TGIF HCV Review - Merck Discontinues MK-3682B and MK-3682C Development Programs

Happy Friday! Here are a few updates on viral hepatitis you may have missed this week.

Quick Links
Weekly news recap at HepCBC.

In The News
Merck Discontinues MK-3682B and MK-3682C Development Programs
Sep 29, 2017
Company to Focus on Maximizing the Potential of ZEPATIER ^® (Elbasvir and Grazoprevir)
Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced its strategic decision to discontinue the development of the investigational combination regimens MK-3682B (grazoprevir/ruzasvir/ uprifosbuvir) and MK-3682C (ruzasvir/uprifosbuvir) for the treatment of chronic hepatitis C virus (HCV) infection. This decision was made based on a review of available Phase 2 efficacy data and in consideration of the evolving marketplace and the growing number of treatment options available for patients with chronic HCV infection, including ZEPATIER^® (elbasvir and grazoprevir).

8 top stories on injection drug users, HIV/HCV coinfection
Sep 29, 2017
At the recent International Symposium on Hepatitis Care in Substance Users, researchers presented new data on injection drug users and their unique risk factors for hepatitis C infection and transmission, including younger age, and the critical need for HCV education among addiction clinic workers.

Flu Updates
Sept 29, 2017

Read all past and current Seasonal Flu Vaccine articles posted on this blog.

Is HCV Drug Development Nearing Its End?

Sep 28,2017
by Liz Highleyman
The FDA recently approved two new combination regimens for hepatitis C, raising the question of whether further drug development is warranted in this area.
Gilead's Vosevi (sofosbuvir/velpatasvir/voxilaprevir) and AbbVie's Mavyret (glecaprevir/pibrentasvir) work against all hepatitis C virus (HCV) genotypes, with cure rates exceeding 95%. And Mavyret, which many patients will be able to take for just 8 weeks, brings a lower cost option to the market.* Free registration required

CDC
Weekly / September 29, 2017 / 66(38);1031
QuickStats: Death Rates* for Chronic Liver Disease and Cirrhosis, by Sex and Age Group — National Vital Statistics System, United States, 2000 and 2015
From 2000 to 2015, death rates for chronic liver disease and cirrhosis in the United States increased 31% (from 20.1 per 100,000 to 26.4) among persons aged 45–64 years. Rates in that age group increased 21% for men (from 29.8 to 36.2) and 57% for women (from 10.8 to 17.0). Among persons aged 25–44 years, the death rate for men decreased 10% (from 6.1 to 5.5), and the rate for women increased 18% (from 2.8 to 3.3). Overall, among persons aged ≥65 years, rates increased 3% (from 29.4 to 30.2). Death rates for both men and women increased with age.

CDC - Mandating HCV Screening Increased Newly Diagnosed and Access to Care

Sept 28, 2017

Implementation of the New York law mandating health care providers to offer HCV testing to persons born during 1945–1965 was associated with an increase in HCV testing, and an increase in the percentage of persons with newly diagnosed HCV infections who were linked to care. Marked increases in the number of HCV tests performed and rates of testing were observed immediately after enactment of the law and remained steady over a 12-month period. Smaller increases were noted in the number of persons who accessed care after receiving a positive HCV screening test result....

Related: Does Mandating HCV Screening Among Baby Boomers Improve Outcomes?

Does Sustained Virologic Response Improve Glycemic Control in HCV?
Sept 29, 2017
Eradicating hepatitis C virus (HCV) infection with direct-acting antiviral (DAA) agents in patients with diabetes reduced the amount of diabetic medication needed and significantly reduced the need for insulin, according to a study in Diabetes Care.

Hepatitis C Formulary Choices for 2018: Will CVS Risk Looking Bad?

Sep 28, 2017
AbbVie’s aggressive list pricing for its new Hepatitis C Virus (HCV) drug Mavyret is disruptive to the current PBM business model.  It essentially asks PBMs to align with client interests by adding a cost-effective drug to their national formularies despite little to no possibility for retained rebates.
On September 15, 2017 Express Scripts (ESRX) chose to align with client interests by opening up the HCV therapeutic class to include Mavyret as well as other HCV drugs previously excluded.   If CVS chooses not to add Mavyret, it will be a sign that CVS is so desperate for rebate income that it is willing incur a very public case of misaligned interests.

FDA improves access to reports of adverse drug reactions
Sep 28, 2017
The U.S. Food and Drug Administration today launched a new user-friendly search tool that improves access to data on adverse events associated with drug and biologic products through the FDA’s Adverse Event Reporting System (FAERS). The tool is designed to make it easier for consumers, providers, and researchers to access this information.

Japan - AbbVie Announces Approval of MAVIRET™ (glecaprevir/pibrentasvir) of Chronic Hepatitis C in All Major Genotypes (GT1-6)

Sept. 27, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global research and development-based biopharmaceutical company, today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) approved MAVIRET™ (glecaprevir/pibrentasvir), a once-daily, ribavirin-free treatment for adults with chronic hepatitis C virus (HCV) infection across all major genotypes

(GT1-6).

Most patients with HCV genotypes 2, 4, 5, 6 achieve SVR with Mavyret

Sep 26,2017

Most patients with hepatitis C genotype 2, 4, 5 or 6 who received Mavyret for 8 weeks achieved sustained virologic response with a high safety profile, according to results from three phase 3 studies. The rate of virologic failure was less than 1%.

Communication of the Alcohol Guidelines ‘needs to be improved’

Posted on 25th September 2017

A study published today concludes that more needs to be done to communicate the drinking guidelines to the public. The study, published in the Journal …

Fibrosis

Factors associated with hepatitis C prevalence differ by the stage of liver fibrosis

September 28, 2017

There is a considerable burden of hepatitis C in Europe related to the lack of prompt diagnosis. We aimed to estimate the prevalence and related risk factors of HCV infections by the stages of liver fibrosis, using non-invasive methods, to understand testing needs in Poland.

Portal pressure & liver stiffness measurements in prediction of fibrosis regression after SVR in recurrent HCV

Accepted manuscript online: 27 September 2017

We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and portal hypertension after viral clearance. 

Article provided by @HenryEChang via Twitter

Cirrhosis

Muscle Volume Loss Linked to Mortality in Patients with Liver Cirrhosis

September 26, 2017

In a recent study, researchers examined whether muscle volume loss or portal hypertension were predictive of mortality among patients with liver cirrhosis.

Cirrhosis deaths: more action is needed now

Gut Health - Deaths from liver disease are soaring and people in deprived areas are at far higher risk. Now doctors are calling for more action to cut the death toll.

In case you missed it
Study of prevalence and pattern of peripheral neuropathy in patients with liver cirrhosis

Mahim Mittal, Pavan Kumar Singh, Sonu Kurian

Peripheral neuropathy is present in more than half of cirrhosis patients and is unrelated to etiology and nutritional status but related to the severity of cirrhosis.

LINK: Download Full Text - PDF

Liver Transplant

Liver transplant, cancer stage increase HCC care costs, survival time

September 28, 2017
A recently published analysis of veterans with hepatocellular carcinoma showed that receipt of liver transplantation, Barcelona Clinic Liver Cancer stage and…

Searching For A Fairer Way To Distribute Donor Livers

September 26, 2017
Patel and Su are among more than 16,000 Americans waiting for a liver transplant because of conditions such as hepatitis, cancer or cirrhosis. But only about 7,000 livers are donated each year. So they know their odds aren't great.

Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C
25 September 2017
We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945–1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH).

Liver Cancer
Quantitative imaging predicts microvascular invasion in hepatocellular carcinoma

Last Updated: 2017-09-28

By Will Boggs MD

NEW YORK (Reuters Health) - Quantitative image analysis of preoperative CT scans can be used to predict microvascular invasion in patients with hepatocellular carcinoma (HCC), researchers report...

Reduce Liver Cancer Risk and Join a Liver Cancer Awareness Twitter Chat Oct. 12

October is Liver Cancer Awareness Month and it’s time to “chat” about reducing liver cancer, particularly in people living with hepatitis B and C. On Thursday, Oct. 12, representatives from Hepatitis B Foundation, CDC’s Division of Viral Hepatitis, and NASTAD (the National Alliance of State and Territorial Aids Directors) will co-host a twitter chat at 2 p.m. EST using the hashtag #liverchat.

Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis
World J Gastroenterol. Oct 7, 2017
AIM - To investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC). Various epidemiological studies around the globe have recognized the role of gender bias in the progression of HCV infection to chronic liver disease and cirrhosis due to poor therapeutic responses or further development of HCV-related HCC in these patients...

Environmental Contributions to Gastrointestinal and Liver Cancer in the Asia-Pacific Region

September 28, 2017

Liver cancer is the second most common digestive cancer in Asia. The high incidence of liver cancer in East Asia and South-East Asia is concordant with the high prevalence of hepatitis B virus and hepatitis C virus infection. Other important risk factors include alcohol use, smoking, and diabetes.

New At Clinical Care Options

* Free registration required
Downloadable Slides: Latest Developments in the Treatment of HCC in Veterans

9/19/2017          

Download this slideset to review the latest data on best practices for the care of patients with HCC across the disease spectrum and to address specific issues unique to treating veterans.   

Quick Reference Guide: HCV Screening and Testing
9/26/2017          

Download this practical guide to help you appropriately screen your patients for hepatitis C virus infection

                                    

At a Glance: Prescribing Information for HCV Treatments

9/26/2017
Download this practical reference sheet on all the FDA-approved regimens for treating hepatitis C virus 

Start here.....

Updated
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C
September 21, 2017
New Genotype 1 & 3 Treatment-Naïve & Treatment-Experienced
This version of the guidance has been updated to reflect several important developments, including the recent approvals of glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir. Updated recommendations reflecting these approvals are provided throughout the guidance.

Blog Updates From Around The Web

Liver Disease and Muscle Loss

September 27, 2017

By Kimberly Morgan Bossley

Liver Disease can cause severe muscle loss and weakness..

Stigma with Hepatitis C: The Danger of Labels

September 27, 2017

By Connie M. Welch

Hepatitis C patients have many obstacles to fight and deal with, one of the first and biggest is stigma, the danger of labels...

Will Health Care Return to the Dark Ages?

September 25, 2017

By Lucinda K. Porter, RN

Before the Affordable Health Care Act (Obamacare), I was uninsurable. Hepatitis C marked me as having a preexisting condition.  This meant that insurance companies could deny me insurance...

Getting Disrespect from Medical Staff for Hep C 

By Kare Hoyt - September 28, 2017
It’s nearly impossible to get medical care without feeling judgment about Hepatitis C. You get used to it, but when you don’t feel good and need help, you expect professionals to show...

Dread and Test Results 

By Debra Walters - September 27, 2017
My first dance with Hepatitis C treatment was in 2008-2009. The only option was Ribavirin and peginterferon, so I signed up for a study at Baylor College of Medicine. I was randomized...

Living with PTSD and Hepatitis C (Part 3) 

By Karen Hoyt - September 25, 2017
Check out Part 1 and Part 2 of Karen’s series on PTSD. Post-Traumatic Stress Disorder or PTSD can come from a lot of little traumas and hepatitis C is one of them....

Off The Cuff

The British Liver Trust highlights the common causes of hepatitis A

Published in July, download it, here

In obese adults and children, the microbiome plays key role in one of the most common and serious liver diseases
September 29, 2017
BUFFALO, N.Y. — New clues to non-alcoholic fatty liver disease (NAFLD), which affects nearly all obese adults and a rising percentage of obese children, have been reported in a paper published earlier this month in the journal Gut.

The cost of drugs confounds this gastroenterologist

Michael Kirsch, MD | Meds | September 25, 2017
Most of us do not know the basics of economics, although we should. It impacts every one of us every day that we are alive. Yet, for most of us, once we get beyond the law of supply and demand, our knowledge of the subject starts to vaporize. I can't explain fiscal or monetary policy. While I regard economics as a science, it seems that experts routinely interpret data differently, ...

Abdominal wall pain as its own diagnosis

Sep 2017
By Mollie Durkin
Internists can diagnose chronic abdominal wall pain with a simple physical exam and some savvy history taking, experts said, and reassure patients that their condition is not serious and may respond to treatment.... 

Diabetes: Adding lifestyle changes to medication can deliver a knockout punch

Posted September 28, 2017 

Monique Tello, MD, MPH, Contributing Editor Plenty of research supports the common-sense notion that a healthy lifestyle can prevent or treat many diseases. A diet high in fruits, veggies, whole grains, and plant protein and low in processed carbs, added sugars, saturated fats; regular physical activity; and emotional well-being are the potent treatments that can prevent the need for or even…

Enjoy the rest of your day!
Tina

(grazoprevir-ruzasvir-uprifosbuvir) Shorter anti-HCV regimen effective in patients with or without cirrhosis

In Case You Missed It

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter

Shorter anti-HCV regimen effective in patients with or without cirrhosis

Last Updated: 2017-08-18
By Will Boggs MD
NEW YORK (Reuters Health) - An eight-week regimen containing grazoprevir-ruzasvir-uprifosbuvir appears to be effective for treating hepatitis C virus (HCV) infection in patients with or without cirrhosis, according to findings from a pair of randomized phase 2 open-label trials.

Dr. Edward J. Gane from Auckland Clinical Studies, in Auckland, New Zealand, and colleagues - in part A of the C-CREST-1 and C-CREST-2 trials - randomly assigned 240 patients with HCV genotype 1, 2 or 3 and without cirrhosis to receive an eight-week course of a daily three-drug combination:

- grazoprevir 100 mg, plus

- either elbasvir 50 mg or ruzasvir 60 mg, plus

- either 300 mg or 450 mg of uprifosbuvir.

The studies were funded by Merck and Co.

Sustained virologic response rates 12 weeks after the end of therapy (SVR12) were 92% with both doses of the grazoprevir-ruzasvir-uprifosbuvir regimen and ranged from 85% to 88% (depending on uprifosbuvir dose) with grazoprevir-elbasvir-uprifosbuvir, according to one of the reports, both online August 9 in The Lancet Gastroenterology and Hepatology.

All four regimens were well-tolerated.

"These results support the selection of grazoprevir plus ruzasvir plus uprifosbuvir 450 mg as the regimen for further clinical investigation in broader populations," the researchers conclude.

Dr. Eric Lawitz from Texas Liver Institute at the University of Texas Health San Antonio and colleagues extended these findings in part B of C-CREST-1 and C-CREST-2. In this trial, 675 patients with HCV-1, -2, -3, -4 or -6, with or without cirrhosis, received eight, 12, or 16 weeks of grazoprevir-ruzasvir-uprifosbuvir 450 mg, with or without ribavirin.

SVR12 rates with eight weeks of therapy were 93% in individuals with genotype 1a, 98% with genotype 1b, 86% with genotype 2 (without cirrhosis; patients with HCV-2 and cirrhosis received a longer course), 95% with genotype 3 (treatment naive, without cirrhosis) and 100% with genotypes 4 and 6.

"We were surprised by the relatively lower efficacy of an 8-week duration of this regimen among those with genotype 2 infection," Dr. Lawitz told Reuters Health by email. "However, extending therapy to 12 weeks overcame this effect."

SVR12 rates were generally higher among participants with or without cirrhosis who received 12 or 16 weeks of therapy.

There were no documented virologic failures after week 12 of follow-up, although 10 participants who achieved SVR12 were lost to follow-up.

As in part A of the study, treatment with this fixed-dose combination with or without ribavirin was generally well tolerated.

"Results from the current studies support further investigation of grazoprevir, ruzasvir, and uprifosbuvir as a pan-genotypic regimen in individuals infected with HCV with and without cirrhosis, and suggest that this combination has the potential to provide a safe, single-duration regimen in most populations, including individuals with cirrhosis infected with genotype 3 who had previously received treatment with pegylated interferon and ribavirin," the researchers conclude.

"We await data from phase 3 to know how this regimen might impact the current treatment landscape," Dr. Lawitz said. "We hope that this regimen will be able to give providers more options with regard to pan-genotypic regimens for the treatment of HCV."

Dr. Eleanor M. Wilson from the University of Maryland School of Medicine, Baltimore, who coauthored an accompanying comment in the journal, told Reuters Health by email, "The safety and efficacy data seem promising, but it's still investigational, so not sure about its impact on the field of hepatitis C treatment yet."

"With the recent approvals of Vosevi and Mavyret, in addition to the previously available options, I think the overall take-away is that it's fantastic that there are more hepatitis C treatment options for patients and providers," she said. "It's tremendous that previously so-called 'difficult-to-treat patients' including those with previous treatment experience, comorbid conditions like HIV or renal disease, and those with advanced fibrosis and cirrhosis now have a variety of safe and highly effective options to treat their hepatitis C."

"My area of expertise is in novel treatment approaches, including strategies to reduce the treatment duration in order to increase access and decrease treatment cost, as well as options for patients who haven't successfully cleared HCV with first-line therapy (due to problems of adherence or viral resistance), and from that standpoint, it's an exciting time to be a hepatitis C provider," Dr. Wilson said.

Dr. Mark Sulkowski, who directs the viral hepatitis center at Johns Hopkins University in Baltimore, told Reuters Health by email, "We currently have multiple outstanding HCV regimens for the treatment of all genotypes of hepatitis C, which typically include combinations of direct-acting antiviral inhibitors of HCV protein targets NS3 (protease), NS5A and NS5B (polymerase). While we have seen the regulatory approval of multiple inhibitors of the NS3 and NS5A proteins, to date, only one (nucleotide) inhibitor of the NS5B polymerase active site has been approved, sofosbuvir."

"The C-CREST-1 and -2 studies provide a phase 2 evaluation of another (nucleotide) analogue inhibitor of NS5B, uprifosbuvir," said Dr. Sulkowski, who was not involved in the research. "Based on the results of these studies, uprifosbuvir appears to be poised to move to phase 3 studies, and if successful in phase 3 trials, this agent could become a valuable addition to the available drugs to treat hepatitis C."

Dr. Gane did not respond to a request for comment.
Merck funded the trials and employed most of the authors.

SOURCE: Lancet Gastroenterol Hepatol 2017.
Abstract 

Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials

Abstract 

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials

Abstract 

Shortening the duration of therapy for chronic hepatitis C infection

Full Text
Shortening the duration of therapy for chronic HCV
Lancet Published online August 9, 2017
PDF provided by @HenryEChang via Twitter

Hepatitis C Genotype 3 - FDA Approved And Soon To Be Approved Therapies

September: Updated AASLD IDSA HCV Guidance
This page was updated on Aug 3, 2017 to include AbbVie's FDA approval of MAVYRET™ (glecaprevir/pibrentasvir). On July 18, 2017  Gilead announced the FDA approved VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir  - EMA granted marketing authorization for both Vosevi, and AbbVie's MAVIRET® on July 28, 2017.

Hepatitis C genotype 3 isn't a death sentence

Published on Jul 14, 2017
By onewhoknows7
We begin with a family who struggle to access HCV therapy. A video with only one picture and a bit of text for us to read, for me - a powerful video. A story that almost anyone who has treated HCV can relate to; falling through the cracks, not receiving quality care, insurance companies deciding when or if to treat patients, is this your story too? In many ways this video hits home for me also, if not for HCV Advocate, I most certainty would have never treated successfully in 1999.  

An estimated 130-150 million people worldwide are living with chronic HCV infection, within the six major HCV genotypes, genotype 3 represents 22-30% of all infection, 10% in the United States.

Research has shown people infected with genotype 3 have significantly increased rates of steatosis (fatty liver), fibrosis, and hepatocellular carcinoma (liver cancer), thus making this genotype both difficult and urgent to treat. Here is a quick review of key HCV genotype 3 research articles,  with an update from the HCV Guidance .

FDA approved drugs to treat HCV genotype 3
September 2017
AASLD IDSA
HCV Guidance: Updated - Geno 1 & 3 Treatment-Naïve & Treatment-Experienced
Recommendations Reflecting Vosevi and Mavyret .
Stay current with all guideline updates, "click here."
Read more click here.....

October 2017
Over at NEJM Journal Watch, a small study for HCV genotype 3 patients is reviewed by Atif Zaman, MD, MPH, published last week in Hepatology. The study; Glecaprevir/pibrentasvir for HCV genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase III clinical trial, is available for download over at NATAP. 

Watch

June 2017
HCV genotype 3: Work through virtual case study with Dr Doug Dieterich
The HCV Virtual Patient program is an interactive, case-based program featuring real-world case scenarios discussed by HCV thought leaders.

Recommended Reading

July 13, 2017
Sofosbuvir based treatment of chronic hepatitis C genotype 3 infections—A Scandinavian real-life study
We found that sofosbuvir based treatment in a real-life setting could offer SVR rates exceeding 90% in patients with HCV genotype 3 infection and advanced liver disease.

Commentary On This Study
Aug 1, 2017
Hepatitis C Cure Rate Tops 90% in Hard-to-Treat Genotype 3 Patients

Hepatitis C patients with hard-to-treat genotype 3 showed sustained virologic response (SVR) of greater than 90% in a real-life study of a therapy based on the direct-acting antiviral (DAA) drug sofosbuvir (Sovaldi, Gilead Sciences Inc.)

New Drugs FDA Approved 

FDA Approved - Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir 

On July 18, 2017 Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir) was FDA Approved, a few weeks later on July 28, the European Commission Granted Marketing Authorization for Vosevi.

Research Articles

Sofosbuvir, Velpatasvir and Voxilaprevir

Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater.

Link - July 5, 2017: Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C- Review

This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection.  All relevant literature from 2015 through June of 2017 is included..

FDA Approved AbbVie's MAVIRET (Glecaprevir/Pibrentasvir)
Aug 3, 2017 AbbVie Received U.S. FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir). 

On June 28, 2017 the European Commission Granted AbbVie's MAVIRET® (glecaprevir/pibrentasvir) Marketing Authorization for the Treatment of Chronic Hepatitis C in All Major Genotypes (GT1-6)

Glecaprevir/Pibrentasvir

In patients with challenging-to-treat genotype 3 chronic HCV infection with cirrhosis, 95% achieved SVR12 after 8 weeks of therapy.

April 21, 2017 - AbbVie combination cures 97% of genotype 3 hepatitis C

AbbVie's pangenotypic direct-acting antiviral combination of two drugs cured 95% of people with early-stage genotype 3 hepatitis C virus (HCV), the hardest genotype to treat, according to results of the ENDURANCE-3 trial presented at the  International Liver Congress in Amsterdam on Friday. The AbbVie second-generation direct-acting antiviral combination consists of a protease inhibitor and an NS5A inhibitor. Glecaprevir is an HCV NS3/4A protease inhibitor active against all genotypes of hepatitis C. Pibrentasvir is an NS5A inhibitor also active against all genotypes of hepatitis C.

July 26, 2017
Glecaprevir/pibrentasvir is effective for people with HIV/HCV co-infection
Liz Highleyman
Produced in collaboration with hivandhepatitis.com
Published: 26 July 2017

AbbVie's new pangenotypic regimen combining glecaprevir and pibrentasvir cured almost all HIV-positive people with hepatitis C co-infection in the EXPEDITION-2 study, according to a presentation on Monday at the 9th International AIDS Society Conference on HIV Science (IAS 2017) in Paris.

Karine Lacombe of Saint-Antoine Hospital in Paris presented findings from AbbVie's phase 3 EXPEDITION-2 trial, which evaluated an 8-week regimen of glecaprevir/pibrentasvir for people with both HIV and hepatitis C.

Glecaprevir is an HCV NS3/4A protease inhibitor and pibrentasvir is an NS5A inhibitor. Both are pangenotypic, or active against all HCV genotypes. The two drugs have been co-formulated in a once-daily combination pill, to be marketed under the brand name Maviret.

Studies presented at this year's International Liver Congress showed that glecaprevir/pibrentasvir cured 99% of people with hepatitis C with multiple HCV genotypes, as well as 95% of people with hard-to-treat genotype 3.

Continue reading......

Recommended Reading

July 14, 2017

The relationship between hepatitis C infection and hepatic steatosis.

Metabolic Manifestations of Hepatitis C Virus

Lawrence Serfaty

Key Points
Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subject based studies and, to a lesser degree, in population-based studies.

Download PDF.

The above link was provided by @HenryEChang via Twitter, view an index of all HCV extrahepatic manifestations.

Video - March 2017

Genotype 3 Infection - Identification of the Best Direct-Acting Antiviral Regimen for Patients With Hepatitis C Virus
Drs. Drenth and Berden discuss their manuscript "Identification of the Best Direct-Acting Antiviral Regimen for Patients With Hepatitis C Virus Genotype 3 Infection: A Systematic Review and Network Meta-analysis."

HCV Advocate

Clinical Trials Reference Guide
Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype

Stay Updated

Sift through a collection of research articles related to treating HCV according to genotype.

Pangenotypic regimens and the next generation hepatitis C virus therapy

The latest issue of Clinical Liver Disease
Clinical Liver Disease (CLD) is a digital educational resource published on behalf of the American Association for the Study of Liver Diseases (AASLD). CLD publishes easy to read reviews on relevant topics for clinicians diagnosing and managing patients with liver disease. Each article is accompanied by a podcast audio version, and a video interview with the author to help emphasize the key teaching points for a clinical audience.

Issue Publication: June 2017
Volume 9, Issue 6 Pages 131 - 149, June 2017

Reviews
Hepatitis C
Guest Edited by Andrew Muir, MD
Pangenotypic regimens and the next generation hepatitis C virus therapy (pages 131–133)
Nancy S. Reau
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.635
Three new antiviral therapies for viral hepatitis C are anticipated in the next several months: GP, glecaprevir (protease inhibitor [PI])/pibrentasvir (NS5A inhibitor); SOF/VEL/VOX, sofosbuvir (NS5B inhibitor)/velpatasvir (NS5A)/voxilaprevir (NS3); and MK3, grazoprevir (NS3) + MK-3682 (NS5B) + NS5A inhibitor (elbasvir or Ruzasvir).

Each is a pangenotypic all-oral fixed dose combination (FDC) with high potency and efficacy against common NS3 and NS5A polymorphisms. Multiple safety and efficacy abstracts were presented at the 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2016. In this article, I will address why we need new therapies as well as what is still unaddressed in the arsenal against hepatitis C.
Watch a video presentation of this article
Watch the interview with the author
Full Text (HTML)
PDF (140.1KB) 

Noninvasive Diagnosis of Liver Fibrosis in Children and Adults
Guest Edited by Naim Alkhouri, MD and Jean Molleston, MD
Putting it all together: Noninvasive diagnosis of fibrosis in nonalcoholic fatty liver disease in adults and children (pages 134–137)
Naim Alkhouri
Multiple noninvasive tests have been developed and validated in the adult NAFLD population to predict the stage of fibrosis.[6] These tests are being widely used by gastroenterologists and hepatologists to risk-stratify patients with NAFLD without the need for liver biopsy. These tests can be divided into one of three categories: simple fibrosis scores that can be calculated from readily available clinical variables, complex fibrosis scores that rely on measuring serum biomarkers of fibrosis and extracellular matrix turnover, and imaging studies that are based on measuring liver stiffness as an indirect way to determine fibrosis stage.
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.636
Watch a video presentation of this article
Watch the interview with the author
Full Text (HTML)
PDF (178.2KB)  

Antifibrotic therapies in liver disease: Ready for primetime? (pages 138–140)
David A. Rudnick
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.641
Watch a video presentation of this article
Watch the interview with the author

LT in the High MELD Era: Perioperative Management of the Critically Ill Patient
Guest Edited by Julie Heimbach, MD and Michael Schilsky, MD
Transplantation for acute alcoholic hepatitis (pages 141–143)
Patrizia Burra and Giacomo Germani
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.629
Watch a video presentation of this article
Watch the interview with the author

The Practice of Hepatology in a Non-Traditional Setting
Guest Edited by Mitchell Shiffman, MD
Contrasting the academic and nonacademic hepatology practice settings (pages 144–146)
Alexander T. Lalos and Coleman I. Smith
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.638
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Watch the interview with the author

Developing clinical research in a clinical hepatology practice (pages 147–149)
Oren K. Fix, Terri Spinelli and Kris V. Kowdley
Version of Record online: 29 JUN 2017 | DOI: 10.1002/cld.639
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Watch the interview with the author

Begin here.....

The Changing HCV Landscape: Pangenotypic Regimens

Gastroenterology & Endoscopy News

Review Articles
MAY 18, 2017

The Changing HCV Landscape: Update on Treatment

Toward the Future: Pangenotypic Regimens
A novel once-daily RBV-free doublet regimen of ABT-493 (a protease inhibitor) and ABT-530 (an NS5A inhibitor) was studied in an intent-to-treat population of treatment-naive and treatment-experienced patients for 8 to 12 weeks (phase 2 SURVEYOR-1 and SURVEYOR-2). Both drugs are second-generation members of their respective classes, with pangenotypic coverage and coverage of most or all known RAVs relevant to their classes. The results are summarized as follows: SVR12 by 97% to 98% with 8 weeks of treatment in GT1 and GT2 noncirrhotic patients by intention-to-treat analysis,64 96% SVR12 in GT1 patients with cirrhosis treated for 12 weeks,65 and 100% SVR4 for patients with GT4-6 without cirrhosis treated for 12 weeks.66 Additional studies in GT3 patients yielded SVR12 in 97% of noncirrhotics treated for 8 weeks,67 and 100% in cirrhotics treated for 12 weeks.68 These data from phase 2 trials reflect the potential for this regimen to be available in the future as a truly pangenotypic regimen without RBV if phase 3 trials recapitulate these results. A fixed-dose coformulated regimen consisting of SOF-VEL and GS-9857 (a second-generation NS5A inhibitor) received breakthrough therapy designation by the FDA for the treatment of chronic GT1 patients who have previously failed an NS5A-containing regimen. Lawitz et al treated 128 GT1-6 patients, mostly with GT1-3, including 48% with cirrhosis for 12 weeks with the triplet regimen.69 Nearly 80% of patients had prior DAA exposure, including 63 of 63 GT1 patients (100%), and 60% had baseline RAVs. Overall, 127 of 128 (99%) attained SVR12, with the only virologic failure in a GT3 patient. Of 35 patients with prior NS5A exposure, all had SVR12.

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Triple combination cures most hepatitis C patients with prior DAA treatment failure

Triple combination cures most hepatitis C patients with prior DAA treatment failure
Liz Highleyman
Produced in collaboration with hivandhepatitis.com
Published: 28 April 2017

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Almost all people with genotype 1 hepatitis C who were previously unsuccessfully treated with a course of interferon-free direct-acting antiviral therapy achieved sustained response when retreated with a three-drug combination being developed by Merck, researchers reported at the International Liver Congress last week in Amsterdam.

Direct-acting antivirals (DAAs) have revolutionised the treatment of chronic hepatitis C virus (HCV) infection, with cure rates approaching 100% for most groups of patients. But better options are still needed for people who do not respond to a first attempt at interferon-free therapy and may have drug-resistant virus.
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Meeting Updates
Updates On This Blog

Hep C 5-minute videos - Summary Of The International Liver Congress™ (ILC) 2017

On this page of the blog visitors are provided with an index of links pointing to comprehensive coverage of the meeting.  Start by viewing a short video series over at Practice Point presented by Dr. Tran, highlights include clinical studies on new antiviral therapy, data on drug toxicity/adverse events, drug interactions, and strategies for HCV management. On May 1, ViralEd will launch: The Advances in Chronic Hepatitis C: Management and Treatment, a comprehensive program featuring HCV experts reviewing and discussing the most important studies on chronic hepatitis C presented at EASL 2017. Other videos include EASL press conference, and opening ceremony.

Coverage

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Clinical Care Options
HIV and Hepatitis
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Merck Announces New Phase 2 Data on Investigational Triple Combination Therapy MK-3682B for Chronic Hepatitis C

Merck Announces New Phase 2 Data on Investigational Triple Combination Therapy MK-3682B for Chronic Hepatitis C

Merck (MRK), known as MSD outside of the United States and Canada, today announced the first sustained virologic response1 (SVR) results 12 weeks after completion of therapy (SVR12, considered virologic cure) from C-SURGE, an ongoing, open label Phase 2 clinical trial evaluating MK-3682B [uprifosbuvir (MK-3682)2/grazoprevir3/rusazvir4], the company’s investigational triple-combination therapy in treatment-experienced patients with hepatitis C virus (HCV) genotype (GT) 1 infection for whom treatment with approved direct-acting antiviral regimens had failed. The study showed that 100 percent (43/43) of patients who completed 16 weeks of treatment plus ribavirin (RBV) achieved SVR12 and 100 percent (49/49) of patients who completed 24 weeks of treatment achieved SVR12 (abstract PS-159). These results will be presented today at The International Liver Congress™ 2017.

“Despite the significant progress made to address the worldwide epidemic of chronic hepatitis C infection, there remains a need for additional treatment options,” said Dr. Heiner Wedemeyer, lead study investigator and research group leader in the department of gastroenterology, hepatology and endocrinology at Hannover Medical School, Germany. “We are encouraged by the high virologic cure rates in the difficult-to-treat patients observed in the C-SURGE study and look forward to further evaluation of this investigational triple-combination therapy.”

The Phase 2 C-SURGE study enrolled 94 patients who were randomized to receive a once-daily regimen of MK-3682B for either 16 weeks with RBV (n=45) or 24 weeks without RBV (n=49); one patient in the 16-week arm withdrew prior to starting treatment. Of the 93 patients who received treatment (full analysis set), 57 had previously received a regimen of ledipasvir/sofosbuvir (LDV/SOF) for 12 to 24 weeks, 14 had previously received LDV/SOF for 8 weeks and 22 had previously received ZEPATIER® (elbasvir and grazoprevir) for 12 weeks. Seventy-eight patients who received treatment had at least one baseline NS5A resistance-associated substitution (RAS) at positions 28, 30, 31 or 93. Eighty patients who received treatment in C-SURGE had GT1a infection, and 40 patients had compensated cirrhosis. In the full analysis set, 98 percent of patients who received MK-3682B for 16 weeks with RBV (43/44) and 100 percent of patients who received MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.

Results from the modified full analysis set, which excludes one patient in the 16-week arm who withdrew after three doses of treatment, show that 100 percent of patients receiving treatment with MK-3682B for 16 weeks with RBV (43/43) and 100 percent of patients receiving treatment with MK-3682B for 24 weeks without RBV (49/49) achieved SVR12.

Across the combined treatment arms, the most common adverse events (AEs) reported in the full analysis set were fatigue (35%), headache (13%), diarrhea (9%), rash (9%) and pruritus (5%). There were no drug-related serious AEs, and no patients discontinued treatment due to a drug-related AE.

SVR8 results from the C-SURGE study were previously presented at The Liver Meeting® 2016.

About MK-3682B
MK-3682B is Merck’s investigational triple-combination therapy in Phase 2 development for the treatment of chronic HCV infection. MK-3682B combines an HCV nucleotide analogue NS5B polymerase inhibitor (MK-3682), an HCV NS3/4A protease inhibitor (grazoprevir, MK-5172) and an HCV NS5A inhibitor (ruzasvir, MK-8408).

About ZEPATIER® (elbasvir and grazoprevir) 50mg/100mg Tablets
ZEPATIER is a fixed-dose combination product containing elbasvir, a HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor. In the United States, ZEPATIER is indicated for the treatment of chronic HCV GT1 or 4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations.

Selected Safety Information about ZEPATIER (elbasvir and grazoprevir)
The US Prescribing Information for ZEPATIER contains a Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients coinfected with HCV and HBV. Healthcare professionals should test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating treatment with ZEPATIER. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Healthcare professionals should monitor HCV/HBV coinfected patients for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Healthcare professionals should initiate appropriate patient management for HBV infection as clinically indicated.

HBV reactivation has been reported in HBsAg positive patients and also in patients with serologic evidence of resolved HBV infection (ie, HBsAg negative and anti-HBc positive). The risk of HBV reactivation may be increased in patients receiving some immunosuppressant or chemotherapeutic agents. HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection, reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, ie, increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.

ZEPATIER is not for use in patients with moderate or severe hepatic impairment (Child Pugh B or C). ZEPATIER is also not for use with inhibitors of organic anion transporting polypeptides 1B1/3 (OATP1B1/3) that are known or expected to significantly increase grazoprevir plasma concentrations (e.g., atazanavir, darunavir, lopinavir, saquinavir, tipranavir, cyclosporine), strong cytochrome P450 3A (CYP3A) inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s Wort), and efavirenz. If ZEPATIER is administered with RBV, healthcare professionals should refer to the prescribing information for RBV as the contraindications, warnings and precautions, adverse reactions and dosing for RBV also apply to this combination regimen.

Elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in 1% of subjects, generally at or after treatment week 8. These late ALT elevations were typically asymptomatic and most resolved with ongoing or completion of therapy. Healthcare professionals should perform hepatic lab testing on patients prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, additional hepatic lab testing should be performed at treatment week 12.

Patients should be instructed to consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces. Healthcare providers should consider discontinuing ZEPATIER® (elbasvir and grazoprevir) if ALT levels remain persistently greater than 10 times ULN. ZEPATIER should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalized ratio.

The concomitant use of ZEPATIER with certain drugs may lead to adverse reactions or reduced therapeutic effect due to drug interactions. Certain strong CYP3A inhibitors may increase the plasma concentration of ZEPATIER, leading to possibly clinically significant adverse reactions. Moderate CYP3A inducers may decrease the plasma concentration of ZEPATIER, leading to reduced therapeutic effect and possible development of resistance. Coadministration of ZEPATIER with these drugs is not recommended. Physicians should consult the Prescribing Information for potential drug interactions.

In subjects receiving ZEPATIER for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5% in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving ZEPATIER with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5%) were anemia and headache.

Selected Dosage and Administration Information for ZEPATIER

ZEPATIER is a single tablet taken once daily. The recommended dosing is 12 or 16 weeks with or without RBV, depending on HCV genotype, prior treatment history and, for patients with genotype 1a infection, presence of certain baseline NS5A resistance-associated polymorphisms. See Prescribing Information for ZEPATIER for specific dosage regimens and durations. Refer to RBV prescribing information for RBV dosing and dosage modifications when ZEPATIER is given with RBV. To determine dosage regimen and duration of ZEPATIER for genotype 1a patients, testing for the presence of virus with one or more baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31, or 93 is recommended prior to initiating treatment.

http://finance.yahoo.com/news/merck-announces-phase-2-data-110000147.html

Merck to Present New Data on (elbasvir and grazoprevir) and MK-3682B at International Liver Congress™ 2017

Merck to Present New Data on ZEPATIER® (elbasvir and grazoprevir) and Investigational Combination Therapy MK-3682B for the Treatment of Chronic Hepatitis C Infection at The International Liver Congress™ 2017

Merck (MRK), known as MSD outside of the United States and Canada, today announced that new data from the company’s chronic hepatitis C virus (HCV) clinical development programs as well as real-world studies on ZEPATIER^® (elbasvir and grazoprevir) 50mg/100mg tablets will be presented at the upcoming International Liver Congress™ 2017. Seventeen scientific abstracts will be presented, including oral sessions featuring real-world data on chronic HCV-infected patients treated with ZEPATIER from the U.S. Department of Veterans Affairs Healthcare System and new results from the C-SURGE trial evaluating MK-3682B [uprifosbuvir (MK-3682)¹/grazoprevir²/rusazvir³] in patients with chronic HCV infection who have previously failed a HCV direct-acting antiviral regimen. The International Liver Congress™ 2017 will take place in Amsterdam, Netherlands from April 19 – 23, 2017.

“We continue to generate new data on ZEPATIER while advancing our ongoing investigational program evaluating uprifosbuvir in combination with other assets, underscoring our continued commitment to chronic HCV research,” said Dr. Eliav Barr, senior vice president, global clinical development, infectious diseases and vaccines, Merck Research Laboratories. “Findings from both randomized clinical trials and real-world data analyses help us better understand the treatment of diverse patient types, including those who have been historically underserved or for whom unmet needs remain.”

In the United States, ZEPATIER is indicated for the treatment of chronic HCV genotype (GT) 1 or GT4 infection in adults. ZEPATIER is indicated for use with ribavirin (RBV) in certain patient populations. The U.S. Prescribing Information for ZEPATIER contains a Boxed Warning about the risk of hepatitis B virus (HBV) reactivation in patients co-infected with HCV and HBV.

Key presentations at The International Liver Congress™ 2017 will include:

ZEPATIER (elbasvir and grazoprevir)

Thursday, April 20

• Real-World Use of Elbasvir/Grazoprevir and Outcomes in Patients With Chronic Hepatitis C: Retrospective Data Analyses From the TRIO Network (Poster presentation, Abstract THU-239, 8:00 a.m. – 6:00 p.m. CEST)
• Prevention of Liver-Related Complications With Elbasvir/Grazoprevir in Hepatitis C Infected Patients who are Receiving Opioid Agonist Therapy (OAT) (Poster presentation, Abstract THU-246, 8:00 a.m. – 6:00 p.m. CEST)
• Real-World Utilization of the New Fixed-Dose Combination Elbasvir/Grazoprevir in Adult Patients With Chronic Hepatitis C in Canada: Z-PROFILE Study (Poster presentation, Abstract THU-266, 8:00 a.m. – 6:00 p.m. CEST)
• Clinically Meaningful Differences in Health-Related Quality of Life and Fatigue in Patients With Hepatitis C Virus (HCV) Infection Treated With Elbasvir/Grazoprevir (EBR/GZR) Compared to Sofosbuvir (SOF) With Pegylated Interferon and Ribavirin (PR) (Poster presentation, Abstract THU-245, 8:00 a.m. – 6:00 p.m. CEST)
• Projected Long Term Impact of Elbasvir/Grazoprevir (EBR/GZR) Compared to Sofosbuvir Plus Pegylated Interferon/Ribavirin (SOF+PR) in Chronic Hepatitis C Virus Genotype 1 and 4 Patients in Italy: Translation of the C-EDGE Head-2-Head Study Findings (Poster presentation, Abstract THU-247, 8:00 a.m. – 6:00 p.m. CEST)
• Safety and Efficacy of Elbasvir and Grazoprevir With or Without Ribavirin for the Treatment of Hepatitis C Virus Genotype 1: Results of the Hepatitis C Virus-TARGET Study (Poster presentation, Abstract THU-237, 8:00 a.m. – 6:00 p.m. CEST)

Friday, April 21

• Real World Experience With Elbasvir/Grazoprevir in the Veterans Affairs Healthcare System (Oral presentation, Abstract PS-095, 4:00 – 4:15 p.m. CEST)
• Efficacy and Safety of Elbasvir/Grazoprevir in Treatment-Naïve Patients With Chronic HCV GT 1, GT 4 and GT 6 Infection (C-CORAL): A Phase III Randomized Multinational Clinical Trial (Poster presentation, Abstract FRI-266, 8:00 a.m. – 6:00 p.m. CEST)
• Elbasvir/Grazoprevir Plus Sofosbuvir in Treatment-Naive and Treatment-Experienced Cirrhotic Patients With Hepatitis C Virus Genotype 3 Infection Treated for 8, 12, or 16 weeks: Final Results of the C-ISLE Study (Poster presentation, Abstract FRI-213, 8:00 a.m. – 6:00 p.m. CEST)
• Successful Treatment of Patients With HCV GT3 Infection and Cirrhosis with Elbasvir/Grazoprevir Plus Sofosbuvir Does Not Correct Insulin Resistance by 12 weeks Post-Treatment (Poster presentation, Abstract FRI-215, 8:00 a.m. – 6:00 p.m. CEST)
• Impact of Elbasvir/Grazoprevir (EBR/GZR) on Health-Related Quality of Life (HRQOL) and Fatigue in Patients With Chronic Hepatitis C Virus (HCV) Infection and Inherited Blood Disorders (IBLD): Data From the C-EDGE IBLD Study (Poster presentation, Abstract FRI-251, 8:00 a.m. – 6:00 p.m. CEST)

Saturday, April 22

• Elbasvir/Grazoprevir Effectiveness in Patients With Chronic Hepatitis C and Chronic Kidney Disease: Real-World Experience From the TRIO Network (Poster presentation, Abstract SAT-297, 8:00 a.m. – 6:00 p.m. CEST)

MK-3682B, INVESTIGATIONAL TRIPLE THERAPY

Thursday, April 20

• Efficacy and Safety of the Fixed-Dose Combination Regimen of MK3 [MK-3682/Grazoprevir/Ruzasvir] With or Without Ribavirin in Non-Cirrhotic or Cirrhotic Patients With Chronic HCV GT1, 2, 3, 4 or 6 Infection (Parts A & B of C-CREST-1 & 2) (Poster presentation, Abstract THU-285, 8:00 a.m. – 6:00 p.m. CEST)
• High Sustained Virologic Response Rates in Patients With Chronic HCV GT1, 2 or 3 Infection Following 16 Weeks of MK-3682/Grazoprevir/Ruzasvir Plus Ribavirin After Having Failed 8 Weeks of a Triplet Drug Regimen (Part C of C-CREST-1 & 2) (Poster presentation, Abstract THU-264, 8:00 a.m. – 6:00 p.m. CEST)

Saturday, April 22

• Safety and Efficacy of the Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/Ruzasvir in Cirrhotic or Non-Cirrhotic Patients With Chronic HCV GT1 Infection who Previously Failed a Direct-Acting Antiviral Regimen (C-SURGE) (Oral presentation, Abstract PS-159, 9:30 a.m. – 9:45 a.m. CEST)

For more information, including a complete list of abstract titles at the meeting, please visit: http://ilc-congress.eu/.

With hep C franchises languishing, Merck’s MK-3682 goes from blockbuster to bomb

With hep C franchises languishing, Merck’s MK-3682 goes from blockbuster to bomb
by John Carroll

A little less than three years after acquiring the hepatitis C drug MK-3682 (uprifosbuvir) in its $3.85 billion buyout of Idenix, Merck’s prospects in the field have cooled dramatically, and its once great hopes for the drug have been reduced to nearly nothing.

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Of Interest

Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

MK-3682 + grazoprevir + elbasvir or MK-3682 + grazoprevir + MK-8408 There are two triplet therapies and at least one doublet regimen in development by Merck (Kenilworth, NJ) that include MK-3682 (a novel NS5b nucleotide polymerase inhibitor) with or without grazoprevir and with either elbasvir or MK-8408 (a novel NS5A inhibitor). MK-3682 was tested in 300 mg and 450 mg doses in the CREST 1 (for genotypes 1 and 2) and CREST 2 (for genotype 3) studies. The CREST 1 study showed mITT SVR24 of 91–100% for genotypes 1 (n = 93 with 46 GT1a and 47 GT1b) with either elbasvir or MK-8408 at both doses for MK-3682. However, only the MK-3682 (450 mg)/grazoprevir/MK-8408 regimen showed efficacy >90% in genotype 2 patients (n = 61). For genotype 3 patients, both the 300 mg and 450 mg doses of MK-3682 showed SVR24 rates >90% (n = 86).....

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Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

Of Interest

January 18, 2017 - Hepatitis C Treatment: What to Expect in 2017

November 2016 - Summary for AASLD 2016 for Hepatitis C - New HCV two and three drug regimens on their way: what do they promise? And what do clinicians need to look out for under DAA combination therapy and beyond SVR?

Abbvie dual combination Glecaprevir /Pibrentasvir

Gilead fixed dose combination SOF/VEL/VOX

Merck fixed-dose combination tablet MK3 (MK-3682/grazoprevir/ruzasvir)

Therap Adv Gastroenterol. 2017 Feb; 10(2): 277–282.

Published online 2017 Jan 25. doi:  10.1177/1756283X16683875

This update reviews some upcoming therapies for the treatment of chronic hepatitis C
See table 1 below for; Direct-acting combination antiviral therapies expected to be approved in 2017

Novel emerging treatments for hepatitis C infection: a fast-moving pipeline

Ara A. Kardashian and Paul J. Pockros

Abstract
Advances in the treatment of chronic hepatitis C has been one of the pinnacles of medical science in the last 25 years. The age of direct-acting antivirals (DAAs) has led to cure rates >95% with shorter duration and low toxicity regimens, thus changing the landscape of the era of pegylated interferon and ribavirin (RBV). However, there remain some challenges with these therapies as there are multiple regimens available with a fair amount of sophistication required to administer them. Treatment continues to require knowledge of prior treatment status, viral genotype and fibrosis assessment, thus affording an opportunity for improvement in future regimens. This update reviews some upcoming therapies for the treatment of chronic hepatitis C.
Keywords: direct-acting antivirals, emerging treatments, hepatitis C

Introduction
Direct-acting antivirals (DAAs) target viral proteins of the hepatitis C virus (HCV) which are critical for viral replication, resulting in the four classes of antivirals currently approved: nonstructural protein 3 (NS3) protease inhibitors (PI), NS5A inhibitors, NS5b nucleot(s)ide polymerase inhibitors and NS5b non-nucleot(s)ide polymerase inhibitors. It is unlikely that drugs will be developed outside of these classes, other than recent efforts with microRNA-122. Instead, we will see improvements upon the current drugs with second generation compounds. There remain unmet needs for treatment in some patients such as those who have failed NS5A regimens, those who have developed resistance-associated substitutions (RASs) and those who have pre-existing RASs that confer resistance. Other opportunities for improvement include pangenotypic regimens, eliminating the need for ribavirin (RBV), reducing duration of therapy, and reducing the cost of therapy. This review will address novel therapies currently in late phase studies.

Current treatment options
Currently, treatment options are organized by genotype, presence or absence of cirrhosis, and treatment experience. The following is a brief overview of available regimens and their indications, not an indepth review.

Treatment-naïve patients
For genotype 1, treatment options include daily fixed-dose combinations of elbasvir/grazoprevir, ledipasvir/sofosbuvir, paritaprevir/ritonavir/ombitasvir with dasabuvir and RBV, sofosbuvir/velpatasvir, as well as simeprevir plus sofosbuvir, and daclatasvir plus sofosbuvir. Variations in the regimen are based on genotype (1a versus 1b), presence or absence of compensated cirrhosis, and presence of pretreatment RASs. Currently, only one regimen requires pretreatment determination of the presence of NS5A RASs (elbasvir/grazoprevir). If an RAS is present at positions M28, Q30, L31 or Y93, then the patient requires 16 rather than 12 weeks of treatment with the addition of RBV.1 The details of all these regimens are available in the current American Association for the Study of Liver Diseases (AASLD)/ Infectious Diseases Society of America (IDSA) Guideline document.2

For genotypes 2 and 3, sofosbuvir/velpatasvir and daclatasvir plus sofosbuvir are available. Again, duration can vary based on presence of cirrhosis and RBV is required in some patients with genotype 3 HCV infection. Genotype 4 regimens include 12 weeks of daily fixed-dose combinations of paritaprevir/ritonavir/ombitasvir with RBV, sofosbuvir/velpatasvir, elbasvir/grazoprevir, and ledipasvir/sofosbuvir.2 Additionally, in the European Association for the Study of the Liver (EASL) guidelines, sofosbuvir/simeprevir and sofosbuvir/daclatasvir are indicated.3 Treatment-naïve genotype 5 and 6 HCV options are daily fixed-dose combinations of sofosbuvir/velpatasvir or ledipasvir/sofosbuvir, both for 12 weeks for those without cirrhosis or with compensated cirrhosis2,3 and sofosbuvir/daclatasvir for 12 weeks.3

Treatment-experienced patients
Options for those having failed prior therapy depends on what was previously used and presence of RASs in addition to the same factors stated previously (genotype, presence or absence of cirrhosis). In general, the same options are available if the prior treatment was with pegylated interferon (PEG-IFN) and RBV. This is congruent with the guidelines published by EASL.3

If sofosbuvir plus RBV with or without PEG-IFN was used previously, ledipasvir/sofosbuvir with RBV for 12 weeks is recommended in those without cirrhosis while the duration is extended to 24 weeks in the presence of compensated cirrhosis. If an NS3 protease inhibitor (simeprevir, telaprevir, boceprevir) was used previously with PEG-IFN and RBV, then daily fixed-dose combinations of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, daclatasvir plus sofosbuvir or elbasvir/grazoprevir with RBV (at 12 or 16 weeks if baseline NS5A RASs present) are recommended for those with or without compensated cirrhosis.2 Patients who have proved to be particularly difficult to treat are those with genotype 3 who are treatment-experienced and have cirrhosis. Current recommendations for these patients are for sofosbuvir/velpatasvir with weight-based RBV for 12 weeks or daclatasvir plus sofosbuvir with weight-based RBV for 24 weeks. For those with genotype 3 treatment experience who have failed prior sofosbuvir and RBV, whether they have cirrhosis or not, there are less data to support guidance.2

Those failing newer treatments including simeprevir plus sofosbuvir and NS5A inhibitors (daclatasvir, elbasvir, ledipasvir, ombitasvir, velpatasvir) have less formal recommendations. Essentially the AASLD/IDSA guideline recommends testing for NS3 and NS5A RASs, tailoring treatment to the results, and extending dual DAA therapy to 24 weeks with the addition of RBV (if not contraindicated). Triple or quadruple DAA therapy may also be considered.2 In contrast, the EASL guidelines recommend retreatment with a non-IFN regimen with weight-based RBV for 12 weeks with METAVIR fibrosis scores of F0–F2 but for 24 weeks if with F3 fibrosis or cirrhosis.3

For genotype 2 or 3 patients who have previously treated with sofosbuvir plus RBV, daclatasvir plus sofosbuvir with or without RBV for 24 weeks or daily fixed-dose combination sofosbuvir/velpatasvir with RBV for 12 weeks are options. Currently, no formal recommendations exist for the retreatment of DAA failures in those with genotypes 5 or 6.2

EASL guidelines for sofosbuvir failures include retreatment with sofosbuvir/ledipasvir for genotypes 1 and 4–6, sofosbuvir/velpatasvir or sofosbuvir/daclatasvir for all genotypes, ritonavir-boosted paritaprevir with ombitasvir for genotype 4 and the addition of dasabuvir for genotype 1, and sofosbuvir plus simeprevir for genotype 4. If those genotype 1 or 4 patients already failed sofosbuvir plus simeprevir, they can be retreated with a combination of sofosbuvir with ledipasvir, velpatasvir, or daclatasvir. Genotype 1 or 4 patients who have failed NS5A-containing DAA regimens may be retreated with sofosbuvir plus ritonavir-boosted paritaprevir with ombitasvir for genotype 4 or grazoprevir/elbasvir with sofosbuvir for genotypes 1 and 4 or sofosbuvir, simeprevir and daclatasvir for genotypes 1 and 4 for 12 weeks. For those with genotypes 5 or 6 failing an NS5A-containing regimen, the combination of sofosbuvir and velpatasvir with RBV for 24 weeks is recommended.3

Novel regimens expected to be approved in 2017
There are a number of combination regimens currently in phase III development that are expected to be available in 2017. All of these will be pangenotypic, RBV-free and be effective in genotype 1a patients who have failed a DAA regimen containing an NS5A inhibitor. The regimens may be double combinations of very potent pangenotypic protease inhibitors and NS5A inhibitors or triple combinations of protease inhibitors, NS5A inhibitors and NS5b nucleos(t)ide polymerase inhibitors (see Table 1). There are other future regimens beyond these regimens that are anticipated in 2018 or beyond but they are not yet in phase III development so will not be discussed herein.

Table 1.
Direct-acting combination antiviral therapies expected to be approved in 2017.

	GZR + RZV + MK-3682	RZV + MK-3682	SOF + VEL + GS-9857	ABT-493+ABT530
Manufacturer	Merck (Kenilworth, NJ, USA)	Merck (Kenilworth, NJ, USA)	Gilead (Foster City, CA, USA)	AbbVie (Lake Bluff, IL, USA)
Number of drugs	Triplet	Doublet	Triplet	Doublet
Drug classes	PI + NS5A + NS5b	NS5A + NS5b	NS5b + NS5A + PI	PI + NS5A
Requires RBV?	No	No	No	No
Duration of therapy	4–12 weeks	4–12 weeks	12 weeks	8–12 weeks
Genotype efficacy	Pangenotypic	Pangenotypic	Pangenotypic	Pangenotypic
DAA-failure with NS5A RASs	Effective, but may require addition of RBV	Effective, but may require addition of RBV	Effective	Effective

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ABT-493, gleaprevir; ABT-530, pibrentasvir; DAA, direct-acting antivirals; GS-9857, voxilaprevir; GZR, grazoprevir; NS5A, NS5A inhibitor; NS5b, NS5b nucleos(t)ide polymerase inhibitor; PI, NS3/4A protease inhibitor; RAS, resistance-associated substitutions; RBV, ribavirin; RZV, ruzasvir; SOF, sofosbuvir; VEL, velpatasvir

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Addressing treatment failures is becoming increasingly important in the era of DAA therapy. For genotype 1 infection, the single-pill combination of ledipasvir (NS5A inhibitor) with sofosbuvir (NS5b nucleotide polymerase inhibitor; Harvoni™ Gilead Sciences, Foster City, CA) has shown cure rates >95%.4 According to the Center for Disease Control and Prevention, there are 2.7–3.9 million people in the United States (US) with HCV infection.5 Of these, approximately 75% have genotype 1, highlighting the importance of this patient population sustained virologic response at follow-up week 12.6

Glecaprevir (ABT-493) + pibrentasvir (ABT-530)
Glecaprevir (ABT-493) is a pangenotypic NS3/4A protease inhibitor while pibrentasvir (ABT-530) is a pangenotypic NS5A inhibitor active against common single-position NS5A variants. The two compounds are being developed together in a fixed-dose doublet regimen by AbbVie Pharmaceuticals (Lake Bluff, IL). Different durations of therapy are being evaluated between 6–12 weeks and none of the regimens require RBV. The population being studied does not include decompensated cirrhosis due to the previous experience seen in this group with paritaprevir, telaprevir, simeprevir and other first-generation NS3/4 PIs.7

In the replicon model, the second-generation protease inhibitor glecaprevir showed potent activity against all genotypes with half-maximal effective concentration (EC50) ranging from 0.85–2.8 nm. These numbers are on par or superior to those seen with grazoprevir and paritaprevir. The other drug in the second-generation doublet regimen, pibrentasvir, showed an EC50 range of 1–4 pm across all genotypes, better than other currently available pangenotypic NS5A inhibitors. The SURVEYOR-I study demonstrated 98–100% SVR4 in HCV genotype 1 noncirrhotic treatment-naïve or PEG-IFN/RBV null-responders with the combination of the two drugs.8

The MAGELLAN-I study used a combination of glecaprevir and pibrentasvir to treat those with treatment failures to earlier generation DAAs. The patient population included those with NS3 (30%), NS5A (20%), and both NS3 and NS5A (32%) RASs. Using intention-to-treat (ITT) analysis, for glecaprevir/pibrentasvir at doses of 200 mg/120 mg, the sustained virologic response (SVR) at follow-up week 12 was 100% (n=6). For doses of 300 mg/120 mg, SVR12 was 86% (19/22) and with the addition of RBV 800 mg it was 91% (20/22). Using modified ITT analysis (mITT), those same SVR12s were 100%, 95% and 95%, respectively. Failure was due to both viral breakthrough (n=1) and relapse (n=1).9

The same glecaprevir/pibrentasvir combination was used in a partially randomized, phase II trial for genotype 3 patients with cirrhosis.10 Doses were 200 mg or 300 mg for glecaprevir (30 patients in each group) and 40 mg or 120 mg for pibrentasvir with or without RBV (31 and 30 patients respectively). Again, the study group included those patients with NS3 and NS5A variants either alone or together. By ITT analysis, SVR12 was 93–94% for combination therapy both with and without the addition of RBV.11 The 40 mg arm of pibrentasvir performed less well and will thus not be pursued further.

Sofosbuvir/velpatasvir + voxilaprevir (GS-9857)
The single-pill fixed-dose regimen of sofosbuvir 400 mg and velpatasvir 90 mg is currently approved for all genotypes in the US (Epclusa™; Gilead Sciences, Foster City, CA).12 This regimen must be given for 12 weeks and has not been shown to be effective in patients who have failed NS5A-containing DAA regimens with NS5A RASs. As well, although the compound is approved for decompensated cirrhosis, it must be administered with RBV in this population.12 Gilead Sciences, Foster City, CA, is developing a triplet-combination regimen that would include the addition of a protease inhibitor to sofosbuvir/velpatasvir and offer the possibility of a pangenotypic regimen that would be effective against DAA failures.

This fixed-dose combination of sofosbuvir/velpatasvir was studied in conjunction with voxilaprevir (GS-9857), a pangenotypic NS3/4A protease inhibitor, for DAA-experienced patients with genotype 1. SVR12 for triple therapy was 100% while triple therapy with the addition of RBV had an SVR12 of 96% with overall SVR12 of 98%. Overall, 75% of patients had baseline RASs (NS5A, NS3 or both). Within this group, SVR12 was 97% but 100% for those without any baseline RASs.13

The same drug combination was studied for genotypes 1, 2, 3, 4 and 6. SVR12 was 99% overall and 100% for genotype 1 in treatment-naïve patients with (n = 15) or without cirrhosis (n = 30) and treatment-experienced patients with cirrhosis (n = 17) or polymerase inhibitor-experienced patients with or without cirrhosis (n = 28), 100% for genotype 2, 97% for genotype 3 patients with cirrhosis who were treatment-naïve (n = 18) or treatment-experienced (n = 19), and 100% for genotypes 4 and 6. Those without RASs had an SVR12 of 100% while those with NS3, NS5A or both variants had overall SVR12 of 99%.13-15

MK-3682 + grazoprevir + elbasvir or MK-3682 + grazoprevir + MK-8408
There are two triplet therapies and at least one doublet regimen in development by Merck (Kenilworth, NJ) that include MK-3682 (a novel NS5b nucleotide polymerase inhibitor) with or without grazoprevir and with either elbasvir or MK-8408 (a novel NS5A inhibitor). MK-3682 was tested in 300 mg and 450 mg doses in the CREST 1 (for genotypes 1 and 2) and CREST 2 (for genotype 3) studies. The CREST 1 study showed mITT SVR24 of 91–100% for genotypes 1 (n = 93 with 46 GT1a and 47 GT1b) with either elbasvir or MK-8408 at both doses for MK-3682. However, only the MK-3682 (450 mg)/grazoprevir/MK-8408 regimen showed efficacy >90% in genotype 2 patients (n = 61). For genotype 3 patients, both the 300 mg and 450 mg doses of MK-3682 showed SVR24 rates >90% (n = 86).16,17

Importantly, the presence of genotype 1 NS5A RASs had no effect on SVR12 rates, including those at the 28, 30, 31 and 93 positions. However, none of these patients had failed prior NS5A-containing regimens. Patients were also tested for the presence of pre-existing genotype 1 NS3 and NS5b RASs and these had no effect on SVR12 rates. The same was true in genotype 2 patients however the SVR rates in genotype 3 patients with NS5A RASs were slightly lower than in those without RASs. The tolerability and side-effect profile of these regimens proved to be excellent with essentially no late alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations, and very few serious adverse events. The most common side effects seen in the MK-3682 groups were minimal with headache and fatigue.16

A regimen earlier in development, two of whose three components are currently unapproved, consists of simeprevir, odalasvir (NS5A inhibitor), and ALS-335 (nucleotide polymerase inhibitor). In a recent press release of 20 patients with treatment-naïve genotype 1 treated with the triplet regimen for 8 weeks, 100% achieved SVR24. Additional promising preliminary results were presented for 6 or 8-week regimens as well as an 8-week regimen of the doublet combination of odalasvir (50 mg every other day) and AL-335 (800 mg daily) for 8 weeks. Adverse effects were mild except for a single serious adverse event (Mobitz type 1 second-degree atrioventricular block), which was attributed to treatment.18

MicroRNA-122 inhibition
MicroRNAs regulate messenger RNA levels and translation. Liver-expressed microRNA-122 (miR-122), plays a role in HCV infection of all genotypes by interacting with the HCV RNA genome. Jopling and colleagues19 showed that by sequestering miR-122 in liver cells, the replication of HCV RNA could be diminished. Miravirsen (Santaris Pharma; Copenhagen, Denmark), a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide, designed to sequester miR-122 was studied in a phase IIa trial. Although thought to be pangenotypically effective, this trial enrolled only HCV genotype 1 patients (n=36) who received different subcutaneous doses of miravirsen on a weekly basis. Results showed dose-dependent reduction in HCV RNA levels with some durable response. Of note, no viral resistance was noted.20 Another modified oligonucleotide, RG-101, has also been studied in a small trial. A single subcutaneous dose of either 2 or 4 mg/kg was given to 28 total patients. A total of 6 patients in the 2 mg/kg group and 9 patients in the 4 mg/kg group had undetectable levels at 8 weeks while 7 of the 15 responders maintained this at week 20.21 Overall, microRNA-122 targets have shown some promise in small trials however this compound is currently on clinical hold in the US due to Food and Drug Administration concerns about safety. It is unclear what, if any, role these compounds would play in future HCV therapy.

Link Of Interest On This Blog
RG-101
January 31, 2017 Regulus Announces Continuation of RG-101 Clinical Hold - FDA requests longer-term follow-up data from ongoing studies

Conclusion
The value of a single-pill, fixed-dose, RBV-free regimen for all genotypes is obvious as it would obviate the need for genotype and RAS testing prior to treatment and would likely be simple and well tolerated. In addition, the advantage of a shorter duration has been already demonstrated with the use of sofosbuvir/ledipasvir (Harvoni™) in genotype 1 treatment-naïve noncirrhotic patients. The ultimate goal of new regimens will be to remove the complexity of treatment and thus place therapy in the hands of primary care physicians as well as specialists. We think we are well on the road towards this goal and we will likely have multiple drug regimens that afford this simplicity by 2017.

Unresolved issues remain, however, including the cost and access to these drugs and the continued need to evaluate chronic HCV patients for advanced fibrosis or cirrhosis prior to treatment. These patients may be cured with the same regimen however they require assessment for esophageal varices before and after therapy and screening for hepatocellular carcinoma before and at 6 month intervals after successful treatment. Additionally, the safety and efficacy of these fixed-dose regimens will vary in certain populations such as those with end-stage renal disease and decompensated cirrhosis. There will also continue to be drug–drug interactions which preclude their use with other drugs and thus require attention to these details. As such, we think that therapy will remain in the hands of specialists in the near-term but this may change in later years.

Footnotes
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: Research grants paid to Scripps Health: Gilead, Merck, AbbVie, BMS, HCV Target. Honoraria paid to PJP for Advisory Boards and Speaking/Teaching: Gilead, Merck, AbbVie, Intercept.

Contributor Information
Ara A. Kardashian, Fellow, Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA.

Paul J. Pockros, Director of Clinical Research, Scripps Translational Science Institute, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037, USA.

References - Full Text

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298481/