might be caused by the DAA regimen, despite the number of patients included in our study being relatively small,” noted the authors. “The low discontinuation rate reflects that AEs possibly induced by DAA treatment are rarely treatment limiting, even when DAA treatment is given in combination with RBV,” they concluded.

This study received support from the Faculty of Health and Medical Sciences, University of Copenhagen and from Hvidovre Hospital Research Foundation, the Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, the Capital Region of Denmark’s Research Foundation, the Innovation Fund Denmark project 060-2009-3, the Novo Nordisk Foundation, and the Danish Research Council.

https://www.mdlinx.com/infectious-disease/article/2470

Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt

Alimentary Pharmacology and Therapeutics - November 29, 2017

Generic daclatasvir plus sofosbuvir, with or without ribavirin, in treatment of chronic hepatitis C: real-world results from 18 378 patients in Egypt
H. Omar, W. El Akel, T. Elbaz, M. El Kassas, K. Elsaeed, H. El Shazly, M. Said, M. Yousif, A. A. Gomaa, A. Nasr, M. AbdAllah, M. Korany, S. A. Ismail, M. K. Shaker, W. Doss, G. Esmat, I. Waked, Y. El Shazly

Full Text Article - http://onlinelibrary.wiley.com/doi/10.1111/apt.14428/full

Abstract

Summary

Background
Treatment of chronic hepatitis C using combination of sofosbuvir (SOF) and daclatasvir (DCV) was used in several clinical trials and multicentre studies, which were somewhat limited to genotypes 1-3. The national program in Egypt is using SOF-DCV combination for large scale treatment.

Aim
To assess the efficacy and safety of combined SOF-DCV in treating patients with HCV-G4 in a real-world setting.

Methods
Data and outcome of chronic HCV patients who were treated for 12 weeks with generic medications: DCV 60 mg plus SOF 400 mg ± ribavirin (RBV) within the national hepatitis C treatment program in Egypt are presented. Treatment-naïve patients without cirrhosis were treated without RBV, and those who had cirrhosis or were treatment-experienced (interferon experienced or SOF experienced) received RBV. Efficacy and safety were assessed, and baseline factors associated with sustained virological response at post-treatment week 12 (SVR12) were explored.

Results
During the first 2 months of the programme, 18 378 patients with HCV-G4 started treatment with SOF-DCV with or without RBV. Overall, 95.1% achieved SVR12 (95.4% among patients treated without RBV and 94.7% for patients treated with RBV, P = .32). Treatment was prematurely discontinued in only 1.5% of patients. The most common events leading to discontinuation were patient withdrawal (n = 76) and pregnancy (n = 5). Five deaths occurred within this group.

Conclusions
Real-world experience of generic SOF-DCV in patients with chronic HCV-G4 proved to be safe and associated with a high SVR12 rate, in patients with different stages of fibrosis.

Continue to full text article... http://onlinelibrary.wiley.com/doi/10.1111/apt.14428/full

Effectiveness and Safety of Sofosbuvir-based Regimens Plus an NS5A Inhibitor for Patients With HCV Genotype 3 Infection and Cirrhosis Results of a Multicenter Real-life

Effectiveness and Safety of Sofosbuvir-based Regimens Plus an NS5A Inhibitor for Patients With HCV Genotype 3 Infection and Cirrhosis Results of a Multicenter Real-life
Cohort S. Alonso; M. Riveiro-Barciela; I. Fernandez; D. Rincón; Y. Real; S. Llerena; F. Gea; A. Olveira; C. Fernandez-Carrillo; B. Polo; J. A. Carrión; A. Gómez; M. J. Devesa; C. Baliellas; Á. Castro; J. Ampuero; R. Granados; J. M. Pascasio; A. Rubín; J. Salmeron; E. Badia; J. M. M. Planas; S. Lens; J. Turnes; J. L. Montero; M. Buti; R. Esteban; C. M. Fernández-Rodríguez

J Viral Hepat. 2017;24(4):304-311.

Abstract and Introduction
Abstract
Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

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Systematic review: interferon-free regimens for patients with HCV-related Child C cirrhosis

Systematic review: interferon-free regimens for patients with HCV-related Child C cirrhosis
The most recent issue of the Alimentary Pharmacology & Therapeutics assessed the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection.

View Full Text Article
http://onlinelibrary.wiley.com/doi/10.1111/apt.14017/full

Article Summary
Source

It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new protease inhibitors will extend to those with Child C cirrhosis.

Dr Andriulli and colleagues assessed the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection.

The team conducted a systematic Medline to retrieve studies describing the treatment of Child C patients with direct-acting agents. 

Citations from identified studies were cross-referenced and abstracts from European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) meetings were checked. 

Extracted data were evaluated using a meta-analysis to calculate a weighted response rate.

The team retained 7 full-text records, and 2 conference abstracts for analysis from the 649 records identified. 

Data from an Italian real-life trial were also interrogated. 

Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. 

Overall, the researchers found that the weighted mean sustained virological response was 75%. 

The team observed that neither duration of treatment, nor addition of ribavirin influenced these rates. 

The research team noted that the weighted sustained virological response was 65% after sofosbuvir/simeprevir, 76% after sofosbuvir/daclatasvir and 83% after sofosbuvir/ledipasvir. 

Some studies did not provide information on the rate of post-treatment relapse or functional improvement. 

However, in those studies that did provide such data, a relapse was documented in 12% of patients, and an improvement of ≥2 points on the model for end-stage liver disease (MELD) score in 61% of patients.

Dr Andriulli's team concludes, "The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents."

Continue to full text article....

Daclatasvir Plus Sofosbuvir, With or Without Ribavirin, for Hepatitis C Virus Genotype 3 in a French Early Access Programme

Daclatasvir Plus Sofosbuvir, With or Without Ribavirin, for Hepatitis C
Virus Genotype 3 in a French Early Access Programme
Christophe Hézode, Pascal Lebray, Victor De Ledinghen, Fabien Zoulim, Vincent Di Martino, Nathalie Boyer, Dominique Larrey, Danielle Botta-Fridlund, Christine Silvain, Hélène Fontaine, Louis D'Alteroche, Vincent Leroy, Marc Bourliere, Isabelle Hubert-Fouchard, Dominique Guyader, Isabelle Rosa, Eric Nguyen-Khac, Larysa Fedchuk, Raoudha Akremi, Yacia Bennai, Anne Filipovics, Yue Zhao, Jean-Pierre Bronowicki

Download Accepted Article
Accepted manuscript online: 8 February 2017
DOI: 10.1111/liv.13383

Key Points 
• A real-world early-access programme treated HCV genotype 3-infected patients with
highly advanced disease and no other treatment options with daclatasvir plus
sofosbuvir. Many would have been ineligible for a randomized study.
• Sustained virologic response after 24 weeks of treatment was 89%: 98% without
cirrhosis; 86% with cirrhosis (including decompensated cirrhosis). There was no
incremental benefit with concomitant ribavirin.
• Only 1% of patients were recorded to have discontinued for an adverse event
• Daclatasvir and sofosbuvir, with or without ribavirin, was effective and well tolerated
in this real-world cohort of HCV genotype 3 infected patients with advanced disease.

Abstract
Background and aims
Optimally effective treatment for hepatitis C virus (HCV) genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir (DCV) plus sofosbuvir (SOF) was efficacious in phase 3 studies. Real-world data for DCV+SOF in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to DCV ahead of its market authorization.

Methods
Patients with F3/F4 fibrosis and/or extrahepatic HCV manifestations, post-liver-transplant HCV recurrence, and/or indication for liver/kidney transplant, were treated with DCV+SOF (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin (RBV) and/or shorter treatment were at physician's discretion. The primary efficacy analysis was sustained virologic response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting.

Results
The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment-experienced (72%). After 24 weeks of DCV+SOF, SVR12 was 89% (174/196) overall (95% CI 83.6–92.5%), 98% (43/44) without cirrhosis (95% CI 88.2–99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5–90.7%), without SVR12 increase in those who received additional RBV for 24 weeks (SVR12 82% [50/61; 95% CI 70.5–89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died.

Conclusions
DCV+SOF achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.
http://onlinelibrary.wiley.com/doi/10.1111/liv.13383/full

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Sofosbuvir, daclatasvir combo best treatment for HCV cryoglobulinemia vasculitis

Conference Coverage
Sofosbuvir, daclatasvir combo best treatment for HCV cryoglobulinemia vasculitis
By: Deepak Chitnis
Frontline Medical News

WASHINGTON – A combined regimen of sofosbuvir and daclatasvir is the best option to treat patients with hepatitis C virus infections experiencing cryoglobulinemia vasculitis, according to the findings of a new study presented at the annual meeting of the American College of Rheumatology.

“The HCV cryoglobulinemia vasculitis is a very important vasculitis because it represents 5% of chronically infected HCV patients in the world,” explained David Saadoun, MD, of Sorbonne Universities, Paris. “It’s sometimes a life-threatening vasculitis because patients may develop inflammation [so] there’s a need for very active and well-tolerated treatment.”​

Continue reading...

A Continued Role for Ribavirin in HCV Genotype 3 Infection with Advanced Liver Disease

A Continued Role for Ribavirin in HCV Genotype 3 Infection with Advanced Liver Disease
Atif Zaman, MD, MPH reviewing Leroy V et al. Hepatology 2016 May.

12-week regimen of sofosbuvir, daclatasvir, and ribavirin achieved sustained response in >85% of patients with cirrhosis regardless of treatment experience.

Although current treatment regimens for hepatitis C virus (HCV) infection are effective in most scenarios, sustained virologic response (SVR) rates tend to be lower among HCV genotype 3 patients with advanced liver disease (e.g., SVR rates are approximately 65% in patients with cirrhosis versus >95% in those without cirrhosis).

In the current industry-funded, open-label, randomized, phase III study, investigators evaluated the efficacy of daclatasvir 60 mg daily and sofosbuvir 400 mg daily plus ribavirin 1000–1200 mg daily for 12 or 16 weeks (randomized in a 1:1 fashion) in patients with treatment-naive or treatment-experienced HCV genotype 3 infection and well-compensated stage 3 fibrosis or cirrhosis. The primary endpoint was SVR at 12 weeks after treatment completion (SVR12).

Among 50 study participants, 37 were treatment-experienced and 36 had cirrhosis. The SVR12 rate was 90% (45 of 50) overall, 88% among those treated for 12 weeks, and 92% among those treated for 16 weeks. SVR12 was 100% among patients with stage 3 fibrosis and 86% among those with cirrhosis (83% in the 12-week arm and 89% in the 16-week arm). SVR12 rates for treatment-experienced patients with cirrhosis were similar and ranged from 86% to 88%. Four patients relapsed after treatment. The most common adverse effects were insomnia, fatigue, and headache.

Comment
Adding ribavirin to daclatasvir and sofosbuvir in patients with HCV genotype 3 infection and advanced fibrosis or cirrhosis markedly improved SVR rates, even in those who had failed HCV treatment previously. This was accomplished without extending treatment duration beyond 12 weeks, thus being cost-effective as well. It seems that ribavirin use still has a role in HCV treatment.

Editor Disclosures at Time of Publication
Disclosures for Atif Zaman, MD, MPH at time of publication Nothing to disclose

Citation(s):
Leroy V et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+).
(http://dx.doi.org/10.1002/hep.28473 Open Url PubMed abstract (Free)

Source http://www.jwatch.org/na41316/2016/05/12/continued-role-ribavirin-hcv-genotype-3-infection-with

FDA Okays Hep-C Investigational Combo for Post-Transplant Patients

Press Release
Bristol-Myers Squibb Receives Amended U.S. FDA Breakthrough Therapy Designation for Investigational Daclatasvir-based Hepatitis C Regimen

Breakthrough Designation for daclatasvir and sofosbuvir combination is supported by the recently presented ALLY-1 trial in patients with advanced cirrhosis or recurrent hepatitis C (HCV) after liver transplant

FDA Designation signifies that high unmet need still exists among these patient populations despite other available therapies

This Designation is separate from the FDA’s ongoing NDA review of a daclatasvir-sofosbuvir regimen for the treatment of patients with genotype 3 HCV

FDA Okays Hep-C Investigational Combo for Post-Transplant Patients

May 20, 2015 | Gale Scott

Based on favorable results from the ALLY-1 trial, the US Food and Drug Administration (FDA) has amended its breakthrough therapy designation for a hepatitis-C drug combo.

The change means that daclatasvir (Daklinza/ Bristol-Myers Squibb) and sofosbuvir (Sovaldi/Gilead ) may now be given to patients who have hepatitis C infections with either advanced cirrhosis or infections that have come back after patients received a liver transplant.

The trial results were presented last month at the 2015 International Liver Congress in Vienna, Austria.

The trial found the treatment worked for patients with hepatitis C viral genotype 1, a common type in the US.

These patients had advanced liver disease, classified as Child-Pugh class B or class C and are difficult to cure.

Discussing the trial results in an interview in Vienna last month, investigator Fred Poordad, MD, of the University of Texas Health Science Center in San Antonio, TX, said eradicating the virus is difficult, even after transplantation. The virus continues to live in the patient’s blood and most patients who get a transplant who were infected before the surgery will develop cirrhosis within 5 years, Poordad said.

The FDA first granted a breakthrough therapy designation for the drug combo in 2013. It is given for 12 weeks, once daily, in combination with ribavirin.

The ALLY-1 study was the third to be reported as part of the Bristol-Myers Squibb ALLY research program. Two others, ALLY-2 and ALLY-3, were presented at the 2015 Conference for Retroviral and Opportunistic Infections and the 2014 American Association for the Study of Liver Diseases' The Liver Meeting, respectively. Additionally, the European Association for the Study of the Liver included the ALLY regimen in HCV treatment guidelines it issued last month.

The FDA is currently reviewing a new drug application for the use of daclatasvir and sofosbuvir to treat patients with HCV genotype 3. Daclatasvir was approved in Europe in August 2014 for use in combination with other drugs across genotypes 1, 2, 3 and 4 for the treatment of HCV infection in adults. Beyond Europe, it is approved in Japan, as well as multiple countries in Latin and South America, the Middle East and Asia Pacific.

Source - http://www.hcplive.com/product-news/FDA-Okays-Hep-C-Investigational-Combo-for-Post-Transplant-Patients#sthash.ygQiBWqa.dpuf

Related:
Hep C landscape shifts again as BMS combo nabs breakthrough tag

Bristol-Myers pointed out that this is separate from the FDA's consideration of the combo drug for treatment of patients with genotype 3 hep C. The combo drug has been approved in Japan and in some countries in Europe but has yet to get an FDA nod so that it can find its place in a market that Gilead had to itself for a year before AbbVie got its combo drug approved late last year.

AbbVie is just getting started in the market, but ...

BMS announces 12-week HCV regimen of daclatasvir and sofosbuvir at EASL

ALLY-1 Trial Results Show Investigational Daclatasvir-Based Regimen Cures 94% of Post-Liver Transplant Patients with Hepatitis C and Up to 94% of Hepatitis C Patients with Cirrhosis (Child-Pugh Class A or B)

97% of post-transplant patients with HCV genotype 1a achieved cure

91% of post-transplant patients with HCV genotype 3 achieved cure

No need seen to alter existing transplantation medication regimens

Saturday, April 25, 2015 10:00 am EDT

(PRINCETON, N.J., APRIL 25, 2015) – Bristol-Myers Squibb Company (NYSE:BMY) today announced that primary endpoints were successfully met in ALLY-1, a Phase III clinical trial evaluating a 12-week regimen of daclatasvir and sofosbuvir once-daily with ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) with either advanced cirrhosis or post-liver transplant recurrence of HCV. The data was presented as a late-breaker at The International Liver Congress™ 2015, the 50th annual meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria from April 22-26.

“The results of the ALLY-1 trial point to the potential of this investigational daclatasvir-based regimen in a patient population with high unmet needs despite recent advances in hepatitis C treatment,” said Fred Poordad, M.D., ALLY-1 Lead Investigator and Clinical Professor of Medicine at The University of Texas Health Science Center at San Antonio. “Transplant patients take a variety of immunosuppressive medications to prevent organ rejection; that complicates the treatment of hepatitis C. In ALLY-1, we saw no drug-drug interactions between transplant and hepatitis C therapies and no need to make dose adjustments to patients’ transplant-related drugs while they received the daclatasvir-based regimen that resulted in high SVR12 rates.”

The study’s primary endpoints were reached, with 95% of post-transplant genotype 1 patients and 82% of genotype 1 patients with advanced cirrhosis achieving SVR12. Among all ALLY-1 patients, 94% of those with post-transplant HCV recurrence and 83% of all participants with advanced cirrhosis achieved cure (sustained virologic response 12 weeks after treatment; SVR12).

The Child-Pugh scoring system is commonly used to assess the severity and prognosis of chronic liver disease and cirrhosis, and uses an A through C classification (C being the most advanced) to categorize disease progression. Patients with class C cirrhosis are decompensated, often with later-stage conditions such as ascites (the build-up of fluid in the abdomen), hepatic encephalopathy (confusion or altered level of consciousness due to the liver’s inability to remove toxins from the blood), and abnormal liver function, which can complicate treatment. The ALLY-1 trial included 16 patients with decompensated cirrhosis Child-Pugh class C; nine (56%) achieved SVR12.

Over the course of the study, four advanced cirrhotic patients received a liver transplant during treatment; 3 of 4 extended treatment post-transplant (see study design below), and all 4 achieved SVR12.

In the study, there were no serious adverse events related to study medications throughout the treatment phase. The most common adverse events (≥10%) were headache (15%, 36%), fatigue (18%, 28%), anemia (20%, 19%), diarrhea (8%, 19%), nausea (17%, 6%), and arthralgia (2%, 13%) in the advanced cirrhotic and post-transplant cohorts, respectively. One patient discontinued therapy after 31 days due to headache, but still achieved SVR12. Nine patients in the cirrhosis cohort relapsed post-treatment, and one had detectable HCV RNA at the end of treatment; there were no on-treatment virologic breakthroughs. Three patients (genotypes 1a, 1b, 3) in the post-transplantation cohort relapsed. All 12 patients with relapse are being retreated with daclatasvir and sofosbuvir with ribavirin for 24 weeks.

HCV is the leading indication for liver transplantation worldwide. Without treatment, HCV infection of the new liver after transplant is inevitable, and is associated with rapid progression to cirrhosis and death in up to 30% of patients within 5 years. The ALLY-1 study is the third study to report out of the Phase III ALLY program, which evaluates daclatasvir in combination with sofosbuvir in multiple high-unmet need patient populations and is at the center of Bristol-Myers Squibb’s HCV research focus. The ALLY-2 and ALLY-3 studies have previously been presented at the 2015 Conference for Retroviral and Opportunistic Infections and the 2014 American Association for the Study of the Liver’s The Liver Meeting, respectively, and subanalyses from each study with the ribavirin-free regimen of daclatasvir and sofosbuvir were presented as posters during EASL 2015.

Additionally, EASL issued 2015 Hepatitis C treatment guidelines that include a regimen of daclatasvir+sofosbuvir as the first 12-week treatment for patients with genotype-3 virus. The EASL guidelines now list daclatasvir+sofosbuvir regimens as options for treating all HCV genotypes and for use with patients coinfected with HCV/HIV. (Guidelines available here.)

Other Bristol-Myers Squibb presentations at The International Liver Congress included data from compassionate use programs in the EU that add to the real-world clinical evidence informing the use of daclatasvir-based regimens to treat patients with HCV conditions posing high unmet medical needs.

“The ALLY-1 trial results build off the ALLY-2 and ALLY-3 studies by demonstrating the versatility of the daclatasvir-based regimen to provide HCV cure in multiple patient populations that have been historically hard to manage, such as HCV genotype 3 patients, HIV/HCV coinfected patients, and patients with decompensated cirrhosis,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “Post-liver transplant and cirrhotic patients represent a still-unmet need and continue to present challenges to currently available regimens.”

About ALLY-1: Study Design

This Phase III open-label clinical trial enrolled treatment-naïve and treatment-experienced patients with HCV infection of any genotype in 2 cohorts: advanced cirrhosis (n=60) and post-liver transplant with HCV recurrence (n=53). All patients received daclatasvir 60 mg plus sofosbuvir 400 mg once-daily with ribavirin initially dosed at 600 mg/d (with potential for adjustment based on hemoglobin levels and creatinine clearance) for 12 weeks. Patients receiving a variety of immunosuppressive agents were permitted. In the cirrhosis cohort, patients transplanted during treatment could receive 12 weeks of extended treatment immediately post-transplant, regardless of treatment duration before transplant. The primary endpoint was the SVR12 rate (defined as HCV RNA <LLOQ (25 IU/mL) at post-treatment week 12) among genotype 1 patients in each cohort.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Approximately 170 million people worldwide are infected with hepatitis C. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 20 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with co-morbidities.

Daclatasvir was approved in Europe in August 2014 for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Beyond Europe, it is approved in Japan, as well as multiple countries in Latin and South America, the Middle East and Asia Pacific. Additionally, the U.S. FDA currently is reviewing a New Drug Application (NDA) for the use of daclatasvir and sofosbuvir to treat patients with HCV genotype 3.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that daclatasvir will receive regulatory approval in the United States, or if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Media:
Robert Perry, Office: 609-419-5378, Cell: 407-492-4616, rob.perry@bms.com

Investors:
Ranya Dajani, 609-252-5330, ranya.dajani@bms.com

EMA recommends avoidance of certain hepatitis C medicines and amiodarone together

EMA recommends avoidance of certain hepatitis C medicines and amiodarone together

Concomitant use may increase risk of slow heart rate and related problems

EMA has confirmed a risk of severe bradycardia (slow heart rate) or heart block (problems with conduction of electrical signals in the heart) when the hepatitis C medicines Harvoni (sofosbuvir with ledipasvir) or a combination of Sovaldi (sofosbuvir) and Daklinza (daclatasvir) are used in patients who are also taking the medicine amiodarone, which is an antiarrhythmic (a medicine used to treat irregular heartbeat).

To manage this risk the Agency recommends that amiodarone should only be used in patients taking these hepatitis C medicines if other antiarrhythmics cannot be given. If concomitant use with amiodarone cannot be avoided, patients should be closely monitored. Because amiodarone persists for a long time in the body, monitoring is also needed if patients start such hepatitis C treatments within a few months of stopping amiodarone.

The recommendations follow a review1 of cases of severe bradycardia or heart block in patients taking amiodarone who started treatment with the hepatitis C combinations. It was considered that there was a likely relationship of these events to the medicines. The possible mechanism behind these effects is unknown and further investigation of other cases with Sovaldi and other hepatitis C medicines is ongoing.

Information for patients
A few cases of severe slow heart rate or interference with electrical signals in the heart have been reported in patients taking the medicines Harvoni or Sovaldi plus Daklinza (used to treat hepatitis C, a liver infection) at the same time as the heart medicine amiodarone.
Most of these cases occurred within 24 hours of starting the hepatitis C medicine but some occurred after up to 12 days. Two of the patients needed treatment with a pacemaker and one patient died.
Patients who need these hepatitis C combinations should not also be given amiodarone unless there is no other suitable alternative.
If there is no alternative to giving amiodarone at the same time as the hepatitis C medicine, patients’ heart function must be carefully monitored by the doctor. This may include monitoring in hospital for 48 hours after starting treatment.
Because amiodarone remains in the body for a long time, monitoring is also needed when the hepatitis C treatment is given to patients who stopped amiodarone treatment within the last few months.
Patients who are taking Harvoni or Sovaldi and Daklinza at the same time as amiodarone, with or without other heart medicines, and who experience symptoms such as slow heartbeat, dizziness, faintness, unusual tiredness, shortness of breath or chest pain during treatment should contact their doctor immediately.
Patients who have any concerns about their treatment should discuss them with their doctor or pharmacist.

Information for healthcare professionals
Severe bradycardia and heart block have been reported in patients taking amiodarone and Harvoni, or amiodarone and a combination of Sovaldi and Daklinza. Of 8 cases reviewed up to April 2015, one case resulted in fatal cardiac arrest and two required pacemaker intervention.
Onset of bradycardia was within 24 hours of initiating hepatitis C treatment in 6 cases and within 2 to 12 days in the other 2 cases. Rechallenge in the context of continued amiodarone treatment resulted in recurrence of symptomatic bradycardia in 2 cases. Recurrence was also seen on rechallenge with the antivirals 8 days after stopping amiodarone, but not 8 weeks after stopping.
Amiodarone should only be initiated in patients treated with Harvoni, or Sovaldi plus Daklinza, if other antiarrhythmics are contra-indicated or not tolerated.
If concomitant use with amiodarone is unavoidable, patients should be closely monitored, particularly during the first weeks of treatment. Those at high risk of bradyarrhythmia should be monitored in an appropriate clinical setting for 48 hours after starting concomitant treatment.
Due to its long half-life, patients who have discontinued amiodarone within the past few months should also be monitored when starting hepatitis C treatment with Harvoni or Sovaldi plus Daklinza.
Patients receiving these hepatitis C medicines with amiodarone, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.

The product information for Harvoni, Sovaldi and Daklinza will be updated appropriately. A letter will also be sent to healthcare professionals involved in hepatitis C treatment explaining these risks and the measures to manage them.

Because the number of patients taking amiodarone who have been exposed to Harvoni or Sovaldi in combination with Daklinza is unknown, it is not possible to estimate the incidence of occurrence of these events. The mechanism behind the findings has not been established.

More about the medicine

Harvoni, Sovaldi and Daklinza are among several novel hepatitis C treatments recently evaluated by EMA, which are available as tablets. They have simplified the management of the disease and allow the prospect of curing the infection. Sovaldi (sofosbuvir) was authorised in the EU in January 2014, Daklinza (dataclasvir) in August 2014 and Harvoni (sofosbuvir/ledipasvir) in November 2014.

The active substance sofosbuvir blocks the action of an enzyme called ‘NS5B RNA-dependent RNA polymerase’, while dataclasvir and ledipasvir target a protein called ‘NS5A’; by blocking these targets the medicines stop the hepatitis C virus from multiplying and infecting new cells.

1The review was in the context of a “safety signal”. A safety signal is information on a new or incompletely documented adverse event that is potentially caused by a medicine and that warrants further investigation. The presence of a safety signal does not necessarily mean that a medicine has caused the reported adverse event.

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