Reconsidering Whether to Treat Genotype 1 HCV Patients or Wait for All-Oral Therapy

Source - Clinical Thoughts @ Clinical Care Options

Post-EASL Update:
Reconsidering Whether to Treat Genotype 1 HCV Patients or Wait for All-Oral Therapy
Paul Y. Kwo, MD
 5/12/2014
 More from this author

At the recent 2014 meeting of the European Association for the Study of Liver Disease (EASL) in London, extraordinary data were presented from large phase III trials involving the direct-acting antiviral (DAA) combinations of sofosbuvir plus ledipasvir and ABT-450/ritonavir plus ombitasvir and dasabuvir, each administered with and without ribavirin. Sustained virologic response (SVR) rates > 94% were reported with use of fixed-dose sofosbuvir/ledipasvir with or without ribavirin in genotype 1 treatment-naive patients and treatment-experienced patients (including protease inhibitor–exposed patients), including high SVR rates among the subsets of patients with cirrhosis. Similarly, the combination of fixed-dose ABT-450/ritonavir/ombitasvir with dasabuvir and ribavirin resulted in SVR rates > 95% in trials for treatment-naive and treatment-experienced patients, and > 90% in a trial for cirrhotic patients. In addition, small phase II studies demonstrated high SVR rates with the use of sofosbuvir/ledipasvir in HCV/HIV-coinfected patients, and with use of ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin in patients with recurrent HCV infection following orthotopic liver transplant. These high SVR rates were achieved without the addition of interferon, the backbone of hepatitis C therapy for the past 2 decades. These investigational therapies are expected to be approved by the FDA before the end of 2014. Clinicians will then be able to offer all-oral therapies for patients across all HCV genotypes with the expectation of high SVR rates.

In the United States, high SVR rates can currently be achieved in genotype 1 HCV–infected patients who are treatment naive and interferon eligible with the use of peginterferon, ribavirin, and sofosbuvir. This combination resulted in an overall SVR rate of 89% with a 12-week treatment course in the phase III NEUTRINO study. For patients who have been treated previously with peginterferon/ribavirin and those who are interferon ineligible, the combination of sofosbuvir and simeprevir with or without ribavirin has been recommended as a therapeutic option in the 2014 AASLD/IDSA treatment guidelines based on high SVR rates demonstrated in the phase II COSMOS study.

How I’m Currently Managing Genotype 1 Patients
In my practice, all genotype 1 patients are candidates for therapy at this time, although histologic disease severity strongly guides my treatment recommendations. For genotype 1 patients, we offer peginterferon, ribavirin, and sofosbuvir as first-line therapy, but we strongly encourage patients to consider waiting for the all-oral regimens that are likely only months away from FDA approval, particularly those individuals with mild disease (F0-F2) in whom deferral of therapy is unlikely to lead to adverse clinical outcomes. Given the phase III data that have been presented, I find that virtually all patients with milder disease wish to defer therapy in order to have the opportunity to achieve SVR without interferon. Moreover, patient monitoring is significantly less complicated without use of interferon, even with the shorter treatment courses currently recommended for genotype 1 patients. This approach also applies to patients with milder disease (F0-F2) who have previously failed treatment.

By contrast, patients with advanced fibrosis, including those with F3/F4 fibrosis, are given the option of receiving therapy now. These individuals require careful assessment of the degree of advanced fibrosis as they are at risk for decompensating and are also screened regularly for hepatocellular cancer. In a subanalysis of the phase III NEUTRINO study, high SVR rates were reported across all degrees of fibrosis following treatment with 12 weeks of sofosbuvir, peginterferon, and ribavirin, with patients having proven histologic cirrhosis by biopsy demonstrating an SVR rate of 78% whereas those with F3 fibrosis demonstrated an SVR rate of 89%. By historical standards, these are excellent SVR rates but are still numerically lower than rates reported from recent phase III all-oral therapy trials. After careful assessment, if I am confident that a patient’s fibrosis level is F3, I can tell them that they can safely defer therapy if they wish and that they will be followed closely, or they are offered peginterferon, ribavirin, and sofosbuvir or simeprevir with sofosbuvir, if available to them.

In my practice, patients with cirrhosis are all offered therapy. The phase II COSMOS study demonstrated high SVR rates with 12 weeks of sofosbuvir plus simeprevir with or without ribavirin in patients with F3/F4 fibrosis (94% to 100% in F3 fibrosis and 86% to 91% in F4) in both treatment-naive patients and null responders, and this is my preferred regimen in this population given the numerically higher SVR rates, regardless of whether the patient can tolerate interferon or not. In the COSMOS study, relapse was only seen in patients with genotype 1a HCV, of whom 2 of 3 relapsers had the Q80K polymorphism that is present in almost one half of genotype 1a individuals in North America and reduces susceptibility to simeprevir. Therefore, in genotype 1b patients, I recommend sofosbuvir plus simeprevir, and in patients with genotype 1a, I recommend sofosbuvir plus simeprevir with ribavirin. This option is particularly beneficial in patients with greater degrees of advanced fibrosis and portal hypertension, who are less likely to tolerate interferon, and in whom the CUPIC cohort study recently demonstrated that platelet count < 100,000/mm3 and albumin < 3.5 g/dL were associated with a significant risk of decompensation and/or severe infections.

There are of course circumstances that may necessitate immediate therapy initiation in patients with milder histologic disease, such as those who have significant extrahepatic manifestations of HCV infection (such as membranoproliferative glomerulonephritis). In addition, some patients do not wish to defer, regardless of disease severity. In my practice, these individuals are offered either peginterferon, ribavirin, and sofosbuvir or simeprevir plus sofosbuvir, if available to them. It is estimated that there are at least 500,000 individuals with advanced fibrosis in the United States, and it is this group that represents the highest priority for initiating therapy now. However, those with genotype 1 HCV will likely have FDA-approved all-oral therapies available to them by the end of 2014, with SVR rates that could not have been imagined 5 years ago.

Your Thoughts?
I’m interested to hear about your own approach to managing patients with genotype 1 HCV, given the recent data presented at EASL 2014 and in anticipation of further drug approvals in the coming year. Which patients are you currently advising to defer therapy, and which are you most concerned to treat now?

Conference Program:
Highlights
•Capsule Summaries (18)
•Expert Analysis (CME) (Coming soon)
•Downloadable slideset

Topics: HCV - Treatment

Just In - Video:EASL Recommendations on Treatment of Hepatitis C, 2014

Watch - EASL Recommendations on Treatment of Hepatitis C, 2014 

Uploaded May 7  EASLEurope

HCV recommendations presented by Prof. Jean-Michel Pawlotsky at the International Liver Congress™ 2014, London, are now publicly available for the benefit of all.

In April the European Medicines Agency (EMA) released new recommendations on the treatment of hepatitis C at the EASL International Liver Congress 2014 meeting, in addition the World Health Organization (WHO) issued its first guidance for the treatment of hepatitis C as well.

Advances in Chronic Hepatitis C Management and Treatment - EASL 1.5-hour Internet symposium

When new education-related information on hepatitis is released online this blog provides background information and links to the new activity.   

ViralEd just released an 1.5-hour Internet symposium discussing key data presented at the 49th Annual Meeting of the European Association for the Study of the Liver (49th EASL) which took place this month in London, England.

Advances in Chronic Hepatitis C Management and Treatment

Highlights
HCV Therapies In Treatment Naive Patients
HCV Therapies In Treatment Experienced Patients 
Studies In HIV/HCV Co-Infection and Other Public Health Issues

Like any site offering continuing medical education (CME), it requires a free quick registration.

1- When prompted type in your name and email address
2- Click "Go To Program"

Be patient, depending on your Internet connection it may take a few moments to load.

 CLICK HERE TO BEGIN

Faculty
Nezam H. Afdhal, MD
Professor of Medicine
Harvard School of Medicine
Chief of Hepatology, Director of Liver Center
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Fred Poordad, MD
VP, Academic and Clinical Affairs
The Texas Liver Institute
Clinical Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas

K. Rajender Reddy, MD
Professor of Medicine
Professor of Medicine in Surgery
Director of Hepatology
Director, Viral Hepatitis Center
University of Pennsylvania
Philadelphia, Pennsylvania

AM News- New Hep C Drugs a Bargain Compared to Alternatives and A Cup Of Joe

Can Coffee Treat Liver Disease?
Rowen K. Zetterman, MD / Medscape Gastroenterology
Coffee and Mortality More than 2.25 billion cups of coffee are consumed each day throughout the world. This requires harvesting and roasting 7 million tons of coffee beans every year.[1] Although coffee consumption varies from country to country, most Americans drink coffee daily. Despite early concerns about the deleterious effects of coffee on health, contemporary studies suggest that coffee is beneficial for many medical disorders, including Parkinson disease, diabetes mellitus, symptomatic gallbladder disease, stroke, and chronic liver diseases......

 New Hep C Medicines a Bargain Compared to Alternatives
Drugmaker Studies Find a Bargain in $84,000 Medicine .... Older approaches required injections of two medicines, the immune-system booster interferon and the antiviral ribavirin, for as long as a year, causing side effects including flu-like symptoms and anemia. Combined with Vertex Pharmaceuticals Inc.’s Incivek, those treatments cost almost $200,000 per cure ....
Continue reading @ Bloomberg

Hepatitis C drugs not reaching poor
Ewen Callaway
15 April 2014
Campaigners in India have been calling for access to cheap hepatitis C treatments. The publication last week of the first treatment guidelines for hepatitis C virus (HCV), and the advent of drugs that can cure most infections of the virus, have left public-health researchers with a touch of déjà vu.

Three decades after wrestling to lower the cost of AIDS drugs (prices fell from about US$10,000 per patient per year in the 1990s to less than $100 in the mid-2000s), they are once again asking how expensive life-saving medicines can be made affordable for patients.
Continue Reading @ Nature News
.
FAQ: The High Cost of Hepatitis C Drugs
WebMD asked experts and the drugmakers to address the most frequently asked questions about these two pricey ''game-changers'' and got some predictions about future treatment costs.

Related - Reducing the cost for Gilead's hepatitis C drug Sovaldi

Investment Commentary
J&J beats forecasts as new drugs shine, shares jump
"Strong pharmaceuticals results showcased a very strong 2014 start for J&J," said Morningstar analyst Damien Conover, referring to sales growth of almost 11 percent for prescription medicines in the quarter. He cited especially strong sales of immunology medicines and for the company's recently approved Olysio treatment for hepatitis C.

Big Pharma
Medicines agency sends report on Roche to EU Commission
The EMA previously said in November it had not uncovered any new safety issues connected with Roche's drugs as a result of the shortcomings in reporting adverse events.
EMA launched its probe into Roche in 2012 after a routine inspection found the firm had failed to properly assess tens of thousands of cases of possible adverse drug reactions, involving 19 drugs, several of which were for cancer.
Full Story

Related 2012
EMA Probes Roche For Reporting Failures  

Liver Cancer
Hepatocellular carcinoma: new advances in diagnosis, staging and treatment all predicted to improve patient outcomes
"Human hepatocellular carcinoma is one of the most prevalent cancers worldwide and the second most frequent cause of cancer-related death," said EASL's Scientific Committee Member Dr Helen Reeves Senior Lecturer & Honorary Consultant Gastroenterologist at Newcastle Hospitals NHS Foundation Trust, UK.

"Because HCC is such an extremely diverse and heterogeneous disease, improving patient outcomes has proved a difficult undertaking. A number of existing therapeutic options have been subjected to rigorous study but have not shown any patient benefit. The findings from these HCC diagnosis, staging and treatment studies are important because they have the potential to significantly improve patient outcomes," Dr Reeves explained.
Full story @ Medical News Today

Tough liver cancer may be treated with immunotherapy
Significant new data presented at the International Liver Congress™ 2014 indicate that liver cancer (Hepatocellular Carcinoma (HCC)) may be treated by adoptive T-cell therapy.

More Than Drugs: The Continuum of HCV Care

Benjamin Young, MD, PhD, Fabienne Laraque, MD, PhD, Mario U. Mondelli, MD, PhD, Kosh Agarwal, MD, Jeffrey Kwong, DNP, MPH, ANP-BC

April 14, 2014 
During the International Conference on Viral Hepatitis, held recently in New York, participants in a panel discussion titled "Strengthening the HCV Continuum of Care"^[1] convened afterward for a discussion. During the conversation, they discussed why the continuum of care is important in treating hepatitis C for both patients and providers....
Continue reading @ Medscape

Medscape Medical News, April 14, 2014
EASL Triple Combination Works in Cirrhotic Hepatitis C Patients  
The all-oral antiviral regimen was highly effective and well tolerated in a hard-to-treat group of patients with hepatitis C genotype 1 and cirrhosis....

Continue reading @ Medscape

Single Daily Pill, No Ribavirin, Eliminated Hep C in 94–99% of Patients 
Trials Advance Hunt for All-Oral HCV Tx
4/14/2014

LONDON -- A single-pill combination of two drugs for hepatitis C (HCV) had impressive results in two large studies, with cure rates ranging from 94% to 99%, researchers said.  

Continue Reading @ Medpage Today

3D Combo Works in Cirrhotic HCV Patients, Too

4/14/2014

LONDON -- A drug combination with striking efficacy in relatively healthy hepatitis C patients had similar outcomes in patients with compensated cirrhosis, a researcher said. 

Continue Reading @ Medpage Today

 

New At Healio

ION 2: Longer sofosbuvir/ledipasvir treatment may be unnecessary in previous failures
LONDON — Twelve weeks of treatment with the fixed-dose combination of Gilead’s sofosbuvir and ledipasvir — without ribavirin — may be sufficient to treat patients with hepatitis C virus who had failed previous therapies, according to findings presented here.

Nezam Afdhal, MD, of the Beth Israel Deaconess Medical Center in Boston, presented findings for 440 patients from the phase 3 ION-2 study, which investigated the fixed-dose formulation of sofosbuvir (Sovaldi) 400 mg/ledipasvir 90 mg in treatment-experienced patients with genotype 1 disease. The study included four patient cohorts: those treated for 12 weeks with or without ribavirin and those treated for 24 weeks with or without ribavirin.
 Full Story....

Sofosbuvir with GS-5816 shows pan-genotypic activity
LONDON — Combination therapy with sofosbuvir and the investigational compound GS-5816 yielded 12-week sustained viral response rates in patients with hepatitis C virus genotypes, according to findings presented by Gregory T. Everson, MD, of the University of Colorado in Denver.
Everson described GS-5816 as an HCV NS5A inhibitor that demonstrated pan-genotypic activity in a previous 3-day monotherapy study.

 

The current study is a phase 2 investigation of GS-5816 (Gilead) with sofosbuvir (Sovaldi, Gilead) in treatment-naive genotype 1 to 6 HCV-infected patients without cirrhosis.
Full Story..

EASL Commentary and Updates From Executive Director of NATAP - National AIDS Treatment Advocacy Project, Mr. Jules Levin

EASL: Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype-1 prior null responders with METAVIR F0-2: COSMOS study subgroup analysis - (04/14/14)

EASL: Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype-1 prior null-responder / treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with METAVIR F3-4 (Cohort 2) - (04/14/14)

Phase 3 Studies:
EASL: All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With Or Without Ribavirin for 12 or 24 Weeks in Treatment-Naive Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study - (04/14/14)

EASL: All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients: The Phase 3 ION-2 Study - (04/14/14)

EASL: Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in Treatment-Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study - (04/11/14)

EASL: TURQUOISE-II: SVR12 RATE OF 92-96% IN 380 HEPATITIS C VIRUS GENOTYPE 1-INFECTED ADULTS WITH COMPENSATED CIRRHOSIS TREATED WITH ABT-450/r/ABT-267 AND ABT-333 PLUS RIBAVIRIN - (04/14/14)

EASL: SAPPHIRE-I: PHASE 3 PLACEBO-CONTROLLED STUDY OF INTERFERON-FREE, 12-WEEK REGIMEN OF ABT-450/r/ABT-267, ABT-333, AND RIBAVIRIN IN 631 TREATMENT-NAïVE ADULTS WITH HEPATITIS C VIRUS GENOTYPE 1 - (04/11/14)

EASL: SAPPHIRE-II: PHASE 3 PLACEBO-CONTROLLED STUDY OF INTERFERON-FREE, 12-WEEK REGIMEN OF ABT-450/r/ABT-267, ABT-333, AND RIBAVIRIN IN 394 TREATMENT-EXPERIENCED ADULTS WITH HEPATITIS C VIRUS GENOTYPE 1 - (04/10/14)

View all updates here........ 

Stay Updated

Link To EASL Coverage, Slide Presentations, Expert Analysis, and Commentary

Categorized by antiviral agent and pharmaceutical company. 

LHC Better Living: Destigmatizing Hepatitis C

.

EASL- Antiviral Regimen for Hepatitis C with Cirrhosis

International Liver Congress 2014 
The New England Journal Of Medicine NEJM 

Original Article
Curing Chronic Hepatitis C: The Arc of a Medical Triumph 
Podcast -  Listen
Chronic hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. Some 130 million to 170 million people, or about 3% of the world's population, are chronically infected with the hepatitis C virus (HCV). In the United States, chronic hepatitis C, the most common cause of liver-related death and reason for liver transplantation, recently eclipsed human immunodeficiency virus (HIV) infection as a cause of death. The development of direct-acting antiviral agents (DAAs) has revolutionized HCV treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans. This success can be traced to important scientific, clinical, and regulatory developments.. 

Treating Hepatitis C in Lower-Income Countries
Just two decades after the identification of hepatitis C virus (HCV), an improved understanding of the viral lifecycle has led to several new classes of highly promising therapies. By as early as 2015, sustained virologic response rates will be in the 90% range for most HCV genotypes, and this effective “cure” will be achieved through short, convenient courses of interferon-free, fixed-dose, single-pill regimens with adverse-effect profiles that are markedly better than those of past treatments. The use of these agents is expected to reduce the intensity of follow-up monitoring, the rate of hospitalizations for adverse effects, dependence on specialist care, and resource demands associated with disease progression, including those for liver transplantation and management of end-stage liver disease and liver cancer. However, with drug costs that may exceed $90,000 per course, it remains to be seen how these remarkable advances will extend to the estimated 150 million people with HCV infection living outside the target high-income markets for these agents...
  
Editorial
Therapy for Hepatitis C: The Costs of Success
Welcomed and exciting results from three large, controlled trials of different regimens of oral antiviral agents for chronic hepatitis C, genotype 1, have now been published in the Journal.1-3 The regimens all included the combination of ledipasvir and sofosbuvir, two new direct-acting antiviral agents with potent activity against hepatitis C virus (HCV). The two drugs were given as a single tablet once daily for 8, 12, or 24 weeks, with or without ribavirin. The results were consistent and striking: the various regimens yielded rates of sustained virologic response of 93% to 99%. The combination of ledipasvir and sofosbuvir alone (without ribavirin) for 12 weeks was associated with response rates of 94% in the ION-2 study and 99% in the ION-1 study.1,2 Extending therapy to 24 weeks increased the rate minimally (to 98% and 99%, respectively). In contrast, adding ribavirin provided no further benefit, regardless of duration. In previously untreated patients without cirrhosis, shortening the duration of therapy (without ribavirin) to 8 weeks did not lessen the rate of response (94%, vs. 95% with 12 weeks of therapy in the ION-1 study).3 Importantly, the single-tablet regimen was easy to administer and had few side effects; among the 539 patients who received ledipasvir and sofosbuvir alone for 12 weeks in these three trials, only 2 stopped therapy early because of adverse events....

Original Article
Retreatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin
In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon–ribavirin. 

Without Cirrhosis
Treatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin  
The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis.

Antiviral Regimen for Hepatitis C with Cirrhosis
ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis
Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis.

Without Cirrhosis
Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis
High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen.

Original Article 
Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection.

EASL-Studies Help Clarify Optimal Use of Combination Therapy in Chronic Hepatitis B Patients

Studies Help Clarify Optimal Use of Combination Therapy in Chronic Hepatitis B Patients

Three new studies presented at the International Liver Congress 2014 have helped clarify the optimal use of combination therapy with peginterferon and nucleoside analogues (NUCs) to achieve the best treatment outcomes in patients with chronic hepatitis B (CHB).

"Together these ground-breaking data will go a long way to influencing future CHB treatment guidelines," says EASL's educational counselor professor Cihan Yurdaydin from the Department of Gastroenterology at the University of Ankara, Turkey.

In the first study , CHB patients who had failed on prior long-term exposure to one of the nucleoside analogue (NUC) antivirals demonstrated high rates of complete response and HBsAg loss when prescribed a sequential combination of peginterferon and NUC.

In the second study , adding peginterferon to the nucleoside analogue entecavir was shown to enhance response rates and viral decline in HBeAg-positive CHB patients with compensated liver-disease, was generally safe and well tolerated, and may facilitate the discontinuation of entecavir.

Finally, data from a third study suggested that adding on a NUC for six weeks to PegIFNalfa-2a does not enhance treatment response, with no increase in HBeAg seroconversion rates beyond that achieved by PegIFNα-2a alone after 24 weeks follow-up.

Sequential combination therapy of peginterferon and nucleoside analogues results in high rates of complete response and HBsAg loss in CHB patients who have failed on prior long-term exposure to NUCs.

Chronic hepatitis B (CHB) patients who have failed on prior long-term exposure to one of the nucleoside analogue (NUC) antivirals may respond to a sequential combination of peginterferon and NUC.

Compared with NUC monotherapy, significantly more patients in the combination therapy group achieved complete response (HBeAg loss composited with HBV DNA< 2000 IU/ml) (60.24% vs. 13.8%) and HBsAg loss (27.7% vs. 0%).

"These new data are likely to result in clinicians giving greater consideration to the potential role of sequential combination therapies and the benefits this can deliver for patients," said Professor Yurdaydin.

192 patients who had received at least two years treatment with NUCs without achieving HBeAg loss or seroconversion were treated with 48-week combination therapy with additional Peg-IFN to on-going NUCs or NUCs monotherapy.

Out of this population, 83 patients were treated with combination therapy and 109 patients were treated with NUCs monotherapy. All patients were followed for a further 24 weeks and the HBsAg level was measured both during treatment and post-treatment.

The HBsAg level at baseline, week 12 and week 24 appeared to be strong predictors of treatment responses in the combination group.

In patients with baseline HBsAg ≥1000IU/mL, the response rate was significantly lower in those who experience no decline in HBsAg level at week 12
However, patients with HBsAg decline of more than 0.5logIU/mL at week 12 or 1.5logIU/mL at week 24 still had a chance to achieve a treatment response

"These data suggest combination therapy can be guided by the baseline level of HBsAg as well as by monitoring the rate of HBsAg decline in response to treatment," Yurdaydin says.

Peginterferon add-on during entecavir treatment enhances response rates and viral decline in HBeAg-positive hep B patients with compensated liver-disease, and may facilitate the discontinuation of entecavir.

Adding peginterferon to the nucleoside analogue entecavir enhances response rates and viral decline in HBeAg-positive CHB patients with compensated liver-disease, and is generally safe and well-tolerated. Importantly, peginterferon add-on appeared to prevent relapse and may therefore facilitate the discontinuation of nucleos(t)ide analogues.

At week 96 of the global ARES study, 31% patients in the peginterferon add-on group achieved combined HBeAg loss with hepatitis B virus (HBV) DNA levels < 200 IU/mL, compared to only 20% in the entecavir monotherapy group (p=0.107). 24% of patients in the add-on versus 11% in the monotherapy-arm achieved HBeAg-seroconversion with HBV DNA< 200IU/ml (p=0.029). After adjustment for the difference in HBV DNA levels at week 24, add-on therapy was independently associated with higher response rates (p=0.007).

In terms of other serological parameters, adding peginterferon to entecavir led to a greater decline in HBsAg (0.27 versus 0.04 log10IU/ml), HBeAg (1.10 versus 0.74 log10IU/ml), HBV DNA (1.24 versus 0.85 log10IU/ml) (all p< 0.05), and to a more sustained response after entecavir discontinuation (64% versus 25%; p=0.076). One patient with add-on therapy experienced HBsAg loss (p=0.302).

Presenting the results from this long-term study, Yurdaydin explained the rationale for using peginterferon in combination with a nucleoside analogue antiviral to treat Hepatitis B.

"Nucleoside analogue antivirals, which interfere with the HBV lifecycle, are standard treatment for chronic hepatitis B. They perform well in terms of lowering HBV DNA levels. However, serological response, including HBeAg and HBsAg loss or seroconversion, occurs in only a minority of treated patients, with a resultant negative impact on patient outcomes. Because only a minority of CHB patients achieve HBsAg loss with entecavir, treatment is indefinite for the majority of these patients. Interferon, which has long been the mainstay of hepatitis C treatment, is known to stimulate the natural immune response against viral infections. This synergistic effect should theoretically contribute to improved outcomes for hepatitis B as well," Yurdaydin says. "The results of this study indicate that there is a more durable response in those CHB patients who stopped entecavir after a response through the use of peginterferon as add-on therapy. In order to be able to stop entecavir (or nucleos(t)ide analogue treatment), immune control is needed, and this study has shown that this may be achieved with peginterferon add-on."

In this global, multicenter, investigator-initiated randomized-controlled trial, HBeAg-positive chronic hepatitis B (CHB) patients with compensated liver-disease were randomized into two treatment groups: One group was randomly assigned to take 0.5 mg/day entecavir monotherapy for 48 weeks. The other group received the same dose of entecavir but, after 24 weeks of monotherapy, pegylated interferon alfa-2a (Pegasys) 180 mcg/week was added; this combination therapy was continued up until week 48. Patients with a response at week 48 continued ETV monotherapy up until week 72 (consolidation therapy for 24 weeks) and were then followed for 24 weeks off-treatment. All patients who did not achieve a response at week 48 continued ETV monotherapy throughout the study.

Of the 175 patients in the modified intention-to-treat analysis, 85 were allocated to entecavir + peginterferon add-on therapy and 90 to entecavir-monotherapy. HBV-genotype A/B/C/D was present in 7%/19%/42%/32% of patients, respectively.

Finally, Yurdaydin presented data from a study demonstrating that combination therapy with PegIFNα-2a and a nucleoside analogue (NUC), where the NUC was given for a total of six weeks, did not increase HBeAg seroconversion rates beyond that achieved by PegIFNα-2a alone after 24 weeks follow-up.

A total of 280 HBeAg-positive adults aged ≥18 years with HBV DNA >100,000 copies/mL and ALT ≥2 times upper limit of normal were randomised to receive six weeks treatment with either: adefovir 10mg/day and placebo entecavir, entecavir 0.5mg/day and placebo adefovir, or both placebos. At week four, all patients received PegIFN alfa-2a 180ug/week in combination with the NUC therapy. PegIFN alfa-2a was continued for 48 weeks (total treatment duration 52 weeks). The primary endpoint was HBeAg seroconversion.

The percentage of patients who experienced HBeAg seroconversion ranged from 21-27% at the end of treatment, and from 23-36% after 24 weeks of follow-up. Importantly, there were no statistically significant differences in HBeAg seroconversion rates at the end of treatment, or after 24 weeks of follow-up between any treatment arm.

Treatment was well tolerated with low withdrawal rates for adverse events and laboratory abnormalities across the three treatment groups.

To explain this result, Yurdaydin pointed out the relatively short duration of treatment with the NUC in this trial. "In the ARES study, the NUC was prescribed for a total of 48 weeks, with the combination of peginterferon and NUC prescribed for the last 24 of these 48 weeks. In the sequential combination study, the combination of peginterferon and NUC was prescribed for a total of 48 weeks. However, in marked contrast, in this third study, from the total treatment duration of 52 weeks, patients only received a NUC for six weeks. Traditionally, the NUC would be prescribed as a longer-term suppressive therapy," Yurdaydin says.

Source: EASL

HCV Newsletters Updated - 'Mix-and-match` approach to new hepatitis C drugs

Good morning folks, hope everyone is enjoying this fine weekend.

Since our spring summary of news, and related April HCV Newsletters; The HCV Debate - To Treat Or Defer, ALF published a list of frequently asked questions about liver transplantation, answered by Dr. Gordon the medical director of liver transplantation and hepatology at Lahey Hospital and Medical Center.

In addition new guidelines released at EASL 2014 is suggesting that physicians mix and match HCV agents in order to achieve the most potent interferon-free regimens, view the update provided further down this post.

Liver Lowdown is the monthly general interest e-newsletter of the American Liver Foundation.

 April 2014 Edition 

In This Issue

FEATURE: LIVER TRANSPLANT QUESTIONS AND ANSWERS

Approximately 6,000 liver transplants are performed in the U.S. each year. How do you prepare for a transplant and what is life like after? ALF sits down with a renowned transplant surgeon to help you find the answers.

PATIENT PROFILE
Many people may not realize that livers can come from a live donor. It’s an exciting area and with the shortage of cadaver organs, it can help patients desperately waiting for new livers. Read about one young man’s story of survival and friendship.

AROUND TOWN

ALF patient advocates and staff participates in events across the country to raise much-needed funds for our public education and research programs. Here is what we have been up to during the last month.

IN THE NEWS

The American Liver Foundation is making national news on topics including liver wellness, disease prevention, screening and treatment.

NEWS YOU CAN USE

Should you get tested for hepatitis C? Do you want to know about our upcoming webinars or participate in our Faces of Liver Disease campaign? Here is some information you should know.

ALF APRIL/MAY CALENDAR OF EVENTS

ALF hosts a number of events throughout the year to support liver disease awareness.

Check Us Out On Twitter and Facebook

 .
   

Hepatitis C Trust released a news update in April, and also in March which announced a study exploring the issue of late diagnosis. The Hepatitis C Trust needs your input to help understand why people in the UK are not being tested, this information can be used to raise HCV awareness and improve testing strategies.

Have you been diagnosed with hep C in the last 2 years? Do you think you contracted it more than 15 years ago? If you answer yes to these two questions we would love to talk to you.  

If you are interested in participating please get in touch with Emma Ward by email emma.ward@hepctrust.org.uk  or call 020 7089 6220.

Follow Us On Twitter

   

View all April newsletters, here.

 EASL
Annual Meeting/The International Liver Congress™ 2014
April 9-13

European Medicines Agency (EMA) released new recommendations on the treatment of hepatitis C at the EASL International Liver Congress 2014 meeting, the World Health Organization (WHO) issued its first guidance for the treatment of hepatitis C earlier this week.

Read more here....... 

'Mix-and-match` approach to new hepatitis C drugs
EASL 2014 recommendations for use of new direct-acting antivirals receiving European approval in 2014

Recommendations ranked by strength of clinical trial evidence (A1 – C2)

EASL is also encouraging European physicians to combine products from different pharmaceutical companies to achieve the most potent interferon-free regimens, often in advance of full phase III trial data, in its new hepatitis C treatment guidelines issued on Friday at the International Liver Congress in London.

The guidelines move beyond US recommendations issued in January, which incorporated a small number of off-label uses not included in the US licenses for sofosbuvir and simeprevir.The new guidelines also include daclatasvir, a NS5A inhibitor that is likely to receive approval in Europe later this year.

Guidelines panel chair Professor Jean-Michel Pawlotsky, director of the French National Reference Centre for Viral Hepatitis B, C and Delta told reporters that the EASL guidelines were designed to accommodate the diversity of European populations and reimbursement practices. The guidelines were also designed to empower physicians to obtain permission to use new agents under compassionate access arrangements, prior to licensing, said Dr Alessio Aghemo, a member of EASL’s Scientific Committee and a professor of medicine at the University of Milan.

The EASL guidelines are another sign that when making prescribing decisions for patients with hepatitis C, physicians do not intend to be constrained by licensing indications or the quest of pharmaceutical companies to deliver `exclusive` drug combinations that require prescribers to use co-formulated direct-acting antivirals from one company.

The guidelines make recommendations for all genotypes, and include all direct-acting antivirals that are expected to be licensed in Europe during 2014, including the protease inhibitor simeprevir (Olysio) and the NS5A inhibitor daclatasvir. Simeprevir is likely to receive marketing approval in May 2014 and daclatasvir in September 2014. Bristol-Myers Squibb, the developer of daclatasvir, has anticipated the European move towards a `mix-and-match` approach by applying for a license for daclatasvir alone in Europe. In the United States it is seeking a license for daclatasvir in combination with asunaprevir.

The guidelines recommend that the first-generation protease inhibitors telaprevir or boceprevir should be used for treatment of genotype 1 infection only when newer options are not available. For other genotypes, the combination of pegylated interferon and ribavirin is described as `acceptable` where newer options are not available.

The guidelines will be updated as soon as approval dates for new interferon-free combinations of sofosbuvir/ledipasvir (Gilead Sciences) and ABT-450/ritonavir, ombitasvir and dasabuvir (AbbVie) are known. These are likely to be approved in early 2014.

Source: aidsmap.com 

EASL Updates

Watch - Hepatitis C - DAAs: continuing the advance towards a cure.

This forty minute EASL video highlights data on new drugs to treat hepatitis C presented at this months conference, progressions in treating genotype 4, as well as Hepatocellular Carcinoma (HCC) and cirrhosis.

Stay Updated

Link To EASL Coverage, Slide Presentations, Expert Analysis, and Commentary

Categorized by antiviral agent and pharmaceutical company.

EASL Video/Hepatitis C - DAAs: continuing the advance towards a cure.

The final official EASL press conference
Hepatitis C - DAAs: continuing the advance towards a cure. 

Published on Apr 12, 2014
Highlights data discussions on hepatitis C and progressions in treating genotype 4 and continuing towards a cure as well as Hepatocellular Carcinoma (HCC) and cirrhosis

EASL - Simeprevir- and sofosbuvir-based regimens in HCV genotype 4-infected patients

New data showing efficacy of simeprevir- and sofosbuvir-based regimens in HCV genotype 4-infected patients

Simeprevir with peginterferon and ribavirin is effective and well tolerated in treatment-naïve and treatment-experienced patients infected with HCV genotype 4

London, UK, Saturday 12 April 2014: Results from RESTORE[1], a phase III, multicentre, single-arm, open-label study presented today at the International Liver CongressTM 2014 showed that simeprevir 150 mg once-daily for 12 weeks in combination with peginterferon and ribavirin (followed by 12 or 36 weeks of peginterferon and ribavirin) was effective and well tolerated in hepatitis C virus (HCV) genotype 4-infected patients, consistent with previous observations in HCV genotype 1-infected patients.

Overall, 65.4% of patients achieved SVR12 (82.9% of treatment-naïve, 86.4% of prior-relapser, 60.0% of prior partial-responder and 40.0% of prior null-responder patients). The rapid virological response (RVR) rates in the IL28B CT and TT patient sub-groups were 65.5% and 62.2%, respectively, while 65.6% and 59.5% achieved SVR12, respectively. Among those patients with more severe liver fibrosis (METAVIR score F4), 62.1% and 46.7% achieved RVR and SVR12, respectively.

Response-guided therapy criteria used to identify patients eligible for a total treatment duration of 24 weeks were met by 88.6% and 90.9% of treatment-naïve and prior-relapser patients, respectively. Among them, 93.5% and 95.0%, respectively, achieved SVR12. No patients meeting response-guided therapy criteria experienced on-treatment failure, while three patients experienced viral relapse (treatment-naive, n=2; relapsers, n=1).

“HCV genotype 4 is a strain of virus which currently only has limited treatment options,” said EASL’s Secretary General Professor Markus Peck-Radosavljevic. “We therefore welcome these positive results for the simeprevir-based regimen.”

Although HCV genotype 4 is mainly found in the Middle East, Egypt and Central Africa, it has recently spread in several Western countries, particularly in Europe, with rates of 10% to 24%.[2]

Overall simeprevir was well tolerated; most adverse events (AEs) were grade 1 or 2. Serious AEs were infrequent (five patients [4.7%]; no deaths) and considered unrelated to simeprevir. Most frequent AEs (>30% of patients) included influenza-like illness, asthenia and fatigue.

In this phase III study conducted in France and Belgium, 107 patients with chronic HCV genotype 4 received simeprevir once daily with peginterferon and ribavirin for 12 weeks. Treatment-naïve and prior-relapser patients received response-guided therapy with peginterferon and ribavirin continued for up to 24 or 48 weeks. Prior partial responders and prior null responders continued to receive peginterferon and ribavirin for 48 weeks.

Out of a total patient population of 107 patients, 35 were treatment-naïve, 22 relapsers, 10 partial responders, and 40 null responders. The demographics of the patient population were as follows: 78.5% male; median age, 49 years; 28.0% Black; 28.8% METAVIR F4; 92.5% IL28B non-CC host genotype; and 42.5/23.6/33.9% HCV GT4a/4d/4other genotype.

Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB, with antiviral activity against HCV genotypes 1, 2, 4, 5 and 6, and approved in Japan, Canada, the United States and Russia for the treatment of chronic hepatitis C infection in combination with pegylated interferon and ribavirin in HCV genotype 1-infected patients with compensated liver disease, including cirrhosis. Taken as one capsule, once-daily, simeprevir works by blocking the protease enzyme that enables HCV to replicate in host cells.

Patients of Egyptian ancestry infected with Genotype 4 HCV achieve high virological response rates with sofosbuvir plus ribavirin

In a second study[3] involving treatment-naive and treatment-experienced patients of Egyptian ancestry with chronic genotype 4 HCV infection, sofosbuvir plus ribavirin was shown to provide a simple, effective, and well-tolerated, interferon-free regimen.

After 12 weeks of treatment with sofosbuvir plus ribavirin, SVR12 rates were 79% (11/14) in treatment-naïve patients and 59% (10/17) in treatment-experienced patients. Extending treatment duration to 24 weeks resulted in higher SVR12 rates in both treatment-naïve and -experienced patients: 100% (14/14) and 87% (13/15) respectively.

Relapse accounted for all virological failures except in one treatment-naïve subject receiving 12 weeks treatment who had a partial response.

Most AEs were mild or moderate in severity and consistent with the known side effects of ribavirin.

Presenting these results, Professor Peck-Radosavljevic said “the current treatment for GT4 is sofosbuvir + pegylated interferon + ribavirin for 12 weeks which resulted in a 96% (27/28) SVR12 rate in the Phase 3 NEUTRINO trial.

“What makes the results from this new study with sofosbuvir so important is that it included those patients who were interferon-ineligible, -intolerant, and failures, where a significant unmet medical need exists”, Professor Peck-Radosavljevic added.

In this study, patients, born in Egypt and of Egyptian ancestry, with chronic HCV GT4 infection were randomised 1:1, stratified by prior treatment status and cirrhosis status, to receive 12 or 24 weeks sofosbuvir (400 mg/day) + ribavirin (1000-1200 mg/day). Approximately 20% could have compensated cirrhosis.

Of the 60 patients enrolled, 28 were treatment-naïve and 32 treatment-experienced. 68% were male, 23% cirrhotic, and 17% had the IL28B CC host genotype.

Sofosbuvir is a nucleotide polymerase inhibitor with a high barrier to resistance that is taken as an oral, once-daily formulation. With activity against HCV genotypes 1-6, in-vitro activity of sofosbuvir against genotype 4a HCV has been shown to be similar to its activity against other HCV genotypes. With more than 3000 patients treated to date, sofosbuvir appears to be safe and well tolerated.

Disclaimer: the data referenced in this release is based on the submitted abstract. Final SVR results by baseline characteristics, including GT4 subtype, and resistance data will be presented at the International Liver Congress™ 2014.
Source - EASL

EASL Ledipasvir and Sofosbuvir: Therapy for Hepatitis C — The Costs of Success

Editorial

Therapy for Hepatitis C — The Costs of Success
The New England Journal of Medicine Editorial 
Jay H. Hoofnagle, M.D., and Averell H. Sherker, M.D. April 12, 2014
DOI: 10.1056/NEJMe1401508

Welcomed and exciting results from three large, controlled trials of different regimens of oral antiviral agents for chronic hepatitis C, genotype 1, have now been published in the Journal.1-3 The regimens all included the combination of ledipasvir and sofosbuvir, two new direct-acting antiviral agents with potent activity against hepatitis C virus (HCV). The two drugs were given as a single tablet once daily for 8, 12, or 24 weeks, with or without ribavirin. The results were consistent and striking: the various regimens yielded rates of sustained virologic response of 93% to 99%. The combination of ledipasvir and sofosbuvir alone (without ribavirin) for 12 weeks was associated with response rates of 94% in the ION-2 study and 99% in the ION-1 study.1,2 Extending therapy to 24 weeks increased the rate minimally (to 98% and 99%, respectively). In contrast, adding ribavirin provided no further benefit, regardless of duration. In previously untreated patients without cirrhosis, shortening the duration of therapy (without ribavirin) to 8 weeks did not lessen the rate of response (94%, vs. 95% with 12 weeks of therapy in the ION-1 study).3 Importantly, the single-tablet regimen was easy to administer and had few side effects; among the 539 patients who received ledipasvir and sofosbuvir alone for 12 weeks in these three trials, only 2 stopped therapy early because of adverse events.

The rates of response to ledipasvir and sofosbuvir were virtually the same in all subgroups of patients, regardless of patients' age, sex, race, liver-enzyme levels, HCV genotype (1a vs. 1b), preexisting antiviral resistance variants, or host genetic factors. Even in the difficult-to-treat patients who had not had a sustained response to a previous course of the most effective interferon-based therapies,4 the response rate at post-treatment week 12 was 94%. In this group of patients, the presence of cirrhosis was associated with a slightly lower response rate (88%, vs. 95% without cirrhosis), but with the longer course of treatment (24 weeks), these differences disappeared (100% in both groups).2 Preliminary studies with interferon-free drug combinations in patients with other HCV genotypes (2 or 3) suggest that high rates of response can be expected with those HCV strains as well.5
 
The combined results of the three trials include 1952 patients, of whom 97% had a sustained virologic response. Among the 3% who did not have a response, almost half were lost to follow-up or withdrew consent. Only 2 patients did not have an undetectable level of HCV RNA that was maintained during treatment (on-treatment virologic failure). Furthermore, the relapse rate after stopping therapy was only 2%. Relapses were more common with shorter courses of therapy: 5% of patients who received 8 weeks of treatment had a relapse, as did 2% of those who received 12 weeks and 0.2% of those who received 24 weeks of treatment. Trials focusing on retreatment of these rare patients with relapse are ongoing and will provide important guidance.
Ledipasvir and sofosbuvir are not the only promising antiviral agents for hepatitis C on the near horizon. Several other all-oral antiviral regimens have performed similarly in phase 2 studies, with sustained response rates in the range of 90% or higher.6,7 Thus, there are likely to be several options for oral therapy of hepatitis C within the next year.

The availability of effective, oral regimens of therapy for hepatitis C will lead to major changes in the management of this disease and probably affect both its morbidity and its mortality. Since the first use of antiviral therapy for chronic hepatitis C almost 30 years ago,8 treatment has been based on alpha interferon and was limited by the common and sometimes serious side effects of this cytokine, as well as the need for up to a year of therapy and the limited response rates of 50% or less, even among carefully selected patients. In patients with coexisting conditions such as human immunodeficiency virus (HIV) infection, an autoimmune disorder, solid-organ transplant, active substance abuse, or serious heart, renal, or psychiatric disease, interferon was usually contraindicated and, if given, had a high rate of adverse events and was often not effective. In real-life situations, fewer than half the HCV-infected persons qualify for interferon therapy, many patients decline treatment, and response rates can be far lower than 50%.9 Furthermore, the management of therapy requires physicians and health care staff with special expertise and experience. It is hardly surprising that, despite the availability of interferon-based therapy for more than 20 years, the mortality from hepatitis C in the United States has continued to increase and now exceeds that from HIV infection.10
 
The limitations and medical barriers to treatment, however, may now largely disappear. The ease of administration, short duration of treatment, and minimal side effects of all-oral regimens will probably mean that most persons will qualify for therapy. Collectively, these regimens promise to transform hepatitis C from a condition requiring complex, unsatisfactory therapies and specialist care to one that can be effectively treated and easily managed by a general physician with few contraindications and side effects.

Unfortunately, not all barriers to treatment will be lifted. The major limitation remaining will be economic. The current cost of a 12-week regimen of sofosbuvir alone is $84,000, or $1,000 per tablet.11 The addition of ledipasvir will add to the costs, and these estimates do not include expenses for diagnostic assays, monitoring, and physician visits.

The predicted costs of the new oral antiviral agents are as breathtaking as their effectiveness. Chronic hepatitis C is estimated to affect 3.2 million Americans, half of whom may not be aware that they are infected.12 Public health efforts are now under way to identify persons with HCV infection and to direct them to medical care.13 With the present estimates of costs, however, treating even half the HCV-infected persons in the United States would add billions of dollars to an already overburdened medical care system. Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a safe and effective therapy for hepatitis C.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on April 12, 2014, at NEJM.org.

Source Information

From the Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

References

1. 1
   Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1316366.
2. 2
   Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. DOI: 10.1056/NEJMoa1402454.
3. 3
   Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. DOI: 10.1056/NEJMoa1402355.
4. 4
   Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med 2013;368:1907-1917
   Full Text | Web of Science | Medline
5. 5
   Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34-44
   Free Full Text | Web of Science | Medline
6. 6
   Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol 2013;58:655-662
   CrossRef | Medline
7. 7
   Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med 2014;370:222-232
   Full Text | Web of Science | Medline
8. 8
   Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: a preliminary report. N Engl J Med 1986;315:1575-1578
   Full Text | Web of Science | Medline
9. 9
   Kramer JR, Kanwal F, Richardson P, Mei M, El-Serag HB. Gaps in the achievement of effectiveness of HCV treatment in national VA practice. J Hepatol 2012;56:320-325
   CrossRef | Web of Science | Medline
10. 10
    Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-278[Erratum, Ann Intern Med 2012;156:840.]
    CrossRef | Web of Science | Medline
11. 11
    Sofosbuvir (Sovaldi) for chronic hepatitis C. Med Lett Drugs Ther 2014;56:51-56
12. 12
    Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med 2013;368:1859-1861
    Full Text | Web of Science | Medline
13. 13
    Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 2012;61:1-32
    Medline

EASL - Merck’s MK-5172/MK-8742 Demonstrates Antiviral Activity in Hard-to-Cure Patients

 Also See -EASL-Merck reports mid-stage data for MK-5172 and MK-8742, all-oral hepatitis C regimen  

Merck’s Investigational Chronic Hepatitis C Combination Therapy MK-5172/MK-8742 Demonstrates Antiviral Activity in Hard-to-Cure Patients with HCV Genotype 1 Infection
April 11

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced interim results from the ongoing C-WORTHy study, a multi-arm Phase 2 clinical trial evaluating the efficacy and safety of an all-oral, once-daily regimen combining MK-5172, an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor, among patients with chronic HCV Genotype 1 infection (GT1). Interim analysis of hard-to-cure¹ patients administered MK-5172/MK-8742 with and without ribavirin (RBV) for 12 or 18 weeks showed sustained viral response² (SVR), 4 to 8 weeks after the completion of therapy (SVR4/8):
.

• HCV GT1 infected, treatment-naïve cirrhotic patients, MK-5172/MK-8742 treated - 97 percent (28/29 and 29/30) for 12 and 18 weeks, and MK-5172/MK-8742 plus RBV - 90 percent (28/31) and 97 percent (30/31) for 12 and 18 weeks, respectively.
• HCV GT1 infected prior-null responder patients (with or without cirrhosis), MK-5172/MK-8742 treated - 91 percent (30/33) and 97 percent (29/30) for 12 and 18 weeks, respectively, and MK-5172/MK-8742 plus RBV treated 94 percent (30/32) and 100 percent (32/32) for the 12 and 18 weeks, respectively.
• Treatment-naïve, non-cirrhotic patients with HCV/HIV co-infection, MK-5172/MK-8742 treated for 12 weeks - 90 percent (26/29) and MK-5172/MK-8742 plus RBV for 12 weeks 97 percent (28/29).

These data were presented at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL), also known as The International Liver Congress™ 2014 in London, UK.
“There is still a need for further options for the most difficult-to-cure patients, including those with cirrhosis and HCV/HIV co-infection,” said Dr. Eric Lawitz, MD, vice president, Scientific and Research Development, The Texas Liver Institute, and clinical professor of medicine, University of Texas Health Science Center in San Antonio. “These findings provide additional clinical evidence regarding the potential of MK-5172/MK-8742 in treating a broad spectrum of HCV patients.”
.
C-WORTHy Study Design
C-WORTHy is a randomized, dose-responsive, parallel-group, multiple-site, double-blind clinical trial comparing different patient populations exposed to different durations of treatment of MK-5172 (100 mg once daily) in combination with MK-8742 (50 mg once daily) with or without RBV in subjects with chronic HCV infection. A total of 471 patients with chronic HCV GT1 and HCV RNA levels of ≥10,000 IU/mL were enrolled in C-WORTHy and randomized across 16 arms. These results examine hard-to-cure subpopulations, including treatment-naïve patients with liver cirrhosis (12- and 18-week arms, with and without RBV), prior-null responder patients with and without cirrhosis (12- and 18-week arms, with and without RBV) and patients with HIV/HCV co-infection (12-week arms).
 .
Key Findings for MK-5172/MK-8742
Viral suppression (HCV RNA levels less than 25 IU/mL) was demonstrated for treatment-naïve patients with cirrhosis, prior-null responder patients with and without cirrhosis and HIV/HCV co-infected patients by Treatment Week (TW)12. These levels were maintained at rates between 90 and 100 percent across patient subgroups through the completion of dosing and at the four-week treatment follow-up time point (FU4).

. Table 1
Interim Analysis of the C-WORTHy Trial: Treatment-Naïve, Cirrhotic Patients with HCV GT1 Infection (Intention-to-Treat Analysis (ITT), Excluding Patients Yet to Reach FU4)
Parameter		MK-5172 + MK-8742 + RBV (12 Weeks) (N = 31)		MK-5172 + MK-8742 (NO RBV) (12 Weeks) (N = 29)		MK-5172 + MK-8742 + RBV (18 Weeks) (N = 32)		MK-5172 + MK-8742 (NO RBV) (18 weeks) (N = 31)
SVR4/8, % (n/m†)		90% (28/31)		97% (28/29)		97% (30/31)		97% (29/30)
No SVR, % (n)
Breakthrough		3% (1)		0% (0)		0% (0)		0% (0)
Relapse		7% (2)		3% (1)		0% (0)		3% (1)
Non-virologic Discontinuation		0% (0)		0% (0)		3% (1)		0% (0)
† m = patients who have reached the FU4 visits (all patients in the 12-week arms, and 61/63 patients in the 18-week arms have reached FU4).

, Table 2
Interim Analysis of the C-WORTHy Trial: Prior Null Responders (~50% Cirrhotics), Cirrhotic Patients with HCV GT1 Infection (ITT, Excluding Patients Yet to Reach FU4)
Parameter		MK-5172 + MK-8742 + RBV (12 Weeks) (N = 32)		MK-5172 + MK-8742 (NO RBV) (12 Weeks) (N = 33)		MK-5172 + MK-8742 + RBV (18 Weeks) (N = 33)		MK-5172 + MK-8742 (NO RBV) (18 weeks) (N = 32)
SVR4/8, % (n/m†)		94% (30/32)		91% (30/33)		100% (32/32)		97% (29/30)
No SVR, % (n)
Breakthrough		0% (0)		0% (0)		0% (0)		3% (1)
Relapse		0% (0)		9% (3)		0% (0)		0% (0)
Non-virologic Discontinuation		6% (2)		0% (0)		0% (0)		0% (0)
† m = patients who have reached the FU4 visits (all patients in the 12-week arms, and 62/65 patients in the 18-week arms have reached FU4).

. Table 3
Interim Analysis of the C-WORTHy Trial:Treatment-Naïve Non-Cirrhotic HCV GT1-Infected Patients with HIV Co-Infection (ITT, Excluding Patients Yet to Reach FU4)
Parameter		MK-5172 + MK-8742 + RBV (12 Weeks) (N = 29)		MK-5172 + MK-8742 (NO RBV) (12 Weeks) (N = 30)
SVR4/8, % (n/m†)		97% (28/29)		90% (26/29)
No SVR, % (n)
Breakthrough		0% (0)		7% (2)
Relapse		3% (1)		0% (0)
Non-virologic Discontinuation		0% (0)		3% (1)
† m = patients who have reached the FU4 visits (only one patient in the RBV-free arm has not yet reached FU4).

The most common adverse events observed among treatment-naïve patients with cirrhosis and prior-null responder patients with and without cirrhosis were fatigue (23% and 28%, respectively), headache (24% and 24%, respectively), and asthenia (8% and 19%, respectively). The most common adverse events observed among HIV co-infected patients were headache (8%), asthenia (8%), fatigue (7%), and sleep disorder (7%). There were no early discontinuations due to drug-related adverse events and no clinically significant abnormalities observed in routine laboratory analysis of hematologic markers.
 .
About Merck’s Phase 3 HCV Program: C-EDGE
Based on the results of the Phase 2 clinical program, Merck has initiated Phase 3 clinical trials for MK-5172/MK-8742. The Phase 3 program, called C-EDGE, will evaluate the safety and efficacy of MK-5172/MK-8742 with and without ribavirin in various genotypes and across a broad range of patient populations with chronic HCV. Study cohorts will include: C-EDGE TN (GT1, GT4-6; treatment-naive ± cirrhosis), C-EDGE CO-INFXN (GT1, GT4-6; treatment-naive ± cirrhosis with HIV/HCV co-infection), C-EDGE RECOVERY (GT1, GT4-6; treatment-naive ± cirrhosis; ± HIV/HCV co-infection on opiate substitution therapy), and C-EDGE TE (GT1, GT4-6; prior failed treatment with peginterferon/ribavirin; ± HIV/HCV co-infection). Study information can be found at www.clinicaltrials.gov.
.
Merck’s Commitment to HCV
For more than 25 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver healthcare solutions that support people living with HCV worldwide.

Source